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Background: Antipsychotics are widely used for neuropsychiatric symptoms (NPSs) in dementia including Alzheimer's disease (AD), yet balancing efficacy and safety remains a major clinical challenge. Methods: Relevant randomized controlled trials were identified through a comprehensive literature search of CENTRAL, PubMed, CINAHL, and ClinicalTrials.gov. We conducted a dose-response model-based network meta-analysis to evaluate the efficacy as the change in overall NPS severity and the tolerability as treatment discontinuation due to adverse events of aripiprazole, brexpiprazole, risperidone, quetiapine and olanzapine at varying doses in patients with dementia including AD. Results: Twenty trials involving 5844 participants were included. Most of the included antipsychotics exhibited a generally positive dose-response relationship with respect to both efficacy and tolerability, except for olanzapine, which showed a bell-shaped curve in terms of efficacy. Only aripiprazole 10 mg, brexpiprazole 1-2.5 mg, risperidone 1-2 mg, and olanzapine 2.5-5 mg were significantly more effective than placebo. Tolerability did not significantly decrease compared to placebo for aripiprazole up to 10 mg, brexpiprazole up to 3 mg, risperidone up to 1 mg, olanzapine up to 2.5 mg and at 15 mg, and quetiapine up to 200 mg. Furthermore, significant differences in efficacy and tolerability were observed between certain doses of several antipsychotics. Conclusions: Aripiprazole 10 mg, brexpiprazole 1-2.5 mg, risperidone 1 mg, and olanzapine 2.5 mg were both effective and well tolerated, indicating their potential as favorable treatment options. As the present model incorporates several sources of uncertainty, its findings should be interpreted with caution and regarded as a provisional framework to support clinical decision-making.

Introduction: Posttraumatic stress disorder (PTSD) is a mental disorder resulting from exposure to traumatic events. Evidence suggests that ketamine may be efficacious in treating PTSD, however, ketamine's mechanisms in treating PTSD remain unclear. Herein, this review aims to evaluate the clinical outcomes of ketamine treatment in persons with PTSD and investigate the possible neurobiological mechanisms underlying ketamine's therapeutic effect in PTSD. Methods: A systematic search was conducted on PubMed and OVID (MEDLINE, Embase, PsychINFO) from inception until September 2025. Randomized controlled trials reporting on the effects of intravenous ketamine to treat PTSD were included. Results: Seven studies with a total of 323 participants were included in this review. Ketamine administration meaningfully improved PTSD symptoms in two trials as evidenced by significant improvement on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and the Impact of Event Scale-Revised (IES-R) compared to control/placebo. Multi-infusion administration schedules achieved greater clinical outcomes when compared to single-dose administration schedules. Preliminary evidence suggests that repeated lower doses (0.2mg/kg) of ketamine were more efficacious in sustaining treatment effects than standard doses (0.5mg/kg). For persons receiving ketamine, an association was observed between top-down inhibition of the amygdala originating in the ventromedial prefrontal cortex (vmPFC) and symptom improvement. Conclusion: Our results suggest that intravenous ketamine may be efficacious in the treatment of PTSD. Subsequent studies should attempt to evaluate the additive effect of combining ketamine with psychotherapeutic interventions as well as determining mechanistic pathways mediating symptom relief in persons with PTSD. Keywords: Ketalar; N‐methyl‐D‐aspartate (NMDA) receptor; ketamine; posttraumatic stress symptoms; post‐traumatic stress disorder; trauma‐related stress.

Early intervention services (EIS) for psychosis have demonstrated superiority to usual care/modular care (UC/MC) until the end of their delivery. However, the maintenance effects of EIS care after transition to UC/MC are less clear. We aimed to compare these effects vs. UC/MC at least one year after the end of EIS care. This PRISMA and MOOSE-compliant systematic review searched PubMed, EMBASE, PsycINFO and Web of Science databases and Cochrane Central Register of Reviews, without time or language restrictions. We included studies initially designed as randomized controlled trials (RCTs) comparing EIS vs. UC/MC in patients with early-phase psychosis, in which both the intervention and control groups were followed for at least 12 months after cessation of EIS care in the intervention group. Co-primary outcomes were psychiatric hospitalization, duration of hospitalization, and drop-out at the end of follow-up (preferably 5 years post-EIS initiation). Secondary outcomes were severity of total, positive and negative symptoms; quality of life, work involvement, remission, legal offences, antipsychotic use, and suicide attempts. We meta-analyzed six RCTs with data from 13 papers, including 1,416 individuals (mean age: 23.9 years, females: 36.7%). After 2-3 years of receiving UC/MC, subsequent to 2-3 years of EIS care or UC/MC, individuals who originally received EIS care spent less days hospitalized than those continuing UC/MC (n=5, standardized mean difference, SMD=0.128, 95% CI: 0.019-0.237, p=0.021). However, although we confirmed the superiority of EIS care to UC/MC at the end of the intervention period (except for work involvement and legal offences), the two groups did not differ significantly at 2-3 years post-EIS care regarding hospitalization, all-cause drop-out, quality of life; severity of total, positive and negative symptoms; work involvement, remission, legal offences, antipsychotic use, and suicide attempts. In summary, EIS care did not maintain its superiority over UC/MC 2-3 years after its cessation across meta-analyzable outcomes, except for duration of hospitalizations. These results support the need to further develop and potentially extend full or individualized EIS delivery.

Stanford neuromodulation therapy (SNT) is a rapid-acting, high-dose, intermittent theta-burst stimulation protocol. Although it has previously demonstrated efficacy for treatment-resistant depression (TRD) in a randomized controlled trial (RCT), replication in a larger sample is needed. Additionally, the electrophysiological effects of SNT remain unknown. Here we report results from a new double-blind, sham-controlled RCT along with electroencephalography (EEG) findings from the initial and current trials. In the current RCT, 53 participants with TRD were enrolled, and 48 who continued to meet entry criteria were randomized to receive active (N=24) or sham (N=24) SNT. At 1-month, remission (primary outcome) was achieved in 50.0% of active vs. 20.8% of sham participants (χ2 1,48=4.5, p=0.035), and response (secondary outcome) similarly favored active treatment (54.2% vs. 25.0%; χ2 1,48=4.3, p=0.039). Beta band EEG findings converged across trials: frontal beta power decreased significantly following active but not sham SNT in both the initial pilot study and the current trial. Additionally, beta baseline activity and post-SNT changes related to treatment efficacy in the current study. Specifically, greater post-SNT reduction in left anterior cingulate cortex (L-ACC) beta power correlated with greater clinical improvement immediately (rho=0.48, p=0.019) and 1-month after (rho=0.51, p=0.012) active SNT. Moreover, higher pre-treatment L-ACC beta power predicted greater subsequent clinical benefit from active SNT (immediate-post: β=-10.26, p=0.0042; 1-month after: β=-9.00, p=0.024). Neither of these L-ACC beta power findings was observed with sham stimulation. In sum, this study replicates SNT's therapeutic efficacy, identifies left frontal beta suppression as a potential mechanism of action, and highlights baseline L-ACC beta power as a candidate scalable pre-treatment biomarker of efficacy.

Background: Evidence regarding the effects of antipsychotic medication on cognitive functioning after a first-episode psychosis (FEP) remains inconclusive. This study examined whether dopamine D2 receptor occupancy, affinity, and antipsychotic dose are related to cognitive functioning in people in remission from FEP. Methods: 278 remitted FEP participants from the HAMLETT-trial were included. Cognitive functioning was assessed with the Brief Assessment of Cognition in Schizophrenia, 3-6 months after remission. D2 receptor occupancy was estimated based on antipsychotic type and dose. Antipsychotics were categorized into partial agonists, or antagonists with high or low D2 receptor affinity. Linear regression analyses were performed with inverse probability of treatment weighting to control for differences in characteristics between groups. Results: D2 receptor occupancy was negatively related to global cognition (β = -0.18), verbal fluency (β = -0.22), and attention and processing speed (β = -0.17, all p < 0.003). The interaction between daily dose and D2 receptor affinity category was significant for global cognition (p = 0.0046) and working memory (p = 0.0019), but not for verbal fluency after correction for multiple testing (p = 0.029). Interactions showed that higher daily dose was related to lower cognitive functioning, with significantly stronger negative effects in high-affinity antagonists compared to other antipsychotics. Conclusions: The current findings underscore the importance of antipsychotic D2 receptor occupancy and affinity for cognitive functioning and suggest better cognitive functioning in users of partial agonists and low D2 receptor affinity antipsychotics. This can be important when selecting antipsychotics for individuals with FEP.

Background: Selective serotonin reuptake inhibitors (SSRIs) are a common treatment for depression and anxiety in adolescents but are associated with an increased incidence of bipolar disorder (BD). Whether this relationship is causal remains unclear. Objective: We applied a quasi-experimental design to national registry data, using an instrumental variable (IV) approach (regional variation in prescribing practice) to investigate for a causal relationship between adolescent SSRI treatment and subsequent risk of BD. Methods: We used national electronic health register data on individuals born 1991-1998 followed to maximum age 32 years, looking at individuals diagnosed with unipolar depression in adolescence. Using regional variation in prescribing practice as an IV, we compared risk of BD in adolescents prescribed vs not prescribed SSRIs (fluoxetine, sertraline or citalopram). Findings: In non-IV analyses, adolescents who were prescribed SSRIs had an increased risk of BD, in keeping with previous research. Subsequent IV analyses, however, did not support a causal relationship between SSRI treatment and BD risk, either in the short or long term. Clinical implications: These findings do not support a causal relationship between SSRI treatment and risk of BD. Rather, they suggest that the apparent relationship between SSRI treatment and later BD may be a result of unmeasured confounding.

Accelerated brain aging has been consistently reported in patients with schizophrenia. Over the past decade, these findings have been replicated using the Brain Age paradigm, which applies machine learning techniques to estimate brain age from neuroimaging data. This approach yields a single index, the Brain Age Gap, defined as the difference between predicted and chronological age. Nevertheless, both the progressive nature of this phenomenon and the potential role of antipsychotic medication remain unclear. To investigate its progression, we compared the Brain Age Gap between individuals experiencing a first episode of psychosis and healthy controls using ANCOVA, adjusting for age, sex, body mass index, and estimated total intracranial volume. To enhance the robustness of our findings, we employed two distinct models: a transformer-inspired model based on harmonized volumetric brain features extracted with FastSurfer, and a previously trained deep learning model. To assess the potential effect of medication, we further compared bipolar patients who received antipsychotic treatment with those who did not. Mann-Whitney U test consistently showed that medicated bipolar patients did not exhibit a significantly larger Brain Age Gap. Both models converge on the conclusion that accelerated brain aging is unlikely to be explained by antipsychotic medication alone. Longitudinal studies are therefore required to clarify the temporal dynamics of brain aging in schizophrenia.

Emerging adulthood is a period associated with increases in mental health problems, with those who have faced adverse life experiences (ALEs; adversity experienced during childhood and adulthood) being at greater risk for poor mental health outcomes. Experiencing multiple ALEs is associated with worse outcomes; however, limited research exists that looks at how patterns of ALEs relate to various mental health outcomes among emerging adults. The present study sought to understand patterns of co-occurring ALEs and their relationship to symptom severity of various mental health outcomes (e.g., depression, anxiety, substance use) by utilizing a person-centered approach (i.e., Latent Class Analysis; LCA). Data from 442 emerging adults from a university in Southern California were analyzed using Latent Class Analysis to identify various classes of ALEs. Analysis of variance with Bonferroni-adjusted post-hoc test was utilized to assess whether classes related to an array of mental health outcomes. The use of LCA suggested that a five-class mode fit the data best: (1) Low Adversity, (2) Witnessing Adversity, (3) Experiencing Death, (4) Child Maltreatment and Adult Victimization, and (5) High Adversity. Individuals in the High Adversity and Child Maltreatment and Adult Victimization classes had the highest average severity levels on most mental health outcomes relative to those in the other classes. These findings point to the importance of examining the specificity of adverse experiences rather than using the standard cumulative risk approach. Research implications include further assessment of specific co-morbidities of ALEs and their impact on mental health to establish consistency, as well as examining the weight of individual ALEs in predicting mental health problems.

The strength of a given transcranial magnetic stimulation (TMS) pulse decays rapidly with distance. Male and female bone structure reliably differs by the shape of the frontal bone, mandible, and inion. Given the morphology of these structures constitutes much of the scalp-to-cortex distance (STCD), we hypothesized that females have shorter STCDs and thereby receive stronger TMS electrical field strengths, relative to males. Head models (n = 411; 197 female, 214 male) were constructed from MRIs of healthy participants (ages 18-90). STCD and peak electrical field strength were measured at 50 EEG 10-20 sites (SimNIBSv3.2). Linear models (bootstrapped and Benajamini-Hochberg multiple comparison-corrected) evaluated the influence of sex on STCD and electrical field strength. Females had significantly shorter STCDs at 27/50 sites and stronger TMS electrical fields at 18/50. When normalized by data collected at the motor cortex, females had significantly shorter STCD at 40/49 sites and stronger TMS electrical fields at 29/49 sites. The largest effect size differences were detected at the frontal, temporal, and occipital poles, and the cerebellum. Interestingly, STCD at the motor cortex was not different between sexes, suggesting the motor cortex-based dosing strategies produce unequal electrical fields between sexes. These data provide a mathematically grounded explanation for sex-differences in clinical outcome and may be relevant to other modalities that depend on electromagnetic signals (e.g., EEG, MEG).

Introduction: Posttraumatic stress disorder (PTSD) presents a significant challenge within the treatment of mental health issues, particularly in veterans and first responders who often experience resistance to standard treatments. This study evaluated the effectiveness of a virtual reality exposure-based treatment with motion as compared to treatment as usual (TAU), as first-line treatment for PTSD within these populations. Methods: This multicenter, parallel, single-blind, non-inferiority randomized controlled trial was conducted in three centers across the Netherlands. We included adults diagnosed with occupational or combat-related PTSD, without prior treatment history. Participants were randomized (1:1) to receive either manualized multi-modal motion-assisted memory desensitization and reconsolidation (3MDR) therapy or manualized regular trauma-focused psychotherapy (TAU). 3MDR was applied in fewer sessions than TAU. Primary outcome was self-reported PTSD severity, based on the PTSD Checklist for DSM-5, assessed at baseline, post-treatment, 3 and 6 months post-treatment. Secondary outcomes were clinician-rated PTSD, avoidance, comorbid disorders and symptoms, and functioning. The trial was prospectively registered in the Dutch Trial Register, NL-OMON55588. Results: Between February 15, 2018, and July 22, 2022, 134 participants with PTSD were enrolled, with 67 (50%) randomized to 3MDR and 67 (50%) to TAU of whom 106 (79%) were veterans, and 28 (21%) were first responders. Significant time effects were demonstrated in self-reported and clinician-rated PTSD severity for both groups, as well as in avoidance, comorbid disorders, and functioning. At 6 months post-treatment, 3MDR proved to be non-inferior to TAU in terms of self-reported PTSD (mean difference = -2.91 [95% CI -7.92, 2.10], p = 0.25). Conclusion: 3MDR demonstrates to be an effective alternative first-line treatment for PTSD stemming from occupational traumatic events. Even though it leans on infrastructure with a treadmill and other hardware components, it may offer an alternative over conventional trauma-focused psychotherapies for PTSD that yields savings of a quarter of time spent within therapy.

Importance: Low-level lead exposure during early brain development is associated with lower cognitive abilities and externalizing behavioral problems in children. However, the association of lead exposure with depression and anxiety remains understudied, particularly in later childhood, when these symptoms often manifest. Objective: To examine associations between low-level, serial blood lead concentrations in children and symptoms of depression and anxiety and to investigate for periods of susceptibility. Design, setting, and participants: This cohort study used data from a prospective population of 218 caregiver-child dyads (218 children and 218 parents in the Health Outcomes and Measures of Environment [HOME] Study) recruited from 2003 to 2006 in Cincinnati, Ohio. Children and their families were followed up from the second trimester to age 12 years (2016-2019). Data were analyzed between June 2024 to November 2025. Exposure: Serial blood lead concentrations in children were measured at ages 1, 2, 3, 4, 5, 8, and 12 years. Main outcomes and measures: We measured self- and caregiver-reported child depressive and anxiety symptoms at age 12 years using the Behavioral Assessment System for Children-3 (BASC-3), Children's Depression Inventory-II (CDI-II), and Screen for Child Anxiety Related Disorders (SCARED). Results: Among 218 children (121 female [55.5%]; 78 Black [35.8%] and 140 White and other race or ethnicity [64.2%]; mean [SD] age, 12.4 [0.7] years), the median (IQR; range) mean within-child blood lead concentration was 9.6 (7.8 to 12.6; 4.8 to 32.4) μg/L. Each doubling in mean childhood blood lead concentrations was associated with increased risk of elevated child-reported depressive symptoms on the BASC-3 (relative risk [RR], 1.90; 95% CI, 1.00 to 3.66; P = .05) and increased risk of child- and caregiver-reported child depressive symptoms (RR, 1.76; 95% CI, 1.12 to 2.78; P = .02). By blood lead concentration, there were increasing adjusted mean differences in self-reported BASC-3 depression scores from age 1 year (1.82; 95% CI, -1.10 to 4.74; P = .22), a nonsignificant outcome, through age 8 years (3.22; 95% CI, 0.53 to 5.90; P = .02), a significant outcome. There were no associations between blood lead concentrations and self-reported depression measured with the Children's Depression Inventory-II or anxiety measured with the SCARED. Child sex and race did not modify these associations. Conclusions and relevance: In this study, low-level childhood blood lead concentrations were associated with self-reported depressive symptoms in later childhood, with particularly large increases in risk for exposures occurring in late childhood and early adolescence. These findings suggest that lead exposure during childhood may be associated with mental health in later childhood, highlighting the need for continued efforts to prevent lead exposure.

Importance: An increasing number of sexual assaults (SAs) are reported. Prior studies show that SA is associated with functional somatic disorder (FSD). Objective: To investigate whether SA is associated with the development of incident FSD, including 3 functional somatic syndromes (FSSs), chronic widespread pain (CWP), irritable bowel syndrome (IBS), and chronic fatigue (CF), over 5 years. Design, setting, and participants: A large prospective cohort study was conducted based on 5-year follow-up data (2017-2020) from the Danish Study of Functional Disorders (DanFunD). Incident FSD cases were identified through symptom questionnaires and diagnostic interviews among the population-based cohort aged 18 to 72 years from the western greater Copenhagen area. Completion of baseline SA measures and follow-up assessments was required for eligibility. Data analysis was conducted between January and September 2024. Exposures: SA was assessed at baseline via 2 items from the self-reported Cumulative Lifetime Adversity Measure, dichotomized into exposed and nonexposed. Main outcomes and measures: Incident FSD cases were defined using standardized criteria for single-organ and multiorgan FSD, CWP, IBS, and CF. Risk ratios (RRs) for FSD outcomes were estimated using generalized linear models adjusted for sex, emotional distress, life adversity or trauma, subjective social status, somatic comorbidities, neuroticism, health anxiety, perceived stress, and self-efficacy. Results: Among the 4229 adults (53.9% women; median age, 56 [IQR, 47-64] years) from the DanFunD cohort, SA was associated with incident FSD (RR, 1.69; 95% CI, 1.17-2.44), single-organ FSD (RR, 1.65; 95% CI, 1.14-2.38), multiorgan FSD (RR, 6.47; 95% CI, 1.93-21.75), FSS (RR, 1.54; 95% CI, 1.14-2.07), and CWP (RR, 1.89; 95% CI, 1.11-3.23), while findings with IBS (RR, 1.60; 95% CI, 0.81-3.16) and CF (RR, 1.47; 95% CI, 0.89-2.42) were not significant. Overall, those who reported exposure to SA experienced a significantly higher frequency of incident somatic symptoms than individuals not exposed to SA, including musculoskeletal, gastrointestinal, cardiopulmonary, and fatigue-related symptoms. Baseline emotional distress (eg, anxiety or depression) did not modify the findings for SA and FSD. Sensitivity analysis based on diagnostic interviews confirmed these results. Conclusions and relevance: Findings of this cohort study suggest that SA may increase the risk of developing FSD, involving multiple body systems. Despite limitations from small case samples in some FSD subtypes, the pooled analysis underscores the high risk of FSD, emphasizing the critical need for further research and targeted interventions to address the long-term biopsychosocial consequences of SA.

Importance: Traditional adoption studies examine disorder-to-disorder parent-offspring transmission. The role of parental genetic risk in offspring disorder transmission can capture indirect genetic effects from parental genotype to parental phenotype to offspring risk. Objective: To assess the relative importance of genetic and rearing effects from paternal family genetic risk scores (FGRSs) in 3 pairs of disorders: internalizing (major depression [MD] and anxiety disorders [AD]), substance use (alcohol use disorder [AUD] and drug use disorder [DUD]), and severe (bipolar disorder [BD] and schizophrenia [SZ]). Design, setting, and participants: This cohort study examined fathers in intact families, not-lived-with fathers, stepfathers, adoptive fathers of adoptees, and biological fathers of adoptees, all born in Sweden, and their biological and adoptive offspring born between 1955 and 1990 using data from Swedish National Registries. Follow-up extended through December 2018. Data were analyzed from May to August 2025. Exposures: Paternal FGRSs for MD, AD, AUD, DUD, BD, and SZ. Main outcomes and measures: Cox proportional hazard ratios (HRs) for offspring diagnoses focusing on the paternal effect of genes-and-rearing fathers in intact families, genes only (not-lived-with fathers and biological fathers of adoptees), and rearing only (stepfathers and adoptive fathers of adoptees). Results: The study sample included 2 584 384 offspring (mean [SD] age at follow-up, 41.7 [10.5] years; 1 329 558 [51.5%] male). We present results for MD, AUD, and BD with findings broadly similar for, respectively, AD, DUD, and SZ. The HRs (95% CIs) for genes and rearing fathers, genes-only, and rearing-only relationships were, respectively, for MD 1.19 (1.18-1.19), 1.13 (1.12-1.15), and 1.02 (1.01-1.04); for AUD 1.25 (1.25-1.26), 1.16 (1.14-1.18), and 1.08 (1.06-1.09), and for BD, 1.19 (1.18-1.20), 1.17 (1.14-1.20), and 1.01 (0.98-1.05). In rearing-only relationships, offspring risks for MD and AUD were significantly predicted by paternal genetic risk for DUD, AUD, AD, and MD, while offspring risk for BD was not predicted by any paternal genetic risk. Conclusions and relevance: Using a more incisive measure of genetic effects, the novel adoption design used in this cohort study provides findings broadly similar to traditional adoption models. Rearing effects were strongest for substance use disorders, modest for internalizing disorders, and absent for severe disorders. Indirect genetic effects in the father on offspring risk were clearly observed and were not diagnostically specific. In rearing-only paternal-offspring relationships, elevated paternal genetic risk for internalizing and substance use disorders increased offspring risk for MD and AUD.

Objective: This meta-analysis evaluated the efficacy of behavioral activation (BA) in adolescents with subthreshold depression (SD) or major depressive disorder (MDD), exploring dose-response relationships and moderating factors. Method: We searched PubMed, EMBASE, Web of Science, EBSCO, Scopus, and the Cochrane Library for randomized controlled trials (RCTs) through December 31, 2024. Risk of bias was assessed using RoB-2, and evidence quality with GRADE. Analyses were performed using R, employing SMD for continuous variables and meta-regression for dose-response relationships. Subgroup analyses included symptom severity, intervention setting, delivery format, and parental involvement. The primary outcome was the reduction in depressive symptoms (PROSPERO: CRD42023444273). Results: Fourteen studies were included (11 RCTs meta-analyzed, comprising 572 participants). BA demonstrated a moderate effect size compared to treatment-as-usual (SMD = -0.42) and a large effect size compared to no-treatment controls (SMD = -0.87). BA was more effective for mild depressive symptoms (SMD = -0.93) than severe symptoms (SMD = -0.43), with significant efficacy in university settings (SMD = -0.94). Intervention without parental involvement exhibited significantly larger effects than those with parental participation (SMD = -0.94 vs. -0.38; p < 0.0001), though this finding is likely confounded by age, symptom severity, and intervention setting. BA moderately improved both behavioral activation levels and functioning (SMD = 0.49). Conclusion: Short-term, school-based BA is significantly beneficial for older adolescents with mild depressive symptoms. Findings provide practical guidance for optimizing BA implementation and highlight directions for future research, including the need for larger sample sizes, standardized follow-up assessments, and more representative samples.

Objective: Second-generation antipsychotic (SGA) treatment has increased in youth globally. However, their effects on real-world outcomes are largely unknown, especially for non-approved indications. Method: This study included a national cohort of incident SGA recipients aged 7-17 in Sweden from 2007 to 2020. Youth were followed from one year before SGA initiation through up to one year afterward, and in recurrent treatment analyses, up to 13 years after initiation. Within-individual comparisons were used to examine the risk of psychiatric hospitalization, self-harm, accidental injury, and violent crime before and after treatment. Results: The study included 21,306 SGA initiators (53.1% male; median age 14.8 years at baseline). Indications included psychosis-related disorders (1,966 [9.2%]), autism spectrum disorders (5,140 [24.1%]), depression/other mood disorders (3,669 [17.2%]), intellectual disability (987 [4.6%]), and attention-deficit/hyperactivity disorder (2,992 [14.0%]). Within a year of initiation, 5,604 (26.3%) experienced psychiatric hospitalization, 1,749 (8.2%) self-harm, 954 (13.6% of those aged 16 and above) violent crime, and 3,134 (14.7%) accidental injury. Risks were generally elevated immediately prior to SGA initiation and decreased across subsequent treatment without fully returning to baseline, although there was variation across indications. For example, psychiatric hospitalization and self-harm displayed larger pre-initiation elevations and subsequent decreases for youth with psychosis-related disorders (e.g., psychiatric hospitalization: pre-initiation odds ratio [ORpre], 11.30 [95% CI, 9.84-12.97]; ORpost, 2.59 [95% CI, 2.21-3.02]). Conversely, youth with neurodevelopmental disorders demonstrated greater decreases in violent crime (e.g., attention-deficit/hyperactivity disorder: ORpre, 1.66 [95% CI, 1.23-2.26]; ORpost, 1.26 [95% CI, 0.94-1.70]). Accidental injury risk did not statistically significantly differ (e.g. , asd: ORpost, 0.90 [95% CI, 0.77-1.07]). Conclusion: After having escalated before initiation, risk of psychiatric hospitalization, self-harm, and violent crime decreased during SGA treatment without fully returning to baseline. There was little evidence of associations with accidental injury.

Objective: This study evaluated the impact of co-occurring SUD on ADHD treatment patterns and examined clinical outcomes associated with ADHD treatment in adolescents and young adults with both ADHD and SUD. Method: This retrospective cohort study used TriNetX US Collaborative Network data on 1.23 million individuals 15 to 25 years of age who were diagnosed with ADHD from 2007 to 2024. About 23% (n = 288,159) had co-occurring SUD. Prescription patterns for ADHD medications and associated clinical outcomes were analyzed over 1 year. Relative risks (RRs), hazard ratios (HRs), and 95% CIs were calculated using propensity score matching and Cox proportional hazards models to adjust for confounders. Results: Central nervous system (CNS) stimulant prescriptions were less frequent in the ADHD with SUD cohort (RR = 0.63, 95% CI = 0.62-0.63), whereas new bupropion prescriptions were slightly more frequent (RR = 1.05, 95% CI = 1.02-1.08) compared with ADHD without SUD. In ADHD with SUD, ADHD treatment (including prescriptions for CNS stimulants and nonstimulants) was associated with fewer hospitalizations, reduced emergency care, lower risk of suicidal ideation/attempts (range of RRs = 0.74-0.82), and continuous use of psychiatric services (RR = 1.23), but fewer methadone prescriptions (RR = 0.74). Compared with nonstimulants, stimulant treatment was associated with fewer hospitalizations, accidental overdoses, and suicidal ideation/attempts (range of RRs = 0.63-0.79). Overall, ADHD treatment was associated with a 30% lower risk of mortality (aHR = 0.70, 95% CI = 0.65-0.75). Conclusion: Clinicians appear to be hesitant to prescribe CNS stimulants in the context of SUD; however, these findings align with clinical trials suggesting potential benefits of ADHD medication for individuals with co-occurring SUD. Bridging the gap between clinical practice and the evidence base will require ongoing research, clinician education, and policy change.

Objective: This study aims to assess trends in psychotropic medication use and polypharmacy, to investigate clinical indications for use, and to evaluate the prevalence of potential contraindicated or major drug-drug interactions (DDIs) among US residents 6 to 24 years of age. Method: We conducted a descriptive, repeated cross-sectional study using nationally representative data from the US National Health and Nutrition Examination Survey (NHANES) collected between 2001 and March 2020. Participants were stratified into children (6-11 years), adolescents (12-19 years), and young adults (20-24 years). Psychotropic medication use, including stimulants, antidepressants, antipsychotics, and benzodiazepine-related drugs, was assessed based on reported use within the past 30 days, and psychotropic polypharmacy as the concurrent use of 2 or more psychotropic medications. Trends were evaluated using survey-weighted linear regression across 4-year intervals, with 95% confidence intervals. Reported indications were analyzed separately for each age group. Potential DDIs among psychotropic medications were identified using Micromedex. Results: Psychotropic medication use among youth increased from 5.3% in 2001-2004 to 8.3% in 2017-March 2020 (adjusted time trend: 0.7 percentage points over 4 years; 95% CI: 0.3-1.1), with statistical increases observed among children and young adults, driven mainly by stimulants. Psychotropic polypharmacy prevalence rose from 1.8% to 3.3% during the same period (adjusted time trend: 0.3 percentage points; 95% CI: 0.01-0.5). Reported indications for psychotropic medication use varied by age, with neurodevelopmental conditions more common in children, and depression, anxiety, or bipolar disorders more common in young adults. Among psychotropic medication users, 26.0% were exposed to potential contraindicated or major DDIs, mainly from antipsychotics and antidepressants. Conclusion: Psychotropic medication use increased in specific subgroups of US youth from 2001 to March 2020, most notably among children and young adults. A quarter of psychotropic medication users were exposed to potential contraindicated or major DDIs. These findings underscore the need for further real-world research focusing on medication safety, effectiveness, and DDI risks of psychotropic medications in youth populations to inform safer and more effective treatment strategies. Diversity & inclusion statement: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way.

Importance: Despite increasingly widespread use of artificial intelligence (AI)-driven ambient scribes in medicine, the extent to which they are associated with clinician practice is not well studied. Objective: To characterize differences in documentation and treatment of psychiatric symptoms in primary care outpatient notes generated using ambient scribes compared with human or no scribes. Design, setting, and participants: This cohort study used a matched retrospective case-control design to evaluate primary care annual visit notes from the Massachusetts General and Brigham and Women's Hospital systems between February 2023 and February 2025. A random sample of notes from 4 types of visits, matched 1:1 using sociodemographic and clinical features, was used: those using an ambient scribe, those using a human scribe, those occurring during the same period without a scribe (contemporaneous), and those occurring prior to scribe deployment. Data analysis was performed from April 25 to May 1, 2025. Exposure: Use of an AI ambient scribe. Main outcomes and measures: Neuropsychiatric symptom documentation, in terms of estimated Research Domain Criteria (RDoC), using a Health Insurance Portability and Accountability Act-compliant large language model (GPT-4o version gpt-4o-11-20; OpenAI); antidepressant prescriptions and diagnostic codes; and referral for mental health follow-up. Results: Among 20 302 notes, the mean (SD) age of the patients was 48 (14) years and 11 960 (59%) were for visits by female patients; 1026 (5%) met criteria for moderate or greater depressive symptoms by Patient Health Questionnaire-9 score. Estimated levels of RDoC symptoms in all 6 domains were significantly greater in the AI-scribed notes compared with other groups. In a multiple logistic regression model, likelihood of a psychiatric intervention (referral, new diagnosis, or antidepressant prescription) was significantly lower among AI-scribed visits compared with contemporaneous unscribed visits (adjusted odds ratio, 0.83; 95% CI, 0.72-0.95), but not for human-scribed visits compared with contemporaneous unscribed visits (adjusted odds ratio, 0.97; 95% CI, 0.85-1.11). Conclusions and relevance: In this retrospective cohort study using a matched case-control design examining outpatient primary care notes, incorporation of AI ambient scribes in primary care was associated with greater levels of neuropsychiatric symptom documentation but lesser likelihood of documented management of psychiatric symptoms. Further study will be required to determine whether these changes are associated with differential outcomes.

Importance: Glucagon-like peptide-1 (GLP-1) therapies have revolutionized the management of chronic conditions like obesity and diabetes. Consistent with the overlap between feeding and metabolic pathways and those mediating addictive behaviors, growing evidence suggests that GLP-1 therapies may also be beneficial for treating alcohol and other substance use disorders (ASUDs). This review discusses the current landscape of GLP-1 therapies in the context of ASUDs, mental health considerations, and gaps and opportunities in this field. Observations: Preclinical evidence across several experimental models and species consistently shows that GLP-1 receptor agonists (GLP-1RAs) reduce drug intake and other addictive behaviors. Research to date has primarily focused on alcohol; however, nicotine, opioids, and psychostimulants have also been studied. Observational cohort studies using electronic health records suggest improvements in ASUD-related outcomes among people treated with GLP-1RAs for other indications. Randomized clinical trials (RCTs) have been limited, yielding mixed results but overall promising signals. Several RCTs are ongoing or about to start. Despite some early pharmacovigilance alarms, GLP-1RAs do not seem to cause or increase the risk of psychopathology (eg, depression, suicidal ideation and/or behavior). Some recent studies suggest beneficial effects of GLP-1RAs on mental health outcomes, but more work is needed. Conclusions and relevance: The rationale for studying GLP-1 therapies for ASUDs is supported by preclinical and observational clinical evidence. RCTs are emerging and critically needed at this juncture to determine the safety and efficacy of GLP-1 therapies in people with ASUDs. Pending results from RCTs, GLP-1 therapies have the potential to be repurposed for ASUDs. However, there are several relevant questions in need of further investigation, including the specifics of treatment with GLP-1 therapies in the context of addiction (eg, dose, duration, tachyphylaxis, impact of discontinuation), individual differences and potential predictors of response, mechanisms of action, intersection with mental health and medical comorbidities, cost, and fair access to these treatments.

Importance: Restless legs syndrome (RLS) is a sleep-related movement disorder that affects approximately 3% of US adults to a clinically significant extent and can cause substantial sleep disturbance. Observations: Restless legs syndrome is characterized by an overwhelming urge to move the limbs, typically the legs, often accompanied by unpleasant limb sensations (eg, achiness, tingling). Symptoms, provoked by immobility, are relieved while moving and are typically present or most severe in the evening or at night. Restless legs syndrome symptoms may lead to difficulty falling asleep, staying asleep, or returning to sleep. According to population-based studies, approximately 8% of US adults experience RLS symptoms of any frequency annually and 3% experience moderately or severely distressing symptoms at least twice weekly. Patients with RLS have impaired quality of life and elevated rates of cardiovascular disease (29.6% with coronary artery disease, stroke, or heart failure), depression (30.4%), and suicidal ideation or self-harm (0.35 cases/1000 person-years). Restless legs syndrome is common among patients with multiple sclerosis (27.5%), end-stage kidney disease (24%), and iron deficiency anemia (23.9%); during pregnancy and especially in the third trimester (22%); with peripheral neuropathy (eg, diabetic, idiopathic; 21.5%); and with Parkinson disease (20%). Other risk factors include family history of RLS, northern European descent, female sex (2:1 vs male sex), and older age (RLS prevalence of 10% in adults ≥65 years). Restless legs syndrome is diagnosed based on clinical history; polysomnography is not recommended for diagnosis. Iron supplementation with ferrous sulfate (325-650 mg daily or every other day) or intravenous iron (1000 mg) should be initiated for serum ferritin level less than or equal to 100 ng/mL or transferrin saturation less than 20%. If possible, medications associated with RLS, including serotonergic antidepressants, dopamine antagonists, and centrally acting H1 antihistamines (eg, diphenhydramine), should be discontinued. Gabapentinoids (eg, gabapentin, gabapentin enacarbil, pregabalin) are first-line pharmacologic therapy. In randomized clinical trials, approximately 70% of patients treated with gabapentinoids had much or very much improved RLS symptoms vs approximately 40% with placebo (P < .001). Dopamine agonists (eg, ropinirole, pramipexole, rotigotine) are no longer recommended as first-line medications due to the risk of augmentation, an iatrogenic worsening of RLS symptoms, which has an annual incidence of 7% to 10% with these medications. Patients who do not improve with first-line treatment or have augmented RLS often benefit from low-dose opioids (eg, methadone 5-10 mg daily). Conclusions and relevance: Restless legs syndrome affects approximately 3% of adults and can have negative effects on sleep and quality of life. Initial management includes cessation of exacerbating medications, as well as iron supplementation for patients with low-normal iron indices. If medication therapy is indicated, gabapentinoids are first-line treatment.

This JAMA Clinical Guidelines Synopsis summarizes the 2024 Canadian Research Initiative in Substance Matters (CRISM) guideline on management of opioid use disorder (OUD).

Forthcoming changes to clozapine monitoring present an opportunity to expand, not dilute, specialist care for chronic schizophrenia. Reduced administrative burden should support timely clozapine use, structured assessment, access to psychological therapies and embedded physical health care. Experience from Cambridgeshire shows that secondary-plus clinics within community mental health teams can deliver sustained, equitable long-term care.

Half a century of neuroimaging has transformed our understanding of psychiatric disorders but not our clinical practice. This piece examines why that promise remains unfulfilled and argues that the future lies not in ever newer tools but in rigorous, mechanistically grounded and clinically embedded imaging approaches that bridge brains, behaviours and treatments.

Purpose: To assess the association between prescription stimulant medication use and mortality through an analysis of data in the FDA Adverse Event Reporting System (FAERS) and of electronic health records (EHR) of adult patients at a large metropolitan health care center. Methods: The first analysis estimated the associations between the report of a sudden death event in FAERS with stimulants (methylphenidate, dextroamphetamine, dextroamphetamine-amphetamine, and lisdexamfetamine) and with 30 medications unlikely to be associated with serious adverse cardiovascular events and sudden death (control medications); propensity score matching was used to control for confounding. The second analysis estimated the associations between all-cause mortality with stimulants and with control medications in an self-controlled case series (SCCS) of EHR data; the SCCS method assessed whether, within individuals, there was an association between initiation of stimulant medication and mortality in a subsequent risk period. Data from the FDA Adverse Event Reporting System (FAERS) and from electronic health records (EHR) of adult at a large metropolitan health care center were analyzed. Results: In the FAERS analyses, dextroamphetamine and methylphenidate, as well as the combined stimulant class, were significantly associated with sudden death [dextroamphetamine: RR = 2.24 (95% CI: 1.37-3.65; adjusted P < 0.001); methylphenidate: RR = 2.30 (95% CI: 1.62-3.27; adjusted P < 0.001); stimulant class: RR = 2.02 (95% CI: 1.46-2.79; adjusted P < 0.001)]. In the SCCS analyses, these 2 stimulants as well as the stimulant class were significantly associated with all-cause mortality [dextroamphetamine: RR = 3.96 [95% CI: 2.07-7.56; adjusted P < 0.001); methylphenidate: RR = 4.11 (95% CI: 1.78-9.50; adjusted P < 0.001); stimulant class: RR = 3.53 (95% CI: 1.73-7.20; adjusted P < 0.001)]. In the SCCS analysis, for all stimulants except lisdexamfetamine, the RR increased with the age at first stimulant use. Conclusions: The current results document a significant association between stimulant use and mortality and underscore existing guidance to assess current cardiovascular disease and risk factors when prescribing stimulants, especially for older adults.

Introduction: The use of off-label, low doses of second-generation antipsychotics (SGAs), in particular quetiapine, has risen significantly. SGAs are known to cause metabolic adverse effects, including weight gain. The aim of this systematic review and meta-analysis was to assess the impact of low-dose quetiapine on metabolic outcomes, such as weight, glycemic, and lipid metabolism. Methods: Following the PRISMA statement, PubMed, Web of Science Core Collection, Cochrane Library, ClinicalTrials.gov, Google Scholar, and PsycINFO were systematically searched for randomized controlled trials > 4 weeks, reporting metabolic outcomes of quetiapine < 200 mg. RoB2 was used to assess bias. SPSS was used for quantitative data management and aggregation. Results: Eight unique studies (n = 3085) were included, six of which were included in the meta-analysis. Low doses of quetiapine led to significant weight gain (mean difference [MD] = 0.58 kg, 95% CI: 0.32-0.83) and HDL cholesterol reduction (MD = -1.25 mg/dL, 95% CI: -1.86 to -0.65). Patients gaining ≥ 7% of baseline weight was 2.12 times more likely to have taken quetiapine. Conclusion: Despite limited generalizability, these findings suggest that, even at low doses, quetiapine has an impact on metabolism. Further research is needed to clarify its role in metabolic dysregulation. This study was registered in the international database of prospectively registered systematic reviews (PROSPERO CRD420250588527).

Background: Antidepressant tolerance/ tachyphylaxis (AT) is defined as initial response (≥ 50% improvement) to antidepressant treatment followed by relapse while on the same adequate dose. The impact of AT as prognostic indicator for response to subsequent antidepressant treatment is unknown. Objective: To test the efficacy of esmethadone (REL-1017) in a subgroup of patients with major depressive disorder (MDD) and AT. Methods: A phase 3, double-blind, randomized, placebo-controlled trial of esmethadone was conducted in adult outpatients with MDD. Prior to randomization, AT was independently assessed by clinicians from the Massachusetts General Hospital Clinical Trials Network and Institute using the MGH Antidepressant Treatment Response Questionnaire. Data for the primary efficacy end point were analyzed using mean difference in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to primary end point (Day 28) in the AT subgroup from the intent to treat (ITT) population, the per-protocol (PP) population, and in patients with severe depression (baseline MADRS ≥35). Results: Among 227 ITT patients, 87 experienced AT. For this subgroup, there was a nominally statistically significant mean difference of 5.4 (P=.023, Cohen effect size 0.53) for esmethadone vs placebo in MADRS total score change from baseline to primary end point (Day 28). Additionally, there was a nominally statistically significant difference in response rate (P=.0004). Consistent results were seen in the PP population with AT and in the severely depressed subgroup of patients with AT. Conclusions: These post hoc analyses, based on data collected independently pre-randomization, suggest that esmethadone may be an effective adjunctive treatment for patients with AT. These results need to be confirmed in larger prospective clinical trials.

Purpose/background: Multiple meta-analyses have suggested that pharmacogenomic (PGx) testing may be a valuable tool to improve clinical outcomes for patients with major depressive disorder (MDD) who have failed at least one treatment. However, these meta-analyses included studies with different PGx tests and different trial designs, which produce uncertainty when interpreting results. To investigate the clinical utility of a single weighted multigene PGx test, a meta-analysis was performed for prospective studies utilizing this PGx test in adult patients with MDD. Methods/procedures: MEDLINE/PubMed and Cochrane [including Embase, clinicaltrials.gov, and International Clinical Trials Registry Platform (ICTRP)] were searched through May 2025 for studies evaluating the impact of pharmacogenomic testing on outcomes for patients with MDD. Using PRISMA guidelines, 243 records were identified, and 6 studies were included that compared PGx-guided care to unguided care in adult patients with MDD, using a single weighted multigene test. Findings/results: Overall, 3,532 patients were included, with outcomes evaluated at week 8 or week 10. Patients with MDD whose care was guided by the weighted multigene PGx test were 30% more likely to achieve response [relative risk ratio (RR)=1.30, 95% CI: 1.16-1.47, P <0.001] and 41% more likely to achieve remission [RR=1.41, 95% CI: 1.19-1.66, P <0.001] compared to unguided care. No heterogeneity in outcomes across studies was detected. Implications/conclusions: Prescribing informed by a weighted multigene PGx test significantly improved response and remission rates among adult patients with MDD who experienced at least 1 prior treatment failure, further demonstrating the clinical utility of weighted multigene PGx testing. Inform and do no harm: Nocebo education reduces false self-diagnosis caused by mental health awareness Mental health awareness efforts are increasing, especially for ADHD. There is growing evidence that such efforts may also cause unnecessary self-diagnosis and worsening symptoms for some disorders; however, there are no validated approaches to avoid these potential harms without reducing the awareness efforts themselves. We developed a multifaceted intervention, called nocebo education. The intervention was based on the principles of the nocebo effect, where negative expectations may cause symptom misattribution and worsening. We tested whether teaching about the nocebo effect could mitigate the potential false self-diagnosis and symptom worsening from ADHD awareness. In a double-blind randomized controlled trial with a week-long follow-up (NCT06638411), 215 healthy young adults (77% women) were randomized to participate in a group workshop on either ADHD awareness, ADHD combined with nocebo education, or control (sleep). We measured changes in self-diagnosis and ADHD symptoms immediately after the workshop (self-diagnosis), and 1-week later (self-diagnosis and symptoms). ADHD group reported substantially higher self-diagnosis scores immediately ) and 1 week after the workshop ) compared to controls. These effects persisted despite no changes in reported symptoms. Nocebo education halved the false self-diagnosis scores immediately after the workshop () and eliminated the false self-diagnosis entirely at follow-up ). Conclusions We show that being exposed to ADHD awareness reliably increases false self-diagnosis among healthy young adults for at least one week; a brief nocebo education intervention is efficacious in substantially reducing and later eliminating it. Nocebo education is a promising adjunct for balanced awareness efforts that could be applied in various contexts.

Postpartum psychosis (PP) is an acute and severe psychiatric illness with onset within weeks after delivery, and a high risk of suicide and infanticide. Most women with PP experience severe mood symptoms, including mania, mixed episodes, or depression with psychotic features. Impaired cognition, irritability, and agitation are also common. The specific timing of PP strongly suggests a biological basis, because the postpartum time period is characterized by profound endocrine, immune, neuroanatomical and physiological changes in the brain. Genetic studies show a unique risk architecture, partly shared with bipolar disorder. PP stands out as one of the most distinct clinical phenotypes in psychiatry due to its characteristic rapid onset, severity, phenomenology, treatment response, and prognosis. Despite this, as of August 2025, PP does not have a distinct diagnostic classification in the DSM. This expert consensus panel, in close collaboration with patient organizations and key interested partners, recommends classifying PP as a distinct category within DSM-5 and ICD 11. We recommend classification within the bipolar disorders chapter of the DSM because 1) most women with PP have prominent affective symptoms; 2) treatment response to lithium and ECT is excellent; 3) in half of cases, first-onset PP is also the first onset of bipolar disorder; 4) pregnant women with bipolar disorder are at very high risk of PP; and 5) the genetic risk architecture for PP is distinct but overlapping with bipolar disorder. This consensus statement summarizes scientific evidence that PP is a distinct mental illness within the bipolar spectrum; correct classification will improve detection and treatment.

Importance: Individuals with attention-deficit/hyperactivity disorder (ADHD) may present with psychosis or bipolar disorder (BD) following treatment with stimulants. The extent to which this occurs is currently unclear. Objective: To meta-analytically quantify the occurrence of psychosis or BD after exposure to stimulants in individuals with ADHD and assess possible moderating factors. Data sources: PubMed, Web of Science, Ovid/PsycINFO, and Cochrane Central Register of Reviews were searched from inception until October 1, 2024, without language restrictions. Study selection: Studies of any design with DSM or International Classification of Diseases-defined ADHD populations exposed to stimulants, where psychosis or BD outcomes were evaluated. Data extraction and synthesis: PRISMA Preferred Reporting Items for Systematic Reviews and Meta-analyses and MOOSE Meta-analysis of Observational Studies in Epidemiology guidelines were followed, the protocol was registered, and the Newcastle-Ottawa scale and Cochrane risk of bias-2 tool were used for quality appraisal. Random-effects meta-analysis, subgroup analyses, and meta-regressions were conducted. Main outcomes and measures: For the proportion of individuals developing psychotic symptoms, psychotic disorders, and BD, effect sizes are reported as percentages with 95% CIs. For the comparison between amphetamines and methylphenidate, effect sizes are presented as odds ratios with 95% CIs. Results: Sixteen studies (N = 391 043; mean [range] age, 12.6 [8.5-31.1] years; 288 199 [73.7%] male) were eligible. Among individuals with ADHD prescribed stimulants, 2.76% (95% CI, 0.73-9.88; k = 10; n = 237 035), 2.29% (95% CI, 1.52-3.40; k = 4; n = 91 437), and 3.72% (95% CI, 0.77-16.05; k = 4; n = 92 945) developed psychotic symptoms, a psychotic disorder, and BD, respectively. Heterogeneity across the studies was significant (I2 > 95%). Psychosis occurrence risk was significantly higher in individuals exposed to amphetamines than to methylphenidate (odds ratio [OR], 1.57, 95% CI, 1.15-2.16; k = 3, n = 231 325). Subgroup analyses showed significantly higher prevalence of psychotic symptoms in studies from North America and in those with longer follow-up periods. Increased psychosis occurrence was associated with a higher proportion of female participants, smaller sample sizes, and higher dose of stimulants. Conclusions and relevance: This systematic review and meta-analysis found a nonnegligible occurrence of psychotic symptoms, psychotic disorders, or BD in individuals with ADHD treated with stimulants. Amphetamines were associated with higher occurrence compared to methylphenidate. The included studies cannot establish causality, highlighting the need for further research, including randomized clinical trials and mirror-image studies comparing individuals exposed and not exposed to stimulants. Nonetheless, clinicians should inform patients about the increased occurrence of psychosis or BD when discussing stimulant pharmacotherapy and systematically monitor for these conditions throughout treatment.

Alcohol and other substance use disorders (ASUDs) are complex, multifaceted, but treatable medical conditions with widespread medical, psychological, and societal consequences. However, treatment options remain limited, therefore the discovery and development of new treatments for ASUDs is critical. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), currently approved for the treatment of type 2 diabetes mellitus, obesity, and obstructive sleep apnea, have recently emerged as potential new pharmacotherapies for ASUDs. Following an overview of the epidemiology, biology, consequences, and treatments of ASUDs, this review provides a summary of the emerging role of GLP-1RAs in the treatment of ASUDs by elucidating their interactions with various neurobiological pathways involved in addiction. We also highlight existing gaps in research, future directions, and broader implications related to the potential use of GLP-1RAs for addiction treatment.

