Mac Giollabhui N, Madison AA, Lydston M
… +3 more, Lenoel Quang E, Miller AH, Liu RT
Am J Psychiatry
· 2026 Jan · PMID 41366844
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OBJECTIVE: Studies evaluating the effect of anti-inflammatory treatment on depressive symptom severity and anhedonia in depressed individuals report mixed results. In this preregistered systematic review and meta-analysi...OBJECTIVE: Studies evaluating the effect of anti-inflammatory treatment on depressive symptom severity and anhedonia in depressed individuals report mixed results. In this preregistered systematic review and meta-analysis, the authors evaluated whether anti-inflammatory treatments, compared to placebo, reduce anhedonia and depressive symptom severity in depressed individuals with an inflammatory phenotype. METHODS: The authors included randomized controlled trials of pharmacological anti-inflammatory treatments that assessed anhedonia or depressive symptom severity and recruited depressed individuals with an inflammatory phenotype or measured baseline inflammatory biomarkers that permitted post hoc analysis. A search was conducted in February 2025 of MEDLINE, Embase, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and PsycINFO. Multiple reviewers independently applied criteria, and discrepancies were resolved via consensus. Two reviewers independently extracted data and cross-checked for errors. RESULTS: In randomized controlled trials (k=11) using an established cutoff for elevated inflammation (C-reactive protein ≥2 mg/L), both anhedonia (Hedges' g=0.40, 95% CI=0.08, 0.71) and depressive symptoms (Hedges' g=0.35, 95% CI=0.05, 0.64) were reduced, but no differences in treatment response (relative risk=1.28, 95% CI=0.997, 1.64) or remission rates (relative risk=1.18, 95% CI=0.71, 1.95) were observed. Results did not vary by clinical, interventional, or demographic characteristics. CONCLUSIONS: Anti-inflammatory treatments may be safe and effective at reducing depressive symptoms and anhedonia in depressed individuals with heightened inflammation. Not accounting for inflammatory status may help explain prior mixed findings.
Naples AJ, Yang Y, Gravel P
… +22 more, Toyonaga T, Sadabad FE, Koohsari S, Pittman B, Gallezot JD, Pisani L, Finn C, Cramer-Benjamin S, Herman N, Rosenthal LH, Franke CJ, Walicki BM, Rodden IG, Hillmer AT, Esterlis I, Ropchan J, Nabulsi N, Huang Y, Wolf JM, Carson RE, McPartland JC, Matuskey D
Am J Psychiatry
· 2026 Jan · PMID 41366835
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OBJECTIVE: Autism spectrum disorder is a prevalent and heterogeneous condition with features ranging from social and communication differences to sensory sensitivities. Differences in excitatory neurotransmission have be...OBJECTIVE: Autism spectrum disorder is a prevalent and heterogeneous condition with features ranging from social and communication differences to sensory sensitivities. Differences in excitatory neurotransmission have been identified in autism, but the molecular underpinnings are poorly understood. To investigate the mechanism underlying these observed differences, the authors assessed glutamatergic receptor density in autistic adults using positron emission tomography (PET) and related it to a functional EEG measure of excitatory activity. METHODS: Metabotropic glutamate receptor 5 (mGlu5) availability was compared in autistic (N=16) and neurotypical (N=16) adults between 18 and 36 years of age, using the PET tracer 3-[F]fluoro-5-(2-pyridinylethynyl) benzonitrile ([F]FPEB). The PET outcome measure was volume of distribution (V) computed with equilibrium analysis using a venous input function and partial volume correction. Group differences were quantified using mixed-model analyses. Heterogeneity was further parsed within the autistic group by quantifying the relationship between receptor availability and the slope of the EEG power spectrum, an index of excitatory-inhibitory balance. Correlations between EEG and V were calculated using Spearman's rho. RESULTS: Across all brain regions, mGlu5 availability was significantly lower (by ~15%) in autistic relative to neurotypical control participants. Group differences were generally greatest in the cerebral cortex. Within the autistic group, mGlu5 availability in all regions was significantly correlated with the slope of the EEG (e.g., cerebral cortex, r=0.67), such that shallower slope was associated with lower mGlu5 availability. CONCLUSIONS: This brain-wide investigation of mGlu5 availability with PET revealed pervasive lower mGlu5 availability across multiple brain areas in autism. Additionally, multimethod analyses revealed associations with a noninvasive electrophysiological index of excitatory neurotransmission. These results indicate that lower brain-wide mGlu5 availability may represent a molecular mechanism underlying altered excitatory neurotransmission that has the potential to stratify the heterogeneous autism phenotype.
