Journal of Clinical Psychiatry最新文献

{"title":"Nonmedical Use and Substance Use Disorder Symptoms Among US Adults Coprescribed Opioids and Benzodiazepines.","authors":"Emily Pasman, Phil Veliz, Elizabeth Hoffman, Rebecca Evans-Polce, Ty S Schepis, Megan E Patrick, Joshua Truchan, Timothy E Wilens, John Jardine, Vita V McCabe, Sean Esteban McCabe","doi":"10.4088/JCP.25br15937","DOIUrl":"https://doi.org/10.4088/JCP.25br15937","url":null,"abstract":"","PeriodicalId":50234,"journal":{"name":"Journal of Clinical Psychiatry","volume":"86 4","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145082283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy, Tolerability, and Safety of TRPC4/5 Inhibitor BI 1358894 in Patients With Major Depressive Disorder and Inadequate Response to Antidepressants: A Phase 2 Randomized, Placebo-Controlled, Parallel Group, Dose-Ranging Trial.","authors":"Richard C Shelton, Diego A Pizzagalli, Elan A Cohen, Hikaru Hori, Ute Dickschat, Josephine Asafu-Adjei, Alla Feldbarg, Stefan Just, Michael Roehrle, Stephanie Sommer, Sigurd D Süssmuth","doi":"10.4088/JCP.25m15868","DOIUrl":"10.4088/JCP.25m15868","url":null,"abstract":"<p><p><b>Objective:</b> To assess proof-of-concept (PoC) for efficacy, tolerability, and safety of TRPC4/5 inhibitor BI 1358894 vs placebo in patients with major depressive disorder (MDD) with inadequate response to ongoing antidepressants.</p><p><p><b>Methods:</b> In this phase 2, multicenter, randomized, double-blind, dose-finding trial (December 2020-February 2024), patients with MDD (per <i>DSM-5</i>) and current depressive episode of ≥8 weeks and ≤24 months were randomized (3.5:1:1:1:2:2) to receive placebo or BI 1358894 (5 mg, 25 mg, 75 mg, or 125 mg) or quetiapine 150-300 mg orally, once daily for 6 weeks. Primary end point was change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 6. Secondary end points included ≥50% reduction from baseline in MADRS total score at Week 6, change from baseline in State-Trait Anxiety Inventory scores, Clinical Global Impression Severity Scale score, and Symptoms of Major Depressive Disorder Scale total score at Week 6.</p><p><p><b>Results:</b> Of 940 enrolled patients, 389 were randomized, and 361 (93.0%) completed the trial. No differences were observed between BI 1358894 treatment groups and placebo for primary and secondary end points. Adverse events were slightly more frequent in the BI 1358894-total group (66.7%) vs placebo (53.9%). No worsening of Columbia-Suicide Severity Rating Scale was observed for most patients; serious adverse events of suicidal ideation were reported for 4.7% (placebo), 5.1% (BI 1358894 75 mg group), and 1.4% (quetiapine) of patients.</p><p><p><b>Conclusion:</b> Although this was a negative trial in MDD with PoC not established, BI 1358894 was well tolerated with no increase in self-harm or suicidality.</p><p><p><b>Trial Registration:</b> ClinicalTrials.gov identifier: NCT04521478.</p>","PeriodicalId":50234,"journal":{"name":"Journal of Clinical Psychiatry","volume":"86 3","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144976830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparing the Cognitive Effects of Repeated Intravenous Ketamine and Electroconvulsive Therapy in Patients With Treatment-Resistant Depression: A Secondary Analysis of the ELEKT-D Trial.","authors":"Kristina T Kumpf, Samuel T Wilkinson, Bo Hu, Ruoying Chen, Kamini Krishnan, Shinjon Chakrabarti, Taeho Greg Rhee, Tiffany Grezmak, Sanjay J Mathew, Gerard Sanacora, James W Murrough, Fernando S Goes, Katherine A Collins, Brian S Barnett, Amit Anand","doi":"10.4088/JCP.25m15781","DOIUrl":"10.4088/JCP.25m15781","url":null,"abstract":"<p><p><b>Objective:</b> Electroconvulsive therapy (ECT) has potent antidepressant effects yet can lead to neurocognitive side effects. Ketamine is a rapid-acting antidepressant, which may be an alternative to ECT. Few have directly compared the cognitive effects of ECT and ketamine treatment.