Brodsky BS, Galfalvy H, Mann JJ
… +2 more, Grunebaum MF, Stanley B
Am J Psychiatry
· 2025 Dec · PMID 41190740
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OBJECTIVE: The authors compared the efficacy of 6 months of dialectical behavior therapy (DBT) to 6 months of selective serotonin reuptake inhibitors with clinical management (SSRI/M) in reducing suicide-related events (...OBJECTIVE: The authors compared the efficacy of 6 months of dialectical behavior therapy (DBT) to 6 months of selective serotonin reuptake inhibitors with clinical management (SSRI/M) in reducing suicide-related events (SREs), suicide attempts, nonsuicidal self-injury (NSSI), and related clinical outcomes in individuals diagnosed with borderline personality disorder. METHODS: The study sample comprised 84 individuals with borderline personality disorder; more than one suicide attempt, SRE, or NSSI episode in the past 6 months; and another of these behaviors in the past year. Two-thirds had comorbid major depressive disorder. Participants were randomly assigned to receive DBT or SSRI/M. Poisson models were used to analyze numbers of suicide attempts and SREs, and a zero-inflated Poisson model was used for NSSI behaviors. Survival analysis was performed with the log-rank test for time to first suicide attempt or SRE. Follow-up assessments at 12 months were analyzed in a separate model. Mixed-effects regression was used to compare quantitative outcomes. RESULTS: Significantly fewer SREs occurred in the DBT arm compared with the SSRI/M arm during the 6-month treatment phase. Significantly fewer suicide attempts occurred in the DBT arm compared with the SSRI/M arm. Survival analysis indicated significantly lower risk for having any SRE in the DBT arm compared with the SSRI/M arm, but no difference in risk of suicide attempt. DBT participants had significantly lower NSSI counts than SSRI/M participants. Severity of depression and suicidal ideation decreased comparably in both treatment groups. After 6 months of treatment, the rate of major depressive disorder was significantly lower in the SSRI/M arm compared with the DBT arm. At 12-month follow-up (6 months after completion of the treatment phase), outcomes were comparable between the two groups. CONCLUSIONS: Six months of DBT showed greater efficacy than 6 months of SSRI/M in reducing SRE and NSSI behaviors in patients with borderline personality disorder.
Lång U, Metsälä J, Ramsay H
… +9 more, Boland F, Heikkilä K, Pulakka A, Lawlor A, O'Connor K, Veijola J, Kajantie E, Healy C, Kelleher I
Am J Psychiatry
· 2026 Feb · PMID 41190738
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OBJECTIVE: As many as half of individuals who develop psychosis had attended child and adolescent psychiatric services at some stage in childhood, highlighting substantial opportunities for prevention within these servic...OBJECTIVE: As many as half of individuals who develop psychosis had attended child and adolescent psychiatric services at some stage in childhood, highlighting substantial opportunities for prevention within these services if an effective preventive intervention were identified. The authors hypothesized that adolescent psychiatric patients exposed to doxycycline, an antibiotic with putative neuroprotective properties, would have a lower risk of developing schizophrenia. METHODS: This was an emulated target trial using nationwide Finnish health register data on all individuals born between 1987 and 1997 who attended adolescent psychiatric services between ages 13 and 18 and had used any antibiotics. Individuals were followed from first dispensed antibiotic prescription up to age 30. The main outcome was recorded schizophrenia diagnosis. The g-formula was used to estimate schizophrenia risk across doxycycline exposure levels (cumulative dose doxycycline use: no doxycycline use; low use, <1,499 mg; medium use, 1,500-2,999 mg; high use, ≥3,000 mg) during different follow-up periods. RESULTS: A total of 56,395 individuals had attended adolescent psychiatric services and had used antibiotics; of these, 16,189 (28.7%) had used doxycycline. The risk of schizophrenia after 10 years of follow-up was 2.1% (95% CI=1.9, 2.3) for individuals who had used non-doxycycline antibiotics. In comparison, the risk of schizophrenia at 10 years was significantly lower in adolescent psychiatric patients treated with doxycycline (low cumulative dose: 1.4%, risk ratio=0.70, 95% CI=0.48, 0.85; medium cumulative dose: 1.4%, risk ratio=0.65, 95% CI=0.25, 1.04; high cumulative dose: 1.5%, risk ratio=0.70, 95% CI=0.43, 0.97). CONCLUSIONS: These findings raise the tentative but exciting possibility that doxycycline treatment may reduce schizophrenia risk in adolescent psychiatric patients.
