December/January 2025-2026

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.