</p><p><p><b>Methods:</b> We compared cognitive effects of intravenous ketamine and ECT in patients with treatment-resistant depression (TRD), collected through a multisite, randomized trial conducted between April 2017 and November 2022 (the ELEKT-D study). Participants received 6 IV ketamine treatments or 9 ECT sessions. Cognitive functioning was assessed through 4 validated cognitive tasks at pre- and posttreatment visits. The Squire Memory Complaint Questionnaire (SMCQ) and Global Self-Evaluation of Memory (GSE-My) were used to measure changes in memory functioning. Responders (those who achieved ≥50% reduction in depressive symptoms) were evaluated again at 1-, 3-, and 6-month follow-up visits.</p><p><p><b>Results:</b> In the intent-to-treat sample (N = 365), ECT recipients performed significantly worse than ketamine recipients on all cognitive tasks at end of treatment (<i>P</i> < .001), with no significant differences in task performance associated with response to either treatment. Among responders, we observed no significant group differences at 1-, 3-, and 6-month follow-up. Analyses of subjective memory questionnaires were mixed. SMCQ scores improved for both groups with ketamine recipients reporting greater functional gains; ketamine-treated patients reported improvements in GSE-My scores while ECT-treated patients reported a decline in GSE-My scores. Within-group analyses in the ketamine group found improvements in executive functioning and cognitive flexibility. This survived adjustments for changes in depression, suggesting partial independence of cognitive and mood effects.</p><p><p><b>Conclusions:</b> Patients treated with ketamine demonstrated superior cognitive functioning compared with those treated with ECT following a 3-week treatment course, with no differences between treatments observed among responders in follow-up. Findings support the short-term superiority of ketamine on cognitive functioning and the long-term cognitive safety of both treatments for TRD.</p><p><p><b>Trial Registration:</b> ClinicalTrials.gov identifier: NCT03113968.</p>","PeriodicalId":50234,"journal":{"name":"Journal of Clinical Psychiatry","volume":"86 4","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Year in the Shadow of Terror: Longitudinal Effects of the October 7, 2023, Terrorist Attack on PTSD, Depression, Anxiety, and Suicidal Ideation Across Distinct Exposure Groups.","authors":"Yossi Levi-Belz, Doron Amsalem, Yoav Groweiss, Carmel Blank, Iris Shachar-Lavie, Yuval Neria","doi":"10.4088/JCP.25m15970","DOIUrl":"10.4088/JCP.25m15970","url":null,"abstract":"<p><p><b>Background:</b> On October 7, 2023, Israel experienced a large-scale terrorist attack followed by a prolonged war, exposing civilians and military personnel to acute and sustained trauma. While prior studies have documented short-term psychological effects of mass trauma, few have included baseline assessments or addressed long-term trajectories across distinct exposure groups. In this study, we aimed to examine changes over time in both probable diagnoses and symptom severity of posttraumatic stress disorder (PTSD), depression, anxiety, and suicidal ideation (SI), while accounting for preattack symptom levels among different exposed groups.</p><p><p><b>Methods:</b> A prospective, representative study assessed 614 Israeli participants (309 females; 50.3%) through an online survey conducted across 3 time points: prior to the attack (T1), 1 month after (T2), and 1 year later (T3). Participants were categorized into 4 mutually exclusive exposure groups based on a predefined hierarchy prioritizing the most impactful exposure: direct exposure, bereavement (loss of a close other), reserve-duty combatants, and indirect exposure. Probable diagnoses of PTSD (using the International Trauma Questionnaire), depression (Patient Health Questionnaire-2), and anxiety (Generalized Anxiety Disorder-2) were assessed along with symptom severity and SI (SI by the Columbia-Suicide Severity Rating Scale). Generalized estimating equations were used to examine main and interaction effects of exposure type and time (T2 to T3), controlling for baseline symptom levels (T1).</p><p><p><b>Results:</b> Overall, prevalence and severity of psychiatric symptoms declined between T2 and T3. However, exposure group moderated these changes. Reserve-duty combatants exhibited the highest rates of probable diagnoses and symptoms at both time points, with minimal improvement over time. In contrast, indirectly exposed participants demonstrated significant symptom reduction. Uniquely, SI increased over time among reserve-duty participants, highlighting their vulnerability.