Yalcinbas EA, Ajanaku B, Nelson ED
… +19 more, Garcia-Flores R, Eagles NJ, Montgomery KD, Stolz JM, Wu J, Divecha HR, Chandra A, Bharadwaj RA, Bach SV, Rajpurohit A, Tao R, Pertea G, Shin JH, Kleinman JE, Hyde TM, Weinberger DR, Huuki-Myers LA, Collado-Torres L, Maynard KR
Am J Psychiatry
· 2025 Nov · PMID 41174894
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OBJECTIVE: The objective of this study was to define the molecular neuroanatomy of the human habenula (Hb) and identify transcriptomic differences between brains of individuals with schizophrenia and nonpsychiatric contr...OBJECTIVE: The objective of this study was to define the molecular neuroanatomy of the human habenula (Hb) and identify transcriptomic differences between brains of individuals with schizophrenia and nonpsychiatric control brains. METHODS: This study utilized Hb-enriched postmortem human brain tissue. Single-nucleus RNA sequencing (snRNA-seq) was conducted to identify molecularly defined Hb cell types (N=7 donors), and single-molecule fluorescent in situ hybridization (smFISH) was performed to validate cell types and map their spatial locations (N=5 independent donors). Bulk RNA sequencing (RNA-seq) (schizophrenia, N=35; nonpsychiatric control, N=33) and cell type deconvolution were used to identify differentially expressed genes (DEGs), which were then compared to dorsolateral prefrontal cortex, hippocampus, and caudate schizophrenia DEGs. Expression quantitative trait loci (eQTLs) and schizophrenia risk colocalization analyses were performed. RESULTS: snRNA-seq identified 17 cell type clusters across 16,437 nuclei, including three medial and seven lateral Hb populations, several of which were conserved in rodents. smFISH validated snRNA-seq Hb cell types and depicted their spatial organization. Bulk RNA-seq analyses yielded 173 schizophrenia-associated DEGs (false discovery rate<0.1), of which 129 (75%) were unique to Hb-enriched tissue. eQTL analysis identified 717 independent single-nucleotide polymorphism (SNP)-gene pairs (false discovery rate<0.05). Of these, 16 pairs included a SNP that is a schizophrenia risk variant, and seven different pairs included a schizophrenia DEG. eQTL and schizophrenia risk colocalization analysis identified 16 colocalized genes, nine of which have not been previously identified. CONCLUSIONS: These results identify topographically organized cell types with distinct molecular signatures in the human habenula and demonstrate unique genetic differences associated with schizophrenia, thereby providing novel molecular insights into the role of the habenula in neuropsychiatric disorders.
