Journal of Clinical Psychiatry最新文献

Background: 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.

Methods: 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).

Results: 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.

Conclusions: 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.

Introduction: 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.

Methods: 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.

Results: 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; P=.021). Female sex was a significant risk factor for multiple reattempts (OR, 2.388; 95% CI, 1.036-5.507; P=.041). High-lethality FSAs significantly increased the risk of suicide deaths (hazard ratio [HR], 5.430; 95% CI, 1.189-24.792; P=.029), while older age was associated with a higher risk of nonsuicidal deaths (HR, 1.093; 95% CI, 1.035-1.153; P=.001).

Conclusions: 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.

Objective: 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.

Methods: This randomized, double-blind, placebo-controlled trial examined the efficacy of N-acetylcysteine (NAC; 2,400 mg/day) among individuals (N=182, aged 21-65 years) who met DSM-5 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 DSM-5 (CAPS-5), PTSD Checklist for DSM-5 (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.

Results: Intent-to-treat analyses showed that participants in both the NAC and placebo groups evidenced significant reductions in the CAPS-5 (B=-0.19, P<.001) and PCL-5 (B=-0.20, P<.001) during treatment, with no significant group differences. Both groups also showed significant reductions in alcohol use (drinks per drinking day [B=-0.02, P<.001], percent heavy drinking days [B=-0.14, P<.001], percent days abstinent [B=0.29, P=.022]) and craving (B=-0.12, P<.001) during treatment, but with no significant group differences. There were no group differences in retention or adverse events.

Conclusions: 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.

Trial Registration: ClinicalTrials.gov identifier: NCT02966873.

Background: 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.

Methods: 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.

Results: 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 (P = .153). There were more remitters in the active (n = 12, 28.6%) than in the active-control (0%) group (P = .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, P = .03).

Conclusions: 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.

Trial Registration: ClinicalTrials.gov identifier: NCT04655924.

Objective: 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.

Methods: From July 2021 to February 2024, eligible adult outpatients (18-65 years) had DSM-5-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.

Results: 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; P < .0001) and CGI-S score (LSMD =-0.7; ES = -0.67; P <.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; P < .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%).

Conclusions: 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.

Trial Registration: ClinicalTrials.gov identifier: NCT04985942.

Objective: The primary aim of this study was to establish that levomilnacipran potently inhibits norepinephrine (NE) reuptake in human participants starting at a minimally efficacious regimen in major depressive disorder (MDD) and to determine the dose needed to significantly inhibit serotonin (5-HT) reuptake. The secondary aim was to confirm that duloxetine is a selective 5-HT reuptake inhibitor at its minimally effective regimen in MDD and that it significantly inhibits NE reuptake only with dose escalation.

Methods: Inhibition of the NE reuptake process was estimated by assessing the attenuation of the systolic blood pressure produced by intravenous injections of small doses of tyramine. Inhibition of the 5-HT reuptake process was estimated using depletion of whole blood 5-HT. Healthy male participants took ascending daily doses of levomilnacipran (40, 80, and 120 mg), duloxetine (60, 90, and 120 mg) each for 7 days, or a placebo pill (n=10, 9, and 10, respectively), and all assays were carried out 2-6 hours after the last dose. The study took place between February 2018 and October 2022.

Results: Plasma levels of both medications increased in dose-dependent levels. Neither the tyramine pressor responses nor 5-HT levels were significantly altered in the placebo group. For the attenuation of the tyramine pressor response, levomilnacipran separated from baseline starting at 40 mg and duloxetine separated from baseline only at 120 mg. Both drugs robustly decreased 5-HT levels to the same extent at all 3 doses.

Conclusions: Levomilnacipran is a potent dual reuptake inhibitor from its minimally effective dose in MDD, whereas the dose of duloxetine needs to reach 120 mg/day to consistently inhibit NE reuptake.

Trial Registration: ClinicalTrials.gov identifier: NCT03249311.

Schizophrenia is a major mental illness with a median lifetime prevalence, across studies, of 0.5%. Across definitions of treatment resistance, about 37% of schizophrenia patients do not respond to treatment, and about 24% are treatment resistant from the first-episode, itself. Treatment resistance is addressed by trialing different antipsychotics and with antipsychotic augmentation strategies; what augmenting agent is used depends on what the target symptoms are. A landmark study in 1988 demonstrated the efficacy of clozapine in treatment resistant schizophrenia (TRS). Confirmatory studies and meta-analyses followed, establishing clozapine as the drug of choice for TRS in schizophrenia treatment guidelines across the world. Between 2016 and 2025, 2 network meta analyses (NMAs) and 1 individual participant data meta-analysis (IPD-MA) examined randomized controlled trials (RCTs) of clozapine vs other antipsychotics in TRS. The NMAs found that clozapine was superior to first-generation antipsychotics; however, clozapine did not head rankings for overall symptoms, positive symptoms, or negative symptoms, and, in pairwise analyses, there was little difference between clozapine and olanzapine and clozapine and risperidone for overall symptoms, positive symptoms, and negative symptoms. The IPD-MA found that clozapine was no better than comparator second-generation antipsychotics, considered singly or together, for overall symptoms, positive symptoms, and negative symptoms, in the short term, intermediate term, and long term. These findings fly in the face of clinical experience and treatment guideline recommendations. Among possible explanations, notable was that clozapine was significantly superior to comparator drugs when disregarding RCTs sponsored by the manufacturer of olanzapine. Clozapine is associated with many inconveniencing, distressing, and serious adverse effects that may be rare or common. Given the findings that olanzapine and risperidone may be as good as clozapine in TRS, it may be worth trialing these drugs before clozapine in patients with TRS. These and related issues, including nuances, are discussed.

Bipolar I disorder (BP-I) is a severe and chronic psychiatric condition characterized by recurrent episodes of mania and depression that significantly impact quality of life and functioning. Early recurrence, high relapse rates, and poor adherence to daily oral medications complicate long-term management and increase the risk of hospitalization and suicide. Long-acting injectable antipsychotics (LAIs) offer a potential solution to these challenges by promoting sustained medication delivery and efficacy, reducing pharmacokinetic variability, and improving treatment adherence. Among available LAIs, aripiprazole is the only partial dopamine D₂ receptor agonist, which may contribute to its favorable tolerability and mood-stabilizing properties. Despite the robust evidence for the efficacy and tolerability of aripiprazole monohydrate LAIs in patients with BP-I, this agent remains underutilized in this population. Misperceptions about efficacy and tolerability, coupled with systemic and prescriber-level barriers, have limited broader clinical adoption. To address these issues, a round table panel of experts in psychopharmacology, the clinical treatment of bipolar disorder, and antipsychotic prescribing was convened to evaluate the clinical rationale for earlier use of aripiprazole monohydrate LAIs in BP-I and to identify key challenges limiting its use. This article summarizes their consensus on the pharmacological distinctiveness, practical advantages, and potential of aripiprazole monohydrate LAIs in improving long-term outcomes in individuals with BP-I.