</p><p><p><b>Conclusions:</b> Recovery following mass trauma such as the October 7th attack is not uniform. Exposure type and initial distress levels shape distinct psychological trajectories. Findings underscore the importance of differentiated, long-term, and trauma-informed interventions-especially for bereaved and reserve-duty individuals. Integration of baseline mental health data enhances risk identification and has critical implications for both clinical care and policy planning in the context of ongoing national crises.</p>","PeriodicalId":50234,"journal":{"name":"Journal of Clinical Psychiatry","volume":"86 4","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144976951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Five-Year Outcomes of First Suicide Attempts: Insights on Lethality, Recurrence, and Mortality.","authors":"Eugènia Nicolau-Subires, Maria Irigoyen-Otiñano, Laura Arenas-Pijoan, Marina Adrados-Pérez, Carla Albert-Porcar, Lucía Ibarra-Pertusa, María Mur-Laín, Jorge Lopez-Castroman, Vicent Llorca-Bofí","doi":"10.4088/JCP.24m15754","DOIUrl":"10.4088/JCP.24m15754","url":null,"abstract":"<p><p><b>Introduction:</b> Suicide is a leading cause of death globally. Although prior suicidal behavior is the strongest predictor of future attempts, clinical outcomes following a first suicide attempt (FSA) remain poorly understood. This study evaluates 5-year outcomes after an FSA, focusing on recurrence, lethality, and mortality to address gaps in understanding clinical trajectories and risk factors.</p><p><p><b>Methods:</b> A cohort of 387 FSA patients was followed for 5 years. Sociodemographic and clinical data were collected at baseline and during follow-up. Outcomes included recurrence, lethality of subsequent attempts, and all-cause mortality. Multivariable logistic and Cox regression models were used to identify risk factors.</p><p><p><b>Results:</b> During follow-up, 37.2% of patients experienced recurrence, with 27.8% classified as frequent reattempters (≥3 attempts). Overall, 5.7% of participants died, including 1.8% by suicide. High-lethality FSAs were observed in 17.3% of the sample and were strongly associated with alcohol use (odds ratio [OR], 2.142; 95% CI, 1.231-3.724; <i>P</i>=.021). Female sex was a significant risk factor for multiple reattempts (OR, 2.388; 95% CI, 1.036-5.507; <i>P</i>=.041). High-lethality FSAs significantly increased the risk of suicide deaths (hazard ratio [HR], 5.430; 95% CI, 1.189-24.792; <i>P</i>=.029), while older age was associated with a higher risk of nonsuicidal deaths (HR, 1.093; 95% CI, 1.035-1.153; <i>P</i>=.001).</p><p><p><b>Conclusions:</b> Lethality, recurrence, and mortality following an FSA are influenced by distinct risk factors. Alcohol use predicted high-lethality FSAs, female sex predicted multiple reattempts, high-lethality FSAs predicted suicide deaths, and age predicted nonsuicidal deaths. Targeted interventions for these high-risk populations are needed.</p>","PeriodicalId":50234,"journal":{"name":"Journal of Clinical Psychiatry","volume":"86 4","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toward Consensus in Psychedelic-Assisted Therapy: The Critical Role of Psychotherapeutic Support.","authors":"Vania Modesto-Lowe, Deanna Sgambato, Pa-C Margaret Chaplin","doi":"10.4088/JCP.25lr15978","DOIUrl":"https://doi.org/10.4088/JCP.25lr15978","url":null,"abstract":"","PeriodicalId":50234,"journal":{"name":"Journal of Clinical Psychiatry","volume":"86 4","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Psychedelic Therapies: One Drug, Multiple Treatments Reply to Modesto-Lowe et al.","authors":"David A Bender, Sandeep M Nayak, Joshua S Siegel, David J Hellerstein, Baris C Ercal, Eric J Lenze","doi":"10.4088/JCP.25lr15978a","DOIUrl":"https://doi.org/10.4088/JCP.25lr15978a","url":null,"abstract":"","PeriodicalId":50234,"journal":{"name":"Journal of Clinical Psychiatry","volume":"86 4","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N-Acetylcysteine