Zhao G, Sun Y, Zhang Y
… +21 more, Lu T, Lu Z, Kang Z, Schneider-Thoma J, Xie W, Yang Y, Guo J, Zhu Y, Yuan R, Sun J, Feng X, Liao Y, Chen D, Li L, Li T, Yang F, Wang C, Zhang D, Yan H, Leucht S, Yue W
Am J Psychiatry
· 2026 Feb · PMID 41152254
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OBJECTIVE: Antipsychotic drugs are the mainstay of schizophrenia treatment; yet, controversy persists regarding their relative efficacy and side effects, and guideline recommendations on efficacy differences are particul...OBJECTIVE: Antipsychotic drugs are the mainstay of schizophrenia treatment; yet, controversy persists regarding their relative efficacy and side effects, and guideline recommendations on efficacy differences are particularly vague. The aim of this trial was to compare seven antipsychotics in acutely ill patients with schizophrenia. METHODS: The authors performed a multicenter (32 hospitals), industry-independent, parallel, assessor-blinded, flexible-dosage randomized trial (Schizophrenia in Non-Occidental Participants). Eligible inpatients 18-45 years of age with schizophrenia experiencing acute exacerbation were recruited and randomized to 6 weeks of monotherapy with one of seven antipsychotic drugs: olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone, perphenazine, and haloperidol. RESULTS: A total of 3,067 patients were randomized, of whom 82% completed follow-up. The mixed model indicated significant differences in the primary outcome percentage change in Positive and Negative Syndrome Scale (PANSS) score between the antipsychotics. At week 6, olanzapine and risperidone showed a significantly higher percentage change in PANSS score than aripiprazole, ziprasidone, and quetiapine (mean differences: 5.52-7.93) but not haloperidol or perphenazine. Olanzapine was associated with the highest risk of weight gain (relative risk: 1.44-3.22). Aripiprazole was associated with lower risk of hyperprolactinemia than all the other drugs (relative risks: 0.11-0.21). Ziprasidone and aripiprazole were associated with lower risks of weight gain and metabolic side effects. Haloperidol was associated with a higher risk of extrapyramidal symptoms than all other drugs (relative risks: 0.13-0.61). Aripiprazole was least sedating (relative risks: 0.30-0.39). Olanzapine and risperidone showed lower all-cause discontinuation rates than ziprasidone and haloperidol (hazard ratios: 0.61-0.73). CONCLUSIONS: This trial fills important knowledge gaps in acute antipsychotic treatment of schizophrenia. It confirms hierarchies in efficacy and side effects of antipsychotics from related evidence.
Mallard TT, Tubbs JD, Jennings M
… +16 more, Zhang Y, Gustavson DE, Grotzinger AD, Westwater ML, Williams CM, Fortgang RG, Elson SL, Fontanillas P, Davis LK, Raznahan A, Tucker-Drob EM, Choi KW, Ge T, Smoller JW, Palmer AA, Sanchez-Roige S
Am J Psychiatry
· 2026 Jan · PMID 41152253
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OBJECTIVE: Impulsivity is a complex mental construct and a core feature of many psychiatric and neurological conditions. The aim of this study was to formally model the genetic architecture of eight impulsive traits, ide...OBJECTIVE: Impulsivity is a complex mental construct and a core feature of many psychiatric and neurological conditions. The aim of this study was to formally model the genetic architecture of eight impulsive traits, identifying their shared and distinct genetic influences, to advance our biological understanding of impulsivity. METHODS: The authors analyzed genetic data from up to 133,517 individuals using novel multivariate genome-wide association study (GWAS) and transcriptome-wide association study (TWAS) approaches. Bioinformatic analyses were conducted to identify gene expression patterns and neurobiological correlates, and polygenic score analyses were used to examine the ways in which genetic liability for impulsivity relates to clinical outcomes. RESULTS: The analyses revealed pervasive pleiotropy that largely counters theories of impulsivity as a unitary construct. GWAS and TWAS analyses identified 18 loci and 93 genes, respectively, that have diverse effects on self-regulation, including a hotspot at 17q21.31 that harbors genes involved in neurodevelopmental and neurodegenerative disorders. Bioinformatic analyses revealed that many biological correlates have divergent effects on impulsive traits, including upregulated gene expression during early neurodevelopment and altered cortical morphometry of the inferior frontal gyrus in adulthood. Polygenic score analyses suggest that liability for impulsivity may canalize across development, as polygenic influences on clinical outcomes tended to operate via shared pathways early in life but not in adulthood. CONCLUSIONS: These findings provide new insights into the pleiotropic architecture of impulsivity, its multifaceted biology, and its diverse relationships with mental health. The study underscores the importance of considering impulsivity as a genetically heterogeneous construct and highlights key neurodevelopmental pathways that shape its expression across the lifespan.
