Interleukin 6 (IL-6), a keystone inflammatory cytokine, is a credible mechanistic candidate for causing depression. However, randomized clinical trials testing its treatment potential remain scarce. To identify likely treatment-sensitive outcomes and effect size for systemic IL-6 inhibition in patients with difficult-to-treat depression. This 4-week, proof-of-concept, double-blind, parallel-arm, placebo-controlled randomized clinical trial recruited adults with moderate-to-severe International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) depression, poor antidepressant response, low-grade systemic inflammation (high-sensitivity C-reactive protein [hs-CRP] level ≥0.3 mg/dL on 2 tests), and depression somatic symptoms (Beck Depression Inventory II somatic symptoms score ≥7) from primary and secondary care and self-referral from 2018 to 2022. Participants were randomized into minimization balanced groups on depression severity and sex. Assessments were conducted at baseline and 7, 14, and 28 days after infusion. Data were analyzed from 2023 to 2025. Single intravenous infusion of IL-6R antagonist tocilizumab (8 mg/kg, maximum 800 mg/patient) or normal saline. The primary outcome was depression somatic symptoms at 14 days after infusion. The secondary outcome was total depression severity. Exploratory outcomes included fatigue, anxiety, anhedonia, quality of life, and cognition. Outcomes were assessed using validated scales and interpreted against clinically meaningful thresholds. A total of 30 participants (mean [SD] age, 41.1 [12.3] years; 24 [80.0%] female) were randomized, including 14 in the tocilizumab group and 16 in the placebo group. Of these, 29 participants received the assigned infusion and completed follow-up. As expected for a small proof-of-concept study, no results reached statistical significance, including little improvement in depression somatic symptoms at day 14 (adjusted mean difference: -0.12; 95% CI, -2.51 to 2.28). However, a pattern of greater stepwise improvement over time was observed with tocilizumab in somatic symptoms, depression severity, fatigue, psychological symptoms, state anxiety, and quality of life, with the largest effects observed at the final follow-up (day 28). Tocilizumab may also improve more individual depressive symptoms. Treatment effects were within ranges considered clinically meaningful for depression severity, fatigue, anxiety, and quality of life. At the final follow-up, remission (7 participants [53.9%] vs 5 participants [31.3%]; number needed to treat [NNT] = 5) and response (6 participants [46.2%] vs 3 participants [18.8%]; NNT = 4) rates favored tocilizumab compared with placebo. Baseline hs-CRP level, but not IL-6 level, tracked depression improvement, suggesting hs-CRP may better predict immunotherapy response in depression than drug-specific biomarkers. Tocilizumab was well tolerated, with no serious adverse events or withdrawals. These findings highlight treatment-sensitive outcomes, effect sizes, and patient selection methods for testing systemic IL-6 inhibition in patients with difficult-to-treat depression, and call for a large-scale efficacy trial of anti-IL-6 treatment in depression. isrctn.org Identifier: ISRCTN16942542.

Individuals with mental disorders often experience multiple disease episodes and diagnostic changes after initial psychiatric contact. However, studies that comprehensively investigate heterogeneity in disease development beyond pairs of comorbid diseases and mortality from a transdiagnostic perspective have been lacking. To comprehensively study sex and age patterns of disease development for 7 major groups of mental disorders. This cohort study included data from linkage of national Danish registers of all adult individuals living in Denmark between 2000 and 2018. Adult individuals with 1 of the following first-time mental disorder diagnoses were included: substance use disorder, schizophrenia, psychotic disorder other than schizophrenia, mania and bipolar disorder, major depressive disorder, anxiety-related disorders, or personality disorders. Data were analyzed from August 2023 to December 2025. For each of the 7 mental disorder categories, age- and sex-specific estimates of (1) the number of diagnostic shifts, (2) the absolute risk of pairwise diagnostic shifts, (3) the absolute risk of diagnostic recurrence, and (4) the number of psychiatric contacts encompassing inpatient admissions, outpatient treatment courses, and emergency department visits were calculated using age groups 18 to 24 years, 25 to 39 years, 40 to 59 years, and 60 years or older and male and female sex. A total of 273 400 individuals (mean [SD] age at first contact, 41.4 [18.7] years; 150 349 female [55.0%]) with mental disorders were included and followed up for 2.1 million person-years. Diagnostic shifts were observed among 66 474 individuals (24.3%), and 30 558 (11.8%) had multiple diagnostic shifts. Individuals with psychotic disorders had the highest number of psychiatric contacts and diagnostic shifts. Younger age at first contact was associated with more psychiatric contacts and higher number of diagnostic shifts irrespective of diagnosis given at first contact as well as higher probabilities for most pairwise diagnostic shifts and diagnostic recurrence. Males showed a pattern of higher absolute risk of diagnostic shifts to substance use disorders and schizophrenia spectrum disorders than females, whereas females had a higher probability of diagnostic shifts to mood disorders, anxiety-related disorders, and personality disorders. This study found that disease development across the 4 outcomes was highly dependent on the specific diagnosis given at first contact as well as the patient's sex and age group. These findings are important for treatment planning and follow-up strategies to ensure that preventive initiatives are offered to high-risk individuals.