for the Treatment of Co-Occurring Posttraumatic Stress Disorder and Alcohol Use Disorder: A Double-Blind, Randomized Controlled Trial.","authors":"Sudie E Back, Kevin Gray, Amber M Jarnecke, Tanya C Saraiya, Elizabeth J Santa Ana, Therese Killeen, Jane E Joseph, James J Prisciandaro, Delisa G Brown, Paul J Nietert, Tracy Stecker, Alex Rothbaum, Jennifer L Jones, Julianne C Flanagan, Kathleen T Brady","doi":"10.4088/JCP.25m15803","DOIUrl":"10.4088/JCP.25m15803","url":null,"abstract":"<p><p><b>Objective:</b> Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) are common co-occurring conditions associated with a more severe clinical profile and poorer treatment outcomes than either disorder alone. To date, no medications have proven efficacious in the treatment of co-occurring PTSD/AUD.</p><p><p><b>Methods:</b> This randomized, double-blind, placebo-controlled trial examined the efficacy of <i>N-</i>acetylcysteine (NAC; 2,400 mg/day) among individuals (N=182, aged 21-65 years) who met <i>DSM-5</i> criteria for current PTSD/AUD. Participants were randomized 1:1 to receive 12 weeks of NAC (n=93) or placebo (n=89). All participants received weekly, individual, cognitive behavioral therapy (CBT) for AUD. Follow-up visits occurred at 3-, 6-, and 12-months posttreatment. Primary outcomes included the Clinician Administered PTSD Scale for <i>DSM-5</i> (CAPS-5), PTSD Checklist for <i>DSM-5</i> (PCL-5), Timeline Follow-Back (TLFB), and the Obsessive Compulsive Drinking Scale at 12 weeks. The TLFB evaluated the frequency and amount of alcohol consumption. A secondary measure evaluated depression symptoms.</p><p><p><b>Results:</b> Intent-to-treat analyses showed that participants in both the NAC and placebo groups evidenced significant reductions in the CAPS-5 (B=-0.19, <i>P</i><.001) and PCL-5 (B=-0.20, <i>P</i><.001) during treatment, with no significant group differences. Both groups also showed significant reductions in alcohol use (drinks per drinking day [B=-0.02, <i>P</i><.001], percent heavy drinking days [B=-0.14, <i>P</i><.001], percent days abstinent [B=0.29, <i>P</i>=.022]) and craving (B=-0.12, <i>P</i><.001) during treatment, but with no significant group differences. There were no group differences in retention or adverse events.</p><p><p><b>Conclusions:</b> Although NAC was well tolerated, it was not more effective than placebo in improving symptoms of PTSD or AUD when added to individual CBT for AUD.</p><p><p><b>Trial Registration:</b> ClinicalTrials.gov identifier: NCT02966873.</p>","PeriodicalId":50234,"journal":{"name":"Journal of Clinical Psychiatry","volume":"86 4","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Artificial Intelligence in Depression-Medication Enhancement (AID-ME): A Cluster Randomized Trial of a Deep-Learning-Enabled Clinical Decision Support System for Personalized Depression Treatment Selection and Management.","authors":"David Benrimoh, Kate Whitmore, Maud Richard, Grace Golden, Kelly Perlman, Sara Jalali, Timothy Friesen, Youcef Barkat, Joseph Mehltretter, Robert Fratila, Caitrin Armstrong, Sonia Israel, Christina Popescu, Jordan F Karp, Sagar V Parikh, Shirin Golchi, Erica E M Moodie, Junwei Shen, Anthony J Gifuni, Manuela Ferrari, Mamta Sapra, Stefan Kloiber, Georges-F Pinard, Boadie W Dunlop, Karl Looper, Mohini Ranganathan, Martin Enault, Serge Beaulieu, Soham Rej, Fanny Hersson-Edery, Warren Steiner, Alexandra Anacleto, Sabrina Qassim, Rebecca McGuire-Snieckus, Howard C Margolese","doi":"10.4088/JCP.24m15634","DOIUrl":"10.4088/JCP.24m15634","url":null,"abstract":"<p><p><b>Background:</b> There has been increasing interest in the use of artificial intelligence (AI)-enabled clinical decision support systems (CDSS) for the personalization of major depressive disorder (MDD) treatment selection and management, but clinical studies are lacking. We tested whether a CDSS that combines an AI which predicts remission probabilities for individual antidepressants and a clinical algorithm based on treatment can improve MDD outcomes.