Importance: Limited clinical evidence is available about the risk of neurodevelopmental disorders (NDD), including autism spectrum disorders and congenital malformations (CM), in offspring following paternal exposure to antiseizure medications. Objective: To investigate the risk of NDD (any subtype) and CM (major and/or minor) in offspring paternally exposed to valproate vs lamotrigine or levetiracetam monotherapy within 3 months prior to conception. Design, setting, and participants: This observational, population-based, nationwide cohort study used Nordic registries data with family linkage (offspring born between 1997-2018 [Denmark], 2010-2019 [Norway], and 2007-2019 [Sweden]). Offspring born within the study period and paternally exposed to either (1) valproate or (2) lamotrigine or levetiracetam were identified and followed-up until 12 years or the end of the study period, whichever came first. Data were obtained from October 2020 (Denmark), June 2021 (Norway), and March 2021 in Sweden)and analyzed from October 2020 to July 2023. Exposures: Paternal exposure to (1) valproate or (2) lamotrigine or levetiracetam during the spermatogenic risk window (derived from each National Prescription Registry). Main outcomes and measures: The primary and secondary outcomes were NDD and CM, respectively, in offspring aged 12 years or younger. Country-specific hazard ratios (HRs) for NDD were estimated using Cox regression models and propensity score weighting (PSW), subsequently pooled via meta-analysis. Odds ratios (ORs) for CM were estimated using unadjusted logistic regression models for Denmark and Norway, but were not estimated for Sweden due to database constraints. Results: NDD analysis included 5721 offspring, with 1950 in Denmark (valproate: 793 offspring; lamotrigine or levetiracetam: 1157 offspring), 1416 in Norway (valproate: 398 offspring; lamotrigine or levetiracetam: 1018 offspring), and 2355 in Sweden (valproate: 930 offspring; lamotrigine or levetiracetam: 1425 offspring). After excluding offspring with outlier weights and/or incomplete observation in the PSW-adjusted analyses, NDD occurrence was observed in 38 of 678 offspring (5.6%) vs 36 of 1118 offspring (3.2%), 13 of 325 offspring (4.0%) vs 21 of 910 offspring (2.3%), and 47 of 841 offspring (5.6%) vs 34 of 1334 offspring (2.5%) exposed to valproate vs lamotrigine or levetiracetam in Denmark, Norway, and Sweden, respectively. PSW-adjusted analyses showed significantly higher risk in the valproate vs lamotrigine or levetiracetam group (pooled adjusted HR, 1.50; 95% CI: 1.09-2.07; P = .01). CM analysis included 1161 offspring, with 648 in Denmark (valproate: 259 offspring; lamotrigine or levetiracetam: 389 offspring) and 513 in Norway (valproate: 169 offspring; lamotrigine or levetiracetam: 344 offspring), and found no increased risk (unadjusted pooled OR, 0.81; 95% CI, 0.48-1.36). Conclusions and relevance: In this cohort study, higher NDD risk was observed in offspring paternally exposed to valproate vs lamotrigine or levetiracetam, but no difference in CM risk was observed between the 2 exposure groups. However, these findings should be interpreted with caution due to the heterogeneity in the unadjusted estimates.

Importance: Serial ketamine infusions are being increasingly adopted as off-label treatment for major depression in routine clinical practice, yet robust psychoactive placebo-controlled trial evidence for short- and long-term efficacy and safety remains limited. Objective: To assess antidepressant efficacy, safety, tolerability, cost-effectiveness, and quality of life during and after serial ketamine infusions compared with midazolam as an adjunct to usual inpatient care. Design, setting, and participants: The KARMA-Dep 2 trial was an investigator-led, double-blind, randomized, midazolam-controlled, pragmatic trial conducted at an academic center in Ireland between September 2021 and August 2024. Participants included adults (≥18 years) hospitalized with a DSM-5 major depressive episode (unipolar or bipolar) and baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥20. Interventions: Participants were randomized 1:1 to receive up to 8 twice-weekly intravenous infusions of either ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) as an adjunct to usual-care pharmacotherapy and other aspects of routine inpatient psychiatric care. Participants were followed up for 6 months. Main outcomes and measures: The primary outcome was change in depression symptom severity measured by the observer-rated MADRS score from baseline to end of treatment. Secondary outcomes included self-reported depression severity, safety, tolerability, health care costs, and quality of life. Results: Of 65 randomized participants (mean [SD] age, 53.5 [18.6] years; 37 [59.7%] male), 62 were included in the final analysis. In the analysis of primary outcome, end-of-treatment MADRS scores did not significantly differ between the ketamine and midazolam groups (adjusted mean difference, -3.16 points, 95% CI, -8.54 to 2.22; P = .25; Cohen d, -0.29). Similarly, there was no significant between-group difference between Quick Inventory of Depressive Symptoms, Self-Report, scores (adjusted mean difference, -0.002; 95% CI, -2.71 to 2.71; P > .99; Cohen d, -0.0004). There were no significant between-group differences on other secondary outcomes, including cognition, cost-effectiveness, or quality of life. Most patients and raters accurately guessed treatment allocation. Conclusions and relevance: Serial adjunctive ketamine infusions were not more effective than serial midazolam infusions in reducing depressive symptoms in inpatients receiving usual psychiatric care.

Background: Second-generation antipsychotics are widely used to treat patients with bipolar spectrum disorders and effectively manage mood symptoms but can often cause substantial weight gain and other metabolic alterations that elevate long-term risks of cardiovascular disease and premature mortality. Metformin has been shown to be safe and efficacious for ameliorating weight gain but has not been evaluated in typical clinical settings or for more than 6 months in this population and is not widely used as standard of care. Therefore, we conducted a pragmatic clinical trial to assess the effect of metformin treatment in young people treated with second-generation antipsychotics who had a bipolar spectrum disorder along with overweight or obesity. Methods: In this multi-site, open-label, pragmatic parallel group study, we enrolled overweight or obese youth aged 8-19 years, previously or currently diagnosed with a bipolar spectrum disorder, and treated with or starting a second-generation antipsychotic. Participants were recruited and followed at 64 clinical sites (community-based mental health centres or academic health centres) in the USA. Sites were eligible for participation if they projected an enrolment rate of at least three patients per month and a minimum total number of 90 patients. Participants were randomly assigned (1:1) to the healthy eating and physical activity (LIFE) or the metformin plus LIFE (MET plus LIFE) interventions, within eight strata defined by baseline BMI percentile (overweight [85th to <95th] vs obese [≥95th]); second-generation antipsychotic-naive (starting vs continuing a second-generation antipsychotic at baseline); and sex assigned at birth, and using block randomisation (blocks of six). The co-primary outcomes were change in age-normalised and sex-normalised BMI Z-score at 6 months and 24 months in the intention-to-treat population. People with lived experience with bipolar disorders were involved in the design, conduct, and reporting of this trial. The Patient-Centered Outcomes Research Institute identification was PCS-1406-19276 and the study was registered at ClinicalTrials.gov, NCT02515773, and is completed. Findings: Between Nov 5, 2015, and Feb 10, 2022, 1633 individuals provided consent for study inclusion, 68 were excluded (26 withdrew before baseline assessments and 42 did not pass screening assessments), and 1565 were randomly assigned (777 assigned to the MET plus LIFE group and 788 assigned to the LIFE group). Data were available from 1252 participants at month 6 (565 in the MET plus LIFE group and 687 in the LIFE group), and 1299 participants at month 24 (579 in the MET plus LIFE group and 720 in the LIFE group). 829 (53%) participants were male and 736 (47%) were female. The mean age of participants was 13·9 years (SD 2·9). 1023 (65%) were White or Caucasian and 290 (19%) were Black or African American. After 6 months and 24 months, assignment to the MET plus LIFE group resulted in greater change in BMI Z-score compared with LIFE alone (month 6: standardised effect size, 0·26 [95% CI 0·15-0·37], p<0·0001; month 24, standardised effect size=0·11 [0·00-0·22]; p=0·047). Among participants taking metformin, 12 attempted suicide once and one attempted suicide twice; among participants not taking metformin, 25 attempted suicide once and three attempted suicide twice. There were no significant differences in proportions of patients with any suicidality during randomised treatment, as assessed using the Patient Health Questionnaire-9 item 9 (MET plus LIFE: 42 [8%] of 519; LIFE: 57 [9%] of 655). Gastrointestinal adverse events were 2-4 times more common in the MET plus LIFE group. Interpretation: Although its effect on weight is modest, we conclude that for most patients, the benefits of metformin outweigh the risks. The findings from this trial suggest that clinicians should consider prescribing metformin for young people with bipolar spectrum disorder and related mood disorders who are overweight or obese and are treated with second-generation antipsychotics.

Background: Pharmacotherapy with clozapine is listed as an optional treatment for several psychiatric disorders in guidelines across the globe. Nonetheless, its transdiagnostic effectiveness across most psychiatric disorders remains uncertain due to scant evidence. We therefore aimed to assess the effectiveness and safety of clozapine across multiple psychiatric disorders. Methods: This cohort study used nationwide register-based data from Finland and Sweden in individuals aged 16 years or older diagnosed with schizophrenia, schizoaffective disorder, delusional disorder, bipolar disorder, psychotic depression, major depressive disorder, and borderline personality disorder (BPD). The effectiveness of clozapine was compared with other oral antipsychotics as a group, and for bipolar disorder additionally against mood stabilisers. The primary outcome was all-cause psychiatric hospitalisation. Secondary outcomes were all-cause hospitalisation or mortality as a composite outcome, all-cause discontinuation (for which clozapine use was compared with olanzapine use), and disorder-specific hospitalisations (eg, hospitalisation due to psychosis for schizophrenia-spectrum disorders and hospitalisation due to mood episodes for affective disorders). A within-individual design was used, where each patient served as their own control, minimising selection bias. Data were analysed separately in each country and combined using meta-analytical methods. People with lived experience were not involved in the research and writing process. Findings: The study population included 505 474 individuals, of whom 283 809 (56·1%) were women and 221 665 (43·9%) were men, with a mean age of 41·6 years (SD 4·4). Data on ethnicity were unavailable. Altogether, clozapine was used by 19 910 individuals. Parsed by disorder, clozapine was used by 12·2-18·7% (n=5258 in Sweden, 10 115 in Finland) of people with schizophrenia, 8·8-20·7% (n=1131, n=1591) with schizoaffective disorder, 1·8% (n=341; data only available in Sweden) with delusional disorder, 0·5% (n=118, n=331) with major depressive disorder, 0·5-0·6% (n=490, n=371) with bipolar disorder, 0·3-0·6% (n=39, n=111) with psychotic depression, and 0·3% (n=36; data only available in Sweden) with BPD. Clozapine use was associated with reduced psychiatric hospitalisation risks versus other oral antipsychotics in all disorders, except for BPD. The greatest reductions were observed in schizophrenia (meta-analysis of adjusted hazard ratios [maHR] 0·70 [95% CI 0·67-0·72]) and schizoaffective disorder (maHR 0·71 [0·67-0·74]), followed by delusional disorder (adjusted hazard ratio 0·73 [0·60-0·89]), major depressive disorder (maHR 0·74 [0·66-0·84]), psychotic depression (maHR 0·76 [0·61-0·96]), and bipolar disorder (maHR 0·77 [0·69-0·87]). Moreover, we found no evidence of increased all-cause hospitalisation or mortality risks associated with clozapine use for all disorders examined. Furthermore, for all disorders studied except for BPD, all-cause discontinuation rates were lower during clozapine than olanzapine use. For bipolar disorder, clozapine outperformed mood stabilisers on all-cause psychiatric hospitalisation and other antipsychotics for several disorder-specific outcomes. Interpretation: These findings support the transdiagnostic effectiveness and safety of clozapine, particularly in schizophrenia-spectrum disorders, bipolar disorder, and severe depression. Given the overall consistent findings across two large national cohorts, these results could inform several treatment guidelines and clinical decision-making for individuals with such severe psychiatric disorders.

Background: Although attention deficit hyperactivity disorder (ADHD) is known to be common in psychotic disorders, reported prevalence rates vary widely, with limited understanding of how different factors (eg, assessment methods, geographical region) may be associated with this variation. The aim was to conduct a systematic review and meta-analysis to determine the prevalence of ADHD in psychotic disorders and factors associated with the variability in reported rates. Study design: Searches were conducted in MEDLINE, Embase, PsycINFO, CINAHL, and Scopus in May 2023. Studies were eligible if the frequency of ADHD was reported in psychotic disorder samples. Pooled prevalence meta-analyses were performed. Subgroup analyses and meta-regressions explored whether demographic and study characteristics were associated with reported rates. Study results: Thirty-six studies were included, involving 30 726 individuals. The pooled lifetime prevalence of ADHD in psychotic disorders was 18.49% (95% CI 11.78%, 27.83%). The between-study heterogeneity was high (I2 = 98.4% [95% CI 98.2%, 98.6%]). Subgroup analyses revealed higher prevalence rates when using ADHD DSM-IV criteria compared to International Classification of Diseases (ICD)-10. Rates in childhood-onset psychotic disorders were higher than adolescent- and adult-onset psychotic disorder samples. Rates were higher in North America compared to other regions. Meta-regressions indicated a decrease in prevalence rates with publication year. Conclusions: The prevalence of ADHD in psychotic disorders appears higher than in the general population, highlighting the need for clinical attention and further research into this comorbidity. Reported rates, however, vary significantly. Reasons may include diagnostic criteria, age of psychosis onset, region, study design, and publication year. Future research should investigate these factors using rigorous ADHD assessment protocols.

Introduction: Depression is a common mental disorder with often persistent consequences. Even after adequate treatment, recovery may be far from optimal. To enhance outcomes, we aimed to identify and synthesize factors that depressed adults themselves perceived as facilitating or hindering recovery. Methods: We searched PubMed, PsycINFO, and SocINDEX (last search: February 2, 2025), screened reference lists, and consulted experts. Eligible studies used a qualitative design, published in English or Dutch since 1980, and explored recovery factors in adults (≥18 years) with depression. Results: From 4,872 records, 3,394 were screened on title and abstract, and 122 on full text. Twenty-seven articles were eligible and included in the qualitative evidence synthesis. These articles described the experiences with recovery from depression of 939 individuals. Most studies were conducted in Europe (N = 11), followed by North America (N = 7), Asia (N = 6), Australia (N = 5), and South America (N = 2). Eight overarching themes emerged: (1) social connections, (2) reconstructing the self, (3) autonomy, (4) professional support, (5) self-management strategies, (6) physical health, (7) instrumental facilitators/barriers, and (8) temporal dimensions. We present an overview of the relative importance of factors and propose a conceptual model illustrating the interconnectedness of themes. Conclusion: Recovery from depression involves a diverse range of interconnected factors. While professional treatment is considered valuable, various other factors also influence individuals' recovery. Our findings underscore the need for an integrated and person-centred approach that combines therapeutic support with personal capacities, self-management strategies, and contextual aspects, emphasizing relational quality, self-reflection, and open dialogue, to optimize subjectively experienced recovery.

Background: Research exploring delusions among individuals with psychosis often focuses on form, rather than content, and on prevalence, rather than change in a cohort over time. While delusional forms are mostly consistent across cultures and historical periods, the content of delusions is shaped by sociopolitical factors. Aims: We explored the form and content of delusions in a modern sample of individuals with psychosis, examining the extent to which the internet and new technologies become incorporated into delusional frameworks. We investigated whether there was a change in the prevalence of technology delusions over time and how gender, age and education level impacted the probability that a subject would experience technology delusions. Method: We reviewed the medical records of 228 adults with psychosis who were seeking treatment at a large academic medical centre between 2016 and 2024 and extracted any description of delusional thought content. We characterised delusions into subtypes and explored the ways these delusions feature the internet and new technologies. To examine temporal trends in the content of delusions, we conducted a binary logistic regression analysis with year as the predictor variable and the presence of technology-related content in delusions as the outcome variable. Results: Most subjects (88.2%) reported delusional thought content, with over half (51.7%) describing technology delusions. Logistic regression between the year and technology-related delusion outcome revealed statistically significant (β = 0.139, p = 0.038, 95% CI (0.008, 0.270)) correlation. For each 1-year increase, the odds of a subject presenting with technology delusions increased by approximately 15% (odds ratio 1.15). Conclusions: Among individuals with psychotic disorders, the internet and new technologies are increasingly salient in delusional frameworks. Clinicians should be aware of these themes while eliciting symptoms from patients and also while educating trainees.

Background: An increase in mental disorders has been suggested, but the interpretation of such trends remains unclear. This study examines changes in the 12-month prevalence of anxiety and mood disorders over 12 years and evaluates whether clinical characteristics or sociodemographic, vulnerability and health-lifestyle risk factors contributed to these trends. Aims: To assess trends in the 12-month prevalence of anxiety disorders (i.e. panic disorder, agoraphobia, social anxiety disorder or generalised anxiety disorder) and mood disorders (major depressive disorder, dysthymia or bipolar disorder) and explore whether changes in clinical profiles or risk factors influenced these trends. Method: Data from 11 615 respondents (mean age 43.5 years, 53.5% female) in the Netherlands Mental Health Survey and Incidence Studies (NEMESIS) were analysed, covering 2007-2009 (NEMESIS-2, n = 6646) and 2019-2022 (NEMESIS-3, n = 4969). Diagnoses were determined using the Composite International Diagnostic Interview 3.0. Results: The 12-month prevalence of all anxiety and mood disorders was significantly higher in 2019-2022 compared to 2007-2009, with relative increases across disorders ranging from approximately a half to more than double their previous rates. Any anxiety or mood disorder increased from 10.2 to 16.7%. Clinical profiles were equally severe in 2019-2022; rather, there was increased mental health care use, a higher number of comorbid disorders and earlier onset. Examination of 14 risk factors showed no consistent evidence of greater prevalence or increased relative impact over time. Conclusions: There was a consistent rise in the 12-month prevalence of anxiety and mood disorders over 12 years. This increase was not explained by changes in risk factors or less severe disorder reporting. Instead, these findings suggest a concerning decline in public mental health, highlighting the need for effective prevention strategies, timely interventions and better mental health resource allocation to address growing clinical demands.

There are a growing number of new tools designed to predict suicide risk. One, OxSATS, developed in Oxford (UK) using Swedish data, produces a probabilistic risk of suicide in people who have self-harmed. It is accompanied by a web-based calculator, and states that it can 'accurately predict 12-month risk of suicide'. It represents a departure from longstanding research arguing that risk prediction provides insufficient information to be clinically useful.We analyse the use of OxSATS from a clinician's perspective using eight illustrative vignettes. For each, we use the OxSATS online tool to calculate the 12-month risk of suicide and consider how clinicians might interpret or act on the results. We highlight several potential harms to patients arising from the tool's use.In our discussion, we explore broader limitations of OxSATS and similar tools, some of which are insidious. These tools can shift resources towards perceived higher-risk patients, often older men, diverting attention away from prevention, younger women and even the treatment of mental illness. Their reductionist approach misunderstands the complexity and stochastic nature of suicide. Tools tend to be disliked by patients and can subvert a clinician's role away from helping patients, towards mitigating perceived risk.We conclude that tools such as OxSATS should be treated with significant caution and require careful scrutiny before being considered for clinical use. At present, psychosocial assessments and understanding patients' narratives remain at the heart of good care for suicidal patients.

Objective: While opioid overdose has begun to decrease in recent years, stimulant overdose has continued to increase and has not been adequately addressed. Unlike opioid use disorder, there are no medications approved by the U.S. Food and Drug Administration to treat stimulant use disorder (StUD). The most effective treatment is contingency management (CM), a behavioral intervention that provides tangible rewards to reinforce target behaviors, such as biochemically verified abstinence. Despite the effectiveness of CM on near-term substance use behaviors, the long-term impact on key outcomes such as mortality are unclear. The objective of this work was to examine whether patients with StUD who receive CM have a decreased risk of mortality. Methods: This was a retrospective cohort study of patients with StUD who received or did not receive CM, using linked electronic health records and death records in the largest integrated health system in the United States, the Veterans Health Administration (VHA), from July 2018 through December 2020. The primary outcome was mortality in the year following the index CM visit. All-cause mortality data were obtained from the National Death Index and linked to electronic health record data. Adjusted hazard ratios were estimated using stratified Cox proportional hazards models. Results: A total of 1,481 patients with StUD who received CM were included alongside 1,481 matched control subjects. Over the 1-year follow-up period, those who received CM were 41% less likely to die (adjusted hazard ratio=0.59, 95% CI=0.36, 0.95) than those who did not receive CM. Conclusions: This study provides the first evidence that CM use in real-world health care settings is associated with reduced risk of mortality among patients with StUD.

Importance: Lithium augmentation is an effective treatment for patients with major depression after inadequate antidepressant response, but therapeutic outcomes vary considerably between individuals. Molecular studies may provide novel insights into treatment prediction and guide personalized therapy. Objective: To investigate the association of polygenic risk scores (PRS) for schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) with clinical outcomes after lithium augmentation. Design, setting, and participants: This cohort study analyzed prospectively assessed treatment outcomes in patients who underwent lithium augmentation. Disorder-specific PRS were calculated using well-powered genome-wide association study summary statistics. Participants were recruited from 13 psychiatric hospitals, primarily in the greater Berlin area, between 2008 and 2020. They were patients with MDD who showed inadequate response to at least 1 antidepressant, a baseline score of 12 or more on the 17-item Hamilton Depression Rating Scale (HAMD-17), adequate treatment duration (≥4 weeks), and no diagnostic or co-medication changes. Data analysis was conducted between June 2022 and November 2023. Exposure: Polygenic risk scores for MDD, SCZ, or BIP. Main outcomes and measures: Response was defined as a 50% or greater reduction in HAMD-17 score, remission as a HAMD-17 score of 7 or less. Cox proportional hazards models, adjusted for ancestry, demographic, and clinical covariates, were used to estimate hazard ratios (HRs) for favorable outcomes. Results: Among 193 patients (mean [SD] age, 49.5 [13.4] years; 118 [61.1%] female and 75 [38.9%] male), higher BIP-PRS were associated with both response (HR, 1.29; 95% CI, 1.02-1.63; P = .03) and remission (HR, 1.52; 95% CI, 1.14-2.04; P = .004), explaining 2.51% and 4.53% of the variability in treatment outcomes, respectively. Individuals in the highest tertile of the BIP-PRS distribution had a 2.02-fold (95% CI, 1.15-3.53) higher likelihood of response and a 2.26-fold (95% CI, 1.17-4.36) higher chance of remission compared with those in the lowest tertile. Additionally, lower MDD-PRS was associated with better response to lithium augmentation (HR, 0.81; 95% CI, 0.66-1.00; P = .048; Nagelkerke R2 = 1.99%). No significant associations were observed between SCZ-PRS and response (HR, 1.00; 95% CI, 0.80-1.24; P = .97) or remission (HR, 1.12; 95% CI, 0.85-1.48; P = .42). Conclusions and relevance: Individuals carrying a higher polygenic burden for BIP and lower polygenic risk for MDD are more likely to benefit from lithium augmentation. Our findings suggest that disease-related PRS may aid in developing treatment prediction models for lithium augmentation response in depression, potentially informing clinical decision-making.

Importance: While clinical guidelines generally advise caution with benzodiazepine use following trauma, prescribing patterns during mass traumatic events reveal tensions between formal recommendations and frontline care delivery. Objective: To assess changes in benzodiazepine prescribing patterns following the October 7, 2023, terrorist attacks in Israel and examine factors associated with prescribing decisions. Design, setting, and participants: This population-based retrospective cohort study was conducted using the electronic database of Clalit Health Services in Israel, the country's largest health care service, covering approximately 54% of the population. The number of individuals receiving benzodiazepine prescriptions in the 7- and 30-day periods following the October 7 attacks, in all Clalit Health Services' members aged 18 years or older who were actively insured as of October 7, 2023, were compared with the same population in 2022. Main outcomes and measures: The primary outcome was changes in overall and first-time benzodiazepine prescriptions during the 7-day and 30-day periods following October 7, 2023, compared with the same periods in 2022. Secondary outcomes included prescriber characteristics and factors associated with receiving new prescriptions. Results: In a population of nearly 4 million individuals, total benzodiazepine prescriptions increased by 219% in the first week (from 8600 to 27 408) and 57% over 30 days (from 54 969 to 86 568) compared with 2022. First-time prescriptions showed a 10-fold increase in the first week (from 329 to 3690) and a 268% increase over 30 days (from 2751 to 10 135). Primary care physicians issued 92.5% of new prescriptions. Geographic proximity to conflict zones (adjusted odds ratio, 2.34; 95% CI, 1.89-2.90) and preexisting anxiety diagnoses (adjusted odds ratio, 1.79; 95% CI, 1.63-1.96) were significantly associated with receiving new prescriptions. Conclusions and relevance: In this study, the October 7 attacks were associated with substantial increases in benzodiazepine prescribing, particularly among primary care physicians, revealing the tension between clinical guidelines and pragmatic crisis management. These findings suggest a need to better understand and support frontline prescribing decisions during mass trauma events through enhanced clinician training and support systems.

Generative Large Language Models (LLMs) are transforming mental health care by enabling the generation and understanding of human-like text with increasing nuance and contextual awareness. However, mental health is a complex, multidimensional domain that often requires richer sources of information beyond text. This narrative review explores the emerging role of Multimodal LLMs (MLLMs), which are models that integrate diverse input modalities such as speech, images, video, and physiological signals, to incorporate the multifaceted nature of mental states and human interactions. We first outline the foundational principles of MLLMs and their distinction from traditional text-only LLMs. We then synthesize recent empirical studies and experimental applications of MLLMs in mental health research and clinical settings, highlighting their potential to improve diagnostic accuracy, enable real-time monitoring, and support context-aware, personalized interventions. Finally, we outline opportunities for future research and innovation, and discuss key implementation challenges in MLLM-based mental health care.

Lithium is a classic, primary treatment for bipolar disorder that has paradoxically been used less over time, especially in North America, which goes against the accumulating evidence for its efficacy. Bipolar disorder is increasingly conceptualised as a chronic, potentially progressive condition worsened and accelerated by each mood episode, which might resemble multiple sclerosis or rheumatoid arthritis as a condition that requires disease-modifying treatments to change illness trajectory. In this Personal View, we argue that lithium acts like a disease-modifying drug in bipolar disorder. Although the pathophysiology of bipolar disorder remains unclear, many of the mechanisms implicated in bipolar disorder, and the surrogate markers associated with this condition, are uniquely affected by lithium treatment from the DNA and cellular levels to the structure and function of the brain and other body systems. Clinical trial and cohort study evidence shows that lithium is effective and probably superior to other medications used to treat bipolar disorder, and that long-term outcomes are better with lithium than non-lithium regimens. Conceptualisation of lithium as a disease-modifying agent might help to increase clinical use by doctors, especially early in the disease course to better serve our patients.

This review examines ketamine's neurotoxic potential across preclinical and clinical studies. The authors synthesized data from preclinical models, then integrated findings from human clinical trials of esketamine and observational studies in recreational users. Animal studies have found that repeated or high-dose subanesthetic ketamine administration results in consistent excitotoxic neuronal damage and lasting cognitive deficits, especially in perinatal animals. Infrequently administered relatively low and moderate subanesthetic doses (<1 mg/kg approximate human intravenous equivalent) do not yield overt histopathology in rat and nonhuman primate models. In humans, observational studies in frequent high-dose (>1 g/day) ketamine users show memory and executive function impairments. In contrast, a large clinical trial found that intranasal esketamine at doses up to 84 mg, administered weekly or every other week for several years, is associated with maintained or slightly improved cognitive function in adults with major depression. Lower cognitive function (attention, processing speed) showed some potential worsening among elderly patients; the clinical significance of this is unknown. Direct comparisons of esketamine and off-label racemic ketamine at higher doses have not been done. These studies underscore the potential for neurotoxic effects when ketamine is used at doses or frequencies beyond those utilized in clinical trials, highlighting a critical need for robust longitudinal research. Clinicians are advised to exercise caution, particularly when prescribing ketamine off-label at doses significantly higher than those used in clinical trials. When deviating from this in clinical practice, strong consideration should be given to conducting repeated cognitive assessments. Funding agencies should incentivize preclinical researchers to conduct studies that further elucidate the threshold of ketamine's neurotoxicity.

Background: Hallucinations and delusions are often grouped together as positive symptoms of psychosis. However, recent evidence suggests that they may be driven by distinct computational and neural mechanisms. Examining the time course of their emergence may provide insights into the relationship between these underlying mechanisms. Methods: Participants from the second (N = 719) and third (N = 699) iterations of the North American Prodrome Longitudinal Study (NAPLS 2 and 3) were assessed for timing of clinical high risk for psychosis (CHR-P)-level delusion and hallucination onset. Pre-onset symptom patterns in patients with first-episode psychosis from the Prevention and Early Intervention Program for Psychosis (PEPP-Montréal) (N = 694) were also assessed. Symptom onset was determined at the baseline assessment, and the evolution of symptom patterns was examined over 24 months. Results: In all 3 samples, participants were more likely to report the onset of attenuated/subthreshold delusions prior to attenuated/subthreshold hallucinations (odds ratios [ORs]: NAPLS 2 = 4.09; NAPLS 3 = 4.14; PEPP, z = 7.01, p < .001) and to present with only attenuated/subthreshold delusions compared with only attenuated/subthreshold hallucinations (ORs: NAPLS 2 = 5.6; NAPLS 3 = 11.11; PEPP = 42.75). The reemergence of attenuated/subthreshold delusions after remission was also more common than reemergence of attenuated/subthreshold hallucinations (ps < .05), which more often resolved first (ps < .001). In both CHR-P samples, ratings of delusional ideation decreased with the onset of attenuated hallucinations (p = .007). Conclusions: Attenuated/subthreshold delusions tend to emerge before attenuated/subthreshold hallucinations and may play a role in their development. Future work should examine the relationship between the mechanisms that drive these symptoms and its utility for diagnosis and treatment.

Insomnia is ubiquitous, is comorbid with all major mental disorders, increases the risk of depression, and contributes to inflammatory morbidity and all-cause mortality. This review examines the relationships between insomnia and inflammation in the pathophysiology of depression. The unique role of insomnia on depression risk is examined with interrogation of what aspects of sleep disturbance contribute to depressed mood. Furthermore, the influence of insomnia and its specific aspects (i.e., short sleep duration, disturbance of sleep maintenance) on affective mechanisms are considered, with a focus on reward activation and emotion processing. Given that inflammation contributes to some types of depression, the bidirectional interactions between sleep and inflammation are examined with consideration of how sleep deprivation induces activation of systemic, cellular, and genomic inflammatory outcomes and the causal role of inflammation in precipitating depressed mood and depressive symptoms. Key gaps in the literature linking insomnia and inflammation to depression risk are identified, and maps for future research are proposed. In particular, this review considers how the components of insomnia and inflammation conspire together to exaggerate deficits in reward activation and recognition of emotion, which underlie depression risk and adverse depression outcomes. Finally, informed by this two-hit model of insomnia and inflammation on depression risk, this review examines the efficacy of behavioral interventions that target insomnia and reverse related inflammation and discusses their potential to refine therapeutic approaches for depression treatment and prevention in individuals with insomnia.

Background and objectives: Concomitant use of tramadol and antidepressants with potent inhibition of the cytochrome P450 2D6 (CYP2D6) enzyme is postulated to increase risk of seizures in older adults; yet, such an association has not been empirically tested in populations. We aimed to examine the association of concomitant tramadol and CYP2D6-inhibiting vs CYP2D6-neutral antidepressant use and the risk of seizures among older nursing home (NH) residents. Methods: This population-based cohort study was conducted using a 100% Medicare NH sample from January 2010 to December 2021. We included long-term residents aged 65 years or older who initiated antidepressants on existing tramadol use (tramadol-antidepressant users) or initiated tramadol on existing antidepressant use (antidepressant-tramadol users). Patients were followed up until the end of 1 year, NH discharge, death, or study end. The key exposure was concomitant use of tramadol with CYP2D6-inhibiting vs CYP2D6-neutral antidepressants. The key outcome was incident rates of medical encounters with a diagnosis of seizure and analyzed using negative binomial or Poisson regression models adjusted for baseline covariates (e.g., pain status and depressive, physical, and cognitive function) through the inverse probability of treatment weighting. Results: We identified 11,162 concomitant tramadol-antidepressant users (mean [SD] age, 86.2 [8.5] years; 9,077 [81.3%] female) and 58,994 concomitant antidepressant-tramadol users (mean [SD] age, 85.3 [8.4] years; 47,053 [79.8%] female). The incidence rate of seizures was 16.10 and 20.17 per 100 patient-years, respectively, for the tramadol-antidepressant and antidepressant-tramadol group. In both subgroups, co-use of tramadol with CYP2D6-inhibiting (vs with CYP2D6-neutral) antidepressants was associated with higher adjusted incidence rate ratios of seizures (1.09 [95% CI 1.02-1.18] and 1.06 [95% CI 1.03-1.10]). Findings were corroborated by a negative control exposure analysis in which co-use of hydrocodone with CYPD2D6-inhibiting (vs CYP2D6-neutral) antidepressants was not associated with risk of seizures. Discussion: Concomitant use of tramadol with CYP2D6-inhibiting vs CYP2D6-neutral antidepressants was associated with increased risk of seizures. Findings are only generalizable to long-term NH populations and are subject to residual confounding. Clinicians should be mindful of seizure risk in older patients who use tramadol concomitantly with antidepressants, particularly CYP2D6-inhibiting antidepressants. Classification of evidence: This study provides Class II evidence that the combination of tramadol and CYP2D6-inhibiting antidepressants is associated with a higher risk of seizures compared with the combination of tramadol and CYP2D6-neutral antidepressants.

Background: Depressive symptoms are common in neuropsychiatric disorders, significantly affecting quality of life and posing challenges to treatment. While pharmacological and psychological therapies remain standard, many patients show limited response. Fecal microbiota transplantation (FMT), which aims to restore gut microbial balance, has emerged as a novel approach for alleviating depressive symptoms by modulating the gut-brain axis. This study aims to conduct a comprehensive synthesis and quantitative evaluation of current evidence to elucidate the therapeutic potential of FMT in the management of depressive symptomatology. Methods: Following PRISMA guidelines, we conducted a systematic search across PubMed, Embase, Web of Science, the Cochrane Library, and CINAHL from January 1, 2000, to December 31, 2024. 12 randomized controlled trials (RCTs) with 681 participants were included. The standardized mean difference (SMD) was calculated to evaluate FMT's effect on depressive symptoms. Subgroup analyses examined effects by delivery routes, follow-up duration, and clinical population. Results: FMT significantly reduced depressive symptoms (SMD = -1.21; 95% CI: -1.87 to -0.55; p = 0.0003). Sensitivity analysis confirmed statistical significance (SMD = -0.56; 95% CI: -0.86 to -0.26; p = 0.001). Both oral capsule and direct gastrointestinal administration were effective, with greater effects seen in direct gastrointestinal delivery (SMD = -1.06 vs. -1.29). Improvements were most notable in the short- to mid-term; effects diminished by 6 months. Subgroup analysis showed stronger effects in patients with irritable bowel syndrome (IBS) (SMD = -1.06) than in those with neurological/psychiatric-related conditions (SMD = -0.67), with moderate heterogeneity (I² = 47%). Conclusions: This meta-analysis supports FMT as an effective adjunctive therapy for depressive symptoms, especially in individuals with IBS. Endoscopic or enema routes appear more efficacious than oral capsules. While short- and mid-term benefits are evident, sustained effects require further investigation through long-term, high-quality RCTs.

Importance: The criterion-standard treatment for opioid use disorder (OUD) is medications for OUD (MOUD). However, less than a quarter of people with OUD receive MOUD. The collaborative care model (CCM) is an evidence-based practice that integrates mental and physical health treatment in primary care settings. Expanding CCM to include patients with OUD could improve MOUD initiation. Objective: To compare the effectiveness of CCM for OUD and co-occurring mental health symptoms (intervention) with CCM for mental health symptoms only (active control). Design, setting, and participants: This hybrid type 2a trial cluster-randomized 24 US primary care clinics to intervention or control. Participants included patients with OUD and mental health symptoms who were not receiving specialty mental health care or specialty substance use treatment. Study data were analyzed from February 2024 to January 2025. Interventions: The control care team included primary care practitioners, care managers, and psychiatric consultants. Primary care practitioners prescribed psychotropic medications with psychiatric consultation. Care manager activities included patient education, engagement and self-management, shared decision-making, measurement-based care for mental health symptoms, and brief psychotherapy for mental health. The intervention had the same components as the control, with additional MOUD training and psychiatric consultation for primary care practitioners, measurement-based care for OUD, and brief psychotherapy for OUD. Main outcomes and measures: Participants completed research assessments at baseline, 3 months, and 6 months. The multiple primary outcomes were past-month number of days of using opioids and the Veterans RAND 12 Mental Health Component Summary score. Results: A total of 254 patients (mean [SD] age, 40.9 [12.4] years; 139 women [59.9%]) participated in the trial. Most participants (172 of 212 [81.1%]) were taking MOUD at baseline. Days using opioids decreased in both the control and intervention groups. The intervention significantly reduced opioid use more than the control with a medium effect size (adjusted ratio of odds ratio, 0.10; 95% CI, 0.03-0.38; Cohen d = -0.44; P < .001). Mental Health Component Summary scores improved slightly in both the control and intervention groups. The intervention did not significantly improve scores more than control (adjusted difference in change, -1.20; 95% CI, -4.97 to 2.57; Cohen d = -0.09; P = .53). Conclusions and relevance: Findings of this cluster randomized clinical trial indicate that OUD can be successfully managed in primary care with CCM, especially CCM for OUD and mental health symptoms. Primary care clinics with MOUD prescribers should consider implementing CCM for OUD and mental health.

mportance: Antipsychotic drug (AP)-induced glucose homeostasis changes are often attributed to AP-induced weight gain. Nevertheless, dysregulated glucose control can occur independently of weight gain. Objective: To examine the association between AP use and glucose homeostasis while considering weight gain propensity, medication type, and treatment duration. Data sources: MEDLINE, Embase, PsychINFO, CINAHL, the Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science were searched from inception through February 3, 2025. Study selection: Blinded randomized clinical trials (RCTs) comparing changes in glucose homeostasis-related parameters between patients with severe mental illness or healthy volunteers assigned to AP or control (placebo or no intervention) groups were included. Studies were limited to English-language human studies without restrictions on study length, AP type, or previous AP exposure. Of 22 773 unique citations, 163 RCTs met inclusion criteria, with 127 studies included in the meta-analysis. Data extraction and synthesis: Each article was screened independently by 2 authors using predefined inclusion and exclusion criteria. Data extraction and risk of bias assessment were completed using a standardized spreadsheet. Data were analyzed via random-effects meta-analysis, with subgroup analyses for diagnosis, study length, AP type, age, concomitant medication use, and previous AP exposure. Metaregressions identified covariate effects. Data analysis was completed from October 2023 to February 2025. Main outcomes and measures: Primary study outcomes were changes in fasting glucose, fasting insulin, and glycated hemoglobin (HbA1c) following AP treatment. Secondary outcomes included any other glucose metabolism-related parameters including, but not limited to, insulin resistance and hyperglycemia. Results: A total of 35 952 AP-treated patients and 19 010 placebo-treated patients were included in the qualitative synthesis, while 28 975 AP-treated and 15 101 placebo-treated patients were included in the meta-analysis. AP use was associated with significantly increased fasting glucose (mean difference [MD], 0.72 mg/dL; 95% CI, 0.54-1.08 [to convert to millimoles per liter, multiply by 0.0555]; P < .001), fasting insulin (MD, 1.94 μIU/mL; 95% CI, 1.28-2.61 [to convert to picomoles per liter, multiply by 6]; P < .001), glycated hemoglobin (MD, 0.04%; 95% CI, 0.02%-0.05% [to convert to proportion of total hemoglobin, multiply by 0.01]; P < .001), and hyperglycemia (odds ratio, 1.29; 95% CI, 1.04-1.59; P = .02) vs placebo. Findings were corroborated in healthy volunteers. Subgroup analyses suggested that AP type, diagnosis, age, concomitant medication use, and previous AP exposure do not consistently affect dysglycemia risk. In metaregression analyses, AP-associated dysregulations in glucose homeostasis were independent of study length and AP dose. Conclusions and relevance: In this systematic review and meta-analysis, results indicate that AP exposure significantly disrupts glucose homeostasis independent of exposure time, dose, diagnosis, and weight gain propensity. Increased awareness of AP-induced dysregulations in glucose homeostasis alongside ongoing metabolic monitoring and potential treatment is warranted.

Importance: Energy homeostatic dysregulation may constitute 1 module of the heterogeneous pathophysiology of major depressive disorder (MDD), potentially manifesting as a distinctive symptom profile. Objective: To test whether the shared genetic liability of metabolic, interoceptive, and motivational pathways involved in energy homeostasis regulation is associated with the expression of specific MDD symptoms. Design, setting, and participants: This study used summary-level data from large genome-wide association studies and individual-level data from 2 prospective psychiatric cohorts, the CoLaus|PsyCoLaus (population-based) and Netherlands Study of Depression and Anxiety (NESDA; clinically enriched) cohorts. Data were retrieved and analyzed from May 2023 through November 2024. A lifetime diagnosis of MDD was ascertained with semistructured diagnostic interviews. The sample comprised 1407 MDD cases and 2020 controls from CoLaus|PsyCoLaus and 1803 MDD cases and 266 controls from NESDA. Exposures: Genomic structural equation modeling was applied to model a unique underlying factor capturing the common genetic liability shared among metabolic and interoceptive signals (body mass index, triglycerides, fasting glucose, C-reactive protein, leptin) and motivational (anhedonia) processes. From this underlying factor, a polygenic score (PGS) was derived, indexing the shared genetic liability of traits potentially involved in energy homeostasis regulation. Main outcomes and measures: A total of 15 depressive symptoms endorsed by participants during MDD. Results: Among 1407 MDD cases (66.2% female; median year of birth [YOB], 1956) and 2020 controls (44.3% female; median YOB, 1955) from CoLaus|PsyCoLaus and 1803 MDD cases (68.3% female; median YOB, 1962) and 266 controls (56.0% female; median YOB, 1960) from NESDA, multiple significant bidirectional mendelian randomization estimates and genetic correlations (r = 0.11-0.81) indicated a shared genetic basis between the selected traits, which was modeled as a latent homeostatic factor with genomic structural equation modeling. In cohort data, the PGS indexing the latent homeostatic factor was significantly (false discovery rate, <5%) higher in MDD cases endorsing appetite increase and hypersomnia when contrasted with both controls (appetite increase odds ratio [OR], 2.25 [95% CI, 2.00-2.53]; P = 9.03 × 10-41; hypersomnia OR, 1.22 [95% CI, 1.10-1.35]; P = 1.15 × 10-04) and other MDD cases (appetite increase OR, 1.88 [95% CI, 1.63-2.18]; P = 2.38 × 10-17; hypersomnia OR, 1.18 [95% CI, 1.05-1.33]; P = 5.80 × 10-03). Conclusions and relevance: This study identified a module of depression pathophysiology characterized by altered energy homeostasis and associated with the expression of specific symptoms reflecting energy saving and intake responses. These findings could be used to identify patients with depression at higher metabolic risk and could pave the way for the development of targeted treatments.

Objective: The objective of this study was to comprehensively examine the real-world safety of esketamine using 58 months of postapproval data in the United States. Methods: U.S. safety data from patient monitoring forms submitted to the esketamine Risk Evaluation and Mitigation Strategy (REMS) program and reports submitted to the Janssen U.S. Global Medical Safety (US-GMS) database were evaluated (March 5, 2019, to January 5, 2024). Patient characteristics, use and dosage patterns, adverse events of interest (actively solicited reports of sedation, dissociation, and increased blood pressure), and serious adverse events following esketamine administration were described. The incidence of suicidality and drug abuse/misuse was also evaluated. Results: Most patients were 26-55 years of age (64.3%) and female (61.1%). A total of 1,486,213 outpatient treatment sessions were completed by 58,483 patients who had at least one esketamine treatment session. Sedation, dissociation, and increased blood pressure were reported in 34.7%, 41.0%, and 0.9% of sessions, respectively. Serious adverse events were reported in <0.1% and 0.18% of treatment sessions in REMS and US-GMS, respectively; suicide rates were lower than background rates; and 210 incidences of all-cause abuse/misuse were reported. Conclusions: Analysis of almost 5 years of real-world use of esketamine in the United States remains consistent with the established safety profile from clinical studies and current product labeling. No new safety signals were identified.

Objective: The authors previously demonstrated that symptoms of premenstrual dysphoric disorder (PMDD) remit during ovarian hormone suppression and recur after estradiol or progesterone is reintroduced (addback). In this study, using a substantially expanded sample, they aimed to 1) evaluate the specific contributions of estradiol and progesterone to symptom development, 2) analyze physical symptoms related to ovarian hormones, 3) identify differences between women with PMDD who experienced continued symptom remission and those who experienced symptom recurrence during hormone addback, and 4) determine whether change in hormone levels from baseline to addback is associated with PMDD symptom severity. Methods: Thirty-four women with PMDD (10 from the original cohort) and 76 healthy participants (15 from the original cohort) completed a daily rating form during three hormone conditions: ovarian suppression induced by the gonadotropin-releasing hormone agonist leuprolide, leuprolide+estradiol addback, and leuprolide+progesterone addback. Affective and somatic symptom scores during the last 8 of 12 weeks of leuprolide alone were compared with scores during the first 4 weeks of estradiol addback and the first 4 weeks of progesterone addback. Results: For affective symptoms (anxiety, sadness, irritability, mood swings), there were significant main effects of diagnosis and diagnosis-by-hormone interactions, reflecting a significant increase in symptom severity scores during estradiol addback and progesterone addback compared with leuprolide treatment alone. Compared to healthy comparison participants, women with PMDD had significantly higher symptom scores during each addback. With regard to physical symptoms, bloating and food cravings showed greater severity in women with PMDD regardless of hormone conditions, whereas breast pain increased in severity during estradiol addback compared with leuprolide alone and progesterone. Conclusions: The study confirmed that ovarian suppression in women with PMDD eliminated symptom cyclicity, and that symptoms emerged during ovarian steroid addback in women with PMDD but not in healthy comparison women. In PMDD, irritability and mood swings are tied more closely to progesterone than estradiol. Despite the replication of this hormone-related behavioral phenotype in PMDD, the mechanisms underlying the presumed alteration in steroid signaling require further characterization.

Importance: Dose reduction or discontinuation (DRD) early after remission from first-episode psychosis (FEP) increases short-term relapse risk. Controversy remains regarding potential benefits in functioning over the longer term because studies with long-term outcomes show conflicting findings. Objective: To compare short- and long-term effects between DRD and maintenance medication over a 4-year period in a large sample of patients with FEP. Design, setting, and participants: The Handling Antipsychotic Medication Long-Term Evaluation of Targeted Treatment (HAMLETT) study is a single-blind pragmatic randomized (1:1) clinical trial conducted in 26 specialized psychosis units in the Netherlands from September 2017 to March 2023. Patients remitted for FEP from in- and outpatient services were included. Interventions: DRD within 12 months after remission compared with 12 months maintenance treatment. Main outcomes and measures: The primary outcome was patient-rated functioning, measured by the World Health Organization Disability Assessment Schedule 2.0 (WHODAS-2). Secondary outcomes were researcher-rated global assessment of functioning (GAF), quality of life, relapse, symptom severity (measured by the Positive and Negative Syndrome Scale [PANSS]), serious adverse events, and adverse effects. Results: A total of 347 patients (241 male [69.5%]; mean [SD] age, 27.9 [8.7] years) were included, with 168 randomized to early DRD and 179 to maintenance. WHODAS-2 showed no time × condition interaction. In the first year, DRD was associated with higher risk of relapse (odds ratio, 2.84; 95% CI, 1.08 to 7.66; P = .04) and lower quality of life (β = -3.31; 95% CI, -6.34 to -0.29; P = .03). At 3 years (β = 3.61; 95% CI, 0.28 to 6.95; P = .03) and 4 years (β = 6.13; 95% CI, 2.03 to 10.22; P = .003), a nonlinear effect of time occurred, showing significantly better GAF for patients in the DRD condition, with a similar trend for PANSS at 4 years (P for trend = .06). Although SAEs and adverse effects were similar between groups, 3 confirmed deaths by suicide occurred in the DRD group, against 1 death by suicide in the maintenance group. Conclusions and relevance: This randomized clinical trial found that DRD posed risks of relapse and worse quality of life over the first year but yielded better researcher-rated functioning at the third and fourth year, with a similar trend for symptom severity; because antipsychotic medication doses were comparable in the 2 groups from 1 year onwards, this finding is not a direct result of lower medication but may reflect a learning experience to use antipsychotics to better handle psychotic vulnerability. These findings suggest that the potential learning and empowering element of DRD needs to be weighed carefully against short-term risks.

Background: Antidepressants induce physiological alterations; however, the degree to which these occur in treatment with various antidepressants is unclear. We aimed to compare and rank antidepressants based on physiological side-effects by synthesising data from randomised controlled trials (RCTs). Methods: We searched MEDLINE, EMBASE, PsycINFO, ClinicalTrials.gov, and the US Food and Drug Administration (FDA) website from database inception to April 21, 2025. We included single-blinded and double-blinded RCTs comparing antidepressants and placebo in acute monotherapy of any psychiatric disorder. We did frequentist random-effects network meta-analyses to investigate treatment-induced changes in weight; total cholesterol; glucose; heart rate; systolic and diastolic blood pressure; corrected QT interval (QTc); sodium; potassium; aspartate transferase (AST); alanine transaminase (ALT); alkaline phosphatase (ALP); bilirubin; urea; and creatinine. We did meta-regressions to examine study-level associations between physiological change and age, sex, and baseline weight. We estimated the correlation between depressive symptom severity change and metabolic parameter change. Findings: Of 26 252 citations, 151 studies and 17 FDA reports met inclusion criteria. The overall sample included 58 534 participants, comparing 30 antidepressants with placebo. Median treatment duration was 8 weeks (IQR 6·0-8·5). We observed clinically significant differences between antidepressants in terms of metabolic and haemodynamic effects, including an approximate 4 kg difference in weight-change between agomelatine and maprotiline, over 21 beats-per-minute difference in heart rate change between fluvoxamine and nortriptyline, and over 11 mmHg difference in systolic blood pressure between nortriptyline and doxepin. Paroxetine, duloxetine, desvenlafaxine, and venlafaxine were associated with increases in total cholesterol and, for duloxetine, glucose concentrations, despite all drugs reducing bodyweight. There was strong evidence of duloxetine, desvenlafaxine, and levomilnacipran increasing AST, ALT, and ALP concentrations, although the magnitudes of these alterations were not considered clinically significant. We did not find strong evidence of any antidepressant affecting QTc, or concentrations of sodium, potassium, urea, and creatinine to a clinically significant extent. Higher baseline bodyweight was associated with larger antidepressant-induced increases in systolic blood pressure, ALT, and AST, and higher baseline age was associated with larger antidepressant-induced increases in glucose. We did not observe an association between changes in depressive symptoms and metabolic disturbance. Interpretation: We found strong evidence that antidepressants differ markedly in their physiological effects, particularly for cardiometabolic parameters. Treatment guidelines should be updated to reflect differences in physiological risk, but choice of antidepressant should be made on an individual basis, considering clinical presentation and preferences of patients, carers, and clinicians.

Background: Borderline personality disorder (BPD) typically onsets in adolescence and predicts later functional disability in adulthood. Highly structured evidence-based psychotherapeutic programs, including mentalization-based treatment (MBT), are first choice treatment. The efficacy of MBT for BPD has mainly been tested with adults, and no RCT has examined the effectiveness of MBT in groups (MBT-G) for adolescent BPD. Method: A total of 112 adolescents (111 females) with BPD (106) or BPD symptoms ≥4 DSM-5 criteria (5) referred to child and adolescent psychiatric outpatient clinics were randomized to a 1-year MBT-G, consisting of three introductory, psychoeducative sessions, 37 weekly group sessions, five individual case formulation sessions, and six group sessions for caregivers, or treatment as usual (TAU) with at least 12 monthly individual sessions. The primary outcome was the score on the borderline personality features scale for children (BPFS-C); secondary outcomes included self-harm, depression, externalizing and internalizing symptoms (all self-report), caregiver reports, social functioning, and borderline symptoms rated by blinded clinicians. Outcome assessments were made at baseline, after 10, 20, and 30 weeks, and at end of treatment (EOT). The ClinicalTrials.gov identifier is NCT02068326. Results: At EOT, the primary outcome was 71.3 (SD = 15.0) in the MBT-G group and 71.3 (SD = 15.2) in the TAU group (adjusted mean difference 0.4 BPFS-C units in favor of MBT-G, 95% confidence interval -6.3 to 7.1, p = .91). No significant group differences were found in the secondary outcomes. 29% in both groups remitted. 29% of the MBT group completed less than half of the sessions compared with 7% of the control group. Conclusions: There is no indication for superiority of either therapy method. The low remission rate points to the importance of continued research into early intervention. Specifically, retention problems need to be addressed.

