November 2025

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.