Most adults living with major depressive disorder (MDD) fail to achieve remission with conventional antidepressants. The US Food and Drug Administration (FDA) has approved 5 atypical antipsychotics in MDD on the basis of their substantial evidence of efficacy and safety. To compare the efficacy and acceptability of FDA-approved atypical antipsychotics for the adjunctive treatment of MDD in order to provide decision support to practitioners and persons with lived experience. A systematic search was conducted using PubMed/MEDLINE, PsycINFO, the Cochrane Library, and Embase from database inception through July 15, 2025. Six independent raters screened publications for eligibility. Inclusion criteria were atypical antipsychotics that are FDA approved in the adjunctive treatment of MDD. Two independent raters obtained data and examined risk of bias in accordance with the Cochrane criteria. Effect sizes were synthesized using random-effects models. Data were analyzed from August to September 2025. The primary outcomes were efficacy (ie, ≥50% reduction from baseline in the total Montgomery-Åsberg Depression Rating Scale [MADRS] score) and acceptability (ie, all-cause discontinuation). A total of 22 short-term studies comprising 10 962 participants (aripiprazole: n = 1297; brexpiprazole: n = 1973; cariprazine: n = 1894; lumateperone: n = 483; quetiapine extended release [XR]: n = 719; and placebo: n = 4596) were included for analysis. Lumateperone had the highest effect size for efficacy (risk ratio [RR], 1.72; 95% credible interval [CrI], 1.40-2.15), followed by aripiprazole (RR, 1.53; 95% CrI, 1.32-1.77), brexpiprazole (RR, 1.38; 95% CrI, 1.18-1.65), cariprazine (RR, 1.20; 95% CrI, 1.07-1.36), and quetiapine XR (RR, 1.15; 95% CrI, 0.96-1.35). A hierarchy of acceptability was observed, with aripiprazole exhibiting the highest acceptability (RR, 1.16; 95% CrI, 0.89-1.50), followed by cariprazine (RR, 1.44; 95% CrI, 1.15-1.82), brexpiprazole (RR, 1.47; 95% CrI, 1.18-1.85), quetiapine XR (RR, 1.56; 95% CrI, 1.14-2.12), and lumateperone (RR, 2.30; 95% CrI, 1.45-3.84). Secondary outcomes (eg, symptomatic remission) and exploratory outcomes (eg, clinically significant weight gain) accorded with the coprimary outcomes. This systematic review and meta-analysis indicates that differences exist between adjunctive atypical antipsychotics in the treatment of MDD with respect to overall efficacy and acceptability, which should be simultaneously considered. The absence of adequate and well-controlled studies documenting maintenance efficacy of adjunctive atypical antipsychotics in MDD remains a knowledge gap.