Chronic pain (CP) is closely related with major depressive disorder (MDD) and anxiety disorders (ANX), with high comorbidity and shared risk factors. Prior studies have demonstrated common neural correlates across the three disorders, but their neuroanatomic basis is not fully clear. Hence, the preregistered meta-analysis (CRD42019119709) intended to explore common alterations in cortical thickness among CP, MDD, and ANX, a widely used parameter for quantitatively assessing various cerebral conditions with high sensitivity to pathology in neuropsychology. A total of 68 studies comprising 3072 patients and 3427 healthy controls were finally included. Across the disorders, four common clusters with a significant reduction in cortical thickness were identified, including right insula, left anterior cingulate (AC), triangular part of the left inferior gyrus (IFG), and left middle temporal gyrus (MTG). Our findings suggested the shared cortical deficits involving ACC-insula/IFG circuit and left MTG in CP, MDD and ANX, revealing common neural correlates for cognitive and emotional processing in these highly comorbid disorders.

Importance: Research has consistently shown links between parent and child depression. The prevailing assumption is that parent depression precedes the onset, persistence, and even exacerbation of child depression. However, it is plausible, albeit infrequently tested, that child depression triggers subsequent parent depression. Clarifying the direction and developmental timing of these associations is critical for designing and advocating for family-centered approaches to pediatric care. Objective: To estimate the longitudinal bidirectional associations between maternal and child depression from middle childhood through emerging adolescence during a period that coincided with the COVID-19 pandemic, and to assess whether these associations are moderated by key sociodemographic factors. Design, setting, and participants: This study used data from the All Our Families (Calgary, Alberta, Canada) cohort across multiple waves during and beyond the COVID-19 pandemic when children were aged 10.3 (May 20 to July 15, 2020), 10.9 (March 4 to April 30, 2021), 11.6 (November 22, 2021 to January 17, 2022), and 12.8 (January 16 to July 7, 2024) years. Data were analyzed between March 1 and August 31, 2024, using random-intercept cross-lagged panel models. Exposures: Maternal and child report of depressive symptoms. Main outcomes and measures: The Behavior Assessment System for Children for child depression and the Center for Epidemiologic Studies Depression Scale-10 for maternal depression. Results: The sample included 1801 mother-child dyads (52% boys, 48% girls). Mothers were a mean (SD) 41.6 (4.4) years old at study entry and most had completed postsecondary education (80%), had an annual income more than CAD $100 000 (75%), and were married or in common-law relationships (71.4%). Consistent cross-sectional correlations were observed, reflecting stable between-participant associations for maternal depression and child depression throughout the study period. Within-participant increases in child depression scores at ages 10.3 and 10.9 years were associated with subsequent increases in maternal depression scores at child ages 10.9 (standardized coefficient 0.12; 95% CI, 0.02-0.22) and 11.6 (0.17; 95% CI, 0.07-0.26) years; however, this was not present for maternal depression. These patterns of associations were moderated by household income (difference test for χ212 = 23.0; P = .03) and within-participant increases in child depression were consistently associated with subsequent increases in maternal depression for the higher income group. Conclusions and relevance: Contrary to prevailing assumptions, these findings suggest that children's depression over time may have contributed to worsening maternal depression, rather than the other way around. While these results should be replicated in nonpandemic contexts to confirm their generalizability, they highlight the need for family-centered approaches to mental health care.

Background and objectives: Consumption of low- and no-calorie sweeteners (LNCSs) has been associated with adverse health outcomes. However, little is known about the association between consumption of LNCSs and cognition. The aim of this study was to investigate the association between consumption of LNCSs and cognitive decline. Methods: We conducted a longitudinal observational study using data from civil servants aged 35+ years at baseline who were enrolled in the Brazilian Longitudinal Study of Adult Health and evaluated across 3 study waves (2008-10, 2012-14, and 2017-19). Participants with incomplete dietary data, extreme caloric intake (<1st percentile or >99th percentile), and incomplete data for cognitive tests and covariates at baseline were excluded. A Food Frequency Questionnaire was used to calculate combined and individual consumption of 7 LNCSs (aspartame, saccharin, acesulfame k, erythritol, xylitol, sorbitol, and tagatose). We estimated z-scores across 6 cognitive tests. The association of LNCSs with cognitive decline was evaluated using linear mixed-effects models. Results: Among 12,772 participants (mean age 51.9 ± 9.0 years, 54.8% women, 43.2% Black/mixed race), the mean consumption of LNCSs was 92.1 ± 90.1 mg/d. Among participants aged younger than 60 years, consumption of combined LNCSs in the highest tertiles was associated with a faster decline in verbal fluency (second tertile: β = -0.016, 95% CI -0.040 to -0.008; third tertile: β = -0.040, 95% CI -0.064 to -0.016) and global cognition (second tertile: β = -0.008, 95% CI -0.024 to 0.008; third tertile: β = -0.024, 95% CI -0.040 to -0.008). There was no association between tertiles of LNCSs and cognitive decline in participants aged 60+ years. Consumption of aspartame, saccharin, acesulfame k, erythritol, sorbitol, and xylitol was associated with a faster decline in global cognition, particularly in memory and verbal fluency domains. Consumption of combined LNCSs in the highest tertiles was associated with a faster decline in verbal fluency and global cognition in participants without diabetes and faster decline in memory and global cognition in participants with diabetes. Discussion: Consumption of LNCSs was associated with an accelerated rate of cognitive decline during 8 years of follow-up. Our findings suggest the possibility of long-term harm from LNCS consumption, particularly artificial LNCSs and sugar alcohols, on cognitive function. Study limitations include self-reported dietary data, selection bias from attrition, and residual confounding from co-occurring health behaviors.

Obesity is one of the most prevalent somatic comorbidities in individuals with major depressive disorder and greatly affects the course and prognosis of that disorder. The bidirectional relationship between major depressive disorder and obesity often creates a feedback cycle that challenges both patients and health-care providers. Gaps in interdisciplinary collaboration and limitations in knowledge transfer hinder the effective management of this patient population. This narrative Review synthesises current evidence from obesity and major depressive disorder research, offering a comprehensive risk stratification and monitoring framework that integrates psychological and metabolic parameters to enhance clinical decision making. We examine the latest evidence on pharmacological and psychotherapeutic interventions as well as lifestyle-based strategies-such as exercise, dietary modifications, and weight-loss medications-with the aim of alleviating depressive symptoms while supporting weight management and improving metabolic health. Bariatric surgery, which is a key component in obesity management, is not covered in this Review. Finally, we highlight the crucial need for an integrated, interdisciplinary treatment approach and provide practical guidance for optimising care to improve outcomes for individuals with major depressive disorder and comorbid obesity.

Objective: Neuroimaging studies have independently associated schizophrenia with low iron and elevated dopamine synthesis. While preclinical research demonstrates that midbrain iron deficiency leads to striatal hyperdopaminergia, this relationship has not been studied in schizophrenia. The authors conducted a case-control study to examine differences in tissue magnetic susceptibility, a marker of brain iron, and correlated these with striatal dopamine synthesis capacity. Methods: Magnetic susceptibility in the substantia nigra and ventral tegmental area (SN-VTA) was measured using quantitative susceptibility mapping (QSM) MRI in 159 participants (control subjects, N=80; early-course schizophrenia, N=79, including patients who were antipsychotic-naïve or antipsychotic-free). Because magnetic susceptibility is increased by neuromelanin and reduced by myelin, neuromelanin-sensitive MRI (NM-MRI) and diffusion tensor imaging (DTI) were employed to investigate the influence of neuromelanin and myelin on the QSM findings in 99 participants (control subjects, N=38; schizophrenia patients, N=61). Dopamine synthesis capacity (Ki cer) was then assessed with [18F]-DOPA positron emission tomography in 40 people from the schizophrenia group to test whether low SN-VTA magnetic susceptibility was related to high striatal Ki cer. Results: SN-VTA magnetic susceptibility was lower in patients with schizophrenia than in control subjects (d=-0.66, 95% CI=-0.98, -0.34). This difference remained significant in analyses controlling for mean diffusivity (a DTI measure inversely correlating with myelin concentration) and NM-MRI contrast-to-noise ratios. SN-VTA magnetic susceptibility was significantly inversely correlated with striatal Ki cer, independent of mean diffusivity and NM-MRI contrast-to-noise ratios (r=-0.44). In both analyses, the strongest effects were observed in the ventral SN-VTA. Conclusions: These findings suggest that lower levels of non-neuromelanin-bound iron in the SN-VTA contribute to striatal hyperdopaminergia in schizophrenia. Further investigation is warranted to understand the role of low iron in schizophrenia and its potential as a treatment target.

Objective: The study aim was to identify ethnoracial disparities in the prevalence of schizophrenia spectrum disorders (SSDs) and positive psychotic symptoms in the United States and examine the role of social neighborhood inequities. Methods: Participants in the Mental and Substance Use Disorders Prevalence Study, a national household sample of nonelderly adults (N=4,764), were assessed by clinicians with the Structured Clinical Interview for DSM-5 (SCID-5) for SSDs (past year and lifetime), including schizophrenia, schizoaffective disorder, and schizophreniform disorder, and for psychotic symptoms. Weighted logistic regression models estimated ethnoracial differences in the prevalence of SSDs and psychotic symptoms in unadjusted models, age- and sex-adjusted models, and models further adjusted for a neighborhood Social Vulnerability Metric (SVM) score, a composite index of five social determinants of health domains. Results: Compared to non-Hispanic White individuals, non-Hispanic Black individuals had a significantly higher prevalence of SSDs (4.1% vs. 1.2%; adjusted odds ratio=3.49, 95% CI=1.37, 8.91) and psychotic symptoms (9.3% vs. 4.9%; adjusted odds ratio=2.04, 95% CI=1.15, 3.63), and non-Hispanic multiracial individuals had a significantly higher prevalence of SSDs (5.6%; adjusted odds ratio=4.59, 95% CI=1.53, 13.76). Further adjustment for SVM score lowered the Black-White group difference for SSDs (adjusted odds ratio=2.49, 95% CI=0.63, 9.90) and psychotic symptoms (adjusted odds ratio=1.69, 95% CI=0.83, 3.44), and the associations were no longer statistically significant. The difference in SSDs between the non-Hispanic multiracial and White groups was attenuated after SVM score adjustment (adjusted odds ratio=3.95, 95% CI=1.30, 12.00) but remained significant. Conclusions: This national U.S. household study found ethnoracial differences in the prevalence of clinician-assessed SCID-based schizophrenia spectrum disorders and positive psychotic symptoms. The higher prevalence among minoritized groups, particularly Black individuals, was connected to social inequities and community-level vulnerabilities embedded in neighborhoods and associated with structural racism.

Importance: The incidence and nature of discontinuation symptoms following antidepressant cessation remain unclear. Objective: To examine the presence of discontinuation symptoms using standardized scales (eg, Discontinuation-Emergent Signs and Symptoms [DESS]) and the incidence of individual discontinuation symptoms in individuals who stop taking antidepressants. Data sources: The databases Embase, PsycINFO, Ovid MEDLINE, and Cochrane Library were systematically searched from inception until November 7, 2023. Study selection: Randomized clinical trials (RCTs) reporting discontinuation symptoms using a standardized scale or individual symptoms (eg, adverse events) following antidepressant cessation were included. Data extraction and synthesis: Data extracted were cross-checked by 2 reviewers. Additional unpublished data from 11 RCTs were included. A random-effects meta-analysis was conducted to calculate standardized mean difference between individuals who discontinued an antidepressant vs those who continued an antidepressant or discontinued placebo. A proportion and odds ratio (OR) meta-analysis was performed to assess incidence of individual discontinuation symptoms compared to placebo. Subgroup analyses were conducted to compare different antidepressants. Data analysis was conducted between September 2024 and December 2024. Main outcomes and measures: The primary outcomes were incidence and nature of antidepressant discontinuation symptoms measured using standardized or unstandardized scales. Results: A total of 50 studies were included, 49 of which were included in meta-analyses. The 50 studies included 17 828 participants in total, with 66.9% female participants and mean participant age of 44 years. Follow-up was between 1 day and 52 weeks. The DESS meta-analysis indicated increased discontinuation symptoms at 1 week in participants stopping antidepressants (standardized mean difference, 0.31; 95% CI, 0.23-0.39; number of studies [k] = 11; n = 3915 participants) compared to those taking placebo or continuing antidepressants. The effect size was equivalent to 1 more symptom on the DESS. Discontinuation of antidepressants was associated with increased odds of dizziness (OR, 5.52; 95% CI, 3.81-8.01), nausea (OR, 3.16; 95% CI, 2.01-4.96), vertigo (OR, 6.40; 95% CI, 1.20-34.19), and nervousness (OR, 3.15; 95% CI, 1.29-7.64) compared to placebo discontinuation. Dizziness was the most prevalent discontinuation symptom (risk difference, 6.24%). Discontinuation was not associated with depression symptoms, despite being measured in people with major depressive disorder (k = 5). Conclusions and relevance: This systematic review and meta-analysis indicated that the mean number of discontinuation symptoms at week 1 after stopping antidepressants was below the threshold for clinically significant discontinuation syndrome. Mood worsening was not associated with discontinuation; therefore, later presentation of depression after discontinuation is indicative of depression relapse.

Importance: Insomnia and inflammation are prevalent in older adults, and both are risk factors for late-life depression. Older adults with insomnia who are exposed to inflammatory challenge may be more vulnerable to depression. Objective: To determine whether inflammatory exposure induces greater increases in depressive mood and symptoms in older adults with insomnia disorder compared to those without insomnia. Design, setting, and participants: This assessor-blinded, parallel-condition randomized clinical trial was conducted from August 2017 to November 2022 at a single site in Los Angeles, California, among a community-based sample of 160 nondepressed adults aged 60 years or older (53 with insomnia disorder and 107 without insomnia, or control). Data analysis occurred from July 2023 to August 2024. Interventions: Participant groups stratified by insomnia status were randomized to 2 conditions: endotoxin or placebo. Main outcomes and measures: The primary outcome was depressed mood, assessed by the Profiles of Mood States depression subscale (POMS-D). Secondary outcomes were depressive symptom severity and inflammatory cytokines. Results: Among 160 randomized participants eligible for the study (mean [SD] age, 65.9 [4.6] years; 84 female participants [52.5%]), 79 participants (26 with insomnia, 53 control participants) were randomized to endotoxin and 81 (27 with insomnia, 54 control participants) to placebo. All randomized participants completed the protocol. Compared to placebo, endotoxin induced increases in POMS-D to a significantly greater extent in those with insomnia than controls (condition × group interaction, F10,1478 = 4.7; P < .001), with a similar effect for observer-rated POMS-D mood (condition × group interaction, F3,450 = 5.5; P = .001), as well as clinically meaningful increases in observer-rated measures of depressive symptoms. Endotoxin induced similar increases in inflammatory cytokines in both groups. Moderation analyses found that the inflammatory response was associated with increases in POMS-D in the insomnia group (β = 0.33; 95% CI, 0.26-0.41; P < .001) but not in control participants. Conclusions and relevance: In this randomized clinical trial, older adults with insomnia showed an exaggerated vulnerability to depressive mood and symptoms in response to inflammatory challenge. Older adults with insomnia should undergo vigilant depression monitoring during periods of inflammatory exposure; selective depression prevention strategies that target both insomnia and inflammatory phenotypes are needed.

Importance: Esketamine nasal spray, administered in conjunction with an oral antidepressant, is approved for treatment-resistant depression (TRD). However, the efficacy of esketamine nasal spray administered as monotherapy for patients with TRD has not yet been evaluated. Objective: To assess the efficacy and safety of esketamine monotherapy compared to placebo in reducing depressive symptoms in patients with TRD. Design, setting, and participants: This phase 4, double-blind, placebo-controlled randomized clinical trial was conducted from November 2020 to January 2024 at 51 outpatient centers in the US. Adults with major depressive disorder (DSM-5 criteria) without psychotic features who experienced inadequate response (≤25% improvement) to 2 or more oral antidepressants during the current depressive episode were eligible for inclusion. Data analyses were conducted from March 1, 2024, to July 8, 2024. Interventions: After a 2-week or longer antidepressant-free period, participants were randomized at a 1:1:2 ratio to fixed-dose intranasal esketamine (56 mg or 84 mg) or matching intranasal placebo, administered twice weekly for 4 weeks. Main outcomes and measures: Change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 28 (primary efficacy end point) and to 24 hours post-first dose (day 2; key secondary efficacy end point) were analyzed by a mixed-effects model using repeated measures. Results: In this multicenter randomized clinical trial, 378 participants who met prerandomization MADRS severity criteria received 1 or more study drug doses (esketamine, 56 mg [n = 86]; esketamine, 84 mg [n = 95]; or placebo [n = 197]). Mean (SD) participant age was 45.4 (14.1) years, 231 participants (61.1%) were female, and baseline mean (range) MADRS total score was 37.3 (28-50). At day 28, the least-square (LS) mean difference (SE) between esketamine and placebo was -5.1 (1.42) (95% CI, -7.91 to -2.33) for the 56-mg dose and -6.8 (1.38) (95% CI, -9.48 to -4.07) for the 84-mg dose (for each, 2-sided P < .001). Observed effect sizes were 0.48 and 0.63 for the 56-mg and 84-mg dose groups, respectively. At day 2 (approximately 24 hours post-first dose), the between-group difference was significant for both esketamine doses: -3.8 (1.29) (95% CI, -6.29 to -1.22; 2-sided P = .004) for 56 mg and -3.4 (1.24) (95% CI, -5.89 to -1.00; 2-sided P = .006) for 84 mg. The most common treatment-emergent adverse events reported for esketamine (combined doses) were nausea (56 participants [24.8%]), dissociation (55 [24.3%]), dizziness (49 [21.7%]), and headache (43 [19.0%]). Conclusions and relevance: According to results of this multicenter, double-blind randomized clinical trial, esketamine monotherapy may expand treatment options for adult patients with TRD by addressing an unmet need of patients experiencing treatment-limiting tolerability concerns and nonresponse with oral antidepressants.

Importance: Bariatric surgery, once the criterion standard in obesity treatment, has a small but concerning association with increased suicidality. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs), originally developed to treat diabetes, now provide substantial efficacy in the treatment of obesity. However, concerns of risk of suicidality with these medicines have been raised. Objective: To evaluate the risk of suicidality and self-harm in randomized, placebo-controlled trials of GLP-1 RAs in adults with diabetes or obesity. Data sources: MEDLINE, Embase, ClinicalTrials.gov, and Cochrane databases were systematically searched from inception to August 29, 2023. Study selection: Reports of randomized clinical trials (RCTs) lasting 6 or more months comparing GLP-1 RAs with placebo for the treatment of diabetes or obesity published in peer-reviewed journals were identified. Two independent reviewers screened all search-identified studies for inclusion. Records of outcomes were queried from primary papers, ClinicalTrials.gov entries, and corresponding authors. Data extraction and synthesis: Two independent researchers abstracted data and assessed data quality and validity using PRISMA guidelines. Data were pooled using random-effects models. Main outcomes and measures: Pooled incidence of completed or attempted suicide, occurrences of suicidal ideation, or self-harm. Results: A total of 27 of 144 RCTs meeting inclusion criteria systematically recorded suicide and/or self-harm-related events and included 32 354 individuals receiving GLP-1 RAs and 27 042 treated with placebo, over 69 653 and 63 853 person-years of exposure, respectively. Event incidence was very low in the GLP-1 RA (0.047 per 100 person-years) and placebo (0.042 per 100 person-years) groups, with no statistically significant difference (rate ratio [RR], 0.76; 95% CI, 0.48-1.21; P = .25). Subgroup analyses did not suggest differences in outcomes based on diabetes status or GLP-1 RA used. Five studies were considered at risk of bias due to the loss of more than 5% of participants to follow-up. Otherwise, studies were not found to be heterogeneous nor at high risk of bias. Conclusions and relevance: There is unlikely to be an increase in the very low incidence of suicide-related adverse events among individuals receiving GLP-1 RAs within the context of RCTs. While these findings may further ease concerns about these adverse effects, continued monitoring is warranted to identify particular patients who may be at risk as extended use of GLP-1 RAs expands.

Ketamine, introduced as an anesthetic drug, is now used for many indications beyond anesthesia; it is also increasingly a drug of abuse. Long-term recreational use and abuse of ketamine are associated with urological risks. This article discusses ketamine-associated uropathy from the perspective of prevalence, clinical features, mechanisms, and strategies for risk reduction in patients who require long term maintenance therapy with the drug for psychiatric indications. A systematic review and meta-analysis of 37 studies of uropathy in recreational (ab)users obtained prevalences of 44% to 77% for lower urinary tract symptoms and 8% to 30% for upper urinary tract disease; for reasons explained, these findings are potentially misleading and cannot be extrapolated to therapeutic contexts. More recent studies, using different methods of case ascertainment, present lower risks (2% to 27%). A systematic review of 27 studies of ketamine used to treat psychiatric disorders, mainly depression, found urological symptoms in 0% to 24% of patients; however, in 14 randomized controlled trials, urological symptom prevalences differed little between ketamine and comparison arms. The review presented no convincing evidence of ketamine-associated uropathy arising in therapeutic contexts. The literature on ketamine-associated uropathy is critically examined; reasons for false positive uropathy findings are considered. Ketamine pharmacokinetics are described to assist the understanding of how ketamine and its metabolites may predispose to uropathy. Mechanisms of uropathy, arising from exposure to ketamine and its metabolites in urine (rather than in circulation), are summarized. A reasonable conclusion is that higher doses of ketamine, more frequent dosing with ketamine, longer duration of treatment with ketamine, and oral administration of ketamine are all potential risk factors for ketamine-associated uropathy during maintenance therapy. High hydration and frequent voiding of urine on treatment days can reduce exposure of the bladder to ketamine and its metabolites, reducing urological risks. Fortnightly or monthly urine testing is also advisable.

A ketogenic diet (KD) has shown promise as an adjunctive therapy for neurological and neuropsychiatric disorders, including bipolar disorder and major depressive disorder (MDD). We examined tolerance for a KD in young adults with MDD and assessed symptoms of depression and metabolic health. Students (n = 24) with a confirmed diagnosis of MDD at baseline receiving standard of care counseling and/or medication treatment were enrolled in a 10-12 week KD intervention that included partial provision of ketogenic-appropriate food items, frequent dietary counseling, and daily morning tracking of capillary R-beta-hydroxybutyrate (R-BHB). Primary outcome measures for mood symptoms included the Patient Health Questionnaire (PHQ-9) and Hamilton Rating Scale for Depression (HRSD). Additional outcomes included body composition, neurocognitive function, and blood hormonal and inflammatory markers. Sixteen students (10 women, 6 men, mean age 24 yr) completed the intervention. Nutritional ketosis (R-BHB > 0.5 mM) was achieved 73% of the time. Depressive symptoms decreased by 69% (PHQ-9) and 71% (HRSD) post-intervention (p < 0.001), with improvement occurring within 2-6 weeks. Global well-being increased nearly 3-fold (p < 0.001). Participants lost body mass (-6.2%; p = 0.002) and fat mass (-13.0%; p < 0.001). Serum leptin decreased (-52%; p = 0.009) and brain-derived neurotropic factor increased (+32%; p = 0.029). Performance improved on several cognitive tasks. In students with mild to moderate depression based on PHQ-9 and HRSD, implementation of a WFKD for 10-12 weeks is a feasible adjunctive therapy and may be associated with improvements in depression symptoms, well-being, body composition, and cognition.

Importance: Individuals with attention-deficit/hyperactivity disorder (ADHD) may present with psychosis or bipolar disorder (BD) following treatment with stimulants. The extent to which this occurs is currently unclear. Objective: To meta-analytically quantify the occurrence of psychosis or BD after exposure to stimulants in individuals with ADHD and assess possible moderating factors. Data sources: PubMed, Web of Science, Ovid/PsycINFO, and Cochrane Central Register of Reviews were searched from inception until October 1, 2024, without language restrictions. Study selection: Studies of any design with DSM or International Classification of Diseases-defined ADHD populations exposed to stimulants, where psychosis or BD outcomes were evaluated. Data extraction and synthesis: PRISMA Preferred Reporting Items for Systematic Reviews and Meta-analyses and MOOSE Meta-analysis of Observational Studies in Epidemiology guidelines were followed, the protocol was registered, and the Newcastle-Ottawa scale and Cochrane risk of bias-2 tool were used for quality appraisal. Random-effects meta-analysis, subgroup analyses, and meta-regressions were conducted. Main outcomes and measures: For the proportion of individuals developing psychotic symptoms, psychotic disorders, and BD, effect sizes are reported as percentages with 95% CIs. For the comparison between amphetamines and methylphenidate, effect sizes are presented as odds ratios with 95% CIs. Results: Sixteen studies (N = 391 043; mean [range] age, 12.6 [8.5-31.1] years; 288 199 [73.7%] male) were eligible. Among individuals with ADHD prescribed stimulants, 2.76% (95% CI, 0.73-9.88; k = 10; n = 237 035), 2.29% (95% CI, 1.52-3.40; k = 4; n = 91 437), and 3.72% (95% CI, 0.77-16.05; k = 4; n = 92 945) developed psychotic symptoms, a psychotic disorder, and BD, respectively. Heterogeneity across the studies was significant (I2 > 95%). Psychosis occurrence risk was significantly higher in individuals exposed to amphetamines than to methylphenidate (odds ratio [OR], 1.57, 95% CI, 1.15-2.16; k = 3, n = 231 325). Subgroup analyses showed significantly higher prevalence of psychotic symptoms in studies from North America and in those with longer follow-up periods. Increased psychosis occurrence was associated with a higher proportion of female participants, smaller sample sizes, and higher dose of stimulants. Conclusions and relevance: This systematic review and meta-analysis found a nonnegligible occurrence of psychotic symptoms, psychotic disorders, or BD in individuals with ADHD treated with stimulants. Amphetamines were associated with higher occurrence compared to methylphenidate. The included studies cannot establish causality, highlighting the need for further research, including randomized clinical trials and mirror-image studies comparing individuals exposed and not exposed to stimulants. Nonetheless, clinicians should inform patients about the increased occurrence of psychosis or BD when discussing stimulant pharmacotherapy and systematically monitor for these conditions throughout treatment. New Episodes and Suicidal Risks in Bipolar and Major Depressive Disorder Patients During Versus Before Long‐Term Treatment With Lithium Lithium treatment reduces the risk of recurring episodes in bipolar disorder (BD) and probably also in major depressive disorder (MDD) and has evidence of antisuicidal effects. Study objectives were to test for effects of adding lithium treatment for one year to a year of other treatments on risks of illness recurrence, suicidal ideation, and suicide attempts. We compared 296 major mood disorder outpatients for 12 months with treatment that did not include lithium versus 12 months with lithium included. We considered differences in the recurrence of new episodes of illness, new suicidal ideation and suicide attempts, and estimated time to these outcomes with survival analyses. With lithium treatment included, there were marked reductions in episode recurrences (3.12‐fold), suicidal ideation (4.78‐fold), and suicide attempts (6.54‐fold) in both BD and MDD patients, with corresponding delays to these outcomes. Conclusions Adding lithium treatment was strongly associated with reduced risk and delay of clinical recurrence, suicidal ideation and suicide attempts in both BD and MDD outpatients.

Introduction: Clozapine is the only truly effective treatment for refractory schizophrenia, but its use is constrained by the requirements for frequent monitoring of neutrophil counts. In the UK during the COVID-19 pandemic, the frequency of clozapine blood monitoring was reduced in some units from 4-weekly to 12-weekly. We aimed to investigate the outcomes of reduced monitoring in long-term clozapine patients. Methods: This was an anonymous, retrospective, observational cohort study. No restrictions were applied regarding care setting (i.e., outpatients or inpatients). All patients who registered for reduced frequency haematological monitoring from 1 March 2020 to 1 November 2022 were included and followed up till 1 August 2024. The primary outcome was death resulting from clozapine-induced agranulocytosis (CIA). Secondary outcomes were the proportion of patients with mild to moderate neutropenia during the follow-up period and the proportion of patients who reverted to standard monitoring during the study period. Results: Amongst 1025 patients, there were no cases of agranulocytosis over 3365.9 patient-years of 12-weekly blood monitoring (incident rate 0.0 per 100 person-years). There were 43 episodes of mild neutropenia (so-called amber results-1.5-2.0 × 109/L) or neutropenia (red results < 1.5 × 109/L), an overall incident rate of 1.28 per 100 person-years. During follow-up, 41 patients (4%) reverted permanently to standard 4-weekly monitoring, and 157 patients (15%) temporarily interrupted reduced frequency monitoring but restarted 12-weekly monitoring before the end of the follow-up period. In total, 42 patients (4%) died during the observation period-no death was related to agranulocytosis. Conclusion: Reducing the frequency of clozapine haematological monitoring to 12-weekly was safe in a group of long-term patients. No cases of agranulocytosis occurred and no deaths due to agranulocytosis were recorded. Most patients remained on extended-interval monitoring.

Introduction: ADHD is often associated with comorbid psychiatric conditions. Differential diagnosis between other conditions and ADHD is not always clear, and patients are sometimes initially treated for another disorder instead. ADHD diagnosis and appropriate ADHD treatment potentially reduce the need for medication of the other disorder. Reaching high adherence to and persistence with ADHD medication is challenging. This nationwide cohort study aimed to describe not only ADHD medication use but also the use of other drugs in ADHD patients compared to controls. Methods: Nationwide care and prescription registers were used to identify incident ADHD patients of any age between 2015 and 2020. Four controls were matched to each ADHD patient by age, gender, and residence. Analyses included data from 1.1.2010 to 31.12.2021. Results: Study cohort included 66,146 ADHD patients and 256,270 controls, with a total follow-up of 1,123,412 years. Sustained and extended-release methylphenidate were the two most commonly used first-line ADHD drugs across all age groups. Simultaneous use of different ADHD drugs was rare. Primary adherence was very high, with 95% of the patients purchasing their prescribed medication in general and 80% doing so within 10 days. Persistence with medication was the highest among the youngest patients. A decrease in purchases was observed during the summer holidays in school-age children and adolescents. In adults, antidepressant use often preceded ADHD diagnosis and decreased after ADHD treatment initiation, unlike in controls at the same time. In young children, antibiotics and anti-inflammatory drug use was higher in ADHD patients than in controls, especially before ADHD identification. Conclusion: As far as we know, this is the first study to describe changes in the use of non-ADHD medications in relation to ADHD identification. In adults, antidepressant use decreased after ADHD treatment initiation, and in children, antibiotic and anti-inflammatory use showed more prominent decrease compared to controls of the same age. The data indicated high primary adherence to ADHD medication, and the youngest children remained on continuous ADHD medication the longest. The effect of summer holidays was visible in the purchase data.

Lamotrigine is beneficial in bipolar disorder and is often prescribed to patients during their period of reproductive potential. We summarise aspects of the pharmacology of lamotrigine, highlight its uses in psychiatric practice, drawing attention to recent findings relating to potential hazards arising from lamotrigine exposure in utero, and make some suggestions for clinical management.

Objective: The aim of this study was to determine whether advanced puberty at age 9 and 10 years, relative to that in same-aged peers, predicts current and/or new-onset self-injurious thoughts and behaviors (SITBs). New predictors of SITBs in preadolescence are urgently needed to address this escalating public health crisis of youth self-harm and suicidality. Method: Data from the baseline, 1-year, and 2-year waves of the Adolescent Brain and Cognitive Development Study were used. Bayesian mixed-effects models were estimated for test and replication split halves, and tested whether relatively advanced youth-reported pubertal development at 9 or 10 years predicted SITBs (suicidal ideation, suicide attempts, and nonsuicidal self-injury) as reported by preadolescents (each wave) and their caregiver (baseline, 2-year follow-up) in a computerized version of the Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS). Preadolescents with baseline self-reported puberty, KSADS (N = 8,708; 44.6% female; 60.8% White non-Hispanic), and demographic information were included. Results: Baseline preadolescent-reported puberty predicted the presence of any SITB before or at baseline (odds ratio = 1.50, 95% credible interval = 1.23-1.85) and the new-onset SITBs between baseline and 2-year follow-up in preadolescents SITB-naive at baseline (odds ratio = 2.26, 95% credible interval = 1.66-3.21). Conclusion: Preadolescents reporting relatively advanced puberty were more likely to have experienced SITBs and, if SITB naive, were more likely to experience the onset of SITBs across the following 2 years. Findings were not explained by child psychopathology or other familial and psychosocial factors known to predict SITBs. Screening preadolescents for advanced puberty at ages 9 and 10 years and applying targeted suicide screening for those youth showing advanced puberty should be considered in primary care and mental health settings. Plain language summary: Analyzing data from the Adolescent Brain and Cognitive Development (ABCD) study, the authors found that adolescents reporting advanced puberty at age 9 to 10 were more likely to have experienced self-injurious thoughts and behaviors (SITB) and, if SITB naive, were more likely to experience the onset of SITBs over the following 2 years. These findings were not explained by other child mental health problems or familial or social factors known to predict these behaviors. The authors recommend screening preadolescents for advanced puberty and applying targeted suicide screening for those youth showing advanced puberty in primary care and mental health settings.

No abstract available

Clinicians across medical disciplines are intimately familiar with an unusual feature of descriptive diagnoses. The diagnostic terms, despite their non-aetiological nature, seem to offer an explanatory lens to many patients, at times with profound effects. These experiences highlight a striking, neglected and unchristened medical phenomenon: the therapeutic effect of a clinical diagnosis, independent of any other intervention, where clinical diagnosis refers to situating the person's experiences into a clinical category by either a clinician or the patient. We call this the Rumpelstiltskin effect. This article describes this phenomenon and highlights its importance as a topic of empirical investigation.

No abstract available

This Medical News article is an interview with epidemiologist Brian Lee, PhD, about his study on acetaminophen use during pregnancy and children’s risk of autism and other neurodevelopmental disorders.

Twenty years ago Shitij Kapur's "Psychosis as a state of aberrant salience" captured the attention of clinicians and cognitive and behavioral neuroscientists. It has become the de facto way of talking about delusion formation in labs and clinics. Here, evidence for this theory is critically evaluated in consideration of evolving data since its publication. A particular focus is placed on its specific predictions regarding the neural and behavioral loci of dopamine dysfunction in psychosis and finds them lacking. This examination is informed by recent advances in the understanding of the function of the dopamine system and its impacts on behavior following the explosion of new tools and probes for precise measurement and manipulation of dopaminergic circuits. Contemporary theories that have developed since Kapur-which suggest a role for dopamine in belief formation, belief updating under uncertainty, and abductive inference to the best explanation for some set of circumstances-are argued to form a more cogent theory that fits better with the work in patients with delusions and hallucinations, how they behave, and what is known about the function of their dopamine system. The original salience hypothesis has been influential as it attempted to unite neurochemical dysfunction with clinical phenomenology through computational cognitive neuroscience, which has led to the development of novel predictions that the authors highlight as future directions for the field.

The earliest molecular changes in Alzheimer's disease (AD) are poorly understood1-5. Here we show that endogenous lithium (Li) is dynamically regulated in the brain and contributes to cognitive preservation during ageing. Of the metals we analysed, Li was the only one that was significantly reduced in the brain in individuals with mild cognitive impairment (MCI), a precursor to AD. Li bioavailability was further reduced in AD by amyloid sequestration. We explored the role of endogenous Li in the brain by depleting it from the diet of wild-type and AD mouse models. Reducing endogenous cortical Li by approximately 50% markedly increased the deposition of amyloid-β and the accumulation of phospho-tau, and led to pro-inflammatory microglial activation, the loss of synapses, axons and myelin, and accelerated cognitive decline. These effects were mediated, at least in part, through activation of the kinase GSK3β. Single-nucleus RNA-seq showed that Li deficiency gives rise to transcriptome changes in multiple brain cell types that overlap with transcriptome changes in AD. Replacement therapy with lithium orotate, which is a Li salt with reduced amyloid binding, prevents pathological changes and memory loss in AD mouse models and ageing wild-type mice. These findings reveal physiological effects of endogenous Li in the brain and indicate that disruption of Li homeostasis may be an early event in the pathogenesis of AD. Li replacement with amyloid-evading salts is a potential approach to the prevention and treatment of AD.

Despite its superior effectiveness for treatment-resistant schizophrenia, clozapine has a high burden of adverse drug reactions (ADRs), which require monitoring and treatment. This global Delphi study has established consensus guidelines for absolute neutrophil count (ANC) thresholds for consideration of clozapine cessation and provided monitoring protocols for ADR management. Recommendations include lowering ANC cessation thresholds to 1·0 × 109 cells per L (0·5 × 109 cells per L for Duffy antigen receptor for chemokines-null individuals) and discontinuing routine ANC monitoring after 2 years. Comprehensive ADR monitoring every 3 months should address the metabolic syndrome, constipation, gastro-oesophageal reflux, sialorrhea, nocturnal enuresis, tachycardia, sleep apnoea, sedation, and other ADRs. Consumer representatives underscored the need for shared decision-making, streamlined monitoring, and accessible patient education. Although barriers persist, these findings support updating global policies to reduce burden on patients, enhance adherence, and optimise clinical outcomes. Incorporating evidence-based guidelines into practice could transform clozapine care, balancing safety with practicality to improve the lives of those with treatment-resistant schizophrenia.

In patients with schizophrenia, cannabis use exacerbates symptoms and can lead to a relapse of psychosis. Some experimental studies in healthy volunteers suggest that pre-treatment with cannabidiol (CBD) may reduce these effects, but others do not. Here, we investigated whether pre-treatment with CBD ameliorates the acute adverse effects of cannabis in patients with schizophrenia. Participants (n = 30) had schizophrenia or schizoaffective disorder plus a comorbid cannabis use disorder. In a double-blind, randomised, placebo-controlled, crossover trial, participants received oral CBD 1000 mg or placebo three hours before inhaling vaporised cannabis (containing Δ9-tetrahydrocannabinol (THC) 20-60 mg). The primary outcome was delayed verbal recall measured with the Hopkins Verbal Learning Test-Revised. We also measured psychotic symptoms with the Positive and Negative Syndrome Scale (PANSS) - positive subscale. Delayed verbal recall after cannabis administration was 3.5 words (95% confidence interval [CI]: 2.5-4.5) following pre-treatment with CBD, compared to 4.8 words (95% CI: 3.9 to 5.8) following pre-treatment with placebo (mean difference [MD] = -1.3 [95% CI: -2.0 to -0.6]; p = 0.001). After CBD pre-treatment, inhalation of cannabis was associated with an increase in PANSS-P score of 5.0 (95% CI: 3.6 to 6.5), compared to 2.9 (95% CI: 1.5 to 4.3) following pre-treatment with placebo (MD = 2.2 [95% CI: 0.6 to 3.7]; p = 0.01). Administration of CBD did not have a significant effect on plasma concentration of THC or its active metabolite, 11-hydroxy-THC. In patients with schizophrenia and a comorbid cannabis use disorder, pre-treatment with CBD did not attenuate the acute effects of cannabis on memory impairment or psychotic symptoms, but appeared to exacerbate them.

Anxiety disorders are prevalent psychiatric conditions that frequently emerge during adolescence. Among the neurobiological systems implicated in these disorders, the endocannabinoid (eCB) signaling system plays a crucial role, making it a promising target for therapeutic interventions. In addition to its direct effects on anxiety regulation, eCBs may also influence response to first-line pharmacologic treatments, such as selective serotonin reuptake inhibitors (SSRIs). However, little is known about developmental changes in eCB lipids-N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG)-or their relationship to anxiety symptoms and treatment response. Circulating AEA and 2-AG concentrations were measured in youth (aged 9-17, N = 199) with varying anxiety symptoms, assessed using the Screen for Child Anxiety-Related Disorders (SCARED). We evaluated how eCBs relate to developmental factors (e.g., demographics, biological variables) and anxiety symptoms (SCARED total). Additionally, we examined how eCB concentrations change in response to acute SSRI treatment in a subsample of adolescents (age 12-17, N = 41) with generalized anxiety disorder (GAD), who participated in an 8-week randomized placebo-controlled trial of escitalopram (15 mg/day, titrated to 20 mg/day). Body mass index (BMI) was positively correlated with circulating AEA, while 2-AG showed negative associations with age, female sex, and time-of-day. After adjusting for these variables, more severe anxiety symptoms were associated with higher AEA and lower 2-AG. Greater increases in 2-AG from baseline (without changes in AEA) were linked to improved treatment response in adolescents with GAD. Our study suggests that circulating eCBs may serve as biomarkers for anxiety severity and predictors of treatment response in youth.

Background: Nitrous oxide ("laughing gas") is an NMDA receptor antagonist. In the current study, our aim was to investigate the efficacy, safety, and likely optimal dose of nitrous oxide in adults with major depressive disorder (MDD). Methods: In this phase 2b randomized, double-blind trial, 81 patients with MDD were allocated on a 1:1 basis to receive nitrous oxide or oxygen/air (control); the nitrous group was further randomized to either 50% or 25% inspired nitrous oxide. All participants received four 1-hour-long treatment sessions at 1-week intervals and were followed for an additional 4 weeks. The primary outcome was the change in the 21-item Hamilton Depression Rating Scale (HAM-D) over the 4 treatment sessions. Secondary outcomes included remission (HAM-D ≤7 points), the Computerized Adaptive Test-Depression Inventory (CAT-DI) and Computerized Adaptive Test-Suicide Scale (CAT-SS). Results: The mean averaged change in HAM-D scores over the 4 weeks of treatment was lower with nitrous oxide than with control (-1.9 [95% CI, -3.9 to 0.0], p = .051). In the first week, 15 of 39 (38%) in the nitrous oxide group and 5 of 39 (13%) in the control group were remitted (p = .031). The mean averaged change in CAT-DI scores was -7.7 (95% CI, -14.1 to -1.4), p = .017; the mean averaged change in CAT-SS scores was -8.3 (95% CI, -14.4 to -2.1), p = .008, both favoring nitrous oxide. Conclusions: In this study, we confirmed that nitrous oxide has likely beneficial antidepressant effects in people with MDD.

Background: Although workplace mental health screening is often implemented to aid early identification of mental health symptoms and facilitate access to treatment, supporting evidence is limited. Aims: We aimed to evaluate the effect of independently conducted, confidential, online mental health screening, paired with automated tailored feedback recommending referral services, on help-seeking and psychological distress. Method: We conducted a cluster-randomised controlled trial with firefighters from an Australian fire and rescue service. Randomisation occurred by station (N = 264). Firefighters at stations allocated to the intervention group received tailored information detailing suitable mental health services based on their Kessler-6 psychological distress score (K6). The control group received generic feedback on services irrespective of K6 score. The primary outcome was help-seeking at 3-months post-intervention for those with at least moderate levels of psychological distress at baseline (K6 ≥14). The study was registered with Australian New Zealand Clinical Trials Registry (no. ANZCTR 12621001457831). Results: Of the 459 firefighters screened, 141 (30.72%) scored ≥14 on K6. Among this subgroup at 3 months, no differences were observed in rates of overall help-seeking between the intervention and control groups (P = 0.31). In contrast, levels of psychological distress remained high in the intervention group but declined in the control group (t[111] = 2.29, 95% CI: 0.24, 3.23, P = 0.024). The difference in psychological distress associated with workplace mental health screening equated to an effect size of -0.42 (95% CI: -0.04, -0.79). Conclusions: Our findings suggest that independent, confidential online mental health screening, paired with tailored online feedback and information on available treatment, does not significantly increase help-seeking and may sustain psychological distress over time compared with receiving generic information. As such, it should not be implemented to promote help-seeking and reduce levels of psychological distress. These findings are relevant for workplaces, mental health researchers and practitioners alike, highlighting the potential risk and potential harm of mental health screening conducted in this way on individuals.

Background: About 30% of patients with depression treated with antidepressant medication do not respond sufficiently to the first agents used. Pramipexole might usefully augment antidepressant medication in such cases of treatment-resistant depression, but data on its effects and tolerability are scarce. We aimed to assess the efficacy and tolerability of pramipexole augmentation of ongoing antidepressant treatment, over 48 weeks, in patients with treatment-resistant depression. Methods: We did a multicentre, double-blind, placebo-controlled randomised trial in which adults with resistant major depressive disorder were randomly assigned (1:1; using an online randomisation system) to 48 weeks of pramipexole (titrated to 2·5 mg) or placebo added to their ongoing antidepressant medication. The study was conducted in nine National Health Service Trusts in England. Participants, investigators, and researchers involved in recruitment and assessment were masked to group allocation, and the central pharmacy team dispensing the medication was not masked. The primary outcome was change from baseline to week 12 in the total score of the 16-item Quick Inventory of Depressive Symptomology self-report version (QIDS-SR16). The primary analysis was performed on the intention-to-treat population that included all eligible, randomly assigned participants. People with lived experience were involved in the design, oversight, and interpretation of the study. The trial was registered with ISCTRN (ISRCTN84666271) and EudraCT (2019-001023-13) and is complete. Findings: Between Feb 16 and May 29, 2024, 217 participants attended a screening visit, of whom 66 were excluded due to ineligibility. 151 participants were randomly assigned (75 to the pramipexole group and 75 to the placebo group, after one participant was found to be ineligible after randomisation). 84 (56%) participants were female and 66 (44%) were male and the mean age of participants was 44·9 years (SD 14·0). Ethnicity data were not available. The mean QIDS-SR16 total score at baseline was 16·4 (SD 3·4) in the pramipexole group and 16·2 (3·5) in the placebo group. The mean dose of pramipexole received at week 12 was 2·3 mg (SD 0·45). Adjusted mean decrease from baseline to week 12 of the QIDS-SR16 total score was 6·4 (SD 4·9) for the pramipexole group and 2·4 (4·0) for the placebo group; the mean difference between groups was -3·91 (95% CI -5·37 to -2·45; p<0·0001). Termination of trial treatment due to adverse events was more frequent in the pramipexole group (15 participants [20%]) than in the placebo group (four participants [5%]), with reported adverse events consistent with known side-effects of pramipexole, in particular nausea, headache, and sleep disturbance or somnolence. Interpretation: In this trial involving participants with treatment-resistant depression, pramipexole augmentation of antidepressant treatment, at a target dose of 2·5 mg, demonstrated a reduction in symptoms relative to placebo at 12 weeks but was associated with some adverse effects. These results suggest that pramipexole is a clinically effective option for reducing symptoms in patients with treatment-resistant depression. Future trials directly comparing pramipexole with existing treatments for this disorder are needed.

Background: Previous studies investigating the association between pubertal timing and depression in girls primarily use self-reported age at menarche (AAM). This study examines a range of pubertal timing indicators, including anthropometric and self-reported measures. Aims: Compare associations of multiple indicators of pubertal timing with depressive symptoms and depression in girls and explore whether these associations persist into early adulthood. Method: The sample comprised 4607 girls from UK-based Avon Longitudinal Study of Parents and Children. Seven measures of pubertal timing were assessed between ages 7 and 17 (age at: peak height velocity (aPHV); peak weight velocity; peak bone mineral content velocity; Tanner pubic hair and breast development stage 3; axillary hair; and AAM). Depressive symptoms were measured at 14, 17, 18 and 24 years using the Short Mood and Feelings Questionnaire. Depression was assessed at 15, 18 and 24 years using the Development and Well-Being Assessment and Clinical Interview Schedule-Revised. Multivariable logistic regression models were adjusted for socioeconomic status and pre-pubertal body mass index. Results: Later pubertal timing was associated with lower odds of depressive symptoms at age 14 across six measures, including aPHV (adjusted odds ratio (AOR): 0.82; 95% CI 0.72, 0.95) and AAM (AOR: 0.84; 95% CI 0.76, 0.92). Later AAM and Tanner breast stage 3 were associated with lower odds of depression at age 18 (AOR: 0.85; 95% CI 0.75, 0.97 and AOR: 0.83; 95% CI 0.72, 0.95, respectively). Associations attenuated by age 24. Conclusions: Later pubertal timing was associated with reduced odds of depressive symptoms during mid-adolescence, with associations attenuating by adulthood.

Background: Innovative treatments for paranoia, which significantly impairs social functioning in schizophrenia spectrum disorders (SSDs), are urgently needed. The pathophysiology of paranoia implicates the amygdala-prefrontal cortex (PFC) circuits; thus, in this study, we systematically investigated whether transcranial direct current stimulation (tDCS) to the ventrolateral PFC can attenuate paranoia and improve social functioning in SSDs. Methods: A double-blind, within-subjects, crossover design was used to compare active versus sham tDCS effects in 50 participants with SSDs (ClinicalTrials.gov identifier: NCT05746494). Participants completed 2 stimulation visits, each including 2 tDCS sessions about 1 week apart, with active (2 mA for 20 minutes) and sham conditions counterbalanced across the 2 visits. Alongside laboratory-based measurements of state paranoia and its associated social cognitive biases, ecological momentary assessment (EMA) was used. This involved daily evaluations of paranoia and social functioning administered 3 times per day for 7 days during each EMA period (EMA-baseline, EMA-active, EMA-sham). Results: For laboratory-based assessments, participants showed greater reductions in state paranoia and improvements in paranoia-related social cognitive biases after active stimulation compared with sham, including lower self-reported hostility and hostile attributions in ambiguous situations post active versus post sham. Similarly, in the EMA-active period, participants had lower daily paranoia than in the EMA-sham period and higher social interaction motivation with better attitudes compared with baseline and the EMA-sham period. Conclusions: Extending our pilot study, the current findings further supported the efficacy of tDCS in mitigating paranoia and enhancing social functioning in patients with SSDs. This work sheds light on the neuropathology of paranoia and identifies a promising avenue for future large-scale interventions.

Background: Auditory verbal hallucinations are a major burden for patients with schizophrenia spectrum disorder and are often resistant to pharmacological and psychotherapeutic interventions. Repetitive transcranial magnetic stimulation (rTMS) of the temporo-parietal cortex has been proposed as a treatment for persistent auditory verbal hallucinations. We aimed to compare the efficacy and safety of bilateral continuous theta burst stimulation (cTBS), a brief and efficient form of rTMS, in adults with auditory verbal hallucinations versus sham cTBS. Methods: This multicentre, randomised, sham-controlled, triple-blind phase 3 clinical trial was conducted at seven German psychiatric university hospitals and followed a planned two-stage adaptive design. Eligible patients were aged 18-65 years, had experienced persistent auditory verbal hallucinations at least once per week for a minimum of 3 months, and scored 3 points or higher on item P3 (hallucinatory behaviour) of the clinician-rated Positive Scale of the Positive and Negative Syndrome Scale (PANSS). 138 adults with treatment-persistent auditory verbal hallucinations and schizophrenia spectrum disorder were randomly assigned (1:1) to receive 15 sessions of active (n=70) or sham cTBS (n=68) administered sequentially as 600 pulses to the left and 600 pulses to the right temporo-parietal cortex over a 3-week period. The primary outcome was the change in the auditory hallucinations subscale of the Psychotic Symptom Rating Scales (PSYRATS-AH) from baseline to the end of treatment at 3 weeks, analysed in the intention-to-treat population, which included all randomly assigned patients who received at least one stimulation session. Safety was assessed in all patients who received at least one stimulation session. Follow-up assessments were performed at 1, 3, and 6 months after the end of treatment. People with lived experience were not involved in the study. Findings: Between Oct 24, 2015, and May 1, 2023, 2583 patients were screened for eligibility, of whom 138 patients were randomly assigned to active cTBS (n=70; 32 [46%] females and 38 [54%] males) or sham treatment (n=68; 24 [35%] females and 44 [65%] males). Race and ethnicity data were not collected. The primary intention-to-treat analysis (66 patients in the active cTBS group; 64 patients in the sham cTBS group), combining stages 1 and 2, showed patients in the active cTBS group had a significantly greater decrease in the PSYRATS-AH score at end of treatment than did patients in the sham cTBS group (-6·36 [SD 7·97] vs -3·74 [SD 5·79]; adjusted difference -2·36 [95% CI -4·71 to -0·01]; p=0·042). Overall, 85 adverse events (43 in the active cTBS group; 42 in the sham cTBS group) were reported in 22 (33%) of 66 patients in the active cTBS group and 21 (33%) of 64 patients in the sham cTBS group. Headache was the most common adverse event in both groups (n=13 active cTBS group vs n=17 sham cTBS group). One serious adverse event occurred in the active group. Interpretation: Sequential bilateral temporo-parietal cTBS over 3 weeks was safe and effective for reducing auditory verbal hallucinations in adults with schizophrenia spectrum disorder. This trial establishes cTBS as a treatment option for the care of these patients. Further research is needed to evaluate maintenance strategies, identify treatment predictors, and assess long-term efficacy.