Howes OD, Bukala BR, Chen EYH
… +90 more, Correll CU, Hasan A, Honer WG, Kane JM, Leucht S, Siafis S, Agid O, Akena D, Arango C, Atwoli L, Barnes TRE, Birnbaum ML, Bitter I, Breier A, Buchanan RW, Citrome L, Cotter DR, Crossley N, Davidson M, de Bartolomeis A, DeLisi LE, Dollfus S, Dursun SM, Ebdrup BH, Elkis H, Emsley R, Falkai P, Fernández-Egea E, Fleischhacker W, Freudenreich O, Gadelha A, Gaebel W, Graff-Guerrero A, Gridley A, Hallak JEC, Homan P, Kahn RS, Kaiser S, Kapi M, Kennedy JL, Kim E, Kinon BJ, Soo Kwon J, Lawrie SM, Lee J, Leweke FM, Li T, Libiger J, Marder SR, Melle I, Meltzer H, Mucci A, Naber D, Nakajima S, Nielsen J, O'Brien O, Ojagbemi A, Omlor W, Pantelis C, Peuskens J, Raedler TJ, Ran MS, Marques TR, Remington G, Rossell S, Rubio JM, Sachs G, Scott J, Si T, Siskind D, Siu CO, Sommer IE, Suzuki T, Takeuchi H, Tandon R, Taylor D, Teferra S, Thomas N, Tiihonen J, Uchida H, Ucok A, Umbricht D, Venkatasubramanian G, Wagner E, Walters JTR, Wang C, Weiser M, Wright C, Yu X, McCutcheon RA
Am J Psychiatry
· 2025 Nov · PMID 41058236
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OBJECTIVE: Relapse prevention is a major goal of schizophrenia treatment. However, there is no standard definition of relapse. To address this, the authors reviewed recent approaches and developed consensus criteria to o...OBJECTIVE: Relapse prevention is a major goal of schizophrenia treatment. However, there is no standard definition of relapse. To address this, the authors reviewed recent approaches and developed consensus criteria to operationally define relapse. METHODS: To evaluate current criteria, a systematic review was performed of randomized controlled trials of relapse conducted from 2012 to 2024. To develop consensus criteria, the authors used a multiphase Delphi approach involving over 100 experts from 37 countries, including people with lived experience of relapse. RESULTS: The review showed only two pairs of studies that used the same criteria. Clinical judgment alone was sufficient to define relapse in 85% of studies, and 58% used relative symptom change. The recommended criteria cover the pre-baseline, baseline, and relapse components with optimum and minimum criteria and provide a reporting checklist. The recommendations include using standardized, validated measures that can be applied across settings, and using absolute symptom change. The authors also identify criteria that should not be used and make reporting recommendations, including for specific symptom domains (positive, negative, or cognitive) and across symptom domains, hospitalization, home treatment, and risky, violent, or suicidal behavior. CONCLUSIONS: There are limitations and heterogeneity in current definitions of relapse, which limit study comparisons, potentially bias meta-analyses, and question the validity of some studies. Adopting the consensus recommendations for a standardized approach should improve the validity and reliability of study outcomes, facilitate cross-study comparisons, and also standardize research into risk factors for relapse.