</p><p><p><b>Methods:</b> This was a multicenter, cluster randomized, patient-and-rater blinded and clinician-partially-blinded, active-controlled trial that recruited outpatient adults with moderate or greater severity MDD. All patients had access to a patient portal to complete questionnaires. Clinicians in the active group had access to the CDSS; clinicians in the active-control group received patient questionnaires; both groups received guideline training. Primary outcome was remission (<11 points on the Montgomery-Asberg Depression Rating Scale [MADRS]) at study exit.</p><p><p><b>Results:</b> Forty-seven clinicians were recruited at 9 sites. Of 74 eligible patients, 61 patients completed a postbaseline MADRS and were analyzed. There were no differences in baseline MADRS (<i>P</i> = .153). There were more remitters in the active (n = 12, 28.6%) than in the active-control (0%) group (<i>P</i> = .012, Fisher's exact). Of 3 serious adverse events, none were caused by the CDSS. Speed of improvement was higher in the active than the control group (1.26 vs 0.37, <i>P</i> = .03).</p><p><p><b>Conclusions:</b> While limited by sample size and the lack of primary care clinicians, these results demonstrate preliminary evidence that longitudinal use of an AI-CDSS can improve outcomes in moderate and greater severity MDD.</p><p><p><b>Trial Registration:</b> ClinicalTrials.gov identifier: NCT04655924.</p>","PeriodicalId":50234,"journal":{"name":"Journal of Clinical Psychiatry","volume":"86 3","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144976634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lumateperone as Adjunctive Therapy in Patients With Major Depressive Disorder: Results From a Randomized, Double-Blind, Phase 3 Trial.","authors":"Suresh Durgam, Willie R Earley, Susan G Kozauer, Changzheng Chen, Hassan Lakkis, Roger S McIntyre, Stephen Stahl","doi":"10.4088/JCP.25m15848","DOIUrl":"10.4088/JCP.25m15848","url":null,"abstract":"<p><p><b>Objective:</b> Lumateperone, a mechanistically novel antipsychotic, simultaneously modulates serotonin, dopamine, and glutamate neurotransmission. This phase 3, randomized, double-blind, placebo-controlled trial investigated efficacy and safety of adjunctive lumateperone 42 mg in patients with major depressive disorder (MDD) with inadequate antidepressant therapy (ADT) response.</p><p><p><b>Methods:</b> From July 2021 to February 2024, eligible adult outpatients (18-65 years) had <i>DSM-5</i>-defined MDD with inadequate response to 1 or 2 ADTs in the current depressive episode and Montgomery-Åsberg Depression Rating Scale (MADRS) Total score ≥24, Clinical Global Impression Scale-Severity (CGI-S) score ≥4, and Quick Inventory of Depressive Symptomatology-Self Report-16 item (QIDS-SR-16) score ≥14. Patients were randomized to 6-week oral adjunctive placebo (n=243) or adjunctive lumateperone 42 mg (n=242). Primary and key secondary end points were change from baseline to day 43 in MADRS Total and CGI-S scores. Safety was assessed.</p><p><p><b>Results:</b> Lumateperone + ADT met primary and key secondary end points, with significantly greater improvement at day 43 vs placebo + ADT in MADRS Total score (least squares mean difference [LSMD] vs placebo= -4.9; effect size [ES]= -0.61; <i>P</i> < .0001) and CGI-S score (LSMD =-0.7; ES = -0.67; <i>P</i> <.0001). Lumateperone + ADT significantly improved patient-reported depression vs placebo + ADT at day 43 (QIDS-SR-16 Total score, LSMD= -2.4; ES= -0.50; <i>P</i> < .0001). Lumateperone + ADT was generally well tolerated. Treatment-emergent adverse events (≥5%, twice placebo) were dry mouth (placebo + ADT, 2.1%; lumateperone + ADT, 10.8%), fatigue (2.1%; 9.5%), and tremor (0.4%; 5.0%), with minimal risk for weight gain or cardiometabolic abnormalities. Emergence of suicidal ideation was low (placebo + ADT, 3.5%; lumateperone + ADT, 1.4%).</p><p><p><b>Conclusions:</b> Lumateperone 42 mg adjunctive to ADT significantly improved depression symptoms and disease severity vs adjunctive placebo and was generally well tolerated in patients with MDD with inadequate ADT response.</p><p><p><b>Trial Registration:</b> ClinicalTrials.gov identifier: NCT04985942.</p>","PeriodicalId":50234,"journal":{"name":"Journal of Clinical Psychiatry","volume":"86 4","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}