Importance: Treatment-resistant depression (TRD) remains a critical challenge in psychiatry, with limited effective options. Esketamine, a rapid-acting antidepressant, is usually combined with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), but comparative evidence of these combinations' effectiveness in real-world settings is sparse. Objective: To determine whether the combination of esketamine + SNRI shows differences in clinical outcomes compared to esketamine + SSRI in patients with TRD. Design, setting, and participants: This retrospective cohort study was conducted in September 2024 using data from the TriNetX global health research network, with a 5-year time window from the first esketamine trial. TriNetX data are drawn from real-world clinical settings and use electronic medical records from more than 90 health care centers across 20 countries. Adults with TRD who were treated with esketamine combined with either an SSRI or an SNRI were eligible for inclusion. Exposure: Treatment with esketamine combined with an SSRI (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, or vilazodone) or an SNRI (desvenlafaxine, duloxetine, levomilnacipran, milnacipran, or venlafaxine). Main outcomes and measures: The primary outcomes were all-cause mortality, hospitalization, depression relapse, and suicide attempts. Kaplan-Meier survival analysis was used to estimate survival probabilities, while risk ratios and odds ratios were calculated for all outcomes. Results: In a population-based sample of 61 882 adult participants with TRD who were treated with esketamine combined with either an SSRI or an SNRI, 55 480 participants were selected after applying propensity score matching for age and sex. These patients were divided into 2 matched cohorts: 27 740 patients treated with esketamine + SSRI (16 007 female participants [57.7%]; mean [SD] age, 46.0 [21.3] years) and 27 740 treated with esketamine + SNRI (16 242 female participants [58.6%]; mean [SD] age, 45.9 [21.9] years). In the entire study population, the incidence of mortality, hospitalizations, depressive relapses, and suicide attempts was low throughout the study period. Patients in the esketamine + SNRI group had significantly lower all-cause mortality (5.3% vs 9.1%; P < .001), hospitalization rates (0.1% vs 0.2%; P < .001), and depression relapses (14.8% vs 21.2%; P < .001) compared to the esketamine + SSRI group, which instead showed a lower incidence of suicidal attempts (0.3% vs 0.5%; P = .04). Conclusions and relevance: In this retrospective comparative effectiveness study, among the study sample, incidence of mortality, hospitalizations, depressive relapses, and suicide attempts was low. The esketamine + SNRI group showed lower incidence of mortality, hospitalizations, and depressive relapses, while the esketamine + SSRI group showed a slightly lower incidence of suicidal attempts.

Background and aims: Dispensing of prescription stimulants to adults has risen dramatically over the past decade. Examining trends in nonprescribed use of prescription stimulants can inform public health responses. Most studies in the United States (U.S.) have faced challenges in assessing trends over time due to changes in survey methodologies and variation in populations assessed. We examined data from the Population Assessment of Tobacco and Health (PATH) Study to assess changes in nonprescribed use of prescription stimulants in the U.S. from 2013 to 2022. Design: The PATH Study is an ongoing longitudinal study of U.S. youth and adults, representative of the civilian noninstitutionalized population. Repeated cross-sectional estimates at each wave were used (8 total waves). Trends from Wave (W) 1 (September 2013-December 2014) to W7 (January 2022-April 2023) were assessed. Full-sample and replicate weights were used; joinpoint analyses and wave-to-wave comparisons were applied to test trends. Setting: Civilian noninstitutionalized U.S. youth and adults. Participants/cases: Youth aged 12-17 and adults aged 18 + were assessed, with a total of 45 727 participants at wave 1 (Ns vary by wave). Measurements: Past 12-month (P12M) prevalence of nonprescribed use of Ritalin or Adderall was assessed. Nonprescribed use of stimulants was assessed across subgroups according to age (12-17, 18-24, 25-39, ≥40) and sex (male, female). Findings: While wave-to-wave comparisons showed fluctuations across certain waves, overall, there were no statistically significant changes in P12M prevalence of Ritalin or Adderall nonprescribed use (1.3% at W1 and 1.5% at W7) across the study period. However, statistically significant differences in trends existed across age groups. Among 12-17 year-olds, nonprescribed use prevalence remained stable (1.4% in W1 and 1.5% in W7). Nonprescribed use prevalence also remained stable for 18-24-year-olds from W1 to W3, but then significantly declined (p = 0.016) from W3 (5.3%) to W7 (2.6%). There were no significant changes in nonprescribed use prevalence among 25-39-year-olds (1.7% in W1 and 2.4% in W7) and those aged ≥40 (0.3% in W1 and 0.9% in W7). Across most waves, young adults aged 18-24 had a statistically significantly higher prevalence of nonprescribed use. Neither sex had significant trends in P12M nonprescribed use prevalence. Conclusions: Despite an increase in dispensing of prescription stimulant medications in the United States, the prevalence of nonprescribed Ritalin or Adderall use does not appear to have increased, as assessed in the nationally representative Population Assessment of Tobacco and Health (PATH) Study. The prevalence of nonprescribed Ritalin or Adderall use among young adults aged 18-24, the age group with the highest nonprescribed use prevalence, declined 2013 to 2022.

Importance: The prescription of attention-deficit/hyperactivity disorder (ADHD) medications has risen substantially in many countries over the last 20 years. However, whether the real-world benefits of ADHD medications change with increased prescription rates within a society remains unknown. Objective: To examine whether the associations between ADHD medications and real-world outcomes (self-harm, unintentional injury, traffic crashes, and crime) change as prescription rates rise. Design, setting, and participants: This study used a self-controlled case series design. It was a population-based study using Swedish National Registers that included individuals who used ADHD medications in Sweden between 2006 and 2020. Data were analyzed from October 2023 to November 2024. Exposure: ADHD medication use. Main outcomes and measures: Rates of self-harm, unintentional injury, traffic crashes, and crime during medicated vs nonmedicated periods. The associations between ADHD medication and these real-world outcomes were examined across 3 time periods, 2006 to 2010, 2011 to 2015, and 2016 to 2020, during which ADHD medication prevalence increased from 0.6% to 2.8%. Results: There were 247 420 individuals identified (99 361 females [40.2%] and 148 059 males [59.8%]) aged 4 to 64 years in Sweden who used ADHD medications between 2006 and 2020. ADHD medication was consistently associated with lower risks for self-harm (incidence rate ratio [IRR] ranged from 0.77; 95% CI, 0.73-0.81 to 0.85; 95% CI, 0.82-0.88), unintentional injury (IRR ranged from 0.87; 95% CI, 0.84-0.89 to 0.93, 95% CI, 0.91-0.95), traffic crashes (IRR ranged from 0.71; 95% CI, 0.67-0.77 to 0.87; 95% CI, 0.83-0.91), and crime (IRR ranged from 0.73; 95% CI, 0.71-0.75 to 0.84; 95% CI, 0.82-0.85) across different age groups, sexes, and over time. However, the associations between ADHD medication use and lower risks of unintentional injury (P value for trend < .01), traffic crashes (P value for trend < .01), and crime (P value for trend < .01) appear to weaken over time as prescription rates increased. Changes in age and sex distribution of individuals receiving ADHD medication did not fully explain the weakening trend for unintentional injury and traffic crashes. Conclusions and relevance: In this study, ADHD medication remained associated with reduced risks of several serious real-world outcomes. However, the magnitude of these associations appears to have decreased alongside rising prescription rates over time. Thus, it is important to regularly evaluate medication use in different patient populations.

Objective: The authors sought to determine 1) whether receiving an initial stimulant prescription for attention deficit hyperactivity disorder (ADHD) from a provider whom a patient has never seen in person is associated with increased risk for stimulant use disorder (stimUD) or other substance use disorders (SUDs), and 2) whether receiving an initial stimulant prescription during a telehealth versus in-person appointment is associated with increased risk for stimUD or SUD. Methods: This was a retrospective cohort study using electronic health record data from March 1, 2020, to August 25, 2023, from a not-for-profit, academically affiliated medical system in the Northeastern United States. Eligible study subjects were ≥12 years old with ADHD and initial receipt of any stimulant prescription during the study period. Exclusion criteria included a non-nicotine SUD diagnosis at the time of initial stimulant prescription. Results: The sample included 7,944 patients. After adjustment for covariates, a purely telehealth-based relationship versus any in-person relationship did not significantly alter risk for SUD (adjusted odds ratio=0.85, 95% CI=0.60, 1.20) or stimUD (adjusted odds ratio=1.28, 95% CI=0.34, 4.85). A telehealth versus in-person appointment at the time of the initial stimulant prescription did not significantly alter risk for subsequent SUD (adjusted odds ratio=1.15, 95% CI=0.92, 1.44) but was associated with significantly higher risk for stimUD (adjusted odds ratio=6.18, 95% CI=1.34, 28.46). Conclusions: The results suggest that receipt of a stimulant prescription for ADHD via telehealth does not alter the risk for SUD, but receipt of an initial stimulant prescription via telehealth may signal increased risk of subsequent stimUD. The results, particularly for stimUD, require replication in other health care settings.

Objective: Previous studies have shown that parental factors are associated with an increased risk for attention deficit hyperactivity disorder (ADHD). However, the pathways by which parental factors are associated with risk of ADHD in offspring are not well understood. These associations can arise directly from parental genotypes inherited by offspring, and/or via environmental effects, some of which may themselves be influenced by the parental genotype (i.e., parental genetic nurture). This study specifically examined the impact of the maternal phenotype on offspring ADHD risk, above and beyond the direct genetic effect of maternally inherited genes. Methods: The study population consisted of 982,544 individuals from the Swedish Medical Birth Register. The authors partitioned the liability of ADHD into direct additive genetic effect, maternal genetic nurture effect, and maternal common environment effect. Results: A total of 66,707 (7%) individuals with an ADHD diagnosis were identified in the birth cohort. Maternal half-siblings were associated with a higher ADHD risk compared to paternal half-siblings, suggesting maternal effect. Estimates indicated 66.1% direct additive genetic effect (95% credible interval=0.647, 0.676) and 14.3% maternal genetic nurture effect (95% credible interval=0.136, 0.151). Additionally, evidence for substantial assortative mating among individuals with ADHD was observed. Conclusions: The findings indicate that maternal genotypes influence offspring's risk of ADHD through environmental pathways beyond the effects of direct genetic transmission. Exploring the impact of the genetics of the mother beyond the maternally inherited genes can lead to new insights into ADHD risk. Future studies should also investigate paternal effects to provide a more comprehensive understanding of the ADHD risk architecture.

Objective: The authors sought to determine whether genetic predispositions to cognitive ability or psychiatric conditions interact with anticholinergic burden (AChB) to impact cognition and brain structure in individuals with psychotic disorders. Methods: Participants with psychosis spectrum disorders (N=1,704) from the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) consortium, 18-65 years of age and representing diverse ancestries, underwent cognitive assessments, structural neuroimaging, genotyping, and a comprehensive medication review. The primary cognitive outcome was the Brief Assessment of Cognition in Schizophrenia (BACS) composite score, and the primary brain structural phenotype was total gray matter volume. AChB scores for scheduled medications were quantified using the CRIDECO Anticholinergic Load Scale. Polygenic scores (PGSs) for cognition, schizophrenia, bipolar disorder, and depression were constructed, and a composite psychiatric PGS was subsequently generated. Linear regression models were used to examine AChB-PGS interactions and their associations with cognitive and brain structure outcomes, adjusting for clinical covariates and multiple testing with false discovery rate. Hypothesis-driven moderated mediation models were used to explore potential association pathways. Results: Higher AChB was significantly associated with lower BACS performance and reduced gray matter volume. Individuals with higher cognitive PGS values exhibited greater adverse effects of AChB on BACS, while those with lower composite psychiatric PGS values showed more pronounced gray matter volume reductions from AChB. AChB associations with cognitive impairment were partially mediated by reduced gray matter volume and were moderated by composite psychiatric PGS. Conclusions: Anticholinergic-polygenic interactions significantly impact cognition and brain structure in individuals with psychotic disorders, highlighting a novel gene-by-environment interaction that advances our mechanistic understanding of cognitive impairments in this population.

Background: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting women of reproductive age. It has been linked to a range of psychiatric disorders. Although premenstrual disorders (PMDs) are characterized by psychiatric symptoms in tandem with hormone changes controlled by the endocrine system, the association between PCOS and PMDs remains unknown. Methods: We conducted a nationwide register-based cohort study including 2,965,178 females during 2001-2018 in Sweden. Individuals with PCOS were identified from clinical diagnoses recorded in the Swedish national registers (n = 41,515) and PMDs were identified based on clinical diagnoses and prescriptions with a clear indication of PMDs during follow-up. Using multivariable Cox regression, hazard ratio (HRs) of PMDs were estimated by comparing individuals with PCOS to those without. To account for confounders such as genetics or family environment, we conducted sibling comparison (N = 160,566). Results: During a median follow-up of 15.3 years, 1308 (1.9%) individuals with PCOS had a premenstrual disorder (PMD) (4.67/1000 person-years). Compared to individuals without PCOS they had more than doubled risk of PMDs (age-adjusted HR: 2.26, 95% CI 2.14- 2.39). The association was attenuated after adjustment for demographic and socioeconomic factors as well as for comorbid psychiatric disorders and obesity yet remained significant (HR: 1.54, 95% CI 1.46-1.63). The sibling comparison showed similar findings (full-adjusted HR: 1.61, 95% CI 1.36-1.92). The association between PCOS and PMDs remained statistically significant regardless of the presence of psychiatric comorbidities, with HR of 1.33 (95% CI 1.20-1.47) for individuals with psychiatric comorbidities and 1.55 (95% CI 1.45-1.65) for those without. Conclusions: Our findings suggest that individuals diagnosed with PCOS were at increased risk for PMDs. This association could not be entirely explained by shared risk factors, including such that sisters share.

Objective: Atypical depression is a depression subtype characterized by atypical and energy-related symptoms such as hypersomnia, weight gain, fatigue, and leaden paralysis. Limited research has examined its clinical characteristics in youth. This study investigates the prevalence, sociodemographic and clinical correlates, and six-month depression trajectories of atypical depression in a statewide youth depression registry. Method: Data from the Texas Youth Depression and Suicide Research Network (TX-YDSRN), a registry of youth aged 11-20 years with depression or suicidal ideation, were analyzed. Atypical depression was defined using the Atypical Energy-Related Symptom Scale (AES) score of ≥6. Sociodemographic data, Body Mass Index (BMI), depression and anxiety severity, suicidality, trauma history, and physical functioning were compared between individuals with atypical and non-atypical depression. Mixed-effects models were used to assess depressive symptom trajectories over six months. Results: Of 1,445 participants (mean age 15.8 years, 72.8% female), 22.4% had atypical depression. Atypical depression was associated with greater baseline depression, anxiety, suicidality, and suicide attempts compared to non-atypical depression. Atypical depression was associated with female sex, trauma history, and obesity. Youth with atypical depression also had poorer physical functioning. Over six months, individuals with atypical depression exhibited persistently higher depressive severity compared to those with non-atypical depression. Conclusion: Atypical depression in youth is associated with more severe clinical profiles and worse depression trajectories relative to non-atypical depression. Future studies should investigate the temporal relationships between variables such as trauma, obesity, and the onset of atypical depression to better understand how these factors may precede or exacerbate atypical depression.

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Background: Peripartum depression (PPD) is a prevalent mental health disorder in the peripartum period. However, a recent systematic review of clinical guidelines relating to PPD has revealed a significant inconsistency in recommendations. Aims: This study aimed to collect up-to-date evidence on the effectiveness of interventions and provide recommendations for prevention, screening and treating PPD. Method: A series of umbrella reviews on the effectiveness of PPD prevention, screening and treatment interventions was conducted. A search was performed in five databases from 2010 until 2023. The guidelines were developed according to the GRADE framework and AGREE II Checklist recommendations. Public stakeholder review was included. Results: One hundred and forty-five systematic reviews were included in the final analysis and used to form the guidelines. Forty-four recommendations were developed, including recommendations for prevention, screening and treatment. Psychological and psychosocial interventions are strongly recommended for preventing PPD in women with no symptoms and women at risk. Screening programmes for depression are strongly recommended during pregnancy and postpartum. Cognitive-behavioural therapy is strongly recommended for PPD treatment for mild to severe depression. Antidepressant medication is strongly recommended for treating severe depression in pregnancy. Electroconvulsive therapy is strongly recommended for therapy-resistant and life-threatening severe depression during pregnancy. Other recommendations are offered to healthcare professionals, stakeholders and researchers in managing PPD in different contexts. Conclusion: Treatment recommendations should be implemented after carefully considering clinical severity, previous history, risk-benefit for mother and foetus/infant and women's values and preferences. Implementation of evidence-based clinical practice guidelines within country-specific contexts should be facilitated.

Background: While biomarkers are widely used in other medical fields, psychiatry has yet to introduce reliable biological diagnostic tools. Female reproductive transitions provide a unique window of opportunity for investigating psychiatric biomarkers. Hormonal changes across menstruation, pregnancy, parturition and perimenopause can have dramatic effects on mental health in vulnerable individuals, enabling the identification of unique biomarkers associated with these fluctuations. Aims: This review integrates current evidence concerning potential biomarkers, with focus on recent human studies in perinatal depression, anxiety and obsessive-compulsive disorder, postpartum psychosis, premenstrual dysphoric disorder and perimenopausal depression. Method: We identified potential articles to be included in this narrative review by using PubMed to obtain articles in English since 2010 on the six conditions listed above, with the additional keywords of 'biomarker', 'epigenetics', 'neuroactive steroid', 'immune', 'inflammatory' and 'neuroimaging'. Results: There is substantial published evidence regarding potential biomarkers of reproductive psychiatric disorders in the areas of epigenetics, neuroactive steroids, immune function and neuroimaging. This body of research holds significant potential to advance biomarker development, uncover disease mechanisms and improve diagnostic and therapeutic strategies, but there is as yet no clinically useful biomarker in commercial development for any reproductive psychiatric disorder. Conclusion: There is an urgent need for longitudinal, large-scale and multi-modal studies to examine potential biomarkers and better understand their functions across various stages of reproduction.

Health care workers (HCWs) faced more stressors during the COVID-19 pandemic, potentially increasing depression, anxiety and post-traumatic stress disorder (PTSD). Insight into mental health dynamics and determinants in HCWs during the pandemic could help to maintain and improve mental health and resilience in future pandemics. In this longitudinal cohort study, HCWs received five surveys from November 2020 to March 2023 assessing self-reported symptoms of depression (PHQ-9), anxiety (GAD-7), PTSD (PCL-5), stress (PSS), burn-out (UBOS-EE), insomnia (ISI), resilience (RS) and work engagement (UWES). In addition to the longitudinal analysis, mental health symptoms were assessed in relation to possible predictors, e.g. patient care roles or prior SARS-CoV-2 infection. A total of 384 HCWs (95% of HCWs given consent) completed at least one survey, 326 (81%) completed two or more. Mental health significantly declined in December 2021 compared to November 2020, with mean increases of 1.16 (95% CI 0.73 to 1.58, d = 0.48), 0.79 (95% CI 0.41 to 1.17, d = 0.37) and 1.96 (95% CI 0.95 to 2.97, d = 0.35) on the PHQ-9 (range 0–27), GAD-7 (range 0–21) and PCL-5 (range 0–80), respectively, with similar results in multivariable analysis. Symptoms returned to November 2020 levels in March 2023. No differences were found regarding patient care roles, prior SARS-CoV-2 infection, years of work experience, or hospital workdays per week. Mental health significantly declined during the COVID-19 pandemic, after which mental health symptoms returned to baseline as the burden of COVID-19 patients decreased and public measures were lifted. This demonstrates this population’s ability to successfully adapt to challenging experiences and emphasizes the need for support strategies tailored to the critical phases of any future healthcare crises.

Importance: The incidence and nature of discontinuation symptoms following antidepressant cessation remain unclear. Objective: To examine the presence of discontinuation symptoms using standardized scales (eg, Discontinuation-Emergent Signs and Symptoms [DESS]) and the incidence of individual discontinuation symptoms in individuals who stop taking antidepressants. Data sources: The databases Embase, PsycINFO, Ovid MEDLINE, and Cochrane Library were systematically searched from inception until November 7, 2023. Study selection: Randomized clinical trials (RCTs) reporting discontinuation symptoms using a standardized scale or individual symptoms (eg, adverse events) following antidepressant cessation were included. Data extraction and synthesis: Data extracted were cross-checked by 2 reviewers. Additional unpublished data from 11 RCTs were included. A random-effects meta-analysis was conducted to calculate standardized mean difference between individuals who discontinued an antidepressant vs those who continued an antidepressant or discontinued placebo. A proportion and odds ratio (OR) meta-analysis was performed to assess incidence of individual discontinuation symptoms compared to placebo. Subgroup analyses were conducted to compare different antidepressants. Data analysis was conducted between September 2024 and December 2024. Main outcomes and measures: The primary outcomes were incidence and nature of antidepressant discontinuation symptoms measured using standardized or unstandardized scales. Results: A total of 50 studies were included, 49 of which were included in meta-analyses. The 50 studies included 17 828 participants in total, with 66.9% female participants and mean participant age of 44 years. Follow-up was between 1 day and 52 weeks. The DESS meta-analysis indicated increased discontinuation symptoms at 1 week in participants stopping antidepressants (standardized mean difference, 0.31; 95% CI, 0.23-0.39; number of studies [k] = 11; n = 3915 participants) compared to those taking placebo or continuing antidepressants. The effect size was equivalent to 1 more symptom on the DESS. Discontinuation of antidepressants was associated with increased odds of dizziness (OR, 5.52; 95% CI, 3.81-8.01), nausea (OR, 3.16; 95% CI, 2.01-4.96), vertigo (OR, 6.40; 95% CI, 1.20-34.19), and nervousness (OR, 3.15; 95% CI, 1.29-7.64) compared to placebo discontinuation. Dizziness was the most prevalent discontinuation symptom (risk difference, 6.24%). Discontinuation was not associated with depression symptoms, despite being measured in people with major depressive disorder (k = 5). Conclusions and relevance: This systematic review and meta-analysis indicated that the mean number of discontinuation symptoms at week 1 after stopping antidepressants was below the threshold for clinically significant discontinuation syndrome. Mood worsening was not associated with discontinuation; therefore, later presentation of depression after discontinuation is indicative of depression relapse.

Background: Medication non-adherence and insufficiently managed disease worsen outcomes in people with schizophrenia. We aimed to compare the bioavailability of a long-acting oral weekly formulation of risperidone, LYN-005, with daily oral risperidone at steady state. Methods: In this open-label, non-randomised, phase 3 trial, clinically stable participants with schizophrenia or schizoaffective disorder were enrolled from five sites across the USA while residing in an inpatient facility for 5 weeks (with the exception of days 9-13). After a 7-day run-in period with immediate-release risperidone (2 mg or 6 mg), participants received five doses of long-acting oral weekly LYN-005 (15 mg or 45 mg, respectively), with a supplemental half dose of daily immediate-release risperidone during week 1. Primary endpoints compared pharmacokinetic parameters of LYN-005 (minimum concentration [Cmin] at weeks 1 and 5, and maximum concentration [Cmax] and average concentration [Cavg] at week 5) with those of immediate-release risperidone on the last day of the run-in period. Prespecified primary endpoint criteria were geometric mean ratios for Cmin at week 1 and week 5 (90% CI ≥0·8), Cmax at week 5 (90% CI ≤1·25), and Cavg at week 5 (0·8 ≤90% CI ≤1·4). No people with lived experience were involved in the study design. This study was registered with ClinicalTrials.gov, NCT05779241, and has been completed. Findings: Between April 13, 2023 and Dec 1, 2023, 83 participants were enrolled in the study (62 [75%] male and 21 [25%] female; 67 [81%] Black or African American, mean age 49·3 years [SD 11·5]), of whom 47 participants completed the 5-week study. In the pharmacokinetic analysis (n=44), sustained release of the active moiety was observed across all doses of LYN-005. Geometric mean ratios of LYN-005 versus immediate-release risperidone were 1·02 (90% CI 0·93-1·12) for Cmin at week 1, and 1·04 (90% CI 0·87-1·23), 0·84 (0·77-0·92), and 1·03 (0·93-1·13) for Cmin, Cmax, and Cavg, respectively, at week 5 and met predetermined criteria. In individuals taking LYN-005 (n=67), gastrointestinal treatment-emergent adverse events were most common (44 [66%] participants), with one serious treatment-emergent adverse event reported. Interpretation: Weekly LYN-005 provided sustained release of risperidone at therapeutic concentrations with similar bioavailability to immediate-release risperidone. Patients remained clinically stable and no unexpected safety signals emerged. This offers a novel long-acting oral drug delivery technology for schizophrenia and schizoaffective disorder.

Background: Early parenting interventions are the gold standard treatment for reducing antisocial behaviour (ASB) in children with conduct problems (CP), but the neurocognitive mechanisms underpinning treatment response are unknown. Methods: We assessed fMRI and performance data from a reward learning task in boys with CP (aged 5-10 years old) before and after gold-standard group parenting intervention. Matched controls were assessed concurrently at two equally spaced time points. The CP group was subdivided into those whose ASB improved or persisted over the course of treatment. Longitudinal group (Control, Improving CP, Persistent CP]) by time (Pre, Post) analyses were then conducted on task-based fMRI and reinforcement learning data. Results: Following intervention, a comparison of the Improving CP group with persistent CP and control groups showed: a) increased neural activity, in the direction of typically developing children, within the ventromedial prefrontal cortex (VMPFC), insula, posterior cingulate cortex and hippocampus in Improving CP, but not in the Persistent CP group; and, b) distinct changes in learning rate, action bias and reward/punishment sensitivity. Further, changes in insula activity and punishment/reward sensitivity correlated with changes in parenting behaviour. Conclusions: Improved ASB after early intervention is associated with changes in reward processing regions and specific reinforcement learning parameters. These changes are not observed in those with persistent CP and correlate with changes in parenting behaviour. These findings highlight the importance of early interventions for CP and reveal potential mechanisms underpinning successful treatment.

Background: Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depressive disorder (MDD), but initial outcomes can be modest. Aims: To compare SSRI dose optimisation with four alternative second-line strategies in MDD patients unresponsive to an SSRI. Method: Of 257 participants, 51 were randomised to SSRI dose optimisation (SSRI-Opt), 46 to lithium augmentation (SSRI+Li), 48 to nortriptyline combination (SSRI+NTP), 55 to switch to venlafaxine (VEN) and 57 to problem-solving therapy (SSRI+PST). Primary outcomes were week-6 response/remission rates, assessed by blinded evaluators using the 17-item Hamilton Depression Rating Scale (HDRS-17). Changes in HDRS-17 scores, global improvement and safety outcomes were also explored. EudraCT No. 2007-002130-11. Results: Alternative second-line strategies led to higher response (28.2% v. 14.3%, odds ratio = 2.36 [95% CI 1.0-5.6], p = 0.05) and remission (16.9% v. 12.2%, odds ratio = 1.46, [95% CI 0.57-3.71], p = 0.27) rates, with greater HDRS-17 score reductions (-2.6 [95% CI -4.9 to -0.4], p = 0.021]) than SSRI-Opt. Significant/marginally significant effects were only observed in both response rates and HDRS-17 decreases for VEN (odds ratio = 2.53 [95% CI 0.94-6.80], p = 0.067; HDRS-17 difference: -2.7 [95% CI -5.5 to 0.0], p = 0.054) and for SSRI+PST (odds ratio = 2.46 [95% CI 0.92 to 6.62], p = 0.074; HDRS-17 difference: -3.1 [95% CI -5.8 to -0.3], p = 0.032). The SSRI+PST group reported the fewest adverse effects, while SSRI+NTP experienced the most (28.1% v. 75%; p < 0.01), largely mild. Conclusions: Patients with MDD and insufficient response to SSRIs would benefit from any other second-line strategy aside from dose optimisation. With limited statistical power, switching to venlafaxine and adding psychotherapy yielded the most consistent results in the DEPRE'5 study.

Depressive disorders are among the most common psychiatric disorders worldwide and associated with half of all suicides. There is robust evidence indicating that both electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS) effectively alleviate depressive symptoms in difficult-to-treat depression and enhance patient outcomes. However, there remains ongoing debate regarding their potential roles in preventing suicide and reducing all-cause mortality. Our study aims to investigate the impact of various neurostimulation techniques, including ECT, rTMS, and vagus nerve stimulation (VNS), on reducing suicidality, including suicidal ideation and completed suicides, as well as on overall mortality among individuals diagnosed with depression. In this systematic review and meta-analysis, we searched on MEDLINE via PubMed until January 9, 2024 for randomised controlled trials and controlled observational studies that investigated suicide and all-cause mortality outcomes after neurostimulation treatment for depression. Of the 1351 screened records we identified 26 studies eligible for inclusion in our systematic review. We included 11 studies on ECT (involving 17′890 subjects treated with ECT and 25′367 controls receiving treatment as usual), 5 studies on rTMS and 3 studies on VNS in our meta-analysis. In the cumulative cohort, 208 suicide deaths (1.70 %) were observed in the ECT group and 988 suicide deaths (5.02 %) were registered in the control group. Moreover, there were 511 deaths from all causes (3.13 %) in the ECT group, compared to 1325 deaths (6.64 %) in the control group. Thus, treatment with ECT demonstrated a significant 34 % decrease in the odds of suicide (OR 0.66, 95 % CI 0.50–0.88, p = 0.0047) and a 30 % reduction of death from all causes (OR 0.70, 95 % CI 0.62–0.79, p < 0.0001). The standardized mean difference (SMD) for suicidal ideation before and after ECT was −0.58 (95 % CI –0.10 to −1.07, p = 0.0177), suggesting a moderate effect size. We found no significant effect of rTMS on suicidal ideation with an SMD of −0.41 (95 % CI –1.01 – 0.19, p = 0.1795). In patients treated with VNS a 60 % reduction in the odds of death from all causes was observed (OR 0.40, 95 % CI 0.18–0.92, p = 0.0306). To conclude, there is consistent observational data supporting the protective effects of ECT against suicide and overall mortality.

Much is known about the use, benefits, and side-effects, of clozapine in treatment resistant schizophrenia (TRS). However, why clozapine is more effective than other antipsychotics in TRS remains unclear. This paper addresses this question. TRS patients show glutamate abnormalities, and clozapine has widespread effects on glutamate. However, these actions have not been proven different to those of other antipsychotics. Immune dysfunction is also reported in TRS, and clozapine has anti-inflammatory actions, but these have not been correlated with clinical improvement. Currently, there is much interest in muscarinic abnormalities in psychosis. Unlike most antipsychotics, clozapine has important effects on muscarinic receptors, particularly M1 and M4, and its major metabolite, N-desmethylclozapine, is a full agonist at M1. These effects are likely crucial to clozapine's effectiveness. In addition, clozapine's lower D2 receptor occupancy has been postulated to allow gradual resolution of dopamine receptor supersensitivity in the minority of patients with TRS who initially respond to antipsychotics but become resistant following long-term dopamine blockade. This hypothesis, however, remains controversial. Clozapine's multi-receptor profile enables it to have beneficial actions on the non-psychotic symptoms common in TRS: its ability to bind to histamine H1, serotonin 5-HT1A and GABA-B receptors offers an explanation for its anxiolytic actions while effects on 5-HT1A, 5-HT2A and 5-HT7 receptors likely underly its antidepressant properties. Clozapine shares these properties with olanzapine and quetiapine but its affinity for muscarinic receptors may be the mechanism by which it is more effective in TRS.

Schools are key for identifying challenges faced by young people who self-harm (SH). Understanding how school factors influence SH predictors is essential for developing effective school-based interventions. We aimed to conduct a secondary data analysis using the OxWell Student Survey to identify associations between young people's school experiences and SH. Using cross-sectional data from English secondary schools in the 2023 OxWell Student Survey, we conducted multi-level logistic regressions to analyse whether SH was associated with student age, gender, mental health (RCADS) and wellbeing (sWEMWBS). School experience measures included enjoyment, bullying, racism, extracurricular activities, school worry, and adults listening. Individual students' perception that the school did not deal well with bullying were associated with a 38% increase in SH (OR = 1.38; CI 1.20–1.59) and schools not dealing well with racism was associated with a 20% increase in the likelihood of SH (OR = 1.20; CI 1.04–1.38). Similarly, the likelihood of SH was 30% higher in schools with students feeling unfairly picked on by their teacher (OR = 1.30; CI 1.14–1.47). Greater SH was associated with being female (OR = 1.15; CI 0.99–1.32), gender diverse (OR = 3.49; CI 2.38–5.12), or preferring not to say (OR = 2.02; CI 1.44–2.83) compared to males. Lower wellbeing scores (OR = 0.93; CI 0.93–0.95) and higher RCADS scores (OR = 1.12; CI 1.11–1.13) were also linked to higher SH likelihood. Interventions that address bullying, racism, teacher-pupil relationships as well as providing specific support for more vulnerable groups such as females and gender diverse young people are important components of public mental health interventions that might reduce levels of SH. Future research should explore these relationships longitudinally.

Feeling and expressing love in daily life are interconnected and perhaps mutually influential experiences. In this study we examined the reciprocal dynamics of feeling and expressing love and its relation to well-being using an ecological momentary assessment design. Over a four-week period, we asked participants (N = 52; 67% Female; 80% White) to report their levels of feeling loved and expressing love six times a day. Using a continuous-time process model, we explored individual differences in inertia (i.e., persistence of a process over time) and cross-influences of felt and expressed love over time. We found that increases in expressing love led to increased feelings of being loved over time; however, increases in felt love did not lead to increases in expressing love. Notably, participants who experienced more persistent feelings of love (that is, greater inertia over time) indicated higher levels of flourishing. These results suggest new avenues for psychological well-being interventions which target increasing loving feelings through encouraging more expressions of love

Objective: There is tremendous public health interest in cost-efficient, scalable interventions to improve post-disaster mental health. The authors examined the efficacy of Bounce Back Now (BBN), a mobile application, versus an enhanced usual care app (EUC). Methods: A population-based trial was conducted with a diverse sample of 1,357 adults affected by Hurricane Harvey, Irma, Maria, Florence, or Michael in 2017 and 2018. Participants were eligible if they were ≥18 years of age, had access to an Internet-accessible device, were English speaking, and lived in a hurricane-affected area. BBN is designed to address symptoms of posttraumatic stress, depression, and sleep disturbance using evidence-based techniques grounded in behavioral and cognitive principles. Depressive, posttraumatic stress, and sleep symptoms were measured. Results: Participants' accessing of the BBN and EUC apps was similar. Active engagement was significantly greater among BBN users than EUC users (d=0.31), but BBN users engaged more actively in coping skills activities than in more time-intensive elements designed to promote behavior change. Moderate symptom reduction was observed in both conditions; Cohen's d values for the 3-month postbaseline assessment ranged from 0.49 to 0.60 in the BBN condition and from 0.36 to 0.41 in the EUC condition. Latent change models revealed that BBN users had significantly greater reductions in depression, sleep difficulty, and PTSD symptoms than EUC users, and these differences were maintained at the 6-month and 12-month postbaseline assessments. Conclusions: Population impact is driven by reach and effectiveness. The potential reach of BBN is high, which heightens opportunity for population-level impact, but per-user symptom reduction was modest. Per-user impact may be improved by embedding digital health resources in the context of a broader health care strategy.

Objective: Rates of substance use disorders (SUDs) remain significantly above national targets for health promotion and disease prevention in Canada and the United States. This study investigated the 5-year SUD outcomes following a selective drug and alcohol prevention program targeting personality risk factors for adolescent substance misuse. Methods: The Co-Venture trial is a cluster randomized trial involving 31 high schools in the greater Montreal area that agreed to conduct annual health behavior surveys for 5 years on the entire 7th grade cohort of assenting students enrolled at the school in 2012 or 2013. Half of all schools were randomly assigned to be trained and assisted in the delivery of the personality-targeted PreVenture Program to all eligible 7th grade participants. The intervention consisted of a brief (two-session) group cognitive-behavioral intervention that is delivered in a personality-matched fashion to students who have elevated scores on one of four personality traits linked to early-onset substance misuse: impulsivity, sensation seeking, anxiety sensitivity, or hopelessness. Results: Mixed-effects multilevel Bayesian models were used to estimate the effect of the intervention on the year-by-year change in probability of SUD. When baseline differences were controlled for, a time-by-intervention interaction revealed positive growth in SUD rate for the control group (b=1.380, SE=0.143, odds ratio=3.97) and reduced growth for the intervention group (b=-0.423, SE=0.173, 95% CI=-0.771, -0.084, odds ratio=0.655), indicating a 35% reduction in the annual increase in SUD rate in the intervention condition relative to the control condition. Group differences in SUD rates were reliably nonzero (95% confidence) at the fourth and fifth year of assessment. Secondary analyses revealed no significant intervention effects on growth of anxiety, depression, or total mental health difficulties over the four follow-up periods. Conclusions: This study showed for the first time that personality-targeted interventions might protect against longer-term development of SUD.

Importance: Treatment-resistant depression (TRD) is a major challenge in mental health, affecting a significant number of patients and leading to considerable burdens. The etiological factors contributing to TRD are complex and not fully understood. Objective: To investigate the genetic factors associated with TRD using polygenic scores (PGS) across various traits and explore their potential role in the etiology of TRD using large-scale genomic data from the All of Us (AoU) Research Program. Design, setting, and participants: This study was a cohort design with observational data from participants in the AoU Research Program who have both electronic health records and genomic data. Data analysis was performed from March 27 to October 24, 2024. Exposures: PGS for 61 unique traits from 7 domains. Main outcomes and measures: Logistic regressions to test if PGS was associated with treatment-resistant depression (TRD) compared with treatment-responsive major depressive disorder (trMDD). Cox proportional hazard model was used to determine if the progressions from MDD to TRD were associated with PGS. Results: A total of 292 663 participants (median [IQR] age, 57 (41-69) years; 175 981 female [60.1%]) from the AoU Research Program were included in this analysis. In the discovery set (124 945 participants), 11 of the selected PGS were found to have stronger associations with TRD than with trMDD, encompassing PGS from domains in education, cognition, personality, sleep, and temperament. Genetic predisposition for insomnia (odds ratio [OR], 1.11; 95% CI, 1.07-1.15) and specific neuroticism (OR, 1.11; 95% CI, 1.07-1.16) traits were associated with increased TRD risk, whereas higher education (OR, 0.88; 95% CI, 0.85-0.91) and intelligence (OR, 0.91; 95% CI, 0.88-0.94) scores were protective. The associations held across different TRD definitions (meta-analytic R2 >83%) and were consistent across 2 other independent sets within AoU (the whole-genome sequencing Diversity dataset, 104 388, and Microarray dataset, 63 330). Among 28 964 individuals followed up over time, 3854 developed TRD within a mean of 944 days (95% CI, 883-992 days). All 11 previously identified and replicated PGS were found to be modulating the conversion rate from MDD to TRD. Conclusions and relevance: Results of this cohort study suggest that genetic predisposition related to neuroticism, cognitive function, and sleep patterns had a significant association with the development of TRD. These findings underscore the importance of considering psychosocial factors in managing and treating TRD. Future research should focus on integrating genetic data with clinical outcomes to enhance understanding of pathways leading to treatment resistance.

Importance: Maternal inflammation during pregnancy has been associated with an increased risk of neurodevelopmental disorders (NDDs), such as attention-deficit/hyperactivity disorder (ADHD) and autism, and cognitive deficits in early childhood. However, little is known about the contributions of a wider range of inflammatory proteins to this risk. Objective: To determine whether maternal inflammatory proteins during pregnancy are associated with the risk of NDDs and executive functions (EF) in middle childhood and to identify protein patterns associated with NDDs and EF. Design, setting, and participants: This was a 10-year follow-up cohort study of the Danish Copenhagen Prospective Studies on Asthma 2010 mother-child birth cohort, using plasma samples collected at week 24 in pregnancy, where 92 inflammatory proteins were assessed. NDDs and EF were assessed in the offspring at age 10 years, between January 2019 and December 2021. Mother-offspring dyads with available maternal prenatal inflammatory proteins during pregnancy and offspring NDD psychopathology data at follow-up were included. Data analyses took place between December 2023 and August 2024. Exposures: Levels of 92 inflammatory proteins from panel collected at week 24 during pregnancy. Main outcomes and measures: Categorical and dimensional psychopathology of NDDs (primary outcome) and EF (secondary outcome). Results: A total of 555 mothers (mean [SD] age, 32.4 [4.3] years) and their children (285 male [51%]) were included. The principal component analysis showed that higher levels of maternal inflammatory proteins depicted in principal component 1 were associated with a higher risk of any NDD (OR, 1.49; 95% CI, 1.15-1.94; P = .003), particularly autism (OR, 2.76; 95% CI, 1.45-5.63; P = .003) and ADHD with predominantly inattentive presentation (OR, 1.57; 95% CI, 1.05-2.39; P = .03). The single protein analysis showed that 18 of 92 proteins reached false discovery rate (FDR) 5% significance after adjustment. Vascular endothelial growth factor A, C-C motif chemokine ligand, CD5, interleukin 12B, fibroblast growth factor-23, and monocyte chemoattractant protein-1 emerged as top proteins associated with risk of NDDs. The sparse partial least squares approach identified 34 proteins associated with any NDD, and 39 with ADHD with predominantly inattentive presentation. There were no associations with EF after FDR correction. Conclusions and relevance: The maternal inflammatory proteome during pregnancy was associated with NDDs risks in offspring at age 10 years. Further research is warranted to elucidate the specific pathways involving these proteins during pregnancy that could be targeted with prevention strategies to reduce risk of NDDs in children.

Objective: To examine the associations of serotonergic antidepressant exposure during pregnancy with the risk of depression and anxiety disorders in offspring. Method: The Mayo Clinic Rochester Epidemiology Project medical records-linkage system was used to study offspring born to mothers who were prescribed a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor (S/NRI users, n = 837) during pregnancy (1997-2010). Cox regression models were used to calculate hazard ratios to examine associations of S/NRIs with diagnosed depression and anxiety, defined based on a review of medical records by 2 board-certified psychiatrists, vs no maternal antidepressant use during pregnancy (nonusers, n = 863) and maternal antidepressant use in the year prior to pregnancy (former users, n = 399) as control groups. Results: After all adjustments for covariates, children born to S/NRI users during pregnancy did not differ in onset of depression or anxiety from the children of nonusers (adjusted hazard ratio = 1.00, 95% CI [0.74, 1.85]) or former users (adjusted hazard ratio = 0.94, 95% CI [0.69, 1.27]). These associations were similar when exposure was limited only to selective serotonin reuptake inhibitors. Conclusion: The results suggest that higher rates of childhood and adolescent depression or anxiety conditioned on maternal S/NRI use in pregnancy are more likely to be driven by maternal depression or underlying propensity for depression rather than direct pharmacological effects of in utero S/NRI exposure.

Background: Nutraceuticals have been taken as an alternative and add-on treatment for depressive disorders. Direct comparisons between different nutraceuticals and between nutraceuticals and placebo or antidepressants are limited. Thus, it is unclear which nutraceuticals are the most efficacious. Methods: We conducted a network meta-analysis to estimate the comparative efficacy and tolerability of nutraceuticals for the treatment of depressive disorder in adults. The primary outcome was the change in depressive symptoms, as measured by the standard mean difference (SMD). Secondary outcomes included response rate, remission rate, and anxiety. Tolerability was defined as all-cause discontinuation and adverse events. Frequentist random-effect NMA was conducted. Results: Hundred and ninety-two trials involving 17,437 patients and 44 nutraceuticals were eligible for inclusion. Adjunctive nutraceuticals consistently showed better efficacy than antidepressants (ADT) alone in outcomes including SMD, remission, and response. Notable combinations were Eicosapentaenoic acid + Docosahexaenoic Acid plus ADT (EPA + DHA + ADT) (SMD 1.04, 95% confidence interval 0.64-1.44), S-Adenosyl Methionine (SAMe) + ADT (0.99, 0.31-1.68), curcumin + ADT (1.03, 0.55-1.51), Zinc + ADT (1.59, 0.63-2.55), tryptophan + ADT (1.24, 0.32-2.16), and folate + ADT (0.64, 0.17-1.10). Additionally, four nutraceutical monotherapies demonstrated superior efficacy compared to ADT: EPA + DHA (0.6, 0.32-0.88), SAMe (0.52, 0.18-0.87), curcumin (0.62, -0.17 to 1.40) and saffron (0.69, 0.34-1.04). It is noted that EPA + DHA, SAMe, and curcumin showed strong performance as either monotherapies or adjuncts to ADT. Most nutraceuticals showed comparable tolerability to placebo. Conclusions: This extensive systematic review and NMA of nutraceuticals for treating depressive disorders indicated a number of nutraceuticals that could offer benefits, either as adjuncts or monotherapies.

While antipsychotic maintenance treatment effectively prevents relapse after a first psychotic episode, many remitted antipsychotic users wish to reduce or discontinue their medication, due to side effects, long-term health concerns, stigma, or the desire to regain autonomy. Current guidelines suggest gradual tapering, but what the optimal speed of this tapering should be, especially in patients who remitted from a first psychotic episode, remains unclear. Furthermore, D2 receptor affinity of the antipsychotic drug may also affect relapse risk. This study examined relapse risk and time to relapse, within the first 18 months after remission from a first psychotic episode, in 227 individuals who tapered antipsychotic medication. Relapse was defined dichotomously using consensus criteria based on the Positive and Negative Syndrome Scale, hospitalization for psychosis, or explicit clinical judgement of the treating psychiatrist. Tapering speed (in olanzapine equivalents mg/day) was calculated as the difference of antipsychotic dose between the start and the end of tapering, divided by the number of days in between. Antipsychotics were classified into partial D2 agonists, or antagonists with low or high D2 affinity. Logistic and Cox proportional hazards regression analyses were controlled for age, sex, cannabis use, and duration of first psychotic episode, as well as for differences in clinical and sociodemographic characteristics between the three drug D2 affinity groups using inverse probability of treatment weighting. During the follow-up period, 45.8% (N=104) of participants experienced a relapse after tapering. The average tapering speed was 10 mg olanzapine equivalents over 75 days, with an average tapering duration of 124 days (range: 6-334 days). Logistic regression analysis showed that the tapering speed did not predict the risk of relapse (z=0.989, p=0.323). Compared with users of high D2 affinity antagonists (N=57), patients using low D2 affinity antagonists (N=116) and partial D2 agonists (N=54) had a lower risk of relapse (respectively, z=-2.104; odds ratio, OR=0.48, p=0.035; and z=-2.278, OR=0.44, p=0.023). Users of high D2 affinity antagonists had a shorter time between the end of tapering and relapse (mean: 280 days) than low D2 affinity antagonist users (mean: 351 days, p=0.027) and partial D2 agonist users (mean: 357 days, p=0.040). Thus, D2 receptor affinity of the antipsychotic was more important than tapering speed in predicting psychotic relapse risk in individuals remitted from a first psychotic episode. Users of high D2 affinity antipsychotics had an about twice higher risk of relapse than users of other types of antipsychotics. This higher risk of relapse after tapering should be regarded as a relevant factor when selecting an antipsychotic drug for people with a first psychotic episode. For patients using strong D2 antagonists after remission from a first psychotic episode, extra monitoring during tapering is required.

Although clozapine is the most effective medication for treatment-resistant schizophrenia, response is inadequate in over half of people with that condition. There is limited guidance available on effective clozapine augmentation strategies. We studied the comparative effectiveness of specific doses of oral olanzapine, quetiapine, risperidone and aripiprazole augmentation of clozapine treatment on the risk of hospitalization due to a psychotic episode, as a marker for severe relapse, among patients with schizophrenia or schizoaffective disorder. In this population-based study, patients with one of those diagnoses receiving clozapine were identified from Finnish (years 1995-2017, N=14,053) and Swedish (years 2006-2021, N=8,743) nationwide registers. The risk of hospitalization due to a psychotic episode associated with periods of antipsychotic augmentation of clozapine treatment vs. same-dose clozapine monotherapy was assessed by a within-individual design, using each individual as his/her own control to eliminate selection bias, and analyzed with stratified Cox models. The two national cohorts were first analyzed separately; then results were combined using a random-effect meta-analysis. Secondary outcomes were somatic hospitalization, and hospitalization for psychosis or a somatic cause. The only augmentation associated with a significantly decreased risk of hospitalization due to psychosis in both countries was medium-dose (9 to <16.5 mg/day) aripiprazole combined with high-dose (≥330 mg/day) clozapine, and this combination was associated with the best outcome in the meta-analysis (adjusted hazard ratio, aHR=0.68, 95% CI: 0.62-0.75, p<0.0001). Among patients using medium-dose (180 to <330 mg/day) clozapine, medium-dose aripiprazole augmentation was the only treatment more effective than clozapine monotherapy after Bonferroni correction (aHR=0.79, 95% CI: 0.70-0.91, p=0.0006). The use of all high-dose augmentations was associated with an increased risk of hospitalization due to psychosis. Only aripiprazole augmentations were associated with a decreased risk of hospitalization for psychosis or a somatic cause, and the lowest risk was observed for medium-dose aripiprazole plus high-dose clozapine (aHR=0.70, 95% CI: 0.58-0.84, p=0.0001). This meta-analysis of two nationwide cohorts, totaling almost 23,000 patients using clozapine, indicates that medium-dose aripiprazole augmentation of clozapine treatment is associated with a 20-30% decreased risk of severe relapse compared with clozapine monotherapy within the same individuals, while augmentation with higher doses of aripiprazole (as well as with high doses of all other antipsychotics) is associated with an increased relapse risk.

Real-world studies provide valuable insights into long-term outcomes across diverse populations. Here, we contextualise recent findings on the association between antipsychotic use and breast cancer risk in women with schizophrenia. We discuss clinical implications and the strengths and limitations of real-world studies in psychiatry. We conclude with future perspectives.