Default mode network (DMN) activity has been implicated in mechanisms of antidepressant treatment response, particularly expectancy processes that contribute to placebo effects. However, causal evidence is limited. To test whether modulating DMN function via theta burst stimulation (TBS) over the dorsomedial prefrontal cortex (PFC) alters placebo-related neural activity and expectancy-driven mood responses. This randomized clinical trial was conducted from October 2020 to March 2025 and represented a within-person, counterbalanced design. Adults with depressive symptoms aged 18 to 53 years not taking psychotropic medication were included in the analysis. Participants were recruited from the University of Pittsburgh Medical Center. Trial × trial expectancy and mood ratings were recorded. Data analysis was performed on a rolling basis from October 2021 to March 2025. Three TBS sessions over the dorsomedial PFC (electroencephalogram coordinate F2; 80% resting motor threshold, 1 week apart): intermittent (iTBS), continuous (cTBS), and sham (sTBS). One hour later, they completed the antidepressant placebo functional magnetic resonance imaging (MRI) task, which manipulated anticipatory beliefs using expectancy cues and sham neurofeedback. Outcomes included expectancy and mood ratings during the antidepressant placebo functional MRI task and placebo-related neural activation in the DMN. A total of 103 individuals were enrolled in the study. Of those enrolled, 67 completed at least 1 session, and 50 (mean [SD] age, 28.3 [9.5] years; 26 male [52.0%]) composed the final analytic sample. Voxelwise analyses showed that iTBS increased dorsomedial PFC activity relative to cTBS in the DMN (threshold-free cluster enhancement corrected P = .98). Cluster-based analyses confirmed a main effect of stimulation, with a significant monotonic pattern (iTBS > sTBS > cTBS, F2,144 = 4.55; P = .01; η2 = 0.06). In models predicting mood, greater DMN activation predicted stronger expectancy-related mood responses under iTBS compared with sTBS (β = 0.30; 95% credible interval [CrI], 0.07-0.52). In contrast, in models predicting expectancies, greater DMN activation predicted higher expectancy ratings in response to the treatment cue (β = 0.38; 95% CrI, 0.22-0.55), but this coupling was strongest under cTBS (β = -0.22; 95% CrI, -0.44 to 0), likely reflecting engagement of upstream regions. Behaviorally, cTBS increased expectancy ratings relative to the other conditions. Results of this randomized clinical trial show that a single session of iTBS targeting the dorsomedial PFC enhanced expectancy-related modulation of the DMN and amplified placebo-induced mood improvement. These findings implicate DMN plasticity in the rapid shaping of antidepressant expectancy effects and highlight a potential circuit-based mechanism for augmenting treatment response in depression. ClinicalTrials.gov Identifier: NCT04276259.

Twelve million Indian adolescents live in slums, where access to mental health care is limited, a problem compounded by multiple stressors. The present trial seeks to address a critical gap in extant research involving community-based adolescent mental health care with a specific focus on low- and middle-income countries. To assess whether a multimedia antistigma campaign can lower community stigma related to mental illness among adolescents and whether a primary care health worker-led digital intervention can reduce depression risk in adolescents living in slums in 2 Indian cities. This was a parallel, cluster randomized, usual care-controlled trial conducted in 60 slums across New Delhi and Vijayawada from December 2022 to December 2023. Adolescents aged 10 to 19 years at high risk of depression (Patient Health Questionnaire-9 [PHQ-9] score ≥10), including depression, other significant emotional or medically unexplained complaints, and self-harm or suicide risk (hereafter, risk of depression or self-harm). Exclusion criteria included poor physical health that would prevent regular follow-up or temporary residence in the slums. The participants were recruited from the selected slum clusters via door-to-door screening by trained field facilitators. Slum clusters in each site were randomized to the 2 arms in a 1:1 allocation ratio using stratified randomization. Outcome data were collected by external data collectors blinded to the