Linke JO, Naim R, Haller SP
… +8 more, Khosravi P, Scheinberg B, Byrne ME, Harrewijn A, Leibenluft E, Brotman MA, Winkler AM, Pine DS
Am J Psychiatry
· 2026 Jan · PMID 41058235
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OBJECTIVE: Pediatric anxiety disorders are common and predict adult psychopathology, yet current treatments, such as cognitive-behavioral therapy (CBT), produce lasting remission in less than 50% of affected youths. To s...OBJECTIVE: Pediatric anxiety disorders are common and predict adult psychopathology, yet current treatments, such as cognitive-behavioral therapy (CBT), produce lasting remission in less than 50% of affected youths. To support the search for improved, mechanistically grounded interventions, this study evaluated neural efficiency, defined as similarity in functional connectivity between a threat task and rest, as a potential biomarker. The study evaluated neural efficiency in relation to anxiety diagnosis and treatment response. METHODS: The authors compared 103 youths with an anxiety disorder diagnosis (mean age, 12.5 years [SD=2.91], 62% female) to 103 youths with no psychiatric diagnosis (mean age, 13.4 years [SD=2.58], 53% female). Participants completed functional MRI while resting and during a dot-probe task with threatening faces. Neural efficiency was calculated as partial correlations between intrinsic and task-related functional connectivity patterns across the whole brain. Four-month test-retest reliability as well as relationships with anxiety and response to exposure-based CBT were examined. RESULTS: Neural efficiency demonstrated satisfactory test-retest reliability (intraclass correlation coefficient=0.65) in healthy youths over a period of 11 to 18 weeks. Neural efficiency was significantly negatively related to anxiety as both a diagnostic category (t=2.62, d=0.29) and a symptom dimension (r=-0.18). Although it did not change after CBT, lower neural efficiency at baseline was significantly associated with poorer treatment response in a subset of 80 anxious youths who underwent CBT (β=-11.88, χ=9.20). CONCLUSIONS: Neural efficiency, measured as network reconfiguration between rest and task, holds promise as a biomarker in pediatric anxiety. Its association with CBT response suggests that it might aid in patient stratification and offer a target for interventions aimed at enhancing CBT efficacy.
Am J Psychiatry
· 2025 Oct · PMID 41030005
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OBJECTIVE: The authors previously demonstrated that symptoms of premenstrual dysphoric disorder (PMDD) remit during ovarian hormone suppression and recur after estradiol or progesterone is reintroduced (addback). In this...OBJECTIVE: The authors previously demonstrated that symptoms of premenstrual dysphoric disorder (PMDD) remit during ovarian hormone suppression and recur after estradiol or progesterone is reintroduced (addback). In this study, using a substantially expanded sample, they aimed to 1) evaluate the specific contributions of estradiol and progesterone to symptom development, 2) analyze physical symptoms related to ovarian hormones, 3) identify differences between women with PMDD who experienced continued symptom remission and those who experienced symptom recurrence during hormone addback, and 4) determine whether change in hormone levels from baseline to addback is associated with PMDD symptom severity. METHODS: Thirty-four women with PMDD (10 from the original cohort) and 76 healthy participants (15 from the original cohort) completed a daily rating form during three hormone conditions: ovarian suppression induced by the gonadotropin-releasing hormone agonist leuprolide, leuprolide+estradiol addback, and leuprolide+progesterone addback. Affective and somatic symptom scores during the last 8 of 12 weeks of leuprolide alone were compared with scores during the first 4 weeks of estradiol addback and the first 4 weeks of progesterone addback. RESULTS: For affective symptoms (anxiety, sadness, irritability, mood swings), there were significant main effects of diagnosis and diagnosis-by-hormone interactions, reflecting a significant increase in symptom severity scores during estradiol addback and progesterone addback compared with leuprolide treatment alone. Compared to healthy comparison participants, women with PMDD had significantly higher symptom scores during each addback. With regard to physical symptoms, bloating and food cravings showed greater severity in women with PMDD regardless of hormone conditions, whereas breast pain increased in severity during estradiol addback compared with leuprolide alone and progesterone. CONCLUSIONS: The study confirmed that ovarian suppression in women with PMDD eliminated symptom cyclicity, and that symptoms emerged during ovarian steroid addback in women with PMDD but not in healthy comparison women. In PMDD, irritability and mood swings are tied more closely to progesterone than estradiol. Despite the replication of this hormone-related behavioral phenotype in PMDD, the mechanisms underlying the presumed alteration in steroid signaling require further characterization.