Background: Aripiprazole, a prolactin-sparing antipsychotic, is considered relatively safe during pregnancy and has a better metabolic profile compared to other antipsychotics. However, its impact on lactation has not been adequately studied. This study aimed to assess the relationship between aripiprazole use during pregnancy and the postpartum period with lactation outcomes. Methods: Clinical charts of women attending perinatal psychiatry services between January 2016 and December 2021 were reviewed for details of aripiprazole prescription, clinical information, and lactation outcomes. Lactation failure was defined as the total absence of milk flow or secretion of minimal amounts for at least 7 days. Results: Among the 398 women attending perinatal psychiatry services, 60 were prescribed aripiprazole during pregnancy, with lactation data available for 35 women who continued the drug during the postpartum period. The mean age of women in years was 29 (±4.4) years. The most common diagnosis for aripiprazole prescription was schizophrenia (60%). Approximately 54.2% of the women were primiparous. Of the 35 women with available lactation data, 26 (74%) experienced complete lactation failure, and 4 (11%) had insufficient milk production while on aripiprazole. The mean dose of aripiprazole was 16.4 mg/day, with a mean duration of use of 20 months. Conclusions: In this study, most women who continued aripiprazole through pregnancy and postpartum experienced either lactation failure or insufficient milk production. It is important to discuss lactation issues associated with the use of aripiprazole with women during pregnancy and the postpartum period.

Background: Electroconvulsive therapy (ECT) is the most effective treatment of major depression, but autobiographical memory loss may limit its use. Despite previous attempts to synthesise the literature, the nature of autobiographical memory loss after ECT is still debated. Aims: To provide an overview of the effect of ECT on autobiographical memory in patients with depression and explore whether the effect is temporary or permanent. Furthermore, we wanted to analyse if ECT parameters or clinical information are associated with this effect. Method: PubMed, EMBASE, PsycINFO and Web of Science databases were searched on 26 January 2024. We included longitudinal studies measuring autobiographical memory before and after ECT in patients with depression compared to patients with depression receiving other treatment or healthy controls. Synthesis approach was a meta-analysis. PROSPERO ID: CRD42021267901. Results: Nine studies were included (432 patients, 173 controls). At post-ECT, we found that ECT patients had larger autobiographical memory loss than controls (standardised mean difference (SMD) = 0.55; 95% CI = 0.35-0.75). Right unilateral (RUL) ECT entailed a small effect on autobiographical memory (SMD = 0.32; 95% CI = 0.06-0.57), while bilateral ECT yielded a large effect (SMD = 0.82; 95% CI = 0.49-1.15). Higher age was associated with smaller effect. Autobiographical memory was stable at long-term follow-up. Conclusions: The studies suggest that ECT causes autobiographical memory loss in patients with depression. Results also suggest that lost memories are not regained. Furthermore, results support that RUL ECT is less detrimental to autobiographical memory. Strangely, a higher age might mitigate the autobiographical memory loss. Our findings are limited by studies being mainly observational and generally consisting of small sample sizes. Future studies should prioritise long-term follow-up assessments of autobiographical memory.

Background: Selective serotonin reuptake inhibitors (SSRIs) are the preferred pharmacological treatment for obsessive-compulsive disorder (OCD). However, insufficient response is common and it remains unclear whether specific patient-level factors influence the likelihood of treatment response. Aims: To determine the efficacy and acceptability of SSRIs in adult OCD, and to identify patient-level modifiers of efficacy. Methods: We conducted an individual patient data meta-analysis (IPDMA) of industry-sponsored short-term, randomised, placebo-controlled SSRI trials submitted for approval to the Dutch regulatory agency to obtain marketing approval for treating OCD in adults. We performed a two-stage meta-analysis, using crude data of available trials. The primary outcome was the difference in Yale-Brown Obsessive-Compulsive Scale (YBOCS) change between active treatment and placebo. Secondary outcomes were differences in response (defined as the odds ratio of ≥35% YBOCS point reduction) and acceptability (defined as the odds ratio for all-cause discontinuation). We examined the modifying effect of baseline characteristics: age, gender, illness severity, depressive symptoms, weight, illness duration and history of antidepressant use. Results: After excluding three trials because of missing data, we analysed results from 11 trials (79% of all submitted trials, n = 2372). The trial duration ranged from 10 to 13 weeks. Mean difference of SSRIs relative to placebo was 2.65 YBOCS points (95% CI 1.85-3.46, p < 0.0001), equalling a small effect size (0.33 Hedges' g). The odds ratio for response was 2.21 in favour of active treatment (95% CI 1.72-2.83, p < 0.0001), with a number needed to treat of seven. Patient characteristics did not modify symptom change or response. Acceptability was comparable for SSRIs and placebo. Conclusions: Our IPDMA showed that SSRIs are well accepted and superior to placebo for treating OCD. The effects are modest and independent of baseline patient characteristics.

Background: Anhedonia is a core diagnostic symptom of major depressive disorder (MDD). Post hoc analyses evaluated cariprazine plus antidepressant treatment (ADT) in patients with MDD and moderate-to-severe anhedonia. Methods: Data were analyzed from a positive phase 3, randomized, fixed-dose (1.5 or 3 mg/d), double-blind, placebo-controlled, parallel-group cariprazine study (NCT03738215). Post hoc outcomes (e.g., change from baseline to week 6 in MADRS total score, MADRS anhedonia subscale score, MADRS anhedonia subscale item scores including item 8 [inability to feel]) were assessed in 2 anhedonia patient subgroups (baseline MADRS anhedonia subscale score ≥ 18; baseline MADRS anhedonia item 8 score ≥ 4) using a mixed-effects model for repeated measures. Results: Most patients met subgroup inclusion criteria (anhedonia subscale score ≥ 18 = 584 [77.8 %]; anhedonia item 8 score ≥ 4 = 508 [67.6 %]). LSMDs in change from baseline were statistically significant in favor of adjunctive cariprazine versus adjunctive placebo in the MADRS anhedonia subscale score ≥ 18 subgroup (MADRS total score: 1.5 mg/d = -3.4, p = .0006; 3 mg/d = -2.1, p = .0358; anhedonia subscale score: 1.5 mg/d = -2.1, p = .0010; 3 mg/d = -1.26, p = .0399) and in the anhedonia item 8 score ≥ 4 subgroup for adjunctive cariprazine 1.5 mg/d (MADRS total score: -3.2, p = .0037; anhedonia subscale score: -1.9, p = .0066). Significant differences were seen for adjunctive cariprazine versus adjunctive placebo on several anhedonia subscale single items, including anhedonia item 8 for the 1.5 mg/d dose. Limitation: Post hoc analysis. Conclusion: In patients with MDD and moderate-to-severe anhedonia, adjunctive cariprazine improved symptoms of general depression and anhedonia, suggesting a potential benefit for patients with this clinically significant symptom.

Context: High-frequency (HF) transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC) is widely used in Major Depressive Episode (MDE). Optimization of its efficacy with a neuro-navigation system has been proposed based on a small randomized controlled trial (RCT) supporting a large effect. Method: This evaluator- and patient-blind, multicenter RCT assessed the superiority in terms of efficacy of 10 HF rTMS sessions of the left DLPFC targeted with MRI based neuro-navigation versus similar sessions targeted by the standard 5 cm technique. The study was conducted between January 2013 and April 2017, at 4 hospitals centers in France where both in- and out- patients with MDE were included. Randomization was computer-generated (1:1), with allocation concealment implemented within the e-CRF. The main outcome measure was the percentage of responders 44 days (D44) after the rTMS session. Secondary outcomes were percentage of remitters, Beck Depression Inventory and psychomotor retardation assessed with Salpêtrière retardation rating scale (SRRS) for depression at D14 and D44. The results are presented along with their 95% confidence intervals. Results: 105 patients were randomized and 92 were evaluable with respectively 45 patients in the neuronavigation group and 47 in the standard group. A treatment response was observed for 14 (31.8%) of 44 patients analyzed in the intervention group, and for 16 (35.6%) of 45 patients analyzed in the control group with no statistical difference (relative risk 0.89; 95% confidence interval, [0.50;1.61]). No difference was evidenced for secondary outcomes at D44 whether it concerns remission at D44 (relative risk, 0.82; 95% CI, 0.36 to 1.88), or BDI results (difference in means, 0,01; 95% CI, -3.06 to 3.26), or SRRS results (difference in means, 0.11; 95% CI, -2.42 to 5.02). Similar results were observed at D14. Rates of adverse events were similar in both groups with 23 (47.9%) and 1 (2.1%) of adverse events and serious adverse events in the neuro-navigation group versus 20 (40.8%) and 0 (0%) in the standard group. Discussion: This study failed to reproduce previous findings supporting the use of neuro-navigation system to optimize rTMS efficacy. Limitations of this study includes a small sample size and a number of rTMS sessions that may appear substandard in 2025.

Since the COVID-19 pandemic, there has been an exponential rise in mental health crises among youth, particularly with depressive symptoms.1 More than 1 in 5 children and adolescents worldwide experience depressive symptoms or meet criteria for major depressive disorder,2 highlighting a critical public health challenge. Although physical activity has long been considered a protective factor against depression, most published research has relied on cross-sectional or short-term studies. This editorial will review and contextualize the recent study by Steinsbekk and colleagues,3 which provides crucial insights into the dynamic relationship between physical activity and depressive symptoms by leveraging objective measures and a longitudinal, within-person analytical approach from childhood through adolescence.

American conservatives tend to rate their mental health more positively than their liberal counterparts. One explanation for this finding is that conservatives may be more likely to justify existing inequalities in society, leading to a palliative effect on their mental health that does not happen for liberals. Conservatives also score higher on personality and attitude measures, such as religiosity, marital status, and patriotism, which are associated with better mental health. We examine whether this ideological mental health gap holds for a different facet of well-being that is closely related to mental health. Further, we suggest that the ideological mental health gap may have more to do with a stigmatized reaction to the term "mental health" which has become increasingly politicized in the US context since its introduction to literature in the early 20th century. First, we examine whether the conservative-liberal divide in self-assessments of mental health remains once we control for a wide variety of demographics, socioeconomic factors, and recent life experiences. We find that accounting for these alternative explanations reduces the gap by about 40%, but that ideology remains a strong predictor of mental health self-reports. Second, we conducted an experiment where we randomly assigned whether people were asked to evaluate their mental health or their overall mood. While conservatives report much higher mental health ratings, asking instead about overall mood eliminated the gap between liberals and conservatives. One explanation is that rather than a genuine mental health divide, conservatives may inflate their mental health ratings when asked, due to stigma surrounding the term. Another possibility is that ideological differences persist for some aspects of mental well-being, but not others.

Schizophrenia is a mental illness involving multiple symptom domains and is often associated with substantial physical health comorbidities. Guidelines exist, but these tend to be country-specific and are often missing a concise yet comprehensive algorithmic approach. From May 1, 2023, to Jan 1, 2025, International Guidelines for Algorithmic Treatment (INTEGRATE) authors from all UN regions collaborated to develop a consensus guideline focused on the pharmacological treatment of schizophrenia. Following an umbrella review of the literature, input from expert workshops, a consensus survey, and lived experience focus groups, a consensus algorithmic guideline and associated digital tool were developed. Key recommendations include a focus on metabolic health from treatment initiation, timely assessment and management of non-response, symptom domain-specific interventions, mitigation of side-effects, and the prompt use of clozapine in cases of treatment resistance.

Importance: Hormonal contraceptive (HC) use is associated with depression. It is, however, unknown whether this is also true in the postpartum period when women have a heightened depression risk and are routinely offered HC treatment. Objective: To examine whether HC initiation post partum is associated with the development of depression within 12 months post partum. Design, setting, and participants: A population-based cohort study based on nationwide Danish register data was conducted including all primiparous women who gave birth from January 1, 1997, through December 31, 2022. Women were excluded if they had depression within 24 months before delivery, multiple births or stillbirth, or a diagnosis of breast cancer or liver tumor. Data analysis was conducted between March 20, 2023, and January 17, 2025. Exposure: Hormonal contraceptive initiation within 12 months post partum was treated as a time-varying exposure. Hormonal contraceptive types were categorized as combined oral contraceptives (COCs), combined nonoral contraceptives (CNOCs), progestogen-only pills (POPs), and progestogen-only nonoral contraceptives (PNOCs). Main outcomes and measures: Depression within 12 months post partum, defined as filling an antidepressant prescription or receiving a hospital diagnosis of depression, was the main outcome. Adjusted hazard ratios (AHRs) and average absolute risks of depression within 12 months post partum were estimated using Cox proportional hazards regression and a G-formula estimator. Results: Of 610 038 first-time mothers, 248 274 (40.7%) initiated HCs within 12 months post partum (mean [SD] age, 27.6 [4.3] years for HC users vs 29.6 [4.8] years for nonusers). Hormonal contraceptive initiation was associated with subsequent depression, with an AHR of 1.49 (95% CI, 1.42-1.56) compared with no use, resulting in an increase in the 12-month absolute risk from 1.36% (95% CI, 1.32%-1.39%) to 1.54% (95% CI, 1.50%-1.57%). The AHR for COC was 1.72 (95% CI, 1.63-1.82); CNOC, 1.97 (95% CI, 1.64-2.36); and PNOC, 1.40 (95% CI, 1.25-1.56). Progestogen-only pill exposure was associated with an instantaneously reduced risk in the early study period, but it was increased late post partum. The earlier COCs were initiated post partum the higher the associated rate ratio of depression. Conclusions and relevance: In this cohort study, HC initiation post partum was associated with an instantaneous increased risk of developing depression. The associated risk was higher the earlier it was initiated post partum, at least for COC. This finding raises the issue of whether the incidence of depression post partum is increased by routine HC initiation after childbirth.

Purpose: Describe xanomeline and trospium chloride efficacy and safety/tolerability for the treatment of schizophrenia using number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH). Methods: Categorical data were extracted from the three 5-week, randomized, double blind, placebo controlled EMERGENT-1, EMERGENT-2, and EMERGENT-3 clinical trials of xanomeline/trospium in adults with schizophrenia experiencing acute psychosis. Efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Severity (CGI-S), and categorical response criteria. Safety and tolerability were assessed using rates of discontinuation and treatment-emergent adverse events (TEAEs). NNT, NNH, and LHH values were calculated for each individual study as well as pooled. Results: In data from the acute EMERGENT trials, NNT estimates were significant for xanomeline/trospium vs placebo for the pre-specified treatment response threshold of ≥30% reduction from baseline in PANSS total score at Week 5 (NNT=5 [95% CI, 4-8]). NNT estimates for response thresholds of ≥20% and ≥40% reduction from baseline in PANSS total score and ≥1- and ≥2-point decrease from baseline in CGI-S score were <10, indicating a clinically relevant therapeutic benefit of xanomeline/trospium over placebo. Estimates of NNH vs placebo for the most common TEAEs were >10, with the exception of nausea and vomiting; however, rates of discontinuations due to TEAEs of nausea, dyspepsia, or vomiting were low (NNH=49 [95% CI, 28-182]). LHH indicated an overall benefit of xanomeline/trospium vs placebo for all assessed outcomes. In indirect comparisons based on published data from trials of available antipsychotics approved for schizophrenia, xanomeline/trospium exhibited comparable or more robust NNT estimates vs placebo and was the least likely agent to be associated with weight gain or somnolence/sedation. Conclusion: In the 5-week EMERGENT clinical trials, NNT, NNH, and LHH assessments demonstrated a favorable benefit-risk profile for xanomeline/trospium.

Introduction: Previous studies have shown patient preference can have large effects on treatment adherence and patient satisfaction. However, the direct effects of matching treatment with patient preference on efficacy and safety outcomes remain unclear. We aimed to evaluate the effects of patient preference and preference-matching on efficacy, adverse events, and adherence to electroconvulsive therapy (ECT) and intravenous (IV) ketamine treatments in a randomized clinical trial. Methods: Data were collected during the Patient-Centered Outcomes Research Institute (PCORI) funded ECT vs. Ketamine in Patients with Treatment Resistant Depression (ELEKT-D) study, which randomized patients to treatment with either ECT or IV ketamine across five U.S. sites. We performed post hoc-analyses on 255 patients who provided responses to a patient preference survey following treatment phase completion, which allowed us to explore the relationships between treatment preference and several treatment outcome measures. Results: Our analysis showed that (1) Ketamine was preferred by more trial participants than ECT; (2) Preference for ketamine was associated with higher likelihood of treatment response for all patients regardless of treatment assignment; (3) Preference-matching (patients receiving the treatment they indicated a moderate or strong preference for on the survey) was associated with greater likelihood of treatment response to ketamine but not ECT; (4) Preference-matching was associated with reduced rates of adverse events in ECT-treated patients. There was a trend for preference-matching potentially influencing treatment adherence. Conclusions: Our findings suggest treatment preference-matching affects treatment effectiveness, adverse event reporting and possibly adherence. However, these associations may be contextual, modality dependent, and complex.

Introduction: Up to 50% of individuals fail to respond to current depression treatments. Repetitive negative thought and default mode network hyperconnectivity are central in depression and can potentially be targeted using novel neuromodulation techniques. This community-based study assessed whether a treatment using non-invasive transcranial focused ultrasound targeting the default mode network can decrease depression symptoms and repetitive negative thought, and improve quality of life. Methods: Study recruitment began in August 2023 and ended in February 2024. Twenty individuals aged 18 - 50 were enrolled from among 247 screened. Exclusion criteria included history of psychosis/mania, acute suicidality, MRI contraindications, pregnancy, and medical and neurological factors that may complicate diagnosis or brain function. Participants completed up to three weeks of transcranial ultrasound (11 sessions) targeting the anterior medial prefrontal cortex; ten minutes per session. Depression severity (Beck Depression Inventory - II and the Hamilton Depression Rating Scale), repetitive negative thought (Perseverative Thinking Questionnaire), and quality of life (World Health Organization Quality of Life Scale) were outcomes. Results: This sample was young (mean 30.4 years ± 10.0), predominantly female (75%), with moderate to severe depression and high comorbidity. Fifty percent of participants endorsed current psychiatric medication use. Ten percent of subjects dropped out of the study due to time constraints. Significant decreases in depression were observed over the course of treatment on self-report, 10.9 (p < 0.001, CI = -13.55, -7.92) and interview depression ratings, 4.2 (p < 0.001, CI = -5.85, -2.62), as well as significant decreases in repetitive negative thought, 8.4 (p <0.001, CI = -10.55, -6.03). Improvements in physical and psychological well-being were also observed over the course of treatment, 7.2 (p < 0.001, CI = 3.64, 10.63) and 11.2 (p < 0.001, CI = 7.79, 14.49), respectively, as well as improvements in environment satisfaction, 5.0 (p =0.001, CI = 2.24, 7.56). Discussion: Non-invasive transcranial focused ultrasound holds promise as a treatment for depression holds promise as a treatment for depression, however, future work including control arms is required to ascertain its causal role in depression.

Interoception is the awareness of bodily sensations, conveyed by both hormonal and neural signals. The vagus nerve is the primary neural interoceptive conduit, responsible for transmitting information from peripheral organs to the brain. It is widely accepted that vagal signals are essential for purely physiological functions like blood pressure maintenance, or nutrient intake homeostasis. However, a growing body of evidence, taking advantage of new technological advances, suggests that the vagus nerve also orchestrates or tunes emotions. Disruption of vagal interoceptive feedback prevents normal emotional control in rodents. Importantly, accumulating evidence indicates that pathological disruption of vagal afferent signals also occurs in humans and may constitute an important risk factor for emotional disorders. Hence, alleviating vagal interoceptive deficits may constitute a new therapeutic avenue for neurotic and affective disorders. Considering the technical and safety challenges for direct stimulation of brain regions relevant to emotionality disorders, the vagus nerve offers a safer and more practical route of potentially achieving similar outcomes. Here we will highlight the earliest studies which examined the consequences of manipulations of the vagal afferent neurons on anxiety, fear, and mood, and integrate these older findings with new research investigating the necessity of vagal afferent neurons in mediating the anxiety or mood-altering effects of physiological signals. We will also discuss the evolutionary significance of vagal control over emotional states within the boundaries of "normal" physiology and conclude by discussing the challenges of engaging the vagal interoception as novel therapeutics in mental health disorders.

Background: People with dementia (PwD) and their carers often consider maintaining good quality of life (QoL) more important than improvements in cognition or other symptoms of dementia. There is a clinical need for identifying interventions that can improve QoL of PwD. There are currently no evidence-based guidelines to help clinicians, patients and policy makers to make informed decisions regarding QoL in dementia. Aims: To conduct the first comprehensive systematic review of all studies that investigated efficacy of any pharmacological or non-pharmacological intervention for improving QoL of PwD. Method: Our review team identified eligible studies by comprehensively searching nine databases. We completed quality assessment, extracted relevant data and performed GRADE assessment of eligible studies. We conducted meta-analyses when three or more studies investigated an intervention for improving QoL of PwD. Results: We screened 14 389 abstracts and included 324 eligible studies. Our meta-analysis confirmed level 1 evidence supporting the use of group cognitive stimulation therapy for improving QoL (standardised mean difference 0.25; P = 0.003) of PwD. Our narrative data synthesis revealed level 2 evidence supporting 42 non-pharmacological interventions, including those based on cognitive rehabilitation, reminiscence, occupational therapy, robots, exercise or music therapy. Current evidence supporting the use of any pharmacological intervention for improving QoL in dementia is limited. Conclusions: Current evidence highlights the importance of non-pharmacological interventions and multidisciplinary care for supporting QoL of PwD. QoL should be prioritised when agreeing care plans. Further research focusing on QoL outcomes and investigating combined pharmacological and non-pharmacological interventions is urgently needed.

The global prevalence of autism spectrum disorder (ASD) has quadrupled during the past 3 decades; the reasons for this are many and include broadening of the diagnostic concept, increased awareness of the disorder, increased screening (including of adults and of girl children), and, possibly, increased exposure to environmental risk factors. This article examines genetic and especially environmental risk factors for ASD. Unsurprisingly, hundreds of potential genes have been identified, many of which overlap between ASD, schizophrenia, depression, and cardiometabolic disorders. Likewise, over a hundred environmental exposures have been associated with ASD risk. These include exposure to parental and family characteristics, exposure to maternal disorders arising during pregnancy, exposure to chronic maternal disorders present during pregnancy, exposure to fetal and other pregnancy-related problems/events, exposure to neonatal problems/events, exposure to maternal nutritional deficiencies during pregnancy, maternal exposure to substances during pregnancy, maternal exposure to pharmacological agents during pregnancy, in utero exposure to toxic substances, and early life exposure to toxic substances. Some of the risk factors identified may be causal, some may be markers of intermediary mechanisms, and some may be unrelated markers. About 40 of these risk factors have been confirmed in meta-analysis for association with ASD. Nearly 70 maternal diagnoses have also been associated with ASD, but, after correcting for false discovery error and shared risk, only 30 remain; and, of these 30, almost all may be explained by genetic and environmental risk factors shared between mother and child, judging from findings in discordant sibling pair and paternal negative control analyses. Caveats and nuances in the interpretation of risks are briefly discussed.

Background: In recent years, there has been a significant focus on exploring the potential therapeutic impact of altered states of consciousness on treatment outcomes for mental illness, with the goal of enhancing therapeutic strategies and patient results. Methods: This meta-analysis was designed to investigate the potential link between the psychomimetic effects of ketamine and clinical outcomes in mental health, which adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: Eleven studies were selected for meta-analysis, and the main result did not find a significant correlation between the psychoactive effects of ketamine and clinical outcomes either in mental illness (n = 11; n's = 27; r = 0.06 [-0.05, 0.17]; P = 0.268) or depression exclusively (n = 10; n's = 25; r = 0.03 [-0.07, 0.13]; P = 0.561). High heterogeneity was found for general analysis ( I2 = 80.78). Egger's regression did not indicate publication bias (intercept = 1.57; SE = 1.49, P = 0.30). No significant Kendall's rank correlation coefficient was observed ( τ = 0.02, P = 0.88) indicating funnel plot symmetry. The sub-analyses, aimed at minimizing study variability by specifically examining factors such as patient disorders (limited to depression), methods of administration (exclusively intravenous), types of assessment instruments, and the timing of evaluations, also yielded no significant findings. Conclusion: This meta-analysis suggests that the altered states of consciousness experienced during ketamine sessions are not directly linked to clinical outcomes. However, it is important to acknowledge that the limited number of studies and their heterogeneity render this conclusion preliminary, warranting further investigation over time.

Background: Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment for obsessive-compulsive disorder (OCD). The neurobiological mechanisms of rTMS in OCD have been incompletely characterized. We compared clinical outcomes and changes in task-based brain activation following 3 different rTMS protocols, all combined with exposure and response prevention. Methods: In this 3-arm proof-of-concept randomized trial, 61 treatment-refractory adult patients with OCD received 16 sessions of rTMS immediately before exposure and response prevention over 8 weeks, with task-based functional magnetic resonance imaging scans and clinical assessments before and after treatment. Patients received high-frequency rTMS to the left dorsolateral prefrontal cortex (n = 19 [13 women/6 men]), high-frequency rTMS to the left presupplementary motor area (preSMA) (n = 23 [13 women/10 men]), or control rTMS to the vertex (n = 19 [13 women/6 men]). Changes in task-based functional magnetic resonance imaging activation before/after treatment were compared using both a Bayesian region of interest and a general linear model whole-brain approach. Results: Mean OCD symptom severity decreased significantly in all treatment groups (Δ = -10.836, p < .001, 95% CI -12.504 to -9.168), with no differences between groups. Response rate in the entire sample was 57.4%. The dorsolateral prefrontal cortex rTMS group showed decreased planning-related activation after treatment that was associated with greater symptom improvement. No group-level activation changes were observed for the preSMA and vertex rTMS groups. Participants in the preSMA group with greater symptom improvement showed decreased error-related activation, and symptom improvement in the vertex group was associated with increased inhibition-related activation. Conclusions: rTMS to preSMA and dorsolateral prefrontal cortex combined with exposure and response prevention led to activation decreases in targeted task networks in individuals showing greater symptom improvement, although we observed no differences in symptom reduction between groups.

Background: Caregivers of autistic children experience particularly poor levels of mental health and increased caregiving complexities. Proactive post-diagnostic family support is recommended but is inconsistently implemented, largely not evidence based, and does not directly address caregiver mental health. This study aimed to test the clinical effectiveness of the Empower-Autism programme plus treatment as usual versus the usual local post-diagnostic psychoeducation offer plus treatment as usual on caregiver mental health at the 52-week follow-up. Methods: We did a prospective, multicentre, two-parallel-group, randomised controlled superiority trial of the Empower-Autism programme. Empower-Autism is a group-based, manualised, post-diagnostic programme designed to improve the mental health of caregivers of newly diagnosed autistic children. The programme combines autism psychoeducation and psychotherapeutic components based on Acceptance and Commitment Therapy and was delivered online via videoconferencing. Participants were recruited from 11 North-West England autism diagnostic or intervention centres and were parents or primary caregivers of children aged 2-15 years given an autism diagnosis within the past 12 months. Exclusion criteria were insufficient English language skills, significant learning disability, hearing or visual impairment, or psychiatric condition in caregiver and significant current family safeguarding concerns. Participants were randomly assigned to the intervention or treatment as usual (2:1), stratified by centre. Assessors were masked to group assignment but participants were not. The primary outcome was caregiver mental health assessed by the General Health Questionnaire-30 at 52 weeks. All outcomes were analysed following an intention-to-treat approach using linear mixed models on available cases in the first instance, which resulted in a modified intention-to-treat set due to missing data. Sensitivity analyses on multiply imputed data reflected the full intention-to-treat set. People with lived experience were involved in the trial across all stages. The trial was prospectively registered (ISRCTN 45412843) on Sept 11, 2019, and is complete. Findings: Between Sept 16, 2020 and April 14, 2022, 835 potential participants were referred and screened, 384 provided consent, and 379 caregivers were recruited, 255 of whom were randomly assigned to the intervention group and 124 to the treatment as usual group. 333 (88%) participants were female and 46 (12%) were male, with a mean age of 40·6 years (SD 7·3; range 23-69). 294 (78%) of the 379 caregivers were White British, 18 (5%) were White Other, 12 (3%) were Mixed or of multiple ethnicity, 32 (8%) were Asian or Asian British, 16 (4%) were Black or Black British, six (2%) were from any other ethnic group, and one (<1%) had missing ethnicity data. 267 (70%) index children were male, 111 (29%) were female, and one (<1%) was non-binary or other, with a mean age 8·9 years (SD 3·5; range 2·0-16·0). In the available case analysis set (n=319) reflecting a modified intention-to-treat set due to missing data, participants randomly assigned to Empower-Autism had improved mental health at 52 weeks compared with those randomly assigned to treatment as usual (General Health Questionnaire-30 mean difference -4·95 [95% CI -8·21 to -1·68], p=0·0030). 181 adverse events (116 in the Empower-Autism group and 65 in the treatment as usual group) and 15 serious adverse events (nine in the Empower-Autism group and six in the treatment as usual group) were reported; none were deemed to be related to the study intervention. The most common adverse events concerned significant deteriorations in the mental health of caregiver participants or index children and other serious personal issues potentially affecting caregiver mental health. Interpretation: To our knowledge, this is the first fully powered trial to show a statistically and clinically significant sustained effect on mental health in caregivers of newly diagnosed autistic children. In the context of the considerable clinical need in this area, we recommend the use of the Empower-Autism programme to clinicians and policy makers.

Importance: Cognitive behavior therapy (CBT) is a first-line treatment for most mental disorders. However, no meta-analytic study has yet integrated the results of randomized clinical trials on CBT across different disorders, using uniform methodologies and providing a complete overview of the field. Objective: To examine the effect sizes of CBT for 4 anxiety disorders, 2 eating disorders, major depression, obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and psychotic and bipolar disorders on symptoms of the respective disorders using uniform methodologies for data extraction, risk of bias (RoB) assessment, and meta-analytic techniques. Data sources: Major bibliographical databases (PubMed, PsycINFO, and Embase for all disorders) were searched up to January 1, 2024, for each disorder separately. Data analysis was performed from August 2024 to January 2025. Study selection: Randomized clinical trials comparing CBT with inactive control conditions in adults with 1 of the mental disorders established through a clinical interview were included. Data extraction and synthesis: Basic characteristics of patients, CBT, and studies were extracted. RoB was assessed with the Cochrane RoB tool 2. Meta-analyses were conducted using random-effects models. Main outcomes and measures: The primary outcome was the standardized mean difference (Hedges g) indicating the difference between CBT and controls at posttreatment on symptoms of the respective disorders. Results: A total of 375 trials (423 comparisons) between CBT and controls were included among 32 968 patients. The overall mean (SD) patient age was 43.4 (13.7) years, and the mean (SD) proportion of women was 0.68 (0.24). Effect sizes for CBT compared to all control conditions (g) were lower than 0.5 for bipolar and psychotic disorder; between 0.5 and 1.0 for panic, social anxiety, and generalized anxiety disorders, bulimia nervosa, binge eating disorders, depression, and OCD; and larger than 1.0 for PTSD and specific phobias (range of effect sizes: 0.31 for bipolar disorder to 1.27 for PTSD). Large effect sizes (g > 0.94) were observed in waitlist-controlled trials, a control condition mostly used in anxiety and eating disorders, PTSD, and OCD. Trials using care as usual showed more modest effect sizes (0.22-1.13). Study dropout rates within the CBT conditions ranged from 8% for specific phobia to 24% for PTSD. Conclusions and relevance: In this unified series of meta-analyses, CBT was probably effective in the treatment of mental disorders, including major depression, anxiety disorders, PTSD, OCD, and eating disorders, and possibly effective in psychotic and bipolar disorders. However, the effect sizes depended on the type of control condition.

Recent evidence from clinical and animal studies with anti-inflammatory agents in depression is conflicting. One possible reason is the heterogeneity of baseline inflammation levels. Since older adults are generally associated with chronic low-grade inflammation and depression is one of the most common mental disorders in this population, this meta-analysis aimed to evaluate the therapeutic and preventative effects of anti-inflammatory interventions for depression among older adults. PubMed, Cochrane Library, Embase, and PsycINFO were searched for randomized controlled trials (RCTs) up to November 18, 2024. The primary outcomes were mean change scores of depression scores and incidences of depression after treatment. Pooled standard mean differences (SMDs) and odds ratios (ORs) including 95% confidence intervals (95% CI) were calculated. Of 3116 screened articles, 31 RCTs met the inclusion criteria, with 25 studies investigating efficacy and 7 studies investigating the incidence following anti-inflammatory treatment. Anti-inflammatory interventions were statistically significantly more effective than placebo in reducing depressive scores for older adults with depression (SMD = -0.57, 95% CI = -0.98 to -0.15, p = 0.008). Sub-group analyses supported the use of omega-3 fatty acids (SMD = -0.14, 95% CI = -0.27 to -0.02, p = 0.03) and botanical drug or dietary intervention (SMD = -0.86, 95% CI = -1.58 to -0.13, p = 0.02) among older participants. While limited by substantial heterogeneity among included studies, these results reveal the moderate beneficial effects of anti-inflammatory interventions for the treatment and prevention of depression among older adults. Future high-quality RCTs are warranted to determine which anti-inflammatory interventions are most preferential for older patients with depression.

Objective: The authors synthesized evidence from studies quantifying the relationship between anticholinergic medication and cognitive function in psychosis, and additionally explored studies that investigated whether reducing anticholinergic medications affects cognitive function in individuals with psychosis. Methods: A database search was conducted in MEDLINE, Embase, and PsycINFO, from database inception to October 2023, for studies reporting objective cognitive assessment and quantification of anticholinergic burden using clinical scales, serological anticholinergic activity, or tapering of anticholinergic medications. Analyses were carried out in R using the metafor package. Random-effects meta-analysis models were employed, along with assessment of heterogeneity, study quality, and meta-regressions (age, sex, and antipsychotic dosage in chlorpromazine equivalents). Results: Of 1,337 citations retrieved, 40 met inclusion criteria, comprising 25 anticholinergic burden studies (4,620 patients), six serological anticholinergic activity studies (382 patients), and nine tapering studies (186 patients). A negative correlation was identified between anticholinergic burden and global cognition (r=-0.37, 95% CI=-0.48, -0.25), verbal learning (r=-0.28, 95% CI=-0.36, -0.21), visual learning (r=-0.17, 95% CI=-0.28, -0.06), working memory (r=-0.22, 95% CI=-0.29, -0.14), processing speed (r=-0.24, 95% CI=-0.35, -0.13), attention (r=-0.19, 95% CI=-0.29, -0.08), executive functions (r=-0.17, 95% CI=-0.27, -0.06), and social cognition (r=-0.12, 95% CI=-0.19, -0.05), and between serological anticholinergic activity and verbal learning (r=-0.26, 95% CI=-0.38, -0.14), working memory (r=-0.19, 95% CI=-0.35, -0.03), and executive functions (r=-0.16, 95% CI=-0.27, -0.04). Finally, tapering off anticholinergic medication improved the scores in verbal learning (d=0.77, 95% CI=0.44, 1.1), working memory (d=0.94, 95% CI=0.63, 1.26), and executive functions (d=0.44, 95% CI=0.26, 0.62). Conclusions: Anticholinergic burden is associated with the cognitive impairments observed in psychosis. From a clinical perspective, tapering off anticholinergic medication in patients with psychosis may improve cognition. However, randomized clinical trials are needed for an unbiased quantification of benefit.

Objective: It is not known what proportion of patients experience relapse in first-episode schizophrenia despite continuous dopamine D2 receptor blockade and whether breakthrough psychosis is attributable to long-term use of D2-blocking antipsychotics. Using data from a Finnish nationwide cohort, the authors sought to test the hypothesis that the incidence of breakthrough psychosis is accelerated among previously relapse-free patients receiving continuous D2 antagonist treatment beyond 5 years. Methods: All persons age 45 years or younger with first-episode schizophrenia were identified from the nationwide registry of inpatient care for the years 1996-2014. The primary outcome was a severe relapse leading to hospitalization among those treated continuously with long-acting injectable (LAI) antipsychotics. The secondary outcome was the incidence rate ratio (IRR) of relapse during years 2-10, using year 1 as the reference. Results: A total of 305 patients initiated ensured LAI use during the first 30 days of follow-up. Kaplan-Meier analysis showed that during the 10-year follow-up, their cumulative probability of relapse was 45% (95% CI=35-57). The annual relapse incidence per person-year decreased from 0.26 (95% CI=0.20-0.35) during the first year to 0.05 (95% CI=0.01-0.19) during the fifth year, corresponding to an IRR of 0.18 (95% CI=0.04-0.74). During years 6-10, only four relapses occurred during 128 person-years, corresponding to an IRR of 0.12 (95% CI=0.03-0.33) compared with year 1. Conclusions: About 40%-50% of patients with first-episode schizophrenia will relapse despite continuous D2 blockade, apparently due to non-dopaminergic elements of the pathophysiology of the illness, as the results show that long-term dopamine receptor blockade is not associated with an increased risk of breakthrough psychosis.

Objectives: To evaluate cariprazine in adults with older- and younger-age bipolar I disorder (OABD-I and YABD-I) and compare treatment effects between them. Design and setting: Pooled post-hoc analysis of studies in depressive or acute manic/mixed episodes associated with bipolar I disorder. Participants: 475/1383 patients (34.3%) in 3 depression trials and 238/1037 patients (23.0%) in 3 manic/mixed trials were OABD-I. Interventions: Depression: placebo, cariprazine 1.5 mg/day, 3.0 mg/day, pooled 1.5-3.0 mg/day. Manic/mixed: placebo, cariprazine 3.0-6.0 mg/day, and 9.0-12.0 mg/day. Measurements: Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impression of Severity (CGI-S), and Young Mania Rating Scale (YMRS). Results: In bipolar I depression, mean change from baseline in MADRS was significantly greater for the pooled cariprazine group vs. placebo in OABD-I (-13.72 vs. -11.98; p < 0.05) and for each cariprazine group vs. placebo among YABD-I. There was no significant difference in treatment effect between OABD-I and YABD-I for either individual cariprazine group vs. placebo. For mania/mixed states, mean change in YMRS was significantly greater for cariprazine 3.0-6.0 mg/day vs. placebo in OABD-I (-19.04 vs. -12.45; p < 0.001) and for both cariprazine groups in YABD-I (-12.49, -19.66 and -18.05 for placebo, cariprazine 3.0-6.0 mg/day and 9.0-12.0 mg/day, respectively [both p < 0.0001 vs. placebo]). There was no significant difference in treatment effect between OABD-I and YABD-I for cariprazine 3.0-6.0 mg/day vs. placebo; there was a significantly higher treatment effect for cariprazine 9.0-12.0 mg/day vs. placebo in the YABD-I subpopulation vs. OABD-I (4.20; p < 0.05).

Objective: Adolescent offspring of parents with bipolar disorder (BD) are at high risk to develop BD and other psychopathology, yet how this risk continues into middle adulthood remains unknown. This study aimed to determine the window of risk for BD and other psychopathology in offspring of parents with BD followed from adolescence into adulthood. Method: This study reported on the 22-year follow-up assessment of the Dutch Bipolar Offspring Study, a fixed cohort study of 140 participants established in 1997. Offspring (n = 100; mean [SD] age = 38.28 [2.74] years) of parents with bipolar I disorder or bipolar II disorder were assessed at baseline and 1-, 5-, 12-, and 22-year follow-up. Results: No new BD onsets occurred since the 12-year follow-up (lifetime prevalence = 11%-13%; bipolar I disorder = 4%; bipolar II disorder = 7%). Lifetime prevalence of any mood disorder was 65%; for major depressive disorder, prevalence was 36%; and for recurrent mood episodes, prevalence was 37%. Prevalence of major depressive disorder more than doubled in the past decade. Point prevalence of any psychopathology peaked between 20 and 25 years (38%-46%), subsiding to 29% to 35% per year after age 30. Overall, 71% of offspring contacted mental health services since the last assessment. Conclusion: The risk for homotypic transmission of BD in offspring of parents with BD is highest during adolescence. The heterotypic risk for mood disorder onset and recurrences continues over the life course. Severe mood disorders are often preceded by milder psychopathology, emphasizing the need for early identification and interventions. This study allows for better understanding of the onset and course of mood disorders and specific windows of risk in a familial high-risk population.

Objective: Psychiatric disorders are highly prevalent in adults with childhood-onset attention-deficit/hyperactivity disorder (ADHD). Currently, little is known about childhood predictors for these outcomes. Method: PubMed, PsychInfo, WoS, and EMBASE were searched until June 2024. Eligible studies investigated childhood predictors of persistent ADHD, substance use disorders (SUD), conduct disorder, antisocial personality disorder, major depressive disorder (MDD), and/or anxiety disorders in adults diagnosed with childhood ADHD (PROSPERO #CRD42022320887). Meta-analytic models were tested when N ≥3 for a predictor with similar effect measures, otherwise predictors were discussed narratively when N ≥2. Newcastle-Ottawa scale was used to assess study quality. Results: The selected 36 studies included 119 predictors, with 10 predictors eligible for meta-analyses. History of stimulant treatment (OR = 1.88, 95% CI 1.28-2.75, p = .001) was associated with increased, and higher childhood IQ with decreased (OR = 0.99, 95% CI 0.98-1.00, p =.039), risk of ADHD persistence in adulthood. ADHD persistence was associated with increased risk of SUDs (OR = 2.12, 95% CI 1.53-3.17, p =.004) and MDD (OR = 3.19, 95% CI 1.71-5.95, p <.001). Narratively reviewed predictors of fair/good quality studies showed potential predictors for ADHD persistence (i.e., ADHD combined type, hyperactive/impulsive symptoms, anxiety disorders, externalizing problems, social dysfunctioning, and socioeconomic status). Conclusion: We confirmed earlier reported childhood predictors (i.e., stimulant treatment history, ADHD persistence) and identified potential new predictors (i.e., childhood anxiety disorders, social problems, socioeconomic status) for psychiatric outcomes of ADHD. However, the available literature is hampered by methodological shortcomings. Future studies should focus on studying combined effects of potential predictors.

Background: Despite affecting 2-4% of the population worldwide, fibromyalgia often remains refractory to treatment. Here we report the first international randomised double-blind, sham-controlled trial developed to assess the efficacy of repetitive transcranial magnetic stimulation (rTMS) as an add-on therapy for fibromyalgia. Methods: Women aged ≥18 yr with fibromyalgia refractory to best available treatment were enrolled in Brazil, France, and Japan, and randomised to 10 Hz motor cortex (M1) rTMS, 3000 pulses day-1, or sham stimulation. This included 10 induction sessions over 2 weeks, followed by weekly maintenance (6 weeks), and fortnightly extended maintenance (8 weeks). Primary outcome was ≥50% pain reduction at week 8 compared with baseline. Secondary outcomes included pain interference, mood, global impression of change, and Fibromyalgia Impact Questionnaire (FIQ) scores at weeks 8 and 16. Results: We randomised 101 women (mean age 48 [range 25-83] yr) into active (n=52) or sham (n=49) arms. Bayesian analysis revealed a 99.4% probability of ≥50% pain reduction at week 8 in the active group vs sham (odds ratio [OR] 3.04; 95% credible interval [95% CrI] 1.26-8.06), with a number needed to treat of 4.54. Frequentist analysis confirmed that relative pain reduction was higher in the active than in the sham group (40.4% vs 18.4%, P=0.028). At week 16, this probability reduced to 34.2% (OR 0.815; 95% CrI 0.313-2.1), but the likelihood of FIQ score reduction was 79.1%. The intervention appeared safe. Conclusions: Add-on M1-repetitive transcranial magnetic stimulation reduced pain intensity up to 8 weeks in women with fibromyalgia. Although analgesic effects waned, functional improvements remained during extended maintenance at week 16.

Background: Depression in older adults is often undertreated. A 2011 systematic review of treatments for treatment-resistant depression (TRD) in older adults identified one placebo-controlled randomised controlled trial (RCT). We aimed to update this review, synthesising evidence for the effectiveness of treatments for TRD in older people. Methods: We systematically searched electronic databases (PubMed, Cochrane, Web of Science) from 9 January 2011 through 10 December 2023 (updating our search on 7 January 2024 for RCTs investigating TRD therapies in adults aged ≥55 years, defining treatment resistance as ≥1 unsuccessful treatment. We assessed bias with the Cochrane Risk of Bias (RoB) 2 tool, meta-analysed remission rates and evaluated evidence using GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria. Results: 14 studies (11 newly identified, 3 from previous review) involving 1196 participants (mean age 65.0, male/female 548/648) met the inclusion criteria; 10 were placebo controlled and 4 were rated as low RoB. The pooled proportion of participants in intervention arms remitting was 0.35 (17 arms; 95% CI=0.26; 0.45). Relative to placebo, intervention participants were more likely to remit (9 studies; OR 2.42 (95% CI=1.49; 3.92)). Relative to controls, remission rates favoured ketamine (n=3; OR 2.91 (1.11; 7.65)), with a trend towards transcranial magnetic stimulation (TMS) (n=3; 1.99 (0.71; 5.61)), and in single placebo-controlled studies, selegiline, aripiprazole augmentation, pharmacogenetic-guided prescribing (PGP) and cognitive remediation favoured interventions. Conclusions: We identified weak evidence that ketamine therapy and aripiprazole augmentation, and very weak evidence that TMS, PGP and cognitive remediation increased remission. Lack of evidence regarding routinely prescribed antidepressants and psychosocial treatments is problematic, requiring clinicians to extend evidence from younger populations.

Background: Despite the promising therapeutic effects of psilocybin, its efficacy in preventing relapse after withdrawal treatment for alcohol use disorder (AUD) remains unknown. This study aims to assess whether a single dose of psilocybin combined with brief psychotherapy could reduce relapse rates and alcohol use in AUD patients. Methods: This single-center, double-blind, randomized clinical trial was conducted in Switzerland. We recruited participants with AUD between June 8, 2020, and August 16, 2023 who completed withdrawal treatment within six weeks prior to enrollment. Participants were randomized (1:1) to receive either a single oral dose of psilocybin (25 mg) or placebo (mannitol), combined with brief psychotherapy. The primary outcomes were abstinence and mean alcohol use at 4-week follow-up. Participants completed the timeline followback to assess daily alcohol use. The trial is registered on ClinicalTrials.gov (NCT04141501). Findings: We included 37 participants who completed the 4-week follow-up (female:male = 14:23; psilocybin = 18, placebo = 19) in the analysis. There were no significant differences between groups in abstinence duration (p = 0.55, psilocybin mean = 16.80 days, 95% CI: 14.31-19.29; placebo mean = 13.80 days, 95% CI: 10.97-16.63; Cohen's d = 0.151) or mean alcohol use per day (p = 0.51, psilocybin: median = 0.48 standard alcohol units, range: 0-3.99, placebo: median = 0.54 standard alcohol units, range: 0-5.96; Cohen's d = 0.11) at 4-week or 6-month follow-up (abstinence: Cohen's d = 0.10, alcohol use: Cohen's d = 0.075). Participants in both groups reported reduced craving and temptation to drink alcohol after the dosing visit, with an additional reduction observed in the psilocybin group. Thirteen adverse events occurred in the psilocybin and seven in the placebo group. One serious adverse event occurred in the psilocybin and four in the placebo group, all related to inpatient withdrawal treatments. Interpretation: A single dose of psilocybin combined with five psychotherapy sessions may not be sufficient to reduce relapse rates and alcohol use in severely affected AUD patients following withdrawal treatment. However, given the limited sample size of our study, larger trials are needed in the future to confirm these findings.

Importance: Stimulants are increasingly prescribed for US adults. Whether such prescribing is associated with misuse and prescription stimulant use disorder (PSUD) is less understood. Objectives: To examine (1) sex- and age-specific trends in the number of persons dispensed stimulants and trends in dispensed prescription stimulants by prescriber specialty in 2019 through 2022; (2) prevalence of misuse and PSUD by use of prescription amphetamine-type stimulants (hereafter referred to as amphetamines) and methylphenidate; and (3) PSUD prevalence and sociodemographic and behavioral health correlates among persons using prescription stimulants with and without prescription stimulant misuse. Design, setting, and participants: This cross-sectional survey study used the 2019-2022 IQVIA Total Patient Tracker and National Prescription Audit New to Brand databases and the 2021-2022 National Surveys on Drug Use and Health (NSDUH) (community-dwelling 18- to 64-year-old individuals). Data analysis was performed from March to April 2024. Exposure: Past-year use of prescription stimulants. Main outcomes and measures: PSUD using DSM-5 criteria. Results: Of the sampled 83 762 adults aged 18 to 64 years, 33.8% (unweighted) were aged 18 to 25 years, 53.0% (unweighted) were aged 26 to 49 years, and 56.0% (unweighted) were women. Among those using prescription stimulants, 25.3% (95% CI, 23.8%-26.8%) reported misuse, and 9.0% (95% CI, 8.0%-10.0%) had PSUD. Among those with PSUD, 72.9% (95% CI, 68.3%-77.6%) solely used their own prescribed stimulants, 87.1% (95% CI, 82.3%-90.8%) used amphetamines, 42.5% (95% CI, 36.6%-48.5%) reported no misuse, and 63.6% (95% CI, 56.8%-69.8%) had mild PSUD. Individuals using amphetamines, compared with those using methylphenidate, had higher prevalence ratios of misuse (3.1 [95% CI, 2.2-4.3]) and PSUD (2.2 [95% CI, 1.3-3.8]). The largest increase in the number of individuals dispensed prescription stimulants was among women aged 35 to 64 years, from 1.2 million in quarter 1 of 2019 to 1.7 million in quarter 4 of 2022 (average quarterly percentage change, 2.6% [95% CI, 2.1%-3.1%]). The prevalence of prescription stimulant misuse was lower among women aged 35 to 64 years using these medications (13.7% [95% CI, 11.1%-16.8%]) than other sex- and age-specific subgroups (ranging from 22.0% [95% CI, 17.9%-26.7%] for men aged 35-64 years to 36.8% [95% CI, 32.6%-41.2%] for women aged 18-25 years). Conclusions and relevance: High prevalence of prescription stimulant misuse and PSUD (regardless of misuse status) suggests the importance of ensuring clinically appropriate use and of screening for and treating PSUD among all adults prescribed stimulants, especially those using amphetamines. Findings may suggest potential progress in addressing the mental health care gap for middle-aged women and the need for evidence-based clinical guidance and training on benefits and risks of prescription stimulants for adults.

Importance: Bariatric surgery, once the criterion standard in obesity treatment, has a small but concerning association with increased suicidality. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs), originally developed to treat diabetes, now provide substantial efficacy in the treatment of obesity. However, concerns of risk of suicidality with these medicines have been raised. Objective: To evaluate the risk of suicidality and self-harm in randomized, placebo-controlled trials of GLP-1 RAs in adults with diabetes or obesity. Data sources: MEDLINE, Embase, ClinicalTrials.gov, and Cochrane databases were systematically searched from inception to August 29, 2023. Study selection: Reports of randomized clinical trials (RCTs) lasting 6 or more months comparing GLP-1 RAs with placebo for the treatment of diabetes or obesity published in peer-reviewed journals were identified. Two independent reviewers screened all search-identified studies for inclusion. Records of outcomes were queried from primary papers, ClinicalTrials.gov entries, and corresponding authors. Data extraction and synthesis: Two independent researchers abstracted data and assessed data quality and validity using PRISMA guidelines. Data were pooled using random-effects models. Main outcomes and measures: Pooled incidence of completed or attempted suicide, occurrences of suicidal ideation, or self-harm. Results: A total of 27 of 144 RCTs meeting inclusion criteria systematically recorded suicide and/or self-harm-related events and included 32 357 individuals receiving GLP-1 RAs and 27 046 treated with placebo, over 74 740 and 68 095 person-years of follow-up, respectively. Event incidence was very low in the GLP-1 RA (0.044 per 100 person-years) and placebo (0.040 per 100 person-years) groups, with no statistically significant difference (rate ratio [RR], 0.76; 95% CI, 0.48-1.21; P = .24). Subgroup analyses did not suggest differences in outcomes based on diabetes status or GLP-1 RA used. Five studies were considered at risk of bias due to the loss of more than 5% of participants to follow-up. Otherwise, studies were not found to be heterogeneous nor at high risk of bias. Conclusions and relevance: There is unlikely to be an increase in the very low incidence of suicide-related adverse events among individuals receiving GLP-1 RAs within the context of RCTs. While these findings may further ease concerns about these adverse effects, continued monitoring is warranted to identify particular patients who may be at risk as extended use of GLP-1 RAs expands.