intervention. Multimedia antistigma campaign against stigma related to mental illness directed to adolescents and a primary care health worker-led digital intervention to identify and treat adolescents at high risk of depression or self-harm. Coprimary outcomes included change in mean behavior scores of high- and low-risk cohorts at 12 months using the Knowledge, Attitude and Behavior scale and the proportion of adolescents at high risk of depression with remission at 12 months (defined as PHQ-9 score <5). Sixty slums participated, yielding a total study cohort of 3739 adolescents, 1761 (47.1%) of whom were at high risk of depression or self-harm (mean [SD] age, 14.3 [2.7] years; 2049 [55%] female). Implementation fidelity at 12 months was high-1667 of 1842 in the intervention cohort (90%) received all antistigma elements and 743 of 854 (87%) in the high-risk cohort were seen by primary care physicians. Mean (SE) behavior scores (assessed via anticipated behavior toward others with mental illness) were higher (suggestive of improvement) at 12 months in the intervention vs control clusters (17.22 [0.14] vs 16.44 [0.13]; mean difference, 0.78; 95% CI, 0.40 to 1.16; P < .001; standardized mean difference, 0.20). Among those at high risk of depression or self-harm, remission was higher at 12 months in the intervention vs control clusters, but the difference was nonsignificant (534/781 [model estimate, 68.2%] vs 461/833 [model estimate, 59.4%]; odds ratio, 1.47; 95% CI, 0.93-2.32; P = .10; risk difference, 0.07; 95% CI, -0.02 to 0.16). Mean (SE) PHQ-9 scores were lower (suggesting improvement) in intervention vs control at 12 months (4.05 [0.30] vs 4.92 [0.29]; mean difference, -0.87; 95% CI -1.66 to -0.08; P = .03; standardized mean difference, -0.18). The findings demonstrate that the antistigma campaign positively impacted knowledge, attitude, and anticipated behavior related to mental health among adolescents and the model of training primary care professionals had a positive impact on mental health outcomes. Clinical Trial Registry India: CTRI/2022/02/040307.

Head-to-head comparisons of evidence-based treatments for borderline personality disorder (BPD), including dialectical behavior therapy (DBT) and schema therapy (ST), remain scarce, despite their widely recognized relevance. To compare the effectiveness of DBT and ST in a multicenter trial among outpatients with BPD. This 3-year multicenter superiority randomized clinical trial (RCT), part of the BOOTS (Borderline Optimal Treatment Selection) project, was conducted between January 2019 and April 2025. The trial was conducted in 9 Dutch outpatient centers among individuals aged 18 to 65 years with BPD. Assessments were administered by assessors blinded to treatment allocation. Participants were randomized to DBT or ST via computerized covariate-adaptive randomization accounting for sex and BPD severity. Both treatments were delivered over 2 years in a combined group-individual format. The primary outcome was the rate of change in DSM-5 BPD severity from baseline to 1-year posttreatment follow-up (3 years after baseline), assessed by the Borderline Personality Disorder Severity Index, fifth version (BPDSI-5) total score. Secondary outcomes included DSM-5 BPD criteria, general symptom severity, functioning, quality of life, well-being, sleep problems, and treatment dropout. Of 204 participants (172 female [84.3%]; mean [SD] age, 32.21 [9.57] years), 95 (46.6%) received DBT and 109 (53.4%) received ST. Intention-to-treat analysis revealed no significant difference between DBT and ST in reducing BPD severity (P = .27, r = 0.09), with large improvements in both treatments. At 36-month follow-up, the estimated mean difference was -1.09 on the BPDSI-5 (Cohen d = 0.15; 95% CI, -0.17 to 0.47). No significant differences between treatments were observed on any secondary outcome, with marked improvements over time in both treatments. Dropout did not differ significantly (DBT: 34% at 1 year, 52% at 2 years; ST: 29% at 1 year, 46% at 2 years). This multicenter RCT found no significant differences in effectiveness between DBT and ST for outpatients with BPD, with substantial improvements across outcomes. Future research is warranted to assess equivalence and to determine which treatment works best for whom and why. https://onderzoekmetmensen.nl Identifier: NL-OMON49443.