Importance: In the Netherlands, a growing group of young people request medical assistance in dying based on psychiatric suffering (MAID-PS). Little is known about this group, their characteristics, and outcomes. Objective: To assess the proportion of requests for and deaths by MAID-PS among young patients, outcomes of their application and assessment procedures, and characteristics of those patients who died by either MAID or suicide. Design, setting, and participants: This retrospective cohort study included Dutch individuals younger than 24 years requesting MAID-PS between January 1, 2012, and June 30, 2021, whose patient file had been closed by December 1, 2022, at the Expertisecentrum Euthanasie, a specialized health care facility providing MAID consultation and care. Main outcomes and measures: Outcomes of the MAID-PS assessment procedure (discontinued, rejected, or MAID-PS) and clinical characteristics of patients who died by MAID or suicide. Results: The study included 397 processed applications submitted by 353 individuals (73.4% female; mean [SD] age, 20.84 [1.90] years). Between 2012 and the first half of 2021, the number of MAID-PS applications by young patients increased from 10 to 39. The most likely outcome was application retracted by the patient (188 [47.3%]) followed by application rejected (178 [44.8%]). For 12 applications (3.0%), patients died by MAID. Seventeen applications (4.3%) were stopped because the patient died by suicide during the application process and 2 (0.5%) because the patient died after they voluntarily stopped eating and drinking. All patients who died by suicide or MAID (n = 29) had multiple psychiatric diagnoses (most frequently major depression, autism spectrum disorder, personality disorders, eating disorder, and/or trauma-related disorder) and extensive treatment histories. Twenty-eight of these patients (96.5%) had a history of suicidality that included multiple suicide attempts prior to the MAID application. Among 17 patients who died by suicide, 13 of 14 (92.9%) had a history of crisis-related hospital admission, and 9 of 12 patients who died by MAID (75.0%) had a history of self-harm. Conclusions and relevance: This cohort study found that the number of young psychiatric patients in the Netherlands who requested MAID-PS increased between 2012 and 2021 and that applications were retracted or rejected for most. Those who died by MAID or suicide were mostly female and had long treatment histories and prominent suicidality. These findings suggest that there is an urgent need for more knowledge about persistent death wishes and effective suicide prevention strategies for this high-risk group.

Background: Magnetic resonance-guided focused ultrasound (MRgFUS) trials targeting the anterior limb of the internal capsule have shown promising results. We evaluated the long-term safety and efficacy of MRgFUS capsulotomy in patients with obsessive-compulsive disorder (OCD) and major depressive disorder (MDD). Methods: This phase 1, single-center, open-label study recruited patients with treatment-resistant OCD and MDD. Outcomes were measured 6 months, 12 months, and 18 to 24 months (long term) after MRgFUS capsulotomy. Neuropsychological testing and neuroimaging were conducted at baseline and 12 months postoperatively. The primary outcome was safety. The secondary outcome was clinical response, defined for OCD as a ≥35% improvement in Yale-Brown Obsessive Compulsive Scale scores and for MDD as a ≥50% reduction in Hamilton Depression Rating Scale scores compared with baseline. Results: No serious adverse effects were registered. In patients with OCD (n= 15), baseline Yale-Brown Obsessive Compulsive Scale scores (31.9 ± 1.2) were significantly reduced by 23% (p = .01) at 6 months and 35% (p < .0001) at 12 months. In patients with MDD (n = 12), a 26% and 25% nonsignificant reduction in Hamilton Depression Rating Scale scores (baseline 24.3 ± 1.2) was observed at 6 months and 12 months, respectively. Neuropsychological testing revealed no negative effects of capsulotomy. In the OCD and MDD cohorts, we found a correlation between clinical outcome and lesion laterality, with more medial left-placed lesions (OCD, p = .08) and more lateral right-placed lesions (MDD, p < .05) being respectively associated with a stronger response. In the MDD cohort, more ventral tracts appeared to be associated with a poorer response. Conclusions: MRgFUS capsulotomy is safe in patients with OCD and MDD and particularly effective in the former population.

Background: Lithium and quetiapine are first-line augmentation options for treatment-resistant depression; however, few studies have compared them directly, and none for longer than 8 weeks. We aimed to assess whether quetiapine augmentation therapy is more clinically effective and cost-effective than lithium for patients with treatment-resistant depression over 12 months. Methods: We did this pragmatic, open-label, parallel-group, randomised controlled superiority trial at six National Health Service trusts in England. Eligible participants were adults (aged ≥18 years) with a current episode of major depressive disorder meeting DSM-5 criteria, with a score of 14 or higher on the 17-item Hamilton Depression Rating Scale at screening who had responded inadequately to two or more therapeutic antidepressant trials. Exclusion criteria included having a diagnosis of bipolar disorder or current psychosis. Participants were randomly assigned (1:1) to the decision to prescribe lithium or quetiapine, stratified by site, depression severity, and treatment resistance, using block randomisation with randomly varying block sizes. After randomisation, pre-prescribing safety checks were undertaken as per standard care before proceeding to trial medication initiation. The coprimary outcomes were depressive symptom severity over 12 months, measured weekly using the Quick Inventory of Depressive Symptomatology, and time to all-cause treatment discontinuation. Economic analyses compared the cost-effectiveness of the two treatments from both an NHS and personal social services perspective, and a societal perspective. Primary analyses were done in the intention-to-treat population, which included all randomly assigned participants. People with lived experience were involved in the trial. The trial is completed and registered with the International Standard Randomised Controlled Trial registry, ISRCTN16387615. Findings: Between Dec 5, 2016, and July 26, 2021, 212 participants (97 [46%] male gender and 115 [54%] female gender) were randomly assigned to the decision to prescribe quetiapine (n=107) or lithium (n=105). The mean age of participants was 42·4 years (SD 14·0 years) and 188 (89%) of 212 participants were White, seven (3%) were of mixed ethnicity, nine (4%) participants were Asian, four (2%) were Black, three (1%) were of Other ethnicity, and ethnicity was not recorded for one (1%) participant. Participants in the quetiapine group had a significantly lower overall burden of depressive symptom severity than participants in the lithium group (area under the between-group differences curve -68·36 [95% CI -129·95 to -6·76; p=0·0296). Time to discontinuation did not significantly differ between the two groups. Quetiapine was more cost-effective than lithium. 32 serious adverse events were recorded in 18 participants, one of which was deemed possibly related to the trial medication in a female participant in the lithium group. The most common serious adverse event was overdose, occurring in three (3%) of 107 participants in the quetiapine group (seven events) and three (3%) of 105 participants in the lithium group (five events). Interpretation: Results of the trial suggest that quetiapine is more clinically effective than lithium as a first-line augmentation option for reducing symptoms of depression in the long-term management of treatment-resistant depression, and is probably more cost-effective than lithium

Background: Clozapine is recommended by national and international guidelines for people with treatment-resistant schizophrenia. However, available meta-analyses of randomised controlled trials have not shown superior efficacy of clozapine when compared with other second-generation antipsychotics, with heterogeneity identified between the original studies. We aimed to use individual patient data (IPD) to account for potential reasons of variability and to synthesise an adjusted estimate for the difference in efficacy between clozapine and other second-generation antipsychotics for treatment-resistant schizophrenia. Methods: In this systematic review and IPD meta-analysis, we searched the Cochrane Schizophrenia Group's Study-Based Register from inception to Jan 24, 2024, and previous reviews for blinded randomised controlled trials comparing clozapine with other second-generation antipsychotics in participants with treatment-resistant schizophrenia. Trials were eligible if they included patients with treatment-resistant schizophrenia and had a duration of at least 6 weeks. IPD were requested from trial investigators. The primary outcome was change in overall schizophrenia symptoms as measured by the Positive and Negative Syndrome Scale (PANSS) between clozapine and other second-generation antipsychotics after 6-8 weeks of treatment. The effect size measure for the primary outcome was mean difference with 95% credible interval (CrI). We fitted a Bayesian random-effects IPD meta-regression model that included duration of illness, baseline severity, and sex as potential prognostic factors or treatment effect modifiers. Confidence in the evidence was assessed using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). People with lived experience of mental illness were involved in this study. This study is registered with PROSPERO, CRD42021254986. Findings: We screened 13 876 references and included 19 studies with data for 1599 participants; IPD were available for 12 of 19 trials (n=1052; mean age 37·67 years [SD 11·24; range 10-66]; 348 [33·08%] women and 704 [66·92%] men). Data on ethnicity were not available. The estimated mean difference in change from baseline PANSS total score was -0·64 points (95% CrI -3·97 to 2·63; τ=2·68) in favour of other second-generation antipsychotics. Shorter duration of illness and higher baseline severity were prognostic factors associated with a larger reduction in symptoms, but neither those factors nor sex were found to modify the relative effect between clozapine and other second-generation antipsychotics. The confidence in the evidence was graded as very low. Interpretation: This IPD meta-analysis found a small and uncertain advantage of other second-generation antipsychotics, mainly olanzapine and risperidone, and so did not provide evidence for superior efficacy of clozapine compared with other second-generation antipsychotics in treatment-resistant schizophrenia. It is limited by unavailability of IPD for some studies, uncaptured sources of variance, and uncertainty due to premature study discontinuation. Given the side-effects of clozapine, the observed uncertainty regarding clozapine's superiority warrants prudent use and further research.

Background: Although repetitive transcranial magnetic stimulation (rTMS) is an effective and commonly used treatment option for treatment-resistant depression, its cost-effectiveness remains much less studied. In particular, the comparative cost-effectiveness of rTMS and other treatment options, such as antidepressant medication, has not been investigated. Methods: An economic evaluation with 12 months follow-up was conducted in the Dutch care setting as part of a pragmatic multicenter randomized controlled trial, in which patients with treatment-resistant depression were randomized to treatment with rTMS or treatment with the next pharmacological step according to the treatment algorithm. Missing data were handled with single imputations using predictive mean matching (PMM) nested in bootstraps. Incremental cost-effectiveness and cost-utility ratios (ICERs/ICURs) were calculated, as well as cost-effectiveness planes and cost-effectiveness acceptability curves (CEACs). Results: Higher QALYs, response, and remission rates were found for lower costs when comparing the rTMS group to the medication group. After 12 months, QALYs were 0.618 in the rTMS group and 0.545 in the medication group. The response was 27.1% and 24.4% and remission was 25.0% and 17.1%, respectively. Incremental costs for rTMS were -€2.280, resulting in a dominant ICUR for QALYs and ICER for response and remission. Conclusion: rTMS appears to be a cost-effective treatment option for treatment-resistant depression when compared to the next pharmacological treatment step. The results support the implementation of rTMS as a step in the treatment algorithm for depression.

Importance: New pharmacotherapy options are needed for posttraumatic stress disorder (PTSD). Objective: To investigate the efficacy, safety, and tolerability of brexpiprazole and sertraline combination treatment (brexpiprazole + sertraline) compared with sertraline + placebo for PTSD. Design, setting, and participants: This was a parallel-design, double-blind, randomized clinical trial conducted from October 2019 to August 2023. The study had a 1-week, placebo run-in period followed by an 11-week, double-blind, randomized, active-controlled, parallel-arm period (with 21-day follow-up) and took place at 86 clinical trial sites in the US. Adult outpatients with PTSD were enrolled (volunteer sample). Interventions: Oral brexpiprazole 2 to 3 mg per day (flexible dose) + sertraline 150 mg per day or sertraline 150 mg per day + placebo (1:1 ratio) for 11 weeks. Main outcomes and measures: The primary end point was change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total score (which measures the severity of 20 PTSD symptoms) from randomization (week 1) to week 10 for brexpiprazole + sertraline vs sertraline + placebo. Safety assessments included adverse events. Results: A total of 1327 individuals were assessed for eligibility. After 878 screen failures, 416 participants (mean [SD] age, 37.4 [11.9] years; 310 female [74.5%]) were randomized. Completion rates were 137 of 214 participants (64.0%) for brexpiprazole + sertraline and 113 of 202 participants (55.9%) for sertraline + placebo. At week 10, brexpiprazole + sertraline demonstrated statistically significant greater improvement in CAPS-5 total score (mean [SD] at randomization, 38.4 [7.2]; LS mean [SE] change, -19.2 [1.2]; n = 148) than sertraline + placebo (randomization, 38.7 [7.8]; change, -13.6 [1.2]; n = 134), with LS mean difference, -5.59 (95% CI, -8.79 to -2.38; P < .001). All key secondary and other efficacy end points were also met. Treatment-emergent adverse events with incidence of 5% or greater for brexpiprazole + sertraline (and corresponding incidences for sertraline + placebo) were nausea (25 of 205 [12.2%] and 23 of 196 [11.7%]), fatigue (14 of 205 [6.8%] and 8 of 196 [4.1%]), weight increase (12 of 205 [5.9%] and 3 of 196 [1.5%]), and somnolence (11 of 205 [5.4%] and 5 of 196 [2.6%]). Discontinuation rates due to adverse events were 8 of 205 participants (3.9%) for brexpiprazole + sertraline and 20 of 196 participants (10.2%) for sertraline + placebo. Conclusions and relevance: Results of this randomized clinical trial show that brexpiprazole + sertraline combination treatment statistically significantly improved PTSD symptoms vs sertraline + placebo, indicating its potential as a new efficacious treatment for PTSD. Brexpiprazole + sertraline was tolerated by most participants, with a safety profile consistent with that of brexpiprazole in approved indications.

To examine the associations of serotonergic antidepressant exposure during pregnancy with the risk of depression and anxiety disorders in offspring. The Mayo Clinic Rochester Epidemiology Project medical records-linkage system was used to study offspring born to mothers who were prescribed selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors (S/NRI users, n=837) during pregnancy (1997-2010). Cox regression models were used to calculate hazard ratios (HRs) to examine associations of S/NRIs with diagnosed depression and anxiety, defined based on a review of medical records by two board-certified psychiatrists, using no maternal antidepressant use during pregnancy (non-users, n=863) and maternal antidepressant use in the year prior to pregnancy (former users, n=399) as control groups. After all adjustments for covariates, children born to S/NRI users during pregnancy did not differ in onset of depression or anxiety than the children of non-users (Adjusted Hazard Ratios, (aHR [95% CI]=1.00 [0.74, 1.85]) or former users (aHR=0.94 [0.69, 1.27]). The above associations were similar when exposure was limited only to SSRIs. Our results suggest that the higher rates of childhood and adolescent depression or anxiety conditioned on maternal S/NRI use in pregnancy are more likely to be driven by maternal depression or underlying propensity for depression rather than direct pharmacological effects of in utero S/NRI exposure.

The use of Attention-Deficit/Hyperactivity Disorder (ADHD) medications during pregnancy is increasing, raising concerns about potential long-term effects on offspring. This study investigates in utero exposure to methylphenidate, amphetamines and atomoxetine and risk of offspring neurodevelopmental disorders (NDDs). The population-based cohort study identified from Swedish registers included 861,650 children born by 572,731 mothers from 2008-2017. We categorized exposure based on redeemed medication during pregnancy and compared exposed children to those whose mothers discontinued medication before conception. Main outcomes were any NDD, including ADHD and autism spectrum disorder (ASD). Cox proportional hazards regression estimated hazard ratios (HRs), adjusting for maternal psychiatric and sociodemographic factors. Sensitivity analyses included stratifications by medication type, timing, and duration of exposure, and sibling comparisons. We also performed a meta-analysis combining data from the present study with those from a previous Danish study. Results showed no increased risk for any NDD (HRadjusted 0.95, 95% CI 0.82-1.11), ADHD (HRadjusted 0.92, 95% CI 0.78-1.08), or ASD (HRadjusted 0.86, 95% CI 0.63-1.18). Sensitivity analyses showed consistent patterns of no increased risks across different exposure durations, medication types and between siblings. Meta-analyses further supported the findings (pooled HR for any NDD 1.00, 95% CI 0.83;1.20). Our study provides evidence that in utero exposure to ADHD medications does not increase the risk of long-term NDDs in offspring. This study replicates safety data for methylphenidate and extends it with new safety data on amphetamines and atomoxetine. These findings are crucial for informing clinical guidelines and helping healthcare providers and expectant mothers make informed decisions.

Agitation and aggression are challenging behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease (AD), which is diagnosed based on NINCDS-ADRDA criteria. Limited efficacy and safety of existing pharmacotherapies complicate treatment. Agomelatine, a melatonergic agonist and serotonergic antagonist, may provide a safer and more effective alternative. The primary outcome is to evaluate the efficacy of agomelatine as an add-on therapy to non-pharmacological treatment in reducing agitation and aggression in patients with AD, with secondary outcomes assessing its safety and potential neuroprotective effects. In a randomized, triple-blind, placebo-controlled trial, 56 patients with AD (aged ≥65) experiencing agitation and aggression received 12.5 mg agomelatine (n = 28) or placebo (n = 28) daily for six weeks. The primary outcome was the Cohen-Mansfield Agitation Inventory (CMAI) score change. Secondary outcomes included serum brain-derived neurotrophic factor (BDNF) levels and safety. At six weeks, the agomelatine group showed a greater reduction in CMAI scores than placebo (mean difference: –12.39, 95% CI: –19.37 to –5.42; P = 0.001). No significant BDNF changes were detected (P = 0.848). Total adverse events (AEs) were more common in the agomelatine group (50.0% vs. 21.4%, P = 0.050), but no serious AEs or liver enzyme abnormalities were reported. A daily dose of 12.5 mg agomelatine may effectively and safely reduce agitation and aggression in patients with AD when used as an add-on therapy. However, further studies with larger samples and extended durations are needed to definitively confirm agomelatine's role in managing BPSD in AD.

This editorial examines the rise of attention-deficit hyperactivity disorder (ADHD) in the digital age, suggesting that excessive digital media use may mimic or exacerbate ADHD symptoms. We propose examining ADHD through the lens of a spectrum condition, highlighting the importance of considering both genetic and environmental factors in its diagnosis and treatment.

No abstract available

The p-value, introduced by Fisher in the early 20th century [1], remains a dominant feature of null hypothesis significance testing (NHST) in psychological research. Despite its utility as a measure of data compatibility with a null hypothesis, its misinterpretation has fostered flawed practices that undermine the reliability of scientific findings. This issue has far-reaching consequences in psychology, including within mental health research, where statistical errors can affect therapeutic practices and policy decisions. Misinterpretations of p-values perpetuate overconfidence in research findings, often leading to oversights in clinical trials, misallocation of resources, and misguided interventions in mental health [2]. Historical Roots of Misinterpretations Fisher’s original intent for the p-value was as a heuristic tool rather than a definitive decision-making criterion [1]. Its integration with Neyman-Pearson’s decision framework in the mid-20th century created conflicting interpretations. While Fisher viewed the p-value as a continuum of evidence, Neyman-Pearson’s dichotomous thresholds for decision-making fostered binary thinking [3]. This historical duality has left researchers with a fractured understanding of statistical significance, particularly in psychology, where education often overlooks these nuances. Misinterpretations have thus become embedded in research culture, exacerbated by pressures to produce significant findings

This Viewpoint discusses social health, which refers to the quality and quantity of social interactions, relationships, and support networks, as an important independent component of overall health alongside physical and mental health.

Understanding the disparate outcomes of those who have experienced historical trauma is critical to developing interventions for individuals, families, and communities. The authors1 suggest that population health approaches that incorporate traditional knowledge and practices is one powerful approach for Indigenous communities. Efforts at narrative change at the population level will be key to understanding the impact of the past, dealing with current realities, and empowering for the future. There is much to learn from Indigenous peoples about not only the impact of historical trauma, but the response to that and current traumas, as well as the role of empowering narratives of resilience to offset the demoralization of Indigenous peoples and to address health disparities.

Background: Few treatments are available for individuals with marked treatment-resistant depression (TRD). Objective: Evaluate the safety and effectiveness of FDA-approved adjunctive vagus nerve stimulation (VNS) in patients with marked TRD. Methods: This 12-month, multicenter, double-blind, sham-controlled trial included 493 adults with marked treatment-resistant major depression who were randomized to active or no-stimulation sham VNS for 12 months. The primary outcome was percent time in response across months 3-12, with response defined as a ≥50 % change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS). Several secondary endpoints were evaluated. Results: Overall, 88.4 % of participants completed the trial. Percent time in MADRS response did not distinguish active from sham VNS. However, ratings from on-site clinicians (Clinical Global Inventory-Impression [CGI-I]), patients (Quick Inventory of Depressive Symptomology-Self Report [QIDS-SR]), and offsite masked raters (Quick Inventory of Depressive Symptomology-Clinician [QIDS-C]) revealed antidepressant benefits significantly favoring active VNS. Active VNS demonstrated significantly more percent time in response on the CGI-I (P = 0.004) and QIDS-SR (P = 0.049), and significantly more percent time in partial response (PR; symptom improvement ≥30 %) on the CGI-I (P < 0.001) and QIDS-C (P = 0.006) versus sham VNS. Active VNS exceeded sham VNS in rate of dyspnea (P = 0.035), a known side effect of VNS. No new adverse events were identified. Conclusions: Percent time in MADRS response did not distinguish the treatment groups, but on multiple instruments time in response and PR showed a positive treatment effect. VNS was found safe and effective in participants with marked TRD.

Cannabis has been consumed for centuries, but global regulatory changes over the past three decades have increased the availability and consumption of cannabis. Cannabinoids are touted to have therapeutic potential for many diseases and could be a replacement for opioids for analgesia and sedation. However, cannabinoids can cause substantial adverse cardiovascular events that would mitigate any potential benefit. The endocannabinoid system regulates mood, satiety and memory, and modulates the cardiovascular system. The link between cannabinoids and cardiovascular disease, which used to be limited to evidence from preclinical studies, case reports and case series, is now evident in epidemiological studies. Cannabinoids adversely affect the cardiovascular system, causing myocardial infarction, cerebrovascular accidents, arrhythmia and heart failure. The effects of novel cannabinoids are unknown, and synthetic cannabinoids have the potential to cause even more substantial harm than traditional cannabinoids. Therefore, with the increasing availability and use of cannabis, the acute and chronic effects of this drug are becoming apparent.

Objective: Intranasal esketamine has been approved as an adjunctive therapy for treatment-resistant major depressive disorder with acute suicidal ideation and behavior. The authors conducted a systematic review and meta-analysis of the available data on its efficacy against depression and suicidality as well as its side effects. Methods: MEDLINE was searched with the keyword "esketamine" on March 24, 2024, using the PRISMA method. Data processing and statistical analysis were performed with R, version 4.3.3, and the meta-analysis was performed with the METAFOR package. Results: Of 1,115 articles initially identified, 87 were included for analysis and discussion. At weeks 2-4, randomized controlled trials were mostly negative or failed; however, the meta-analysis returned a weak but significant positive effect for depression (effect size range, 0.15-0.23 at weeks 2-4), similar to augmentation strategies with atypical antipsychotics for treatment-resistant depression. The effect size concerning suicidality was not significant at any time point. The sensitivity analysis produced the same results. Conclusions: The study findings suggest that esketamine's efficacy as an add-on to antidepressants is modest in treatment-resistant depression (similar to augmentation strategies with atypical antipsychotics) and is absent against suicidality itself. These findings need to be considered in light of esketamine's abuse potential and the fact that long-term effects are still not fully known. Some alarming signs concerning deaths and emerging suicidality during the testing phase are discussed, along with other regulatory issues.

Can machines be therapists?” is a question receiving increased attention given the relative ease of working with generative artificial intelligence. Although recent (and decades-old) research has found that humans struggle to tell the difference between responses from machines and humans, recent findings suggest that artificial intelligence can write empathically and the generated content is rated highly by therapists and outperforms professionals. It is uncertain whether, in a preregistered competition where therapists and ChatGPT respond to therapeutic vignettes about couple therapy, a) a panel of participants can tell which responses are ChatGPT-generated and which are written by therapists (N = 13), b) the generated responses or the therapist-written responses fall more in line with key therapy principles, and c) linguistic differences between conditions are present. In a large sample (N = 830), we showed that a) participants could rarely tell the difference between responses written by ChatGPT and responses written by a therapist, b) the responses written by ChatGPT were generally rated higher in key psychotherapy principles, and c) the language patterns between ChatGPT and therapists were different. Using different measures, we then confirmed that responses written by ChatGPT were rated higher than the therapist’s responses suggesting these differences may be explained by part-of-speech and response sentiment. This may be an early indication that ChatGPT has the potential to improve psychotherapeutic processes. We anticipate that this work may lead to the development of different methods of testing and creating psychotherapeutic interventions. Further, we discuss limitations (including the lack of the therapeutic context), and how continued research in this area may lead to improved efficacy of psychotherapeutic interventions allowing such interventions to be placed in the hands of individuals who need them the most.

Background: Long-term add-on antidepressant use for bipolar depression remains controversial. This study aimed to investigate primarily the association between psychopharmacological treatments and hospitalisation (ie, hospital admission) for bipolar depression, and secondarily the association between psychopharmacological treatments and hospitalisation for bipolar mania and somatic reasons in a registry-based national Swedish cohort. Methods: In this within-subject analysis, people diagnosed with bipolar disorder were identified from Swedish nationwide registers of inpatient and specialised outpatient care, sickness absence, and disability pension between Jan 1, 2006, and Dec 31, 2021. Data for hospitalisations, and antidepressant, antipsychotic, and mood stabiliser medication use were also retrieved from national databases. Treatment periods were modelled using the PRE2DUP method. Data were analysed with a within-individual design with stratified Cox Regression models, to eliminate selection bias when calculating adjusted hazard ratios (aHRs) and 95% CIs. The main outcome was hospitalisation due to depression and secondary outcomes were mania-related and somatic hospitalisations to address the risk-benefit ratio of antidepressant treatment. The reference was non-use of antidepressant, antipsychotic, and mood stabiliser medications. We also did head-to-head comparisons (ie, comparing different drug use periods within the same individual against each other) between medications to obtain results on comparative effectiveness while minimising confounding by indication. Ethnicity data were not available. People with related lived experience were involved in the research and writing process. Findings: The study cohort included 105 495 individuals (mean age 44·2 years, SD 18·8; 65 607 [62·2%] women and 39 888 [37·8%] men). In medication class-based analyses, a higher risk of depression-related hospitalisation was associated with the use of antidepressant only (aHR 1·25, 95% CI 1·16-1·34), antipsychotic only (1·39, 1·24-1·55), antidepressant-antipsychotic combination (1·28, 1·18-1·39), and antipsychotic-mood stabiliser combination treatment (1·13, 1·03-1·24). By contrast, use of mood stabilisers only (0·89, 0·81-0·98) was associated with lower risk. For specific monotherapies, only lithium was associated with lower depression-related hospitalisation risk (0·75, 0·67-0·85). No specific antidepressant monotherapy was associated with reduced depression-related hospitalisation, while several antidepressants and antipsychotics were related to an increased risk. In head-to-head comparisons, lithium monotherapy was associated with a superior outcome compared with antidepressant monotherapy (0·59, 0·51-0·68), antipsychotic monotherapy (0·54, 0·44-0·66), lamotrigine monotherapy (0·69, 0·53-0·91), and quetiapine monotherapy (0·54, 0·41-0·71). Lithium was associated with the lowest risk of somatic hospitalisation (0·86, 0·80-0·93) when compared with non-use of antidepressants, antipsychotics, and mood stabilisers. Finally, antidepressant-only treatment (1·22, 1·03-1·44) was associated with increased risk of mania-related hospitalisation and other monotherapies and combinations were associated with a lower risk. Interpretation: Since medications are typically started when depressive symptoms re-emerge, all treatments might appear less effective than they actually are when the reference is non-use of medication. Lithium was the only specific monotherapy with significantly reduced risk of depression-related hospitalisations when compared with non-use of antidepressants, antipsychotics, and mood stabilisers, and with more than 30% lower risk than any antidepressant, any antipsychotic, quetiapine, or lamotrigine monotherapy in the head-to-head analysis. Lithium was also associated with the lowest risk of somatic hospitalisation. Our findings supported the use of lithium as the mainstay of treatment in bipolar disorder.

Purpose: To evaluate the risk of bleeding associated with the simultaneous administration of antidepressants (ADs) and direct oral anticoagulants (DOACs). Methods: PubMed, Embase, and Scopus databases were searched for papers that focused on the concomitant administration of ADs and DOACs and presented data on the bleeding outcomes. The comparator group of interest was subjects who received only DOACs. Besides the overall pooled analysis, irrespective of the primary disease condition, we were also interested in studies involving patients with atrial fibrillation (AF). We therefore included studies with relevant comparisons (AD with DOACs, compared to DOACs alone), regardless of the reported underlying condition. Thereafter, we conducted a sensitivity analysis to refine estimates specific to AF. Clinical trials and observational studies were eligible. Pooled effect sizes were reported as relative risk (RR) for studies with cohort design and as odds ratio (OR) for case-control studies. Results: Ten studies were included. Overall pooled analysis showed that treatment with both DOAC and selective serotonin reuptake inhibitor and serotonin and norepinephrine reuptake inhibitor (SSRI/SNRI) was associated with significantly higher risk of major bleeding (cohort: RR 1.25, 95% CI: 1.07-1.47; case-control: OR 1.40, 95% CI: 1.15-1.69). The risk of intracranial bleeding was found to be increased when cohort studies were pooled (RR 1.44, 95% CI: 1.24-1.66), but not with pooling of case-control studies (OR 1.58, 95% CI: 0.43-5.75). The risk of gastrointestinal bleeding and transient ischemic attack (TIA)/ischemic stroke was comparable between the 2 groups (DOAC + SSRI/SNRI vs DOAC only group). Conclusions: Our results indicate that combined SSRIs/SNRIs and DOAC treatment may be associated with increased incidence of major and intracranial bleeding, further emphasizing the importance of caution when considering their concomitant use.

Introduction: Comorbidity between posttraumatic stress disorder (PTSD) and borderline personality disorder (BPD) is prevalent. Despite evidence-based therapies, high rates of non-response and dropout persist. This study therefore aimed to examine whether the concurrent application of eye movement desensitization and reprocessing (EMDR) for PTSD and dialectical behavior therapy (DBT) for BPD yields better results than EMDR alone. Methods: Patients with a PTSD diagnosis and at least four BPD symptoms were randomly assigned to EMDR (n = 63) or concurrent EMDR-DBT (n = 61). Over one year, changes in PTSD symptoms were measured using the Clinician-Administered PTSD Scale for DSM-5. Secondary outcomes included BPD symptoms, global functioning and quality of life. Results: Both treatments led to large reductions in PTSD symptoms, without significant differences after one year (p = .312, d = -0.23, 95% CI = -0.6, 0.1). Both treatments also yielded large and comparable reductions in BPD symptoms and improved quality of life. Global functioning improved only in the EMDR condition according to one measure (WHODAS 2.0), while the other measure (OQ-45) showed improvements in both groups. Additionally, patients in the EMDR-DBT condition were twice as likely to drop out from EMDR treatment compared to those in the EMDR-only condition. Conclusion: Stand-alone EMDR demonstrated safety and efficacy in alleviating PTSD and BPD symptoms, as well as enhancing quality of life. These findings support the use of EMDR as a strong therapeutic option for patients with PTSD and comorbid BPD symptoms. Further research is needed to assess longer-term outcomes beyond one year.

Within precision psychiatry, there is a growing interest in normative models given their ability to parse heterogeneity. While they are intuitive and informative, the technical expertise and resources required to develop normative models may not be accessible to most researchers. Here we present Neurofind, a new freely available tool that bridges this gap by wrapping sound and previously tested methods on data harmonisation and advanced normative models into a web-based platform that requires minimal input from the user. We explain how Neurofind was developed, how to use the Neurofind website in four simple steps ( www.neurofind.ai ), and provide exemplar applications. Neurofind takes as input structural MRI images and outputs two main metrics derived from independent normative models: (1) Outlier Index Score, a deviation score from the normative brain morphology, and (2) Brain Age, the predicted age based on an individual's brain morphometry. The tool was trained on 3362 images of healthy controls aged 20-80 from publicly available datasets. The volume of 101 cortical and subcortical regions was extracted and modelled with an adversarial autoencoder for the Outlier index model and a support vector regression for the Brain age model. To illustrate potential applications, we applied Neurofind to 364 images from three independent datasets of patients diagnosed with Alzheimer's disease and schizophrenia. In Alzheimer's disease, 55.2% of patients had very extreme Outlier Index Scores, mostly driven by larger deviations in temporal-limbic structures and ventricles. Patients were also homogeneous in how they deviated from the norm. Conversely, only 30.1% of schizophrenia patients were extreme outliers, due to deviations in the hippocampus and pallidum, and patients tended to be more heterogeneous than controls. Both groups showed signs of accelerated brain ageing.

Objective: To examine the association between newer generation antidepressants and insomnia as an adverse event (AE) in the treatment of children and adolescents with major depressive disorder (MDD). Method: A systematic search was performed in major databases (inception to August 31, 2023) to retrieve double-blind, placebo-controlled, randomized controlled trials (RCTs) evaluating the safety of 19 antidepressants in the acute treatment (initial 6-12 weeks) of children and adolescents ≤18 years of age with MDD (primary analyses). RCTs in anxiety disorders and obsessive-compulsive disorder (OCD) were retrieved from a recent meta-analysis and included in complementary analyses. A mixed-effects logistic regression model was used to compare the frequency of insomnia in the antidepressant relative to the placebo group. Risk of bias was evaluated using the Cochrane Risk of Bias 2 tool. Results: In total, 20 trials in MDD (N = 5,357) and 8 trials in anxiety disorders and OCD (N = 1,271) evaluating selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) were included. In MDD, antidepressant treatment was associated with a modest increase in the odds of insomnia compared with placebo (odds ratio [OR] = 1.65, 95% CI = 1.21-2.27, p = .002), with no significant difference between SSRIs and SNRIs. The RCTs showed low risk of bias or minor concerns for the assessment of insomnia. The odds of treatment-emergent insomnia were significantly lower in MDD (OR = 1.62; 95% CI = 1.21-2.15) compared to anxiety disorders and OCD (OR = 2.89; 95% CI = 1.83-4.57) for treatment with SSRIs (p = .03). Among individual antidepressants with evidence from ≥3 studies, sertraline had the highest OR (3.45; 95% CI = 1.91-6.24), whereas duloxetine had the lowest OR (1.38; 95% CI = 0.79-2.43). Conclusion: Children and adolescents are at a modestly increased risk for experiencing insomnia during the first 6 to 12 weeks of treatment with SSRIs and SNRIs. Antidepressant- and disorder-specific variability in the risk of treatment-emergent insomnia may be relevant to consider in clinical decision making.

Objective: To evaluate the efficacy, safety, and tolerability of esketamine nasal spray versus psychoactive placebo (oral midazolam) in rapidly reducing depressive symptoms in adolescents with major depressive disorder at imminent risk for suicide. Method: This double-blind, double-dummy, phase 2b study randomized (1:1:1:2) 147 adolescents (12 to <18 years old) to esketamine (28, 56, or 84 mg) or midazolam twice-weekly for 4 weeks. Participants concomitantly received comprehensive standard-of-care (SOC), including initial hospitalization, oral antidepressant, and evidenced-based psychotherapy. The primary efficacy endpoint - change in Children's Depression Rating Scale-Revised (CDRS-R) total score from baseline to 24 hours post-first dose was analyzed using ANCOVA, according to a pooled sequential multiple-testing procedure. Results: All participants were moderately-to-severely depressed at enrollment; approximately 95% were moderately-to-extremely suicidal. Pooled esketamine doses (56 and 84 mg) showed superiority over midazolam in reducing CDRS-R total score at 24 hours post-first dose (between-group difference of LS means [95% CI]: -5.8 [-11.19, -0.35]; p=0.037). The between-group differences for individual 84 mg and 56 mg esketamine doses versus midazolam were -5.7 ([-12.91, 1.55], p=0.123) and -5.9 ([-12.25, 0.53], p=0.072), respectively. Severity of suicidality, per Clinical Global Impression-Severity of Suicidality Revised, improved in all 4 groups (between-group difference of LS means [95% CI]: -0.2 [-0.90, 0.41], -0.3 [-0.93, 0.31], 0.0 [-0.69, 0.72] for esketamine 28, 56, and 84 mg, respectively, at 24 hours post-first dose). Common adverse events (incidence ≥20%) reported for esketamine were dizziness, nausea, dissociation, headache, dysgeusia, somnolence, vomiting, hypoesthesia, and intentional self-injury. Conclusion: The primary efficacy endpoint of the study was met for the pooled esketamine doses (56 and 84 mg): Esketamine in conjunction with comprehensive SOC rapidly improved depressive symptoms among adolescents at imminent risk for suicide.

Objective: Selective serotonin reuptake inhibitors (SSRIs) are the first choice in pharmacotherapy for children and adolescents with obsessive-compulsive disorder (OCD). SSRI trials for pediatric OCD have not been investigated using individual participant data (IPD), which is crucial for detecting patient-level effect modifiers. This study performed an IPD meta-analysis of efficacy of SSRIs compared with placebo and a meta-regression on baseline patient characteristics that might modify efficacy. Method: Crude participant data from short-term, randomized, placebo-controlled SSRI trials for pediatric OCD were obtained from the registry of the Dutch regulatory authority. A systematic literature search was also performed, and authors were approached to provide IPD. A 1- and 2-stage analysis was conducted, with change on Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) as the primary outcome. Odds ratio (OR) with ≥35% CY-BOCS reduction was used as the responder outcome measure. Modifying effect of age, sex, weight, duration of illness, family history, and baseline symptom severity was examined. The Cochrane RoB 2.0 tool was used to examine methodological rigor, and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used to examine certainty of evidence. Results: Data were obtained from 4 studies comprising 614 patients. The sample represented 86% of all participants ever included in double-blind placebo-controlled SSRI trials for pediatric OCD. Meta-analysis showed reduction of 3.0 CY-BOCS points compared with placebo (95% CI 2.5-3.5), corresponding to a small effect size (0.38 Hedges' g). Analysis of response showed an odds ratio of 1.89 (95% CI 1.45-2.45). Of all possible modifiers, severity was correlated negatively with odds ratio for response (β = -0.92, p = .0074). Risk of bias was generally low. All studies were performed in North America with an overrepresentation of White participants. Findings were limited by inability to include data on additional variables such as socioeconomic status and comorbidities. Conclusion: This IPD meta-analysis showed a small effect size of SSRIs in pediatric OCD, with baseline severity as a negative modifier of response. Generalizability of findings might be limited by selective inclusion of White, North American participants.

Importance: Neurofeedback has been proposed for the treatment of attention-deficit/hyperactivity disorder (ADHD) but the efficacy of this intervention remains unclear. Objective: To conduct a meta-analysis of randomized clinical trials (RCTs) using probably blinded (ie, rated by individuals probably or certainly unaware of treatment allocation) or neuropsychological outcomes to test the efficacy of neurofeedback as a treatment for ADHD in terms of core symptom reduction and improved neuropsychological outcomes. Data sources: PubMed (MEDLINE), Ovid (PsycInfo, MEDLINE, Embase + Embase Classic), and Web of Science, as well as the reference lists of eligible records and relevant systematic reviews, were searched until July 25, 2023, with no language limits. Study selection: Parallel-arm RCTs investigating neurofeedback in participants of any age with a clinical ADHD or hyperkinetic syndrome diagnosis were included. Data extraction and synthesis: Standardized mean differences (SMDs) with Hedges g correction were pooled in random effects meta-analyses for all eligible outcomes. Main outcomes and measures: The primary outcome was ADHD total symptom severity assessed at the first postintervention time point, focusing on reports by individuals judged probably or certainly unaware of treatment allocation (probably blinded). Secondary outcomes were inattention and/or hyperactivity-impulsivity symptoms and neuropsychological outcomes postintervention and at a longer-term follow-up (ie, after the last follow-up time point). RCTs were assessed with the Cochrane risk of bias tool version 2.0. Results: A total of 38 RCTs (2472 participants aged 5 to 40 years) were included. Probably blinded reports of ADHD total symptoms showed no significant improvement with neurofeedback (k = 20; n = 1214; SMD, 0.04; 95% CI, -0.10 to 0.18). A small significant improvement was seen when analyses were restricted to RCTs using established standard protocols (k = 9; n = 681; SMD, 0.21; 95% CI, 0.02 to 0.40). Results remained similar with adults excluded or when analyses were restricted to RCTs where cortical learning or self-regulation was established. Of the 5 neuropsychological outcomes analyzed, a significant but small improvement was observed only for processing speed (k = 15; n = 909; SMD, 0.35; 95% CI, 0.01 to 0.69). Heterogeneity was generally low to moderate. Conclusions and relevance: Overall, neurofeedback did not appear to meaningfully benefit individuals with ADHD, clinically or neuropsychologically, at the group level. Future studies seeking to identify individuals with ADHD who may benefit from neurofeedback could focus on using standard neurofeedback protocols, measuring processing speed, and leveraging advances in precision medicine, including neuroimaging technology.

Importance: Pediatric posttraumatic stress disorder (PTSD) is a common and debilitating mental disorder, yet a comprehensive network meta-analysis examining psychological interventions is lacking. Objective: To synthesize all available evidence on psychological interventions for pediatric PTSD in a comprehensive systematic review and network meta-analysis. Data sources: PsycINFO, MEDLINE, Web of Science, and PTSDpubs were searched from inception to January 2, 2024, and 74 related systematic reviews were screened. Study selection: Two independent raters screened publications for eligibility. Inclusion criteria were randomized clinical trial (RCT) with at least 10 patients per arm examining a psychological intervention for pediatric PTSD compared to a control group in children and adolescents (19 years and younger) with full or subthreshold PTSD. Data extraction and synthesis: PRISMA guidelines were followed to synthesize and present evidence. Two independent raters extracted data and assessed risk of bias with Cochrane criteria. Random-effects network meta-analyses were run. Main outcome and measures: Standardized mean differences (Hedges g) in PTSD severity. Results: In total, 70 RCTs (N = 5528 patients) were included. Most RCTs (n = 52 [74%]) examined trauma-focused cognitive behavior therapies (TF-CBTs). At treatment end point, TF-CBTs (g, 1.06; 95% CI, 0.86-1.26; P < .001), eye movement desensitization and reprocessing (EMDR; g, 0.86; 95% CI, 0.54-1.18; P < .001), multidisciplinary treatments (MDTs) (g, 0.88; 95% CI, 0.53-1.23; P < .001), and non-trauma-focused interventions (g, 0.95; 95% CI, 0.62-1.28; P < .001) were all associated with significantly larger reductions in pediatric PTSD than passive control conditions. TF-CBTs were associated with the largest short-term reductions in pediatric PTSD relative to both passive and active control conditions and across all sensitivity analyses. In a sensitivity analysis including only trials with parent involvement, TF-CBTs were associated with significantly larger reductions in pediatric PTSD than non-trauma-focused interventions (g, 0.35; 95% CI, 0.04-0.66; P = .03). Results for midterm (up to 5 months posttreatment) and long-term data (6-24 months posttreatment) were similar. Conclusions and relevance: Results from this systematic review and network meta-analysis indicate that TF-CBTs were associated with significant reductions in pediatric PTSD in the short, mid, and long term. More long-term data are needed for EMDR, MDTs, and non-trauma-focused interventions. Results of TF-CBTs are encouraging, and disseminating these results may help reduce common treatment barriers by counteracting common misconceptions, such as the notion that TF-CBTs are harmful rather than helpful.

Importance: Interest in and use of hallucinogens has been increasing rapidly. While a frequently raised concern is that hallucinogens may be associated with an increased risk of psychosis, there are limited data on this association. Objectives: To examine whether individuals with an emergency department (ED) visit involving hallucinogen use have an increased risk of developing a schizophrenia spectrum disorder (SSD). Design, settings, and participants: This population-based, retrospective cohort study (January 2008 to December 2021) included all individuals aged 14 to 65 years in Ontario, Canada, with no history of psychosis (SSD or substance induced). Data were analyzed from May to August 2024. Exposure: An incident ED visit involving hallucinogen use. Main outcomes and measures: Diagnosis of SSD using a medical record-validated algorithm. Associations between ED visits involving hallucinogens and SSD were estimated using cause-specific adjusted hazard models. Individuals with an incident ED visit involving hallucinogens were compared with members of the general population (primary analysis) or individuals with ED visits involving alcohol or cannabis (secondary analysis). Results: The study included 9 244 292 individuals (mean [SD] age, 40.4 [14.7] years; 50.2% female) without a history of psychosis, with a median follow-up of 5.1 years (IQR, 2.3-8.6 years); 5217 (0.1%) had an incident ED visit involving hallucinogen use. Annual rates of incident ED visits involving hallucinogens were stable between 2008 and 2012 and then increased by 86.4% between 2013 and 2021 (3.4 vs 6.4 per 100 000 individuals). Individuals with ED visits involving hallucinogens had a greater risk of being diagnosed with an SSD within 3 years compared with the general population (age- and sex-adjusted hazard ratio [HR], 21.32 [95% CI, 18.58-24.47]; absolute proportion with SSD at 3 years, 208 of 5217 with hallucinogen use [3.99%] vs 13 639 of 9 239 075 in the general population [0.15%]). After adjustment for comorbid substance use and mental health conditions, individuals with hallucinogen ED visits had a greater risk of SSD compared with the general population (HR, 3.53; 95% CI, 3.05-4.09). Emergency department visits involving hallucinogens were associated with an increased risk of SSD within 3 years compared with ED visits involving alcohol (HR, 4.66; 95% CI, 3.82-5.68) and cannabis (HR, 1.47; 95% CI, 1.21-1.80) in the fully adjusted model. Conclusions and relevance: In this cohort study, individuals with an ED visit involving hallucinogen use had a greater risk of developing an SSD compared with both the general population and with individuals with ED visits for other types of substances. These findings have important clinical and policy implications given the increasing use of hallucinogens and associated ED visits.

Importance: Adolescent cannabis use has been consistently posited to contribute to the onset and progression of psychosis. However, alternative causal models may account for observed associations between cannabis use and psychosis risk, including shared vulnerability for both cannabis use and psychosis or efforts to self-medicate distress from psychosis spectrum symptomology. Objective: To test 3 hypotheses that may explain cannabis-psychosis risk associations by modeling psychosis spectrum symptom trajectories prior to and after cannabis initiation across adolescent development (approximately 10-15 years of age). Design, setting, and participants: This cohort study used data from 5 waves across 4 years of follow-up from the Adolescent Brain Cognitive Development (ABCD) Study. The ABCD study is an ongoing large-scale, longitudinal study of brain development and mental and physical health of children in the US launched in June 2016. Data are collected from 21 research sites. The study included data from 11 868 adolescents aged 9 to 10 years at baseline. Three participants were excluded from the present analysis owing to missing data. Data analysis was performed from September 2023 to July 2024. Main outcomes and measures: Discontinuous growth curve modeling was used to assess trajectories of psychosis spectrum symptoms before and after cannabis initiation. Control variables considered for this investigation were age, sex, internalizing and externalizing symptoms, socioeconomic status, parental mental health, and other substance use. Results: Among the 11 858 participants at wave 1, the mean (SD) age was 9.5 (0.5) years; 6182 (52%) participants were male. Consistent with a shared vulnerability hypothesis, adolescents who used cannabis at any point during the study period reported a greater number of psychosis spectrum symptoms (B, 0.86; 95% CI, 0.68-1.04) and more distress (B, 1.17; 95% CI, 0.96-1.39) from psychosis spectrum symptoms relative to those who never used cannabis. Additionally, consistent with a self-medication hypothesis, the number of psychosis spectrum symptoms (B, 0.16; 95% CI, 0.12-0.20) and distress (B, 0.23; 95% CI, 0.21-0.26) from psychosis spectrum symptoms increased in the time leading up to cannabis initiation. We observed mixed evidence for an increase in psychosis symptoms after cannabis initiation (ie, contributing risk hypothesis). Conclusion and relevance: The findings underscore the importance of accounting for shared vulnerability and self-medication effects when modeling cannabis-psychosis risk associations.

Background: The association between delirium and dementia has been suggested, but mostly in the postoperative setting. This study aims to explore this relationship in a broader inpatient population, leveraging extensive real-world data to provide a more generalized understanding. Methods: In this retrospective cohort study, electronic health records of 11,970,475 hospitalized patients aged over 60 from nine institutions in South Korea were analyzed. Patients with and without delirium were identified, and propensity score matching (PSM) was used to create comparable groups. A 10-year longitudinal analysis was conducted using the Cox proportional hazards model, which calculated the hazard ratio (HR) and 95% confidence interval (CI). Additionally, a meta-analysis was performed, aggregating results from all nine medical institutions. Lastly, we conducted various subgroup and sensitivity analyses to demonstrate the consistency of our study results across diverse conditions. Results: After 1:1 PSM, a total of 47,306 patients were matched in both the delirium and nondelirium groups. Both groups had a median age group of 75-79 years, with 43.1% being female. The delirium group showed a significantly higher risk of all dementia compared with the nondelirium group (HR: 2.70 [95% CI: 2.27-3.20]). The incidence risk for different types of dementia was also notably higher in the delirium group (all dementia or mild cognitive impairment, HR: 2.46 [95% CI: 2.10-2.88]; Alzheimer's disease, HR: 2.74 [95% CI: 2.40-3.13]; vascular dementia, HR: 2.55 [95% CI: 2.07-3.13]). This pattern was consistent across all subgroup and sensitivity analyses. Conclusions: Delirium significantly increases the risk of onset for all types of dementia. These findings highlight the importance of early detection of delirium and prompt intervention. Further research studies are warranted to investigate the mechanisms linking delirium and dementia.

Introduction: The rising prevalence of Alzheimer's disease (AD) and related dementia worldwide underscores the urgent need for effective interventions, particularly for managing neuropsychiatric symptoms (NPS) such as sleep disturbance. This review explores the emerging role of Dual Orexin Receptor Antagonists (DORA) in addressing sleep disturbance in patients with Alzheimer's disease dementia. Methods: A comprehensive literature search identified four relevant publications between 2014 and 2024, detailing the use of DORA medications, including suvorexant and lemborexant, in patients with Alzheimer's disease. Results: Findings suggest that suvorexant may improve total sleep time (TST), wakefulness after sleep onset (WASO), and sleep efficiency (SE) in Alzheimer's patients with insomnia. Lemborexant demonstrated potential in improving circadian rhythm parameters, particularly in patients with irregular sleep-wake rhythm disorder (ISWRD). Safety profiles of DORA medications appeared favorable, with mild to moderate adverse events reported. However, concerns over potential adverse events, such as falls, underscore the need for careful monitoring. Conclusion: While the evidence suggests promise for DORA medications in addressing sleep disturbance in Alzheimer's disease, limitations in study populations and duration highlight the need for further investigation. Future clinical trials should aim for broader inclusion criteria, encompassing diverse dementia subtypes and severity levels, to enhance generalizability. Additionally, longer-term trials are essential to assess the sustained efficacy and safety of DORA interventions in this vulnerable population.

This article explores the potential of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy to enhance exposure and response prevention in obsessive-compulsive disorder treatment. We discuss the mechanisms of MDMA, including fear extinction, psychological flexibility, and empathogenic effects that may improve adherence and efficacy, as well as highlighting important safety considerations for further research.

This systematic review and network meta-analysis (NMA) sought to compare different antidepressant treatments for treatment-resistant depression (TRD) in order to facilitate evidence-based choices. A literature search of PubMed, Cochrane Library, and Embase from inception until April 13th, 2023 identified randomized, controlled trials (RCTs) of adults with depression who had not responded to at least two antidepressant trials; all RCTs had ≥10 participants per study arm, and participants with bipolar or psychotic depression were excluded. The Cochrane Risk of Bias Tool-2 was used to assess study quality. Response rate was the primary outcome measure. Odds ratios (ORs) using a random effects NMA are reported. From 8234 records, 69 RCTs were included in this analysis, encompassing 10,285 participants (5662 F/4623 M) and 25 separate treatments. Six of the 25 treatments demonstrated a higher response rate versus placebo or sham treatment: electroconvulsive therapy (ECT), minocycline, theta-burst stimulation (TBS), repetitive transcranial magnetic stimulation (rTMS), ketamine, and aripiprazole. ORs ranged from 1.9 (95%CI = [1.25; 2.91]) for aripiprazole to 12.86 (95%CI = [4.07; 40.63]) for ECT. Moderate heterogeneity of the model was observed (I2 = 47.3% (95%CI [26.8-62%]). Of the included studies, 12.5% were rated as having high risk of bias, 28.13% as having low risk, and 59.38% as showing some concerns. Several effective treatments for TRD showed robust treatment effects across outcomes (ECT, TBS, rTMS, and ketamine), and others showed promising results for some, but not all, outcomes (minocycline, aripiprazole). These findings may help guide evidence-based treatment choices for TRD.

Background: The comparative benefits and harms of available interventions for ADHD in adults remain unclear. We aimed to address these important knowledge gaps. Methods: In this systematic review and component network meta-analysis (NMA), we searched multiple databases for published and unpublished randomised controlled trials (RCTs) investigating pharmacological and non-pharmacological interventions for ADHD in adults from database inception to Sept 6, 2023. We included aggregate data from RCTs comparing interventions against controls or any other eligible active intervention for the treatment of symptoms in adults (ages ≥18 years) with a formal diagnosis of ADHD. Pharmacological therapies were included only if their maximum planned doses were considered eligible according to international guidelines. We included RCTs of at least 1-week duration for medications, of at least four sessions for psychological therapies, and of any length deemed appropriate for neurostimulation. For RCTs of medications, cognitive training, or neurostimulation alone, we included only double-blind RCTs. At least two authors independently screened the identified records and extracted data from eligible RCTs. Our primary outcomes were efficacy (change in ADHD core symptom severity on self-rated and clinician-rated scales at timepoints closest to 12 weeks) and acceptability (all-cause discontinuation). We estimated standardised mean differences (SMDs) and odds ratios (ORs) using random effects pairwise and component NMA, dismantling interventions into specific therapeutic components. This study was registered with PROSPERO (CRD42021265576). People with relevant lived experience were involved in the conduct of the research and writing process. Findings: Of 32 416 records, 113 unique RCTs encompassing 14 887 participants were eligible for analysis (6787 [45·6%] females, 7638 [51·3%] males, 462 [3·1%] sex not reported). The RCTs encompassed pharmacological therapies (63 [55·8%] of 113 RCTs; 6875 participants), psychological therapies (28 [24·8%] of 113 RCTs; 1116 participants), neurostimulatory therapy and neurofeedback (ten [8·8%] of 113 RCTs; 194 participants), and control conditions (97 [85·8%] of 113 RCTs; 5770 participants). For reduction of ADHD core symptoms at 12 weeks on both self-reported and clinician-reported rating scales, atomoxetine (self-reported scale SMD -0·38, 95% CI -0·56 to -0·21; clinician-reported scale -0·51, -0·64 to -0·37) and stimulants (0·39, -0·52 to -0·26; -0·61, -0·71 to -0·51) had higher efficacy than placebo (Confidence in Network Meta-Analysis [CINeMA] ranging between very low and moderate). Cognitive behavioural therapy (-0·76, -1·26 to -0·26), cognitive remediation (-1·35, -2·42 to -0·27), mindfulness (-0·79, -1·29 to -0·29), psychoeducation (-0·77, -1·35 to -0·18), and transcranial direct current stimulation (-0·78; -1·13 to -0·43) were better than placebo only on clinician-reported measures. Regarding acceptability, all therapeutic components were similar to placebo other than atomoxetine (OR 1·43, 95% CI 1·14 to 1·80; CINeMA moderate) and guanfacine (3·70, 1·22 to 11·19; high), which had lower acceptability compared with placebo. Baseline severity of self-reported ADHD core symptoms, year of publication, percentage of male individuals, and percentage of individuals with ADHD and another mental health condition did not explain the heterogeneity observed in unadjusted non-component models of self-reported ADHD core symptoms. Treatment length had little effect on heterogeneity. Interpretation: Stimulants and atomoxetine were the only interventions with evidence of beneficial effects in terms of reducing ADHD core symptoms in the short term, supported by both self-reported and clinician-reported ratings. However, atomoxetine was less acceptable than placebo. Medications for ADHD were not efficacious on additional relevant outcomes, such as quality of life, and evidence in the longer term is underinvestigated. The effects of non-pharmacological strategies were inconsistent across different raters. Our network meta-analysis represents the most comprehensive synthesis of available evidence to inform future guidelines in the field.

Background: The best pharmacological treatment practices for relapse prevention in patients with first-episode schizophrenia are unclear. We aimed to assess different treatment strategies used before and after the first relapse, and their associations with subsequent relapse risk. Methods: In this population-based cohort study, we enrolled individuals (aged ≤45 years) with first-episode schizophrenia who were hospitalised and subsequently relapsed between 1996 and 2014 from the nationwide Finnish Hospital Discharge Register. Individuals who had not been taking antipsychotics within the year preceeding initial hospitalisation and who had a relapse within 5 years of discharge were included in the analyses. Treatment strategies were assessed during the 30 days before hospitalisation for the first relapse and 30 days after discharge and were categorised as either long-acting injectable, clozapine, non-clozapine oral antipsychotic monotherapy, non-clozapine oral antipsychotic polypharmacy, and antipsychotic non-use. Adjusted hazard ratios (aHRs) of the risk of second relapse based on treatment type were analysed with Cox regression models for 2 years after the first relapse, or until death or end of data linkage (Dec 31, 2017). People with lived experience of schizophrenia were not involved in the research and writing process. Findings: Between Jan 31, 1996 and Dec 31, 2017, 3000 individuals had their first psychosis relapse and were eligible for analysis. Mean age was 30·0 years (SD 7·6), 1069 (35·6%) of patients were women and 1931 (64·4%) men. No ethnicity data were available. 2148 (71·7%) had a second relapse within 2 years. Before first relapse, most individuals were either not using antipsychotics (n=1366 [45·5%]), or were using non-clozapine oral antipsychotic monotherapy (n=973 [32·4%]). Compared with continuing the same treatment strategy used before the first relapse, switching to clozapine was associated with the lowest risk of second relapse compared with continuing any non-clozapine oral antipsychotic monotherapy (aHR 0·66, 95% CI 0·49-0·89; relapse rate 73·2% with oral non-clozapine antipsychotic monotherapy continuation vs 57·1% with switch to clozapine). Switching to another non-clozapine oral antipsychotic monotherapy (0·99, 0·76-1·28) was approximately as unhelpful in preventing the next relapse as switching to antipsychotic non-use (1·07, 0·80-1·42). Interpretation: In patients with first-episode schizophrenia having their first psychosis relapse despite use of non-clozapine oral antipsychotics, continuation with the same antipsychotic modality or switch to another non-clozapine oral antipsychotic did not show evidence of being beneficial in relapse prevention, suggesting that clozapine should be started instead. This finding, together with existing knowledge of decreased risk of mortality associated with clozapine, challenges current treatment guidelines that recommend clozapine as a third-line treatment, resulting in treatment practices characterised by long delays to clozapine initiation

Extinction of traumatic memory, a primary treatment approach (termed exposure therapy) in posttraumatic stress disorder (PTSD), occurs through relearning and may be subserved at the molecular level by long-term potentiation of relevant circuits. In parallel, repetitive transcranial magnetic stimulation (TMS) is thought to work through long-term potentiation-like mechanisms and may provide a novel, safe, and effective treatment for PTSD. In a recent failed randomized controlled trial we emphasized the necessity of correctly identifying cortical targets, the directionality of TMS protocols, and the role of memory activation. Here, we provide a systematic review of TMS for PTSD to further identify how, where, and when TMS treatment should be delivered to alleviate PTSD symptoms. We conducted a systematic review of the literature by searching for repetitive TMS clinical trials involving patients with PTSD and outcomes. We searched MEDLINE through October 25, 2023, for "TMS and PTSD" and "transcranial magnetic stimulation and posttraumatic stress disorder." Thirty-one publications met our inclusion criteria (k = 17 randomized controlled trials, k = 14 open label). Randomized controlled trial protocols were varied in terms of TMS protocols, cortical TMS targets, and memory activation protocols. There was no clear superiority of low-frequency (k = 5) versus high-frequency (k = 6) protocols or by stimulation location. Memory provocation or exposure protocols (k = 7) appear to enhance response. Overall, TMS appears to be effective in treating PTSD symptoms across a variety of TMS frequencies, hemispheric target differences, and exposure protocols. Disparate protocols may be conceptually harmonized when viewed as potentiating proposed anxiolytic networks or suppressing anxiogenic networks.

Importance: Preliminary studies suggest that glucagon-like peptide-1 receptor (GLP-1) agonists, used to treat type 2 diabetes and obesity, may decrease alcohol consumption. Objective: To test whether the risk of hospitalization due to alcohol use disorder (AUD) is decreased during the use of GLP-1 agonists compared with periods of nonuse for the same individual. Design, setting, and participants: This cohort study was an observational study conducted nationwide in Sweden using data from January 2006 to December 2023. The population-based cohort was identified from registers of inpatient care, specialized outpatient care, sickness absence, and disability pension. Participants were all residents aged 16 to 64 years who had a diagnosis of AUD. Exposures: The primary exposure was use of individual GLP-1 agonists (compared with nonuse of GLP-1 agonists), and the secondary exposure was medications with indication for AUD. Main outcomes and measures: The primary outcome was AUD hospitalization analyzed in a Cox regression within-individual model. Secondary outcomes were any substance use disorder (SUD)-related hospitalization, somatic hospitalization, and suicide attempt. Results: The cohort included 227 866 individuals with AUD; 144 714 (63.5%) were male and 83 154 (36.5%) were female, with a mean (SD) age of 40.0 (15.7) years. Median (IQR) follow-up time was 8.8 (4.0-13.3) years. A total of 133 210 individuals (58.5%) experienced AUD hospitalization. Semaglutide (4321 users) was associated with the lowest risk (AUD: adjusted hazard ratio [aHR], 0.64; 95% CI, 0.50-0.83; any SUD: aHR, 0.68; 95% CI, 0.54-0.85) and use of liraglutide (2509 users) with the second lowest risk (AUD: aHR, 0.72; 95% CI, 0.57-0.92; any SUD: aHR, 0.78; 95% CI, 0.64-0.97) of both AUD and SUD hospitalization. Use of any AUD medication was associated with a modestly decreased risk (aHR, 0.98; 95% CI, 0.96-1.00). Semaglutide (aHR, 0.78; 95% CI, 0.68-0.90) and liraglutide (aHR, 0.79; 95% CI, 0.69-0.91) use were also associated with decreased risk of somatic hospitalizations but not associated with suicide attempts (semaglutide: aHR, 0.55; 95% CI, 0.23-1.30; liraglutide: aHR, 1.08; 95% CI, 0.55-2.15). Conclusions and relevance: Among patients with AUD and comorbid obesity/type 2 diabetes, the use of semaglutide and liraglutide were associated with a substantially decreased risk of hospitalization due to AUD. This risk was lower than that of officially approved AUD medications. Semaglutide and liraglutide may be effective in the treatment of AUD, and clinical trials are urgently needed to confirm these findings.

This state-of-the-art review explores the relationship between depression and diabetes, highlighting the two-way influences that make treatment challenging and worsen the outcomes of both conditions. Depression and diabetes often co-occur and share genetic, lifestyle, and psychosocial risk factors. Lifestyle elements such as diet, physical activity, and sleep patterns play a role on the development and management of both conditions, highlighting the need for integrated treatment strategies. The evidence suggests that traditional management strategies focusing on either condition in isolation fall short of addressing the intertwined nature of diabetes and depression. Instead, integrated care models encompassing psychological support and medical management are recommended to improve treatment efficacy and patient adherence. Such models require collaboration across multiple healthcare disciplines, including endocrinology, psychiatry, and primary care, to offer a holistic approach to patient care. This review also identifies significant patient-related barriers to effective management, such as stigma, psychological resistance, and health literacy, which need to be addressed through patient-centered education and support systems. Future directions for research include longitudinal studies in diverse populations to further elucidate causal relationships and the exploration of novel therapeutic targets, as well as the effectiveness of healthcare models aimed at preventing the onset of one condition in individuals diagnosed with the other.

Background: Women with schizophrenia frequently discontinue antipsychotic medications during pregnancy. However, evidence on the risk of postpartum relapse associated with antipsychotic use during pregnancy is lacking. Aims: To investigate the within-individual association between antipsychotic continuation during pregnancy and postpartum relapse in women with schizophrenia. Method: This retrospective cohort study used data of women with schizophrenia who gave live birth between 2007 and 2018 identified from the National Health Information Database of South Korea. Women were classified according to antipsychotic use patterns during the 12 months before delivery as non-users, discontinuers and continuers. Relapse was defined as admission for psychosis (ICD-10, F20-29). The incidence rate ratio (IRR) for admission for psychosis in the 6-month postpartum period was estimated using conditional Poisson regression, with the reference period set between 2 and 1 years before delivery. Additionally, we calculated the relative risk ratios (RRRs) for the IRRs of different antipsychotic use patterns. Results: Among the 3026 women included in the analysis (median age 34 years, interquartile range 31-37), the within-individual risk of admission for psychosis in the 6-month postpartum period was 0.56 times (RRR, 95% CI 0.36-0.87) lower in continuers (IRR = 1.31, 95% CI 0.89-1.72) than in discontinuers (IRR = 2.34, 95% CI 1.87-2.91). Among discontinuers, the IRRs of admission for psychosis in the 6-month postpartum period did not change significantly with the timing of discontinuation (trend P = 0.946). Conclusions: Antipsychotic continuation during pregnancy was associated with a reduced risk of postpartum relapse in women with schizophrenia. Continuing antipsychotics during pregnancy would be recommended after a risk-benefit assessment.

This article updates the prior 2018 consensus statement by the National Network of Depression Centers (NNDC) on the use of transcranial magnetic stimulation (TMS) in the treatment of depression, incorporating recent research and clinical developments. Publications on TMS and depression between September 2016 and April 2024 were identified using methods informed by PRISMA guidelines. The NNDC Neuromodulation Work Group met monthly between October 2022 and April 2024 to define important clinical topics and review pertinent literature. A modified Delphi method was used to achieve consensus. 2,396 abstracts and manuscripts met inclusion criteria for review. The work group generated consensus statements which include an updated narrative review of TMS safety, efficacy, and clinical features of use for depression. Considerations related to training, roles/responsibilities of providers, and documentation are also discussed. TMS continues to demonstrate broad evidence for safety and efficacy in treating depression. Newer forms of TMS are faster and potentially more effective than conventional repetitive TMS. Further exploration of targeting methods, use in special populations, and accelerated protocols is encouraged. This article provides an updated overview of topics relevant to the administration of TMS for depression and summarizes expert, consensus opinion on the practice of TMS in the United States.

Objective: Many psychotropic drugs are highly associated with related weight gain. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are established anti-obesity and glucose-lowering agents. Preliminary evidence also indicates they are fit for purpose in mitigating psychotropic drug-related weight gain (PDWG). This systematic review aims to synthesize the extant evidence from randomized controlled trials (RCTs) on the effects of GLP-1RAs on weight change in persons experiencing PDWG. Methods: Online databases (ie, PubMed, OVID Medline, Google Scholar) were searched to identify relevant studies from inception to January 1, 2024. Articles were screened by title, abstract, and full-text by three independent reviewers against inclusion and exclusion criteria. Results: We identified six studies with participants aged ≥18 (n=374) that were eligible for inclusion in our systematic review. Most studies reported a significant and clinically meaningful effect of GLP-1RAs on anthropometrics and/or metabolics. All RCTs replicated the finding of modest or greater effects of GLP-1RAs; the most studied agents were liraglutide and exenatide. There was insufficient literature to conduct a meta-analysis. Conclusion: Evidence suggests that GLP-1RAs are effective in mitigating weight gain in persons prescribed psychiatric medication. It is hypothesized that GLP-1RAs may moderate weight change in persons prescribed psychiatric medication through direct effects on metabolism and cognitive processes implicated in hunger/satiety. Future studies should aim to explore the long-term safety, tolerability, and efficacy profiles of various GLP-1RAs in the treatment and prevention of abnormal weight and metabolic homeostasis in psychiatric populations.

Background: Psychotherapy outcomes are typically measured in terms of symptom relief. However, this method might overlook important changes from clients' perspectives when they are asked to report on them. A more client-centred approach might bring a deeper understanding of psychotherapy outcomes. We aimed to evaluate the outcomes identified by clients within qualitative psychotherapy research. Methods: The PsycArticles, PsycInfo, and MEDLINE Complete databases were searched for English language studies published until Nov 11, 2023. Additional studies were identified through references in the primary studies and previous meta-analyses or systematic reviews. Search terms were related to psychotherapy and counselling, clients' or patients' experiences, psychotherapy outcomes and changes, post-treatment perspectives, and types of qualitative methods. Qualitative studies on client-identified outcomes of individual psychotherapy were included. Findings related to clients' perceptions of psychotherapy outcomes were extracted (by ML and checked by TR and LT) and analysed (by all authors) using the descriptive-interpretative meta-analytic approach. All authors have personally experienced psychotherapy as clients. This study was pre-registered with PROSPERO (CRD42021277330). Findings: We included 177 studies in the qualitative meta-analysis, from 24 countries, including descriptions from 2908 clients. Most of the studies were of good quality; they covered a wide range of therapeutic approaches and diagnoses. The descriptions of psychotherapy outcomes were classified into 60 meta-categories and grouped into ten clusters. These clusters related to clients' relational and social functioning; their emotional functioning; self-awareness, self-understanding, and more adaptive cognitive processing; behavioural functioning; developing their own resources; clients' attitudes towards themselves; generally embracing life; symptom and problem change; and more general wellbeing. The tenth cluster was outcomes that could not be clearly attributed to psychotherapy, which was considered outside the scope of this study. Interpretation: The meta-analysis showed that clients value outcome dimensions beyond symptom reduction, such as deeper self-understanding, enhanced self-agency, and greater social engagement. By examining psychotherapy outcomes across various diagnoses and therapeutic approaches, we highlight limitations in traditional outcome measures, showing the need for more comprehensive, client-centred assessment tools and the value of incorporating qualitative methods into understanding dimensions of change.

The broad acceptance of evidence-based psychosocial interventions as adjuncts to pharmacotherapy for bipolar disorder has been inhibited by the extensive training, supervision, and fidelity requirements of these approaches. Interventions that emphasize evidence-based strategies drawn from these modalities-rather than the full manualized protocols-may broaden the availability of psychotherapy for patients with bipolar disorder. In this article, psychosocial risk factors relevant to the course of bipolar disorder (stressful life events that disrupt social rhythms, lack of social support, family criticism and conflict, and lack of illness awareness or literacy) are reviewed, along with evidence-based psychosocial interventions (e.g., interpersonal and social rhythm therapy, cognitive-behavioral therapy, family-focused therapy, and group psychoeducation) to address these risk factors. The results of a component network meta-analysis of randomized psychotherapy trials in bipolar disorder are discussed. Manualized psychoeducation protocols-especially those that encourage active skill practice and mood monitoring in a family or group format-were found to be more effective, compared with individual psychoeducation or routine care, in reducing 1-year recurrence rates. Cognitive restructuring, regulation of daily and nightly routines, and communication skills training were core components associated with stabilization of depressive symptoms. The authors describe a novel psychoeducational approach-practical psychosocial management (PPM)-that integrates these core strategies into the personalized care of patients with bipolar disorder to reduce recurrences and enhance mood stability. PPM is designed to be implemented, without time-intensive training and oversight, by physician or nonphysician clinicians. Evaluating the efficacy and coverage of PPM will require implementation trials in community settings.

Introduction: Untreated bipolar disorder in pregnancy is associated with adverse maternal and neonatal outcomes. Despite advances in clinical management, there is concern among obstetric providers and patients about the safety of pharmacological agents for the treatment of bipolar disorder in pregnancy. Recent studies have shown atypical antipsychotics and lamotrigine to have a favorable safety profile; however, little information is published on lurasidone. Objectives: The objective of this retrospective chart review was to evaluate pregnancy and neonatal outcomes in obstetric patients with bipolar disorder who are untreated, compared to those treated with lurasidone, other atypical antipsychotics, and lamotrigine at a tertiary teaching institution. Methods: This retrospective cohort study included neonates whose mothers had a diagnosis of bipolar disorder and were referred to the Maternal & Fetal Care Clinic with two documented visits after January 1, 2014, with delivery by October 31, 2017, within an SSM health-system hospital. Results: In this study, women with untreated bipolar disorder (not on any mood stabilizer) in pregnancy had significantly higher rates of premature delivery and low birth weight compared to women on mood stabilizers of lamotrigine, lurasidone, and other atypical antipsychotics. No difference was observed for pregnancy or neonatal outcomes between patients taking any of the mood stabilizers. Conclusions: This study suggests that the use of lurasidone, other atypical antipsychotics, and lamotrigine have better neonatal outcomes than untreated bipolar disorder in pregnancy.

Aims: Estimates of the occurrence of bipolar disorder among adolescents vary from country to country and from time to time. Long delays from first symptoms to diagnosis of bipolar disorder have been suggested. Studies among adults suggest increased mortality, particularly due to suicide and cardiovascular diseases. We set out to study the prognosis of adolescent onset bipolar disorder in terms of rehospitalizations, diagnostic stability, and mortality. Methods: The study comprised a register-based follow-up of all adolescents admitted to psychiatric inpatient care for the first time in their lives at age 13-17 during the period 1980-2010. They were followed up in the National Care Register for Health Care and Causes of death registers until 31 December 2014. Results: Incidence of bipolar disorder among 13- to 17-year-old adolescents over the whole study period was 2.8 per 100, 000 same aged adolescents, and across decades, the incidence increased six-fold. Patients with bipolar disorder during their first-ever inpatient treatment were rehospitalized more often than those treated for other reasons. Conversion from bipolar disorder to other diagnoses was far more common than the opposite. Mortality did not differ between those first diagnosed with bipolar disorder and those treated for other reasons. Conclusion: The incidence of adolescent onset bipolar disorder has increased across decades. The present study does not call for attention to delayed diagnosis of bipolar disorder. Adolescent onset bipolar disorders are severe disorders that often require rehospitalization, but diagnostic stability is modest. Mortality is comparable to that in other equally serious disorders.

Background: Lithium is our oldest continuously prescribed medication in psychopharmacology, with its history as an agent for treating mood disorders extending from the 19th century. Although clinicians prescribe it less frequently than in the past, its utility in treating bipolar disorder is unquestionable. Novel potential indications for its use in psychiatry have created excitement about broader roles for lithium in treating and preventing other disorders. Content: Lithium is effective both in treating acute mania, as an adjunctive antidepressant, and as a maintenance treatment in bipolar disorder. Lithium has also shown some efficacy in treating and preventing unipolar depression, but less clearly than for bipolar maintenance treatment and acute mania. Common side effects include nausea, polyuria, tremor, weight gain and cognitive dulling. These side effects are typically manageable with reasonable clinical strategies. Lithium affects renal, thyroid and parathyroid function. With clinical monitoring, these effects are easily managed although infrequent cases of severe renal insufficiency may occur with long term use. Although not all studies are positive, a consistent database suggests the efficacy of lithium in decreasing suicide attempts and suicides, likely due to its effect on impulsivity and aggression as well as its prophylaxis against depressive and manic recurrences. Recent data have suggested lithium's potential efficacy for a number of new clinical indications. Lithium's neuroprotective effects suggest potential efficacy in preventing mild cognitive impairment (MCI) and dementia as well as in aiding recovery from strokes. Higher (but still trace) lithium levels in drinking water are associated with lower rates of dementia. It is still not clear how much lithium-and what serum lithium levels- are required for either of these effects. Other preliminary research suggests that lithium may also have antiviral effects and may decrease cancer risk. Conclusions: Lithium continues to be the mainstay treatment of mood disorders in general and in bipolar disorder specifically. Other potential clinical uses for lithium in psychiatry have re-invigorated excitement for research in other areas such as suicide, preventing cognitive impairment and possibly preventing viral infections and diminishing cancer risk.

Introduction: Depression with a history of trauma often responds poorly to conventional antidepressants and has a poor prognosis. Prazosin, an α1-adrenoceptor blocker, has shown promise in treating post-traumatic stress disorder symptoms, particularly nightmares. Its potential in treating depression with trauma history warrants investigation. Aims of the study: This randomised, double-blind, placebo-controlled study aimed to investigate the efficacy and tolerability of low-dose prazosin (0.5-1 mg/day) as an augmentation strategy in patients with depression and a history of trauma. We sought to determine if prazosin could provide rapid symptom improvement and enhance overall treatment response compared to placebo in this difficult-to-treat patient population. Methods: This randomised, double-blind, placebo-controlled clinical study included 59 patients with first-episode or recurrent unipolar or bipolar depression. After basic antidepressant treatment, they were randomly assigned to a prazosin (0.5-1 mg/day) or placebo group for a 6-week double-blind controlled study. The Montgomery-Åsberg Depression Rating Scale, 17-item Hamilton Depression Scale (HAMD-17), and Hamilton Anxiety Scale (HAMA) were used to evaluate efficacy. Results: There were no significant differences in the results of the demographic and clinical symptom assessment between the two groups (p > 0.05). The difference between the HAMD-17 and HAMA scores was statistically significant after 3 days of treatment (p < 0.05). The difference in response rate between the two groups was statistically significant after week 4 of treatment (end of week 4, 56.7% vs. 24.1%, p = 0.011; end of week 6, 80.0% vs. 48.3%, p = 0.011). The incidence of adverse reactions in the prazosin and placebo groups was 20.0% and 24.1%, respectively, with no statistically significant differences (p > 0.05); however, the prazosin group had a lower incidence of sleeplessness or nightmares (3.3% vs. 20.7%, p = 0.039) but a higher incidence of orthostatic hypotension (16.7% vs. 0%, p = 0.007). The severity of orthostatic hypotension was mild to moderate. Conclusion: Low-dose prazosin can effectively improve the emotional symptoms of patients with depression and a history of trauma, and the common adverse reaction is mild-to-moderate orthostatic hypotension.

Objective: This preregistered study compared the effects of the Transdiagnostic Sleep and Circadian Intervention (TranS-C) with psychoeducation (PE) about sleep, health, yoga, meditation, and outdoor appreciation activities on sleep and circadian functioning, health risk, and sleep health behaviors at long-term follow-up (LTFU), an average of 8 years following treatment. We also examined if more sleep health behaviors at LTFU were associated with better sleep and circadian functioning at LTFU and if better sleep and circadian functioning were associated with lower health risk at LTFU. Method: At baseline, we randomly assigned adolescents with an eveningness chronotype to TranS-C (n = 89) or PE (n = 87). Of this sample, we assessed 106 young adults (mean age at follow-up = 22.5 years; n = 55 from TranS-C; n = 51 from PE) an average of 8 years following treatment. Results: Despite TranS-C (vs PE) sustaining improvement in circadian functioning through 12-month follow-up, at LTFU, there were no significant differences between the conditions on any outcome, including sleep and circadian functioning, risks in 5 health domains indexed by self-report and ecological momentary assessment, sleep health behaviors, and physical measurements. Across both conditions, measures indicating poorer sleep and circadian functioning were associated with higher health risk across multiple domains, and more sleep health behaviors were associated with lower levels of eveningness at LTFU. Conclusion: These results provide an important window into the influence of development on long-term outcomes for youth and raise the possibility that interventions for youth could be enhanced with a focus on habit formation.

Objective: To examine the association between newer generation antidepressants and insomnia as an adverse event (AE) in the treatment of children and adolescents with major depressive disorder (MDD). Method: A systematic search was performed in major databases (inception to August 31, 2023) to retrieve double-blind, placebo-controlled, randomized controlled trials (RCTs) evaluating the safety of 19 antidepressants in the acute treatment (initial 6-12 weeks) of children and adolescents ≤18 years of age with MDD (primary analyses). RCTs in anxiety disorders and obsessive-compulsive disorder (OCD) were retrieved from a recent meta-analysis and included in complementary analyses. A mixed-effects logistic regression model was used to compare the frequency of insomnia in the antidepressant relative to the placebo group. Risk of bias was evaluated using the Cochrane Risk of Bias 2 tool. Results: In total, 20 trials in MDD (N = 5,357) and 8 trials in anxiety disorders and OCD (N = 1,271) evaluating selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) were included. In MDD, antidepressant treatment was associated with a modest increase in the odds of insomnia compared with placebo (odds ratio [OR] = 1.65, 95% CI = 1.21-2.27, p = .002), with no significant difference between SSRIs and SNRIs. The RCTs showed low risk of bias or minor concerns for the assessment of insomnia. The odds of treatment-emergent insomnia were significantly lower in MDD (OR = 1.62; 95% CI = 1.21-2.15) compared to anxiety disorders and OCD (OR = 2.89; 95% CI = 1.83-4.57) for treatment with SSRIs (p = .03). Among individual antidepressants with evidence from ≥3 studies, sertraline had the highest OR (3.45; 95% CI = 1.91-6.24), whereas duloxetine had the lowest OR (1.38; 95% CI = 0.79-2.43). Conclusion: Children and adolescents are at a modestly increased risk for experiencing insomnia during the first 6 to 12 weeks of treatment with SSRIs and SNRIs. Antidepressant- and disorder-specific variability in the risk of treatment-emergent insomnia may be relevant to consider in clinical decision making.

Posttraumatic stress disorder (PTSD) is a highly prevalent psychiatric disorder that can become chronic and debilitating when left untreated. The most commonly recommended first-line treatments for PTSD among adults are individual trauma-focused psychotherapies. Other evidence-based treatments include specific antidepressant medications and non-trauma-focused psychotherapies. Despite the effectiveness of these available treatments, many patients' symptoms do not remit. This has led to the search for novel treatments for PTSD. In this review, the authors critically evaluate the data supporting several emerging pharmacological and other somatic interventions in the categories of medication-assisted psychotherapy, novel medication monotherapy strategies, and neuromodulation, selected because of the salience of their mechanisms of action to the pathophysiology of PTSD (e.g., MDMA-assisted psychotherapy, ketamine, cannabidiol, transcranial magnetic stimulation). The authors also evaluate the evidence for treatments that are the focus of increasing scientific or public interest (i.e., hyperbaric oxygen therapy, stellate ganglion block, neurofeedback). To date, the evidence supporting most novel pharmacological and somatic treatments for PTSD is preliminary and highly variable; however, the data for several specific treatments, such as transcranial magnetic stimulation, are encouraging.

Objective: Evidence suggests that psilocybin-assisted therapy (PAT) leads to durable shifts in personality structure. However, such changes have yet to be characterized in disorders of addiction. In this secondary analysis from a randomized controlled trial, the authors examined the effect of PAT on personality dimensions in patients with alcohol use disorder (AUD), hypothesizing that PAT would attenuate personality abnormalities in AUD and that reductions in trait impulsiveness would be associated with lower drinking. Methods: Eighty-four adults with AUD were randomized to two medication sessions of either psilocybin (N=44) or active placebo (diphenhydramine; N=40), received 12 weekly psychotherapy sessions, and completed follow-up for an additional 24 weeks. Changes in personality traits (week 36 vs. baseline) were assessed with the revised NEO Personality Inventory; daily alcohol consumption was quantified using the timeline followback. Results: Relative to the placebo group, the psilocybin group showed significant reductions in neuroticism and increases in extraversion and openness. Secondary analyses showed that reductions in neuroticism were driven by decreases in the facets depression, impulsiveness, and vulnerability; increases in openness were driven by increases in the facets openness toward feelings and fantasy. Across all participants, decreases in impulsiveness were associated with lower posttreatment alcohol consumption, and an exploratory analysis revealed that these associations were strongest among psilocybin-treated participants who continued moderate- or high-risk drinking prior to the first medication session. Conclusions: PAT elicited durable shifts in personality, suggesting normalization of abnormal personality trait expression in AUD. Further study is needed to clarify whether PAT exerts its beneficial effects by reducing impulsiveness or whether impulsive individuals inherently respond better to PAT.

In this narrative medicine essay, an emeritus professor of psychiatry ponders the preparation for and circumstances of achieving a good death and what burdens or benefits are left behind for loved ones.

Hospitalizations related to alcohol use disorder (AUD) are common. Yet, few patients receive pharmacotherapy consistent with guideline recommendations. Previous concerns over the potential hepatotoxicity of naltrexone have been disproven and recent studies have shown its safety and efficacy in patients with cirrhosis. Naltrexone is an effective therapy to reduce heavy alcohol consumption, however, lack of knowledge among prescribers inhibits greater uptake. Hospitalization is an opportune time for change-naltrexone can promote the reduction or cessation of unhealthy alcohol consumption, as well as subsequent readmissions or progression of alcohol-related liver disease. Hospitalists should stop avoiding naltrexone in the treatment of AUD.

Purpose/background: Antipsychotic polypharmacy (APP) is controversial yet applied in 20% of patients with psychotic disorders. We investigated indications for initiating and continuing APP, including the contribution of unfinished cross-titrations. Methods/procedures: This 2-month study was part of a prospective study to reduce inappropriate APP in inpatients. With each new prescription resulting in APP, we asked the prescriber for the indication (eg, switching antipsychotics, sedation for agitation/sleep disorders, treatment refractoriness, other) and repeated this at 30 and 60 days. Secondary outcome was unfinished cross-titration at 60 days. Findings/results: In a consecutive cohort of 55 patients, 80% diagnosed with schizophrenia, switching antipsychotics was the primary initial indication for APP in 31 of 55 patients (56%), followed by sedation in 12 of 55 patients (22%), and treatment refractoriness in 10 of 55 patients (18%). Overall, APP was discontinued after 30 days in 25 of 55 patients (45%) and after 60 days in 28 of 55 patients (51%). At 60 days, APP initiated for switching antipsychotics was ongoing in 9 of 31 patients (29%), APP initiated for sedation was ongoing in 8 of 12 patients (66%), and APP initiated for refractoriness was ongoing in 9 of 10 patients (90%). The initial indication for APP was maintained at 60 days in 21 of 27 patients (78%). Unfinished cross-titration occurred in 9 of 31 patients (29%) with APP initiated for switching antipsychotics. Implications/conclusions: APP was initiated primarily because of cross-titration switching of antipsychotics. The reason for APP was generally maintained consistently over time, particularly when initiated for treatment refractoriness. Of all patients with APP initiated to switch antipsychotics, 29% ended in unfinished cross-titration.

Introduction: Managing body weight in patients with antipsychotic-induced weight gain (AIWG) is challenging. Besides lifestyle interventions, pharmacological interventions may contribute to weight loss. This systematic review and meta-analysis evaluated the effect on weight loss and adverse effects of glucagon-like peptide-1 (GLP-1) agonists in patients with AIWG. Materials and methods: Following PRISMA guidelines, we performed a meta-analysis of blinded and open-label randomised controlled trials (RCTs), non-randomised controlled trials and cohort studies that evaluated treatment with GLP-1 in patients with AIWG, regardless of psychiatric diagnosis. PubMed, Embase, PsycINFO and Cochrane Library databases were searched. Primary outcome measures were changes in body weight and BMI. Secondary outcomes were changes in adverse effects and severity of psychopathology due to GLP-1 agonists. Results: Only data for exenatide and liraglutide could be included, that is, five RCTs and one cohort study. For exenatide the mean weight loss was -2.48 kg (95% Confidence Interval (CI) -5.12 to +0.64; p = 0.07), for liraglutide the mean weight loss was -4.70 kg (95% CI -4.85 to -4.56; p < 0.001). The mean change in BMI was -0.82 (95% CI -1.56 to -0.09; p = 0.03) in the exenatide groups and -1.52 (95% CI -1.83 to -1.22; p < 0.001) in the liraglutide groups. Exenatide and liraglutide did not adversely affect psychopathology. The most common adverse events were nausea, vomiting, and diarrhoea. Conclusion: The GLP-1 agonists exenatide and liraglutide are promising drugs for inducing weight loss in patients with AIWG. The adverse effects are acceptable, and the addition of GLP-1 does not increase the severity of psychopathology. However, more research is needed.

Background: Finding effective treatment regimens for bipolar disorder is challenging, as many patients suffer from significant symptoms despite treatment. This study investigated the risk of relapse (psychiatric hospitalization) and treatment safety (non-psychiatric hospitalization) associated with different doses of antipsychotics and mood stabilizers in persons with bipolar disorder. Methods: Individuals aged 15-65 with bipolar disorder were identified from Finnish national health registers in 1996-2018. Studied antipsychotics included olanzapine, risperidone, quetiapine, aripiprazole; mood stabilizers lithium, valproic acid, lamotrigine, and carbamazepine. Medication use was divided into three time-varying dose categories: low, standard, and high. The studied outcomes were risk of psychiatric hospitalization (relapse) and the risk of non-psychiatric hospitalization (treatment safety). Stratified Cox regression in within-individual design was used. Results: The cohort included 60,045 individuals (mean age 41.7 years, SD 15.8; 56.4% female). Mean follow-up was 8.3 years (SD 5.8). Of antipsychotics, olanzapine and aripiprazole were associated with a decreased risk of relapse in low and standard doses, and risperidone in low dose. The lowest adjusted hazard ratio (aHR) was observed for standard dose aripiprazole (aHR 0.68, 95% CI 0.57-0.82). Quetiapine was not associated with a decreased risk of relapse at any dose. Mood stabilizers were associated with a decreased risk of relapse in low and standard doses; lowest aHR was observed for standard dose lithium (aHR 0.61, 95% CI 0.56-0.65). Apart from lithium, high doses of antipsychotics and mood stabilizers were associated with an increased risk of non-psychiatric hospitalization. Lithium was associated with a decreased risk of non-psychiatric hospitalization in low (aHR 0.88, 95% CI 0.84-0.93) and standard doses (aHR 0.81, 95% CI 0.74-0.88). Conclusions: Standard doses of lithium and aripiprazole were associated with the lowest risk of relapse, and standard dose of lithium with the lowest risk of non-psychiatric hospitalization. Quetiapine was not associated with decreased risk of relapse at any dose.

Background: Antipsychotics increase the risk of developing diabetes, but clinical trials are not generalizable with short follow-up, while observational studies often lack important information, particularly hemoglobin A1c (HbA1c). Methods: We followed two Danish cohorts with schizophrenia. First, using Danish nationwide registers, we identified all individuals diagnosed with first-episode schizophrenia (FES) between 1999 and 2019 (n = 31,856). Exposure was a redeemed prescription for an antipsychotic, and the outcome was diabetes, defined via hospital-based diagnosis and redeemed prescriptions for glucose-lowering drugs. Adjusted Cox regression calculated hazard rate ratios (HRR). Second, using data from the Central Denmark Region, we identified all individuals diagnosed with FES from October 2016 to September 2022 (n = 2671). Using a within-subject design, we analyzed the change in HbA1c during the 2 years after initiation of specific antipsychotics compared to the 2 years before. Results: In the nationwide cohort, 2543 (8.0%) individuals developed diabetes (incidence rate = 9.39 [95% CI = 9.03-9.76] per 1000 person-years). Antipsychotics, compared to periods without, were associated with an increased risk of developing diabetes (HRR = 2.04, 95% CI = 1.75-2.38). We found a dose-response association, particularly for second-generation antipsychotics, and different risk rates for specific antipsychotics. In the Central Denmark Region cohort, a total of 9.2% developed diabetes but mean HbA1c levels remained stable at 37 mmol/mol during the 2 years after initiation of antipsychotic medication. Conclusion: This comprehensive real-world two-cohort study emphasizes that diabetes affects almost 10% of patients with FES. Antipsychotics increase this risk, while HbA1c deterioration requires longer treatment. These findings are important for clinicians and young patients with FES.

Interpersonal psychotherapy (IPT) and antidepressant medications are both first-line interventions for adult depression, but their relative efficacy in the long term and on outcome measures other than depressive symptomatology is unknown. Individual participant data (IPD) meta-analyses can provide more precise effect estimates than conventional meta-analyses. This IPD meta-analysis compared the efficacy of IPT and antidepressants on various outcomes at post-treatment and follow-up (PROSPERO: CRD42020219891). A systematic literature search conducted May 1st, 2023 identified randomized trials comparing IPT and antidepressants in acute-phase treatment of adults with depression. Anonymized IPD were requested and analyzed using mixed-effects models. The prespecified primary outcome was post-treatment depression symptom severity. Secondary outcomes were all post-treatment and follow-up measures assessed in at least two studies. IPD were obtained from 9 of 15 studies identified (N = 1536/1948, 78.9%). No significant comparative treatment effects were found on post-treatment measures of depression (d = 0.088, p = 0.103, N = 1530) and social functioning (d = 0.026, p = 0.624, N = 1213). In smaller samples, antidepressants performed slightly better than IPT on post-treatment measures of general psychopathology (d = 0.276, p = 0.023, N = 307) and dysfunctional attitudes (d = 0.249, p = 0.029, N = 231), but not on any other secondary outcomes, nor at follow-up. This IPD meta-analysis is the first to examine the acute and longer-term efficacy of IPT v. antidepressants on a broad range of outcomes. Depression treatment trials should routinely include multiple outcome measures and follow-up assessments.

Since 2003, the Food and Drug Administration (FDA) has warned that antidepressants may be associated with suicidal thoughts and behaviors among youth. An FDA advisory in 2003 and a black-box warning in 2005 focused on children and adolescents younger than age eighteen. The FDA expanded the black-box warning in 2007 to include young adults. Both warnings were intended to increase physician monitoring of suicidal thoughts and behaviors. Our systematic review identified thirty-four studies of depression and suicide-related outcomes after these warnings; eleven of these studies met research design criteria established to reduce biases. The eleven studies examined monitoring for suicidal thoughts and behaviors, physician visits for depression, depression diagnoses, psychotherapy visits, antidepressant treatment and use, and psychotropic drug poisonings (a proxy for suicide attempts) and suicide deaths. We assessed possible spillover to adults not targeted by the warnings. The one study that measured intended physician monitoring of suicidal thoughts and behaviors did not find evidence of an increase. Multiple studies found significant unintended reductions in mental health care after the warnings. After these reductions, there were marked increases in psychotropic drug poisonings and suicide deaths. These findings support reevaluation of risks and benefits of the FDA's black-box antidepressant warnings.

Importance: Interest in and use of hallucinogens has been increasing rapidly. While a frequently raised concern is that hallucinogens may be associated with an increased risk of psychosis, there are limited data on this association. Objectives: To examine whether individuals with an emergency department (ED) visit involving hallucinogen use have an increased risk of developing a schizophrenia spectrum disorder (SSD). Design, settings, and participants: This population-based, retrospective cohort study (January 2008 to December 2021) included all individuals aged 14 to 65 years in Ontario, Canada, with no history of psychosis (SSD or substance induced). Data were analyzed from May to August 2024. Exposure: An incident ED visit involving hallucinogen use. Main outcomes and measures: Diagnosis of SSD using a medical record-validated algorithm. Associations between ED visits involving hallucinogens and SSD were estimated using cause-specific adjusted hazard models. Individuals with an incident ED visit involving hallucinogens were compared with members of the general population (primary analysis) or individuals with ED visits involving alcohol or cannabis (secondary analysis). Results: The study included 9 244 292 individuals (mean [SD] age, 40.4 [14.7] years; 50.2% female) without a history of psychosis, with a median follow-up of 5.1 years (IQR, 2.3-8.6 years); 5217 (0.1%) had an incident ED visit involving hallucinogen use. Annual rates of incident ED visits involving hallucinogens were stable between 2008 and 2012 and then increased by 86.4% between 2013 and 2021 (3.4 vs 6.4 per 100 000 individuals). Individuals with ED visits involving hallucinogens had a greater risk of being diagnosed with an SSD within 3 years compared with the general population (age- and sex-adjusted hazard ratio [HR], 21.32 [95% CI, 18.58-24.47]; absolute proportion with SSD at 3 years, 208 of 5217 with hallucinogen use [3.99%] vs 13 639 of 9 239 075 in the general population [0.15%]). After adjustment for comorbid substance use and mental health conditions, individuals with hallucinogen ED visits had a greater risk of SSD compared with the general population (HR, 3.53; 95% CI, 3.05-4.09). Emergency department visits involving hallucinogens were associated with an increased risk of SSD within 3 years compared with ED visits involving alcohol (HR, 4.66; 95% CI, 3.82-5.68) and cannabis (HR, 1.47; 95% CI, 1.21-1.80) in the fully adjusted model. Conclusions and relevance: In this cohort study, individuals with an ED visit involving hallucinogen use had a greater risk of developing an SSD compared with both the general population and with individuals with ED visits for other types of substances. These findings have important clinical and policy implications given the increasing use of hallucinogens and associated ED visits.

Background: Given both the large volume and manifold preferences of patients with depression, the availability of various effective treatments is important. Psychodynamic psychotherapy (PDT) has received less research in comparison to cognitive behavioural therapy (CBT) for major depressive disorder (MDD). This study aimed to establish whether short-term psychodynamic supportive psychotherapy (SPSP) is non-inferior to CBT in the treatment of MDD. Methods: A non-inferiority trial was conducted in a Dutch mental health setting, with 290 patients randomised to receive 16 sessions of either CBT or SPSP, over eight weeks. Primary outcome was depressive symptom severity assessed using the self-rated Inventory of Depressive Symptomatology (IDS-SR). The non-inferiority margin was prespecified as a - 5 post-treatment difference on the IDS-SR. Secondary outcome measures were functional impairment caused by symptoms assessed using the Sheehan disability scale (SDS), and wellbeing measured by the Mental Health Continuum-Short Form (MHC-SF). Results: Both intention-to-treat (baseline-adjusted mean difference 1.62, 95 % CI -1.82 to 5.05) and per-protocol analyses (mean difference 2.54; 95 % CI -0.63 to 5.72) showed SPSP to be non-inferior to CBT in reducing depressive symptoms. SPSP showed slightly but significantly higher remission rates and wellbeing scores. Limitations: Patients opting for other therapies or medication did not take part in the trial. Follow-up measures or clinician-rated questionnaires were not included. Conclusions: The findings support SPSP as a viable treatment option for MDD, expanding the available choices for patients and broadening treatment options.

Background: Fibromyalgia (FM) is a common illness with a wide range of symptoms, mainly manifested by unexplained chronic systemic musculoskeletal pain, sleep disorders and fatigue, sometimes accompanied by cognitive impairment, psychiatric symptoms and autonomic dysfunction. Previous studies have indicated a correlation between depression and the risk of FM; however, it remains uncertain whether this association reflects a causal relationship. Methods: We evaluated the etiological association between the genetically predicted depression and the risk of developing FM by conducting a two-sample Mendelian Randomization (MR) study. The data on single nucleotide polymorphisms (SNPs) related to depression were obtained from the UK Biobank (UKB) and the Psychiatric Genomics Consortium (PGC) of White British European ancestry, and the data for FM were from the 5th release of the FinnGen study. We adopted the Inverse Variance Weighted (IVW) approach as the principal standard. In order to detect the existence of horizontal pleiotropy and heterogeneity, we adopted the MR-Egger approach as the sensitivity analysis Results: In our MR analysis, 42 depression-related variants were identified as valid instrumental variables (IVs). The IVW approach's results manifest that there is no etiologic causality between genetically predicted depression and the risk of FM (odds ratio [OR]: 1.673, 95% confidence interval [CI]: 0.852-3.287, P = 0.135). The study did not find any significant heterogeneities or horizontal pleiotropies (P > 0.05). Conclusions: Our results suggest that there is no significant genetic evidence linking depression to an increased risk of FM. However, further research is necessary to investigate the potential relationship and underlying mechanisms between depression and the risk of FM.

Introduction: Traits of borderline personality disorder are important for the determination of the prognosis of mental illnesses and in evaluating risks of negativity as well as impulsivity. But, there is a lack of information about the distribution characteristics of borderline personality disorder traits and symptoms within clinical groups. The goal of the current study was to predict borderline personality disorder based on childhood trauma, using experiential avoidance as a mediator. Methods: All male patients hospitalized in local psychiatric health centers with a diagnosis of borderline personality disorder comprised the statistical population of the current study. The number of 60 patients were selected by the purposeful sampling method. The questionnaire included the Childhood Trauma Questionnaire (CTQ), the Experiential Avoidance Questionnaire (AAQ-II), and the Borderline Personality Disorder Symptoms (BSL-23). Results and discussion: The results demonstrated that there is a considerable and positive relationship between childhood trauma and experiential avoidance (r = 0.711, p< 0.01). In the mediating model, childhood trauma had significant direct predictive effects on borderline personality disorder (β = 0.546, p< 0.01). Also, between childhood trauma and BPD, experienced avoidance acts as a moderating factor. (β = 0.304, p< 0.01).

Psychedelics have long been used by individuals seeking peace and a sense of wellness. This article examines widespread adoption of ketamine as a proxy for psychedelics. For ketamine, there is a need to protect vulnerable persons from exploitation that should be balanced against risks of hypermedicalization. This article suggests strategies for striking such a balance, including by carefully differentiating between persons with psychiatric illnesses, such as treatment-resistant depression, who could benefit from psychedelics, and persons using psychedelics for peace and wellness under careful guidance.

Evidence indicates that ketamine is highly effective, has a lower side effect profile and is better tolerated compared to many augmentation strategies for refractory depression. This, combined with data on psychiatric treatment outcome mediators, suggests that earlier intervention with ketamine could improve outcomes for patients suffering from refractory depression.

Importance: Seasonal humor disorders are prone to have a link with daylight exposure. However, the effect of external light on nonseasonal disorders remains unclear. Evidence is lacking for the validity of bright light therapy (BLT) as an adjunctive treatment for these patients. Objective: To assess BLT effectiveness as an adjunctive treatment for nonseasonal depressive disorders. Data sources: In March 2024, a comprehensive search was performed of publications in the MEDLINE, Embase, and Cochrane databases for randomized clinical trials (RCTs) evaluating BLT effects in patients with nonseasonal depression. Study selection: RCTs published since 2000 were eligible. Comparisons between BLT and dim red light or antidepressant monotherapy alone were considered for inclusion. Data extraction and synthesis: Using the systematic review approach on RCTs published from January 1, 2000, through March 25, 2024, differences between patients treated with and without BLT were estimated using the Mantel-Haenszel method; heterogeneity was assessed using I2 statistics. Main outcomes and measures: Remission of symptoms, response to treatment rates, and depression scales were assessed. Results: In this systematic review and meta-analysis of 11 unique trials with data from 858 patients (649 female [75.6%]), statistically significant better remission and response rates were found in the BLT group (remission: 40.7% vs 23.5%; odds ratio [OR], 2.42; 95% CI, 1.50-3.91; P <.001; I2 = 21%; response: 60.4% vs 38.6%; OR, 2.34; 95% CI, 1.46-3.75; P <.001; I2 = 41%). With BLT, subgroup analysis based on follow-up times also showed better remission (<4 weeks: 27.4% vs 9.2%; OR, 3.59; 95% CI, 1.45-8.88; P = .005; I2 = 0% and >4 weeks: 46.6% vs 29.1%; OR, 2.18; 95% CI, 1.19-4.00; P = .01; I2 = 47%) and response (<4 weeks: 55.6% vs 27.4%; OR, 3.65; 95% CI, 1.81-7.33; P <.001; I2 = 35% and >4 weeks: 63.0% vs 44.9%; OR, 1.79; 95% CI, 1.01-3.17; P = .04; I2 = 32%) rates. Conclusions and relevance: Results of this systematic review and meta-analysis reveal that BLT was an effective adjunctive treatment for nonseasonal depressive disorder. Additionally, results suggest that BLT may improve the response time to the initial treatment.