Healthy individuals typically show attractive serial dependence in working memory tasks, with responses biased toward recent inputs, whereas people with schizophrenia (SZ) reliably show the opposite-repulsive biases. Determining whether individuals with bipolar disorder (BD) and a history of psychosis exhibit similar or distinct serial-dependence patterns is essential for clarifying shared vs disorder-specific cognitive mechanisms across the psychosis spectrum. To determine whether people with BD exhibit the repulsive bias seen in people with SZ or the attractive bias seen in healthy control (HC) individuals. This case-control study included individuals who met DSM-5 criteria for SZ or BD with a history of psychosis, along with matched HC participants recruited across 5 US sites. Clinical samples were recruited from outpatient psychiatric clinics and day programs, and HC participants were recruited from the community. A working memory task was used in which participants remembered the orientation of a teardrop-shaped object and reproduced it using a computer mouse after a variable delay. The Brief Psychiatric Rating Scale was used to quantify symptom severity. The study was conducted from September 2023 to April 2025. The primary outcome measure was the bias index, used to evaluate the extent to which current-trial responses were biased toward or away from previous-trial targets. Diagnostic group and the orientation of the previous trial's target during a spatial working memory paradigm. A total of 41 participants were included in BD group (21 [51%] male; mean [SD] age, 37.02 [11.53] years), 30 in the SZ group (18 [60%] male; mean [SD] age, 37.5 [9.04] years), and 27 in the HC group (16 [59%] male; mean [SD] age, 39.98 [11.01] years). Overall bias differed across groups, with people with SZ (mean, -1.99; 95% CI, -2.74 to 1.23) demonstrating significantly greater repulsive bias than both people with BD (mean, 0.44; 95% CI, -0.25 to 1.13) and HC individuals (mean, 1.82; 95% CI, 1.31 to 2.32). Fifteen of 27 HC individuals exhibited attractive bias, with none showing repulsive bias, whereas 17 of 30 people with SZ exhibited repulsive bias, with none showing attractive bias. Attractive bias was common in people with BD (13 of 41), but some exhibited a repulsive bias (7 of 41). In this case-control study, attractive and repulsive serial biases differed between HC individuals and people with SZ, with some people with BD showing the HC pattern and few showing the SZ pattern. These results suggest that serial bias may serve as a valuable biomarker for pathophysiology and precision psychiatry.

Ketamine has well-known dissociative, analgesic, and antidepressant properties, but it is unknown whether the neurophysiologic effects that are associated with these properties can be modulated separately from one another. Considering that specific cortical oscillations have been associated with specific therapeutic effects, modulating selective aspects of ketamine neurophysiology could inform efforts to develop more targeted therapies. To determine whether the neurophysiologic signatures of ketamine are associated with removal of conscious awareness using general anesthesia (GA). This cohort study was a secondary analysis of participant-level data from 3 prospective studies conducted between 2017 and 2023. The primary analysis included data from 2 study cohorts (University of Michigan and Stanford University), and the supplementary analysis included data from a third cohort (University of Auckland). The study cohorts included healthy volunteers, patients undergoing elective surgery, and patients with a diagnosis of depression (all aged ≥18 years). Participants received a subanesthetic infusion of ketamine (0.5 mg/kg body weight) over 40 minutes or placebo with or without GA. The primary outcome was change in electroencephalographic (EEG) band power during medication infusion. Changes were computed using nonparametric paired statistical text (Wilcoxon signed-rank test). This study included 52 participants in the primary analysis (mean [SD] age, 43.4 [18.3] years; 34 females [65.4%]) and 27 additional participants in the supplementary analysis (mean [SD] age, 30.2 [8.2] years; 15 females [55.6%]). GA differentially altered EEG features commonly associated with ketamine in all 52 participants (100%) in the primary analysis. Compared with awake administration, ketamine administered during GA preserved its βγ power modulation (mean [SEM] increase from 6.3 [11.3] to 11.6 [2.2] dB for awake administration; increase from 8.5 [2.9] to 11.2 [3.8] dB for administration during GA) but lacked its characteristic θ augmentation (increase from 17.3 [10.5] to 22.9 [3.1] dB during awake administration; nonsignificant decrease from 29.0 [3.0] to 27.8 [3.5] dB for administration during GA). In this cohort study, coadministration of ketamine with GA selectively modulated the θ but not the βγ neurophysiologic correlates of ketamine. These findings suggest a potential method to explore the role of these components in the behavioral effects of ketamine.

This quality improvement study presents the results of the 2025 edition of the European Board Examination in Psychiatry.