Importance: Older adults with major depressive disorder (MDD) or mild cognitive impairment (MCI) are at high risk for cognitive decline. Objective: To assess the efficacy of cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) targeting the prefrontal cortex in slowing cognitive decline, acutely improving cognition, and reducing progression to MCI or dementia in older adults with remitted MDD (rMDD), MCI, or both. Design, setting, and participants: This randomized clinical trial was conducted at 5 academic hospitals in Toronto, Ontario, Canada. Participants were older adults who had rMDD (with or without MCI, age ≥65 y) or MCI without rMDD (age ≥60 y). Assessments were made at baseline, month 2, and yearly from baseline for 3 to 7 years. Interventions: CR plus tDCS (hereafter, active) or sham plus sham 5 days a week for 8 weeks followed by twice-a-year 5-day boosters and daily at-home CR or sham CR. Main outcomes and measures: The primary outcome was change in global composite cognitive score. Secondary outcomes included changes in 6 cognitive domains, moderating effect of the diagnosis, moderating effect of APOE ε4 status, change in composite score at month 2, and progression to MCI or dementia over time. Results: Of 486 older adults who provided consent, 375 (with rMDD, MCI, or both) received at least 1 intervention session (mean [SD] age, 72.2 [6.4] years; 232 women [62%] and 143 men [38%]). Over a median follow-up of 48.3 months (range, 2.1-85.9), CR and tDCS slowed cognitive decline in older adults with rMDD or MCI (adjusted z score difference [active - sham] at month 60, 0.21; 95% CI, 0.07 to 0.35; likelihood ratio test [LRT] P = .006). In the preplanned primary analysis, CR and tDCS did not improve cognition acutely (adjusted z score difference [active - sham] at month 2, 0.06, 95% CI, -0.006 to 0.12). Similarly, the effect of CR and tDCS on delaying progression from normal cognition to MCI or MCI to dementia was weak and not significant (hazard ratio, 0.66; 95% CI, 0.40 to 1.08; P = .10). Preplanned analyses showed treatment effects for executive function (LRT P = .04) and verbal memory (LRT P = .02) and interactions with diagnosis (P = .01) and APOE ε4 (P < .001) demonstrating a larger effect among those with rMDD and in noncarriers of APOE ε4. Conclusions and relevance: The study showed that CR and tDCS, both targeting the prefrontal cortex, is efficacious in slowing cognitive decline in older adults at risk of cognitive decline, particularly those with rMDD (with or without MCI) and in those at low genetic risk for Alzheimer disease.

Importance: Brain translocator protein 18k Da (TSPO) binding, a putative marker of neuroinflammatory processes (eg, gliosis), is associated with stress and elevated in depressed and suicidal populations. However, it is unclear whether neuroinflammation moderates the impact of daily life stress on suicidal ideation and negative affect, thereby increasing risk for suicidal behavior. Objective: To examine the association of TSPO binding in participants with depression with real-world daily experiences of acute stress-related suicidal ideation and negative affect, as well as history of suicidal behavior and clinician-rated suicidal ideation. Design, setting, and participants: Data for this cross-sectional study were collected from June 2019 through July 2023. Procedures were conducted at a hospital-based research center in New York, New York. Participants were recruited via clinical referrals, the Columbia University research subject web portal, and from responses to internet advertisements. Of 148 participants who signed informed consent for study protocols, 53 adults aged 18 to 60 years who met DSM-5 diagnostic criteria for current major depressive disorder completed procedures with approved data and were enrolled. Participants were free of schizophrenia spectrum disorders, active physical illness, cognitive impairment, and substance intoxication or withdrawal at the time of scan. Exposures: All participants underwent positron emission tomography imaging of TSPO binding with 11C-ER176 and concurrent arterial blood sampling. Main outcome and measures: A weighted average of 11C-ER176 total distribution volume (VT) was computed across 11 a priori brain regions and made up the primary outcome measure. Clinician-rated suicidal ideation was measured via the Beck Scale for Suicidal Ideation (BSS). A subset of participants (n = 21) completed 7 days of ecological momentary assessment (EMA), reporting daily on suicidal ideation, negative affect, and stressors. Results: In the overall sample of 53 participants (mean [SD] age, 29.5 [9.8] years; 37 [69.8%] female and 16 [30.2%] male), 11C-ER176 VT was associated at trend levels with clinician-rated suicidal ideation severity (β, 0.19; 95% CI, -0.03 to 0.39; P = .09) and did not differ by suicide attempt history (n = 15; β, 0.18; 95% CI, -0.04 to 0.37; P = .11). Exploratory analyses indicated that presence of suicidal ideation (on BSS or EMA) was associated with higher 11C-ER176 VT (β, 0.21; 95% CI, 0.01 to 0.98; P = .045). In 21 participants who completed EMA, 11C-ER176 VT was associated with greater suicidal ideation and negative affect during EMA periods with stressors compared with nonstress periods (β, 0.12; SE, 0.06; 95% CI, 0.01 to 0.23; P = .03 and β, 0.19; SE, 0.06; 95% CI, 0.08 to 0.30; P < .001, respectively). Conclusion and relevance: TSPO binding in individuals with depression may be a marker of vulnerability to acute stress-related increases in suicidal ideation and negative affect. Continued study is needed to determine the causal direction of TSPO binding and stress-related suicidal ideation or negative affect and whether targeting neuroinflammation may improve resilience to life stress in patients with depression.

Digital therapeutics-web-based programs, smartphone applications, and wearable devices designed to prevent, treat, or manage clinical conditions through software-driven, evidence-based intervention-can provide accessible alternatives and/or may supplement standard care for patients with serious mental illnesses, including schizophrenia. In this article, we provide a targeted summary of the rapidly growing field of digital therapeutics for schizophrenia and related serious mental illnesses. First, we define digital therapeutics. Then, we provide a brief summary of the emerging evidence of the efficacy of digital therapeutics for improving clinical outcomes, focusing on potential mechanisms of action for addressing some of the most challenging problems, including negative symptoms of psychosis. Our focus on these promising targets for digital therapeutics, including the latest in prescription models in the commercial space, highlights future directions for research and practice in this exciting field.

Background: Body dysmorphic disorder (BDD) is thought to be associated with considerable suicide risk. This nationwide cohort study quantified the risks of intentional self-harm-including nonsuicidal self-injuries and suicide attempts-and death by suicide in BDD. Methods: Individuals with a validated ICD-10 diagnosis of BDD in the Swedish National Patient Register, registered between January 1, 1997, and December 31, 2020, were matched with 10 unexposed individuals (i.e., without BDD) from the general population on birth year, sex, and county of residence. Conditional Poisson regression models estimated incidence rate ratios and 95% CIs for intentional self-harm. Stratified Cox proportional hazards models estimated hazard ratios and 95% CIs for death by suicide. Models adjusted for sociodemographic variables and lifetime psychiatric comorbidities. Results: Among 2833 individuals with BDD and 28,330 unexposed matched individuals, 466 (16.45%) and 1071 (3.78%), respectively, had at least 1 record of intentional self-harm during the study period (incidence rate ratio = 3.37; 95% CI, 3.02-3.76). In the BDD group, about two-thirds (n = 314; 67%) had their first recorded self-harm event before their first BDD diagnosis. A total of 17 (0.60%) individuals with BDD and 27 (0.10%) unexposed individuals died by suicide (hazard ratio = 3.47; 95% CI, 1.76-6.85). All results remained robust to additional adjustment for lifetime psychiatric comorbidities. A higher proportion of individuals with BDD who died by suicide had at least 1 previous record of intentional self-harm compared with unexposed individuals (52.94% vs. 22.22%; p = .036). Conclusions: BDD was associated with a 3-fold increased risk of intentional self-harm and death by suicide.

Background: Antibodies against the N-methyl-D-aspartate receptor (NMDAR) have been described in the serum of people with schizophrenia spectrum disorders (schizophrenia). However, the prevalence and clinical relevance of these antibodies in schizophrenia is unclear. This knowledge gap includes the possibility of such antibodies being associated with a distinct clinical profile, which in turn might warrant a distinct treatment approach. We aimed to assess the seroprevalence of anti-NMDAR antibodies in schizophrenia, and compare symptoms and psychosocial functioning between patients with schizophrenia who were seropositive and seronegative for these antibodies. Methods: In this case-control comparison, by combining new and existing studies, we included patients diagnosed with schizophrenia from four independent cohorts for whom anti-NMDAR serostatus had been assessed (or could be assessed by us) with live cell-based assays. Included cohorts were from the EULAST study (a trial conducted across 15 European countries and Israel), the OPTiMiSE study (an interventional study in Europe), and the PPiP1 and PPiP2 studies (conducted in the UK). Patients from these cohorts were analysed if they had complete Positive and Negative Syndrome Scale (PANSS) data. No participant had been diagnosed with autoimmune encephalitis or received treatment for this condition. After calculating the prevalence of serum anti-NMDAR antibodies, we examined possible differences in PANSS scores (negative, positive, and general symptom subscales, and total score) between anti-NMDAR-seropositive and anti-NMDAR-seronegative patients. Psychosocial functioning as measured by Personal Social Performance (PSP) score was also compared. All analyses were exploratory and no adjustment was done for multiple testing. People with lived experience were not involved in the conduct of this study. Findings: We collected individual patient data from 1114 patients with schizophrenia across the four cohorts. The study population had a mean age of 28·6 years (SD 7·6) and comprised 382 (34·3%) women and 732 (65·7%) men, including patients of White (929 [83·4%]), Asian (54 [4·8%]), Black (68 [6·1%]), and other (62 [5·6%]) ethnicities. Overall, 41 (3·7%) participants (range 3·1-4·0% across cohorts) tested positive for serum anti-NMDAR antibodies. Lower symptom severity on the negative symptoms PANSS subscale was observed for anti-NMDAR-seropositive patients (mean score 15·8 [SD 6·4]) than for anti-NMDAR-seronegative patients (18·2 [6·8]; Cohen's d=0·36; p=0·026), as well as on the general symptoms PANSS subscale (32·9 [8·9] vs 36·1 [10·1]; d=0·33; p=0·029) and total PANSS score (65·5 [18·5] vs 72·6 [19·3]; d=0·37; p=0·013). Mean PSP score was better in anti-NMDAR-positive patients (62·0 [17·0]) than in anti-NMDAR-negative patients (53·5 [16·3]; d=0·52; p=0·014). Interpretation: Serum NMDAR antibodies are present in 3-4% of patients with schizophrenia and are associated with relatively low severity of negative symptoms and relatively good psychosocial functioning. Thus, although the findings await replication in cohorts from other geographical regions, serum anti-NMDAR antibodies might be associated with a different form of psychotic illness. These findings could inform future prognostic and interventional studies examining whether anti-NMDAR antibodies are associated with a specific course of illness or with treatment response.

Background: Evidence regarding schizophrenia relapse following acute electroconvulsive therapy (ECT) is sparse compared with that for depression, and we have no clear consensus on relapse proportions. We aimed to provide longitudinal information on schizophrenia relapse following acute ECT. Study design: This systematic review and meta-analysis included randomised controlled trials (RCTs) and observational studies on post-acute ECT relapse and rehospitalization for schizophrenia and related disorders. For the primary outcome, we calculated the post-acute ECT pooled relapse estimates at each timepoint (3, 6, 12, and 24 months post-acute ECT) using a random effects model. For subgroup analyses, we investigated post-acute ECT relapse proportions by the type of maintenance therapy. Study results: Among a total of 6413 records, 29 studies (3876 patients) met our inclusion criteria. The risk of bias was consistently low for all included RCTs (4 studies), although it ranged from low to high for observational studies (25 studies). Pooled estimates of relapse proportions among patients with schizophrenia responding to acute ECT were 24% (95% CI: 15-35), 37% (27-47), 41% (34-49), and 55% (40-69) at 3, 6, 12, and 24 months, respectively. When continuation/maintenance ECT was added to antipsychotics post-acute ECT, the 6-month relapse proportion was 20% (11-32). Conclusion: Relapse occurred mostly within 6 months post-acute ECT for schizophrenia, particularly within the first 3 months. Relapse proportions plateaued after 6 months, although more than half of all patients could be expected to relapse within 2 years. Further high-quality research is needed to optimise post-acute ECT treatment strategies in patients with schizophrenia.

Importance: Antipsychotics are the cornerstone of maintenance treatment in schizophrenia spectrum disorders, but it is unclear which agents should be prioritized by prescribers. Objective: To investigate the clinical effectiveness of antipsychotics, including recent market entries, in comparison with oral olanzapine in relapse and treatment failure prevention among individuals with schizophrenia spectrum disorder. Design, setting, and participants: This comparative effectiveness research study with a within-individual analysis included data from Swedish health care registers of inpatient and specialized outpatient care, sickness absence, and disability pensions among all individuals aged 16 to 65 years who were diagnosed with schizophrenia spectrum disorder from January 1, 2006, to December 31, 2021, including an incident cohort and a prevalent cohort. Exposures: Specific antipsychotics. Main outcomes and measures: The risks for psychosis relapse hospitalization and treatment failure (psychiatric hospitalization, death, or change in an antipsychotic medication) were adjusted for the temporal order of treatments, time since cohort entry, and concomitant drugs. Comparisons of all antipsychotics with oral olanzapine, the most commonly used antipsychotic, were investigated. Results: Among the full cohort of 131 476 individuals, the mean (SD) age of the study cohort was 45.7 (16.2) years (70 054 men [53.3%]). During a median follow-up of 12.0 years [IQR, 5.2-16.0 years], 48.5% of patients (N = 63 730) experienced relapse and 71.1% (N = 93 464) underwent treatment failure at least once. Compared with oral olanzapine, paliperidone 3-month long-acting injectable (LAI) was associated with the lowest adjusted hazard ratio (AHR) in the prevention of relapses (AHR, 0.66; 95% CI, 0.51-0.86), followed by aripiprazole LAI (AHR, 0.77 [95% CI, 0.70-0.84]), olanzapine LAI (AHR, 0.79 [95% CI, 0.73-0.86]), and clozapine (AHR, 0.82 [95% CI, 0.79-0.86]). Quetiapine was associated with the highest risk of relapse (AHR, 1.44 [95% CI, 1.38-1.51]). For prevention of treatment failure, paliperidone 3-month LAI was associated with the lowest AHR (AHR, 0.36 [95% CI, 0.31-0.42]), followed by aripiprazole LAI (AHR, 0.60 [95% CI, 0.57-0.63]), olanzapine LAI (AHR, 0.67 [95% CI, 0.63-0.72]), and paliperidone 1-month LAI (AHR, 0.71 [95% CI, 0.68-0.74]). Conclusions and relevance: This comparative effectiveness research study demonstrated large differences in the risk of relapse and treatment failure among specific antipsychotic treatments. The findings contradict the widely held conception that all antipsychotics are equally effective in relapse prevention.

Aims: This study aimed to estimate the strength of association between prescriptions of glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon-like peptide-1 receptor agonists (GLP-1 RA) and the incidence of opioid overdose and alcohol intoxication in patients with opioid use disorder (OUD) and alcohol use disorder (AUD), respectively. This study also aimed to compare the strength of the GIP/GLP-1 RA and substance use-outcome association among patients with comorbid type 2 diabetes and obesity. Design: A retrospective cohort study analyzing de-identified electronic health record data from the Oracle Cerner Real-World Data. Setting: About 136 United States of America health systems, covering over 100 million patients, spanning January 2014 to September 2022. Participants: The study included 503 747 patients with a history of OUD and 817 309 patients with a history of AUD, aged 18 years or older. Measurements: The exposure indicated the presence (one or more) or absence of GIP/GLP-1 RA prescriptions. The outcomes were the incidence rates of opioid overdose in the OUD cohort and alcohol intoxication in the AUD cohort. Potential confounders included comorbidities and demographic factors. Findings: Patients with GIP/GLP-1 RA prescriptions demonstrated statistically significantly lower rates of opioid overdose [adjusted incidence rate ratio (aIRR) in OUD patients: 0.60; 95% confidence interval (CI) = 0.43-0.83] and alcohol intoxication (aIRR in AUD patients: 0.50; 95% CI = 0.40-0.63) compared to those without such prescriptions. When stratified by comorbid conditions, the rate of incident opioid overdose and alcohol intoxication remained similarly protective for those prescribed GIP/GLP-1 RA among patients with OUD and AUD. Conclusions: Prescriptions of glucose-dependent insulinotropic polypeptide and/or glucagon-like peptide-1 receptor agonists appear to be associated with lower rates of opioid overdose and alcohol intoxication in patients with opioid use disorder and alcohol use disorder. The protective effects are consistent across various subgroups, including patients with comorbid type 2 diabetes and obesity.

Importance: Cannabis use during adolescence and young adulthood may affect academic achievement; however, the magnitude of association remains unclear. Objective: To conduct a systematic review evaluating the association between cannabis use and academic performance. Data sources: CINAHL, EMBASE, MEDLINE, PsycInfo, PubMed, Scopus, and Web of Science from inception to November 10, 2023. Study selection: Observational studies examining the association of cannabis use with academic outcomes were selected. The literature search identified 17 622 unique citations. Data extraction and synthesis: Pairs of reviewers independently assessed risk of bias and extracted data. Both random-effects models and fixed-effects models were used for meta-analyses, and the Grading of Recommendations Assessment, Development, and Evaluation approach was applied to evaluate the certainty of evidence for each outcome. Data were analyzed from April 6 to May 25, 2024. Main outcomes and measures: School grades, school dropout, school absenteeism, grade retention, high school completion, university enrollment, postsecondary degree attainment, and unemployment. Results: Sixty-three studies including 438 329 individuals proved eligible for analysis. Moderate-certainty evidence showed cannabis use during adolescence and young adulthood was probably associated with lower school grades (odds ratio [OR], 0.61 [95% CI, 0.52-0.71] for grade B and above); less likelihood of high school completion (OR, 0.50 [95% CI, 0.33-0.76]), university enrollment (OR, 0.72 [95% CI, 0.60-0.87]), and postsecondary degree attainment (OR, 0.69 [95% CI, 0.62-0.77]); and increased school dropout rate (OR, 2.19 [95% CI, 1.73-2.78]) and school absenteeism (OR, 2.31 [95% CI, 1.76-3.03]). Absolute risk effects ranged from 7% to 14%. Low-certainty evidence suggested that cannabis use may be associated with increased unemployment (OR, 1.50 [95% CI, 1.15-1.96]), with an absolute risk increase of 9%. Subgroup analyses with moderate credibility showed worse academic outcomes for frequent cannabis users and for students who began cannabis use earlier. Conclusions and relevance: Cannabis use during adolescence and young adulthood was probably associated with increases in school absenteeism and dropout; reduced likelihood of obtaining high academic grades, graduating high school, enrolling in university, and postsecondary degree attainment; and perhaps increased unemployment. Further research is needed to identify interventions and policies that mitigate upstream and downstream factors associated with early cannabis exposure.

Altered fear conditioning and extinction learning are discussed as key etiological features in anxiety disorders. Women have an increased risk for anxiety disorders and fear conditioning has been shown to be influenced by the menstrual cycle phase and circulating gonadal hormones. The objective of our study was to investigate the effects of separate and combined estradiol and progesterone administration on fear extinction in healthy women. We conducted a placebo-controlled, randomized study in healthy women, who completed a fear conditioning paradigm on three consecutive days: fear acquisition training on day 1, fear extinction training on day 2, and return of fear test on day 3. Skin conductance responses (SCRs) served as main outcome variable. Two hours before testing on day 2, participants received pills containing either placebo, estradiol (2 mg), progesterone (400 mg) or the combination of both. We examined 116 women (mean age 25.7 ± 6.0 years), who showed significantly stronger conditioned SCRs to the CS+ than CS- during fear acquisition training indicating successful fear learning. At the beginning of the fear extinction training, estradiol administration reduced the differentiation between the conditioned stimuli. In the return of fear test, the estradiol groups showed heightened SCR responses to the previously extinguished stimulus, i.e., impaired extinction recall. Administration of progesterone did not have any significant influence on SCRs. There were also no effects on fear potentiated startle response. In our interpretation, exogenous estradiol administration affected the extinction of the conditioned fear response which led subsequently to a stronger return of fear. From a clinical perspective our findings suggest that estradiol levels may have an influence on the success of exposure therapy and could be taken into consideration when planning exposure sessions.

Background: Controlled research examining maintenance treatments for responders to acute interventions for binge-eating disorder (BED) is limited. This study tested efficacy of lisdexamfetamine (LDX) maintenance treatment amongst acute responders. Methods: This prospective randomized double-blind placebo-controlled single-site trial, conducted March 2019 to September 2023, tested LDX as maintenance treatment for responders to acute treatments with LDX-alone or with cognitive-behavioral therapy (CBT + LDX) for BED with obesity. Sixty-one (83.6% women, mean age 44.3, mean BMI 36.1 kg/m2) acute responders were randomized to LDX (N = 32) or placebo (N = 29) for 12 weeks; 95.1% completed posttreatment assessments. Mixed-models and generalized-estimating equations comparing maintenance LDX v. placebo included main/interactive effects of acute (LDX or CBT + LDX) treatments to examine their predictive/moderating effects. Results: Relapse rates (to diagnosis-level binge-eating frequency) following maintenance treatments were 10.0% (N = 3/30) for LDX and 17.9% (N = 5/28) for placebo; intention-to-treat binge-eating remission rates were 59.4% (N = 19/32) and 65.5% (N = 19/29), respectively. Maintenance LDX and placebo did not differ significantly in binge-eating but differed in weight-loss and eating-disorder psychopathology. Maintenance LDX was associated with significant weight-loss (-2.3%) whereas placebo had significant weight-gain (+2.2%); LDX and placebo differed significantly in weight-change throughout treatment and at posttreatment. Eating-disorder psychopathology remained unchanged with LDX but increased significantly with placebo. Acute treatments did not significantly predict/moderate maintenance-treatment outcomes. Conclusions: Adults with BED/obesity who respond to acute lisdexamfetamine treatment (regardless of additionally receiving CBT) had good maintenance during subsequent 12-weeks. Maintenance lisdexamfetamine, relative to placebo, did not provide further benefit for binge-eating but was associated with significantly better eating-disorder psychopathology outcomes and greater weight-loss.

Several studies have highlighted increased psychosis risk in migrant and minority ethnic populations. Migration before age 18 appears to increase risk, but further evidence is required. We investigated this issue in a European case-control study. We hypothesized that migration during two key socio-developmental periods, childhood and adolescence, would be most strongly associated with increased odds of psychosis, and that this would be more pronounced for racialised minorities. We used data from five countries in the EUropean network of national schizophrenia networks studying Gene-Environment Interactions [EU-GEI] study. We examined the association between migration in infancy (0–4 years), childhood (5–10 years), adolescence (11–17 years) or adulthood (18+ years) and first episode psychotic disorder. We fitted unadjusted and adjusted logistic regression models to estimate odds ratios [OR] and 95% confidence intervals [95%CI] for associations between age-at-migration and psychosis. In stratified models, we also examined whether these associations varied by ethnicity. The sample consisted of 937 cases and 1,195 controls. Migration at all ages, including infancy (OR: 2.03, 95%CI: 1.01–4.10), childhood (OR: 2.07, 95%CI: 1.04–4.14), adolescence (OR: 3.26, 95%CI: 1.89–5.63) and adulthood (OR: 1.71, 95%CI: 1.21–2.41), was associated with increased odds of psychosis compared with the white majority non-migrant group, after adjustment for all confounders except ethnoracial identity. After additional adjustment for ethnoracial identity, only migration during adolescence remained associated with psychosis (OR 1.94, 95%CI: 1.11–3.36). In stratified analyses, migration during adolescence was associated with increased odds of psychosis in Black (OR: 6.52, 95%CI: 3.00–14.20) and North African (OR: 16.43, 95%CI: 1.88–143.51) groups.Migration during adolescence increased psychosis risk, particularly in racially minoritised young people. This suggests that development of interventions for minoritised young migrants that alleviate stressors associated with migration and acculturation are warranted.

Background: Traditional treatments for post-traumatic stress disorder (PTSD) often show limited success with high dropout. Ketamine, an N-methyl-D-aspartate antagonist known for rapid antidepressant effects, has decreased PTSD symptoms in some studies but not in others. Administering ketamine in ways that parallel psychedelic-assisted treatments-including preparatory, integration, sensory immersion, and psychotherapy sessions-could decrease PTSD symptoms meaningfully. Methods: A retrospective sample of 117 screened outpatients with elevated PTSD Checklist for DSM-5 (PCL-5) scores received intravenous ketamine in supportive environments. The protocol included preparation, intention-setting, and integration sessions accompanying at least six administrations. Administration sessions included eye shades and evocative music paralleling typical psychedelic therapy trials. Results: Mean PCL scores decreased from 52.54 (SD = 12.01) to 28.78 (SD = 16.61), d = 1.64. Patients tolerated treatment well, with no serious adverse events. Covariates, including age, gender, days between PCL assessments, number of psychiatric medications, and suicidal ideation were not significant moderators; concomitant psychotherapy did reach significance, d = 0.51. Of the 117 patients' final PCL scores, 88 (75.21%) measures suggested clinically meaningful improvement and 72 (61.54%) suggested remission of PTSD symptoms. Conclusion: Intravenous ketamine in supportive environments, with hallmarks of psychedelic therapy, preceded large reductions in PTSD symptoms. These results highlight ketamine's potential when delivered in this manner, suggesting environmental factors might account for some variation seen in previous work. Given the molecule's cost, minimal interaction with other psychiatric medications, and legal status, intravenous ketamine in a psychedelic paradigm may be a promising option for PTSD unresponsive to other treatments.

In response to restrictions on electroconvulsive therapy (ECT) access during COVID-19, we designed a trial to assess the clinical outcomes service impacts, employing an extended course of accelerated intermittent theta burst stimulation (aiTBS), in patients with moderate to severe depression in need of ECT. This open label clinical trial was comprised of 3 phases: (i) an acute phase, where iTBS treatments were administered 8 times daily, for up to 10 days; (ii) a tapering phase of 2 treatment days per week for 2 weeks, followed by 1 treatment day per week for 2 weeks; and (iii) a symptom-based relapse prevention phase, whereby treatments were scheduled based on symptom re-emergence, for up to 6 months. Of the 155 patients who completed the acute phase of the study, the remission rate was 16.1%. The mean reduction from baseline on the HRSD-24 was 29.4% (p < 0.001) and the response rate was 25.2%. Of the 110 patients who completed the tapering phase, the mean reduction from baseline was 42.6% (p < 0.001) and response and remission rates were 49.6% and 34.8%, respectively. Of the 61 patients who were eligible for the relapse prevention phase, 43 completed, with a mean reduction from baseline of 60.1% (p < 0.001); 7 patients relapsed during this phase. This study demonstrated that an extended aiTBS protocol safely led to meaningful clinical outcomes in patients with severe depression, who otherwise would have received ECT, and thus reduced pressure on ECT services during the pandemic.

No abstract available

While clozapine has risks, relative risk of fatality is overestimated. The UK pharmacovigilance programme is efficient, but comparisons with other drugs can mislead because of reporting variations. Clozapine actually lowers mortality, partly by reducing schizophrenia-related suicides, but preventable deaths still occur. Clozapine should be used earlier and more widely, but there should be better monitoring and better management of toxicity.

Objective: Amphetamine prescribing has increased in the United States in recent years. Previous research identified an increased risk of incident psychosis with prescription amphetamines. The purpose of this study was to examine the impact of dose levels of prescription amphetamines on the risk of this rare but serious adverse outcome. Methods: A case-control study using electronic health records was conducted to compare the odds of incident psychosis or mania with past-month exposure to prescription amphetamines. Case subjects were patients ages 16-35 hospitalized at McLean Hospital for incident psychosis or mania between 2005 and 2019. Control subjects were patients with an initial psychiatric hospitalization for other reasons, most commonly depression and/or anxiety. Amphetamine doses were converted to dextroamphetamine equivalents and divided into terciles. Secondary analyses evaluated the odds of psychosis or mania with methylphenidate use. Results: Among 1,374 case subjects and 2,748 control subjects, the odds of psychosis and mania were increased for individuals with past-month prescription amphetamine use compared with no use (adjusted odds ratio=2.68, 95% CI=1.90-3.77). A dose-response relationship was observed; high doses of amphetamines (>30 mg dextroamphetamine equivalents) were associated with 5.28-fold increased odds of psychosis or mania. Past-month methylphenidate use was not associated with increased odds of psychosis or mania compared with no use (adjusted odds ratio=0.91, 95% CI=0.54-1.55). Conclusions: Although use of hospitalized control subjects excludes individuals with less severe disease, leading to selection bias, the study results suggest that caution should be exercised when prescribing high doses of amphetamines, with regular screening for symptoms of psychosis or mania.

Objective: Antipsychotic effectiveness in preventing relapse declines around menopausal age in women with schizophrenia or schizoaffective disorder (SSD). It is not known whether systemic menopausal hormone therapy (MHT) can help to prevent psychosis relapse. Methods: A within-subject study design was used to study the effectiveness of MHT in preventing relapse in a Finnish nationwide cohort of women with SSD between 40 and 62 years of age who used MHT during follow-up (1994-2017). Hazard ratios adjusted for age and psychotropic drug use were calculated for psychosis relapse as main outcome and any psychiatric hospitalization as secondary outcome. Results: The study population comprised 3,488 women using MHT. Use of MHT was associated with a 16% lower relapse risk (adjusted hazard ratio [aHR]=0.84, 95% CI=0.78-0.90) when compared to non-use. Stratified by age, MHT was associated with decreased relapse risks when used between ages 40-49 (aHR=0.86, 95% CI=0.78-0.95) and ages 50-55 (aHR=0.74, 95% CI=0.66-0.83), but not between ages 56-62 (aHR=1.11, 95% CI=0.91-1.37). Similar effectiveness was found for estrogen alone or combined with fixed or sequential progestogens (aHRs between 0.79 and 0.86), transdermal and oral formulations (aHRs 0.75-0.87), and for most specific formulations (aHRs 0.75-0.85), except tibolone (aHR=1.04, 95% CI=0.75-1.44) and formulations with dydrogesterone (aHR=1.05, 95% CI=0.85-1.30). Similar results were observed with any psychiatric hospitalization as outcome measure. Conclusions: The findings underscore the potential value of MHT in preventing psychosis relapse among women with SSD of menopausal age. These findings translate clinical evidence on the neuroprotective effects of estrogens to real-world settings, encompassing a group of women for whom current antipsychotic treatment options may be insufficient.

Weighing risks and benefits of the use of psychotropic medications during pregnancy remains a challenge worldwide. We systematically assessed the strength of associations between psychotropic medication use in pregnant people with mental disorders and various adverse health outcomes in both pregnant people and foetuses. Systematic reviews with meta-analyses of observational studies investigating the association between exposure to psychotropic medication in pregnancy and any adverse health outcomes were included. Credibility was graded into convincing, highly suggestive, suggestive, weak or not significant. Quality of the meta-analyses and of individual studies were assessed with A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) the Newcastle-Ottawa Scale (NOS), respectively. We considered 21 meta-analyses encompassing 17,290,755 participants (AMSTAR 2 high = 1, low = 12, or critically low = 8). Evidence was suggestive for: (1) preterm birth in pregnant people with either any mental disorder (equivalent odds ratio 1.62 (95% confidence interval 1.24-2.12) or depression (1.65 [1.34-2.02]) receiving antidepressants during any trimester of pregnancy; (2) small for gestational age for pregnant people with depression receiving a SSRI during any trimester of pregnancy (1.50 [1.19-1.90]); and (3) major congenital malformation (1.24 [1.09-1.40]) or cardiac malformations (1.28 [1.11-1.47]) in babies for pregnant people with depression or anxiety receiving paroxetine during first trimester of pregnancy. Additional associations were supported by weak evidence, or were not statistically significant. This umbrella review found no convincing or highly suggestive level of evidence of adverse health outcomes associated with psychotropic medication use in pregnant people with mental disorders.

Background: Clozapine is the most effective antipsychotic for treatment-resistant psychosis. However, clozapine is underutilised in part because of potential agranulocytosis. Accumulating evidence indicates that below-threshold haematological readings in isolation are not diagnostic of life-threatening clozapine-induced agranulocytosis (CIA). Aims: To examine the prevalence and timing of CIA using different diagnostic criteria and to explore demographic differences of CIA in patients registered on the UK Central Non-Rechallenge Database (CNRD). Method: We analysed data of all patients registered on the UK Clozaril® Patient Monitoring Service Central Non-Rechallenge Database (at least one absolute neutrophil count (ANC) < 1.5 × 109/L and/or white blood cell count < 3.0 × 109/L) between May 2000 and February 2021. We calculated prevalence rates of agranulocytosis using threshold-based and pattern-based criteria, stratified by demographic factors (gender, age and ethnicity). Differences in epidemiology based on rechallenge status and clozapine indication were explored. The proportion of patients who recorded agranulocytosis from a normal ANC was explored. Results: Of the 3029 patients registered on the CNRD with 283 726 blood measurements, 593 (19.6%) were determined to have threshold-based agranulocytosis and 348 (11.4%) pattern-based agranulocytosis. In the total sample (75 533), the prevalence of threshold-based agranulocytosis and pattern-based agranulocytosis was 0.8% and 0.5%, respectively. The median time to threshold-based agranulocytosis was 32 weeks (IQR 184) and 15 (IQR 170) weeks for pattern-based agranulocytosis. Among age groups, the prevalence of pattern-based agranulocytosis and threshold-based agranulocytosis was highest in the >48 age group. Prevalence rates were greatest for White (18%) and male individuals (13%), and lowest for Black individuals (0.1%). The proportion of people who were determined to have pattern-based agranulocytosis without passing through neutropenia was 70%. Conclusions: Threshold-based definition of agranulocytosis may over-diagnose CIA. Monitoring schemes should take into consideration neutrophil patterns to correctly identify clinically relevant CIA. In marked contrast to previous studies, CIA occurred least in Black individuals and most in White individuals. Accelerated Resolution Therapy (ART) for the treatment of posttraumatic stress disorder in adults: A systematic review Accelerated Resolution Therapy (ART), developed in 2008, uses techniques such as rapid eye movement, in vivo exposure, and image rescripting to recondition stressful memories, and reduce physical and emotional reactions to traumatic memories. There is considerable interest in evidence-based treatments for post-traumatic stress disorder (PTSD). This is the first systematic review examining the efficacy of ART for the treatment of PTSD among adults. We searched MEDLINE, PsycINFO, Embase, CINAHL, Scopus, trial registries, and government and private websites for citations published before October 2023. Studies that reported on the effect of ART for PTSD among adults were included. Meta-analyses could not be undertaken due to heterogeneity in study designs and an insufficient number of studies with a low risk of bias. Risk of bias was assessed, and findings synthesized following the synthesis without meta-analysis (SWiM) guidelines. Of the 112 records screened, five studies (Nenrolled = 337; Ncompleted = 250) and six reports of studies met criteria for inclusion. Included studies reported a significant reduction in symptoms of PTSD from pre- to post-intervention, d = 1.12 to 3.28. Significant reductions were also reported in symptoms of depression, mental distress, anxiety, and sleep dysfunction. ART shows some promise as a time-efficient clinical treatment for symptoms of PTSD in adults; however, more high-quality studies are needed. Effects of diagnostic labels on perceptions of marginal cases of mental ill-health Two experimental studies (Ns = 261, 684) investigated how diagnostic labels affect perceptions of people experiencing marginal levels of mental ill-health. These effects offer insight into the consequences of diagnostic “concept creep”, in which concepts of mental illness broaden to include less severe phenomena. The studies found consistent evidence that diagnostic labeling increases the perception that people experiencing marginal problems require professional treatment, and some evidence that it increases empathy towards them and support for affording them special allowances at work, school, and home. The studies also indicated that labels may reduce the control people are perceived to have over their problems and their likelihood of recovering from them. These findings point to the potential mixed blessings of broad diagnostic concepts and the cultural trends responsible for them. Expansive concepts may promote help-seeking, empathy, and support, but also undermine perceived agency and expectations that problems can be overcome.

Background: The current study seeks to investigate the mechanisms through which mindfulness is related to mental health in a clinical sample of adults by examining (1) whether specific cognitive emotion regulation strategies (rumination, reappraisal, worry, and nonacceptance) mediate associations between mindfulness and depression and anxiety, respectively, and (2) whether these emotion regulation strategies operate uniquely or transdiagnostically in relation to depression and anxiety. Methods: Participants were 187 adults seeking treatment at a mood and anxiety disorders clinic in Connecticut. Participants completed a battery of self-report measures that included assessments of depression and anxiety (Mood and Anxiety Symptom Questionnaire), and emotion regulation (Ruminative Response Scale, Penn State Worry Questionnaire, Emotion Regulation Questionnaire, Difficulties in Emotion Regulation Scale). Results: Simple mediation analyses indicated that rumination and worry significantly mediated associations between mindfulness and anxiety symptoms, whereas rumination and reappraisal significantly mediated associations between mindfulness and depressive symptoms. Multiple mediation analyses showed that worry significantly mediated associations between mindfulness and anxiety symptoms and rumination and reappraisal significantly mediated associations between mindfulness and depressive symptoms. Conclusions: Findings suggest that mindfulness operates through distinct and common mechanisms depending on clinical context.

Objective: Adolescent offspring of parents with bipolar disorder (BD) are at high risk to develop BD and other psychopathology, yet how this risk continues into middle adulthood remains unknown. This study aimed to determine the window of risk for BD and other psychopathology in offspring of parents with BD followed from adolescence into adulthood. Method: This study reported on the 22-year follow-up assessment of the Dutch Bipolar Offspring Study, a fixed cohort study of 140 participants established in 1997. Offspring (n = 100; mean [SD] age = 38.28 [2.74] years) of parents with bipolar I disorder or bipolar II disorder were assessed at baseline and 1-, 5-, 12-, and 22-year follow-up. Results: No new BD onsets occurred since the 12-year follow-up (lifetime prevalence = 11%-13%; bipolar I disorder = 4%; bipolar II disorder = 7%). Lifetime prevalence of any mood disorder was 65%; for major depressive disorder, prevalence was 36%; and for recurrent mood episodes, prevalence was 37%. Prevalence of major depressive disorder more than doubled in the past decade. Point prevalence of any psychopathology peaked between 20 and 25 years (38%-46%), subsiding to 29% to 35% per year after age 30. Overall, 71% of offspring contacted mental health services since the last assessment. Conclusion: The risk for homotypic transmission of BD in offspring of parents with BD is highest during adolescence. The heterotypic risk for mood disorder onset and recurrences continues over the life course. Severe mood disorders are often preceded by milder psychopathology, emphasizing the need for early identification and interventions. This study allows for better understanding of the onset and course of mood disorders and specific windows of risk in a familial high-risk population.

Objective: To compare second-generation antipsychotics (SGAs) and mood stabilizers (MSs) in youth with a bipolar disorder type I (BD-I) manic/mixed episode. Method: A systematic PubMed/Embase/PsycInfo literature search until December 31, 2023, for randomized trials of SGAs or MSs in patients ≤18 years of age with BD-I manic/mixed episode was conducted. The study included a network meta-analysis comparing treatments regarding mania symptoms and mania response (co-primary outcomes), and secondary efficacy and tolerability outcomes. Results: Eighteen studies (n = 2844, mean age = 11.74, female participants = 48.0%, mean study duration = 5.4 weeks) comparing 6 SGAs (aripiprazole, asenapine, olanzapine, quetiapine, risperidone, and ziprasidone) and 4 MSs (lithium, oxcarbazepine, topiramate, and valproate) were meta-analyzed. All 6 SGAs outperformed placebo in reducing manic symptomatology, including risperidone (standardized mean difference [SMD] = -1.18, 95% CI = -0.92, -1.45, Confidence in Network Meta-Analysis [CINeMA] = moderate confidence), olanzapine (SMD = -0.77, 95% CI = -0.36, -1.18, low confidence), aripiprazole (SMD = -0.67, 95% CI = -0.33, -1.01, moderate confidence), quetiapine (SMD = -0.60, 95% CI = -0.32, -0.87, high confidence), asenapine (SMD = -0.54, 95% CI = -0.19, -0.89, moderate confidence), and ziprasidone (SMD = -0.43, 95% CI = -0.17, 0.70, low confidence), whereas no mood stabilizer outperformed placebo. Concerning mania response, risperidone (Risk ratio [RR] = 2.58, 95% CI = 1.88, 3.54, low confidence), olanzapine (RR = 2.42, 95% CI = 1.33, 3.54, very low confidence), aripiprazole (RR = 2.05, 95% CI = 1.44, 2.92, low confidence), quetiapine (RR = 1.89, 95% CI = 1.45n 2.47, moderate confidence), asenapine (RR = 1.81, 95% CI = 1.28, 2.55, very low confidence) and lithium (RR = 1.35, 95% CI = 1.00, 1.83, p = .049, very low confidence) outperformed placebo, without superiority of other MSs vs placebo. Individually, risperidone was more efficacious in reducing manic symptomatology than all other comparators, except olanzapine and topiramate, yet with low/very low confidence, and was associated with increased prolactin and glucose. Pooled together, SGAs outperformed both placebo and MSs for mania symptom reduction (SMD = -0.68, 95% CI = -0.86, -0.51 and SMD = -0.61, 95% CI = -0.82, -0.40, moderate confidence), and mania response (RR = 1.85, 95% CI = 1.53, 2.24 and RR = 1.65, 95% CI = 1.33, 2.04, moderate confidence) without differences between MSs and placebo. There were no significant treatment-placebo differences for all-cause discontinuation, whereas lithium, ziprasidone, and oxcarbazepine were associated with more adverse event-related drop-outs than placebo. Most SGAs were associated with more sedation, weight gain, and metabolic issues vs placebo and MSs. Conclusion: SGAs were more efficacious than placebo and MSs in treating acute mania symptoms, however, their use must be carefully weighed against important side effects.

Objective: The aim of the current study was to identify the age at which sexual orientation disparity in mental health diagnoses can be first identified, as well as gender and sexual identity subgroup differences in such treatment, in a population-based sample. Method: Young people aged 16 to 25 (N = 10,406) participating in the probability-based Swedish National Public Health Survey in 2018 were included. This sample was linked to physician-assessed mental health care treatment history data starting when all participants were 8 years old using national health care registries. Results: Participants reporting a sexual minority identity in adolescence and young adulthood were more than 3 times as likely to have been treated for an internalizing disorder diagnosis (eg, depression, anxiety) and more than twice as likely to have been treated for a neurodevelopmental disorder diagnosis during childhood than participants reporting a heterosexual identity. Sexual minority participants overall and women in particular were more likely to have been treated for an internalizing disorder diagnosis at an early age compared with heterosexual participants, with this disparity starting at age 13. The sexual orientation disparity in likelihood of treatment for a neurodevelopmental disorder diagnosis was particularly elevated among bisexual/pansexual women with this disparity starting in early/middle adolescence. Conclusion: This population-based study linked to physician-assessed mental health diagnoses during childhood and adolescence identifies the age at which sexual orientation differences in treatment for common mental disorders emerge. The early emergence of this disparity suggests a potential benefit of interventions that facilitate social belonging for all youth.

Objective: To examine longitudinal associations between early life threat and deprivation on epigenetic age acceleration at ages 9 and 15 years, and to examine associations of age acceleration on later internalizing and externalizing symptoms. Method: The study examines a large (n = 2,039) and racially diverse (Black/African American = 44%, Latino = 18%, White = 5%) sample from a national dataset. Epigenetic age acceleration was estimated using the pediatric buccal epigenetic clock. Early life threat and deprivation were measured using composites from the Parent-Child Conflict Tactics Scale and county-level violent and property crime rate data. Internalizing and externalizing symptoms came from parent-reported Child Behavior Checklist. Path analysis models examined associations of threat and deprivation at age 3 years on epigenetic age acceleration at ages 9 and 15. Experiences of threat were further broken down into threat experienced in the home and in the community. Results: Home threat experienced at age 3 years predicted age acceleration at 9 and 15, and community threat experienced at 3 predicted age acceleration at 15, but not at 9. Deprivation was not a significant predictor of accelerated aging. Age acceleration at age 9 predicted externalizing, but not internalizing, symptoms at age 15. Community threat had a direct effect on externalizing. No association emerged with internalizing. Conclusion: Findings revealed that threat, not deprivation, was predictive of age acceleration, demonstrating support for this pattern longitudinally, using an epigenetic clock that is accurate in children. The findings provide critical nuance to the examination of threat, and highlight associated risks and possible intervention points for externalizing symptoms.

Insomnia is highly comorbid in patients with psychiatric disorders, including depression, bipolar disorder, and substance use disorders, and should be treated as an independent condition. Dual orexin receptor antagonists (DORAs) have been investigated as a treatment for chronic insomnia. The objective of this systematic review was to examine evidence for two DORAs, lemborexant and suvorexant, as treatments for insomnia comorbid with a psychiatric disorder. We searched PubMed, Cochrane, and Embase from their inception until January and April 2023, and included studies examining suvorexant and lemborexant for treating insomnia comorbid with psychiatric disorders. We also manually searched clinical trial registries ( https://clinicaltrials.gov and https://www.umin.ac.jp/ctr ). Randomized clinical trials and observational/cohort studies were included. We identified 18 studies from PubMed, Cochrane, and Embase and three studies from clinicaltrials.gov and UMIN. Of the 21 reports, four were completed/terminated randomized clinical trials, eight were ongoing clinical trials, and nine were observational studies. We identified evidence for switching from benzodiazepine receptor agonists to a DORA, or using a DORA as add-on therapy and, therefore, discuss this topic as well. Two studies examined switching to or adding on a DORA in patients being treated with a benzodiazepine receptor agonist. DORAs may be as effective and safe for treating psychiatric comorbid insomnia (for most psychiatric conditions) as they are for treating primary insomnia. However, the evidence is limited to a few small studies. Further investigation of DORAs for the treatment of comorbid insomnia in those with coexisting psychiatric conditions is warranted.

Achieving optimal treatment outcomes for individuals living with schizophrenia remains challenging, despite 70 years of drug development efforts. Many chemically distinct antipsychotics have been developed over the past 7 decades with improved safety and tolerability but with only slight variation in efficacy. All antipsychotics currently approved for the treatment of schizophrenia act as antagonists or partial agonists at the dopamine D2 receptor. With only a few possible exceptions, antipsychotic drugs have similar and modest efficacy for treating positive symptoms and are relatively ineffective in addressing the negative and cognitive symptoms of the disease. The development of novel treatments focused on targeting muscarinic acetylcholine receptors (mAChRs) has been of interest for more than 25 years following reports that treatment with a dual M1/M4-preferring mAChR agonist resulted in antipsychotic-like effects and procognitive properties in individuals living with Alzheimer's disease and schizophrenia; more recent clinical trials have confirmed these findings. In addition, advances in our understanding of the receptor binding and activation properties of xanomeline at specific mAChRs have the potential to inform future drug design targeting mAChRs.

Background: Outcome monitoring of depression treatment is recommended but there is a lack of evidence on patient benefit in primary care. Aim: To test monitoring depression using the Patient Health Questionnaire (PHQ-9) with patient feedback. Design and setting: An open cluster-randomised controlled trial was undertaken in 141 group practices. Method: Adults with new depressive episodes were recruited through record searches and opportunistically. The exclusion criteria were as follows: dementia; psychosis; substance misuse; and suicide risk. The PHQ-9 was administered soon after diagnosis, and 10-35 days later. The primary outcome was the Beck Depression Inventory (BDI-II) score at 12 weeks. The secondary outcomes were as follows: BDI-II at 26 weeks; Work and Social Adjustment Scale (WSAS) and EuroQol EQ-5D-5L quality of life at 12 and 26 weeks; antidepressant treatment; mental health and social service contacts; adverse events, and Medical Interview Satisfaction Scale (MISS) over 26 weeks. Results: In total, 302 patients were recruited to the intervention arm and 227 to the controls. At 12 weeks, 254 (84.1%) and 199 (87.7%) were followed-up, respectively. Only 40.9% of patients in the intervention had a GP follow-up PHQ-9 recorded. There was no significant difference in BDI-II score at 12 weeks (mean difference -0.46; 95% confidence interval [CI] = -2.16 to 1.26; adjusted for baseline depression, baseline anxiety, sociodemographic factors, and clustering by practice). EQ-5D-5L quality-of-life scores were higher in the intervention arm at 26 weeks (adjusted mean difference 0.053; 95% CI = 0.013 to 0.093. A clinically significant difference in depression at 26 weeks could not be ruled out. No significant differences were found in social functioning, adverse events, or satisfaction. In a per-protocol analysis, antidepressant use and mental health contacts were significantly greater in patients in the intervention arm with a recorded follow-up PHQ-9 (P = 0.025 and P = 0.010, respectively). Conclusion: No evidence was found of improved depression outcome at 12 weeks from monitoring. The findings of possible benefits over 26 weeks warrant replication, investigating possible mechanisms, preferably with automated delivery of monitoring and more instructive feedback.

Background: Despite strong evidence of efficacy of electroconvulsive therapy (ECT) in the treatment of depression, no sensitive and specific predictors of ECT response have been identified. Previous meta-analyses have suggested some pre-treatment associations with response at a population level. Aims: Using 10 years (2009-2018) of routinely collected Scottish data of people with moderate to severe depression (n = 2074) receiving ECT we tested two hypotheses: (a) that there were significant group-level associations between post-ECT clinical outcomes and pre-ECT clinical variables and (b) that it was possible to develop a method for predicting illness remission for individual patients using machine learning. Method: Data were analysed on a group level using descriptive statistics and association analyses as well as using individual patient prediction with machine learning methodologies, including cross-validation. Results: ECT is highly effective for moderate to severe depression, with a response rate of 73% and remission rate of 51%. ECT response is associated with older age, psychotic symptoms, necessity for urgent intervention, severe distress, psychomotor retardation, previous good response, lack of medication resistance, and consent status. Remission has the same associations except for necessity for urgent intervention and, in addition, history of recurrent depression and low suicide risk. It is possible to predict remission with ECT with an accuracy of 61%. Conclusions: Pre-ECT clinical variables are associated with both response and remission and can help predict individual response to ECT. This predictive tool could inform shared decision-making, prevent the unnecessary use of ECT when it is unlikely to be beneficial and ensure prompt use of ECT when it is likely to be effective.

This editorial describes the Cass Review findings and the extraordinary challenge we all face in managing uncertainty amid a toxic and highly polarised debate. Children and young people will only get the best care if patients and professionals join forces to seek answers collaboratively and respectfully.

This editorial summarises the clinical relevance of 'chronopsychiatry', defined as the interface between circadian science and mental health science. Chronopsychiatry represents a move towards time-variable perspectives on neurobiology and symptoms, with a greater emphasis on chronotherapeutic interventions.

This Viewpoint discusses clinical trial results of glucagon-like peptide 1 receptor agonists for treating the weight gain and cardiovascular disease risk of psychiatric medications.