Durgam S, Earley WR, Kozauer SG
… +5 more, Mo Y, Lakkis H, Edwards JB, Kornstein SG, Fava M
Am J Psychiatry
· 2025 Dec · PMID 41320817
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OBJECTIVE: This phase 3, randomized, double-blind, placebo-controlled trial evaluated lumateperone 42 mg (a simultaneous modulator of serotonin, dopamine, and glutamate neurotransmission) adjunctive to antidepressant the...OBJECTIVE: This phase 3, randomized, double-blind, placebo-controlled trial evaluated lumateperone 42 mg (a simultaneous modulator of serotonin, dopamine, and glutamate neurotransmission) adjunctive to antidepressant therapy (ADT) in patients with major depressive disorder (MDD) and inadequate ADT response. METHODS: Participants were adults (ages 18-65 years) who had -defined MDD and inadequate response to one to two ADTs in the current depressive episode and a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥24. Patients were randomized in a 1:1 ratio to 6 weeks of oral placebo plus ADT (N=238) or lumateperone 42 mg plus ADT (N=242), once daily in the evening; the ADT was the latest drug to which they had inadequate response (i.e., <50% improvement). Primary and key secondary outcomes were change from baseline to day 43 in MADRS total score and Clinical Global Impressions Scale severity (CGI-S) score. Safety measures included adverse events, extrapyramidal symptoms, laboratory assessments, and suicidal ideation and behavior. RESULTS: Lumateperone+ADT met primary and key secondary endpoints, significantly improving MADRS total score (least squares mean difference [LSMD] versus placebo=-4.5; effect size=-0.56) and CGI-S score (LSMD=-0.5; effect size=-0.51) versus placebo+ADT at day 43. Patient-reported depression significantly improved with lumateperone+ADT versus placebo+ADT at day 43 (16-item Quick Inventory of Depressive Symptomatology-Self-Report, total score: LSMD=-2.2; effect size=-0.45). Lumateperone+ADT was generally well tolerated. The most common treatment-emergent adverse events (≥5%, twice the rate in the placebo+ADT group) were dizziness, somnolence, dry mouth, nausea, diarrhea, and fatigue; 12.4% versus 0.8% of patients discontinued treatment due to treatment-emergent adverse events in the lumateperone+ADT arm versus the placebo+ADT arm. There was minimal risk of extrapyramidal symptoms. Cardiometabolic abnormalities and weight gain were similar between the lumateperone+ADT arm and the placebo+ADT arm. Emergence of suicidal ideation was low. CONCLUSIONS: Patients receiving lumateperone 42 mg plus ADT had statistically significant and clinically meaningful improvement in depression symptoms and disease severity compared with those receiving placebo+ADT. Lumateperone+ADT was generally safe and well tolerated in patients with MDD with inadequate ADT response.
Metrik J, Aston ER, Gunn RL
… +3 more, Swift R, MacKillop J, Kahler CW
Am J Psychiatry
· 2026 Feb · PMID 41254853
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OBJECTIVE: Cannabis use is strongly linked with heavy drinking and worse alcohol treatment outcomes; however, it may also contribute to decreased alcohol consumption. To date, no human studies have established a causal e...OBJECTIVE: Cannabis use is strongly linked with heavy drinking and worse alcohol treatment outcomes; however, it may also contribute to decreased alcohol consumption. To date, no human studies have established a causal effect of cannabis on alcohol motivation. The aim of this double-blind crossover randomized clinical trial was to examine dose-dependent acute effects of delta-9-tetrahydrocannabinol (THC) on alcohol craving and consumption. METHODS: Across three experimental days, 157 participants reporting heavy alcohol use and cannabis use two or more times weekly were randomized to smoke cannabis cigarettes containing 7.2% THC, 3.1% THC, or 0.03% THC (placebo), followed by exposures to neutral and personalized alcohol cues and an alcohol choice task for alcohol self-administration. A total of 138 participants completed two or more experimental sessions (mean age, 25.6 years [SD=5.1]; 35% women; 45% racial/ethnic minorities). Primary outcomes included craving, Alcohol Craving Questionnaire-Short Form, Revised (ACQ-SF-R), and an alcohol urge question; the secondary outcome was percent of total available milliliters of alcohol consumed. RESULTS: There were no significant effects of cannabis on ACQ-SF-R ratings after smoking and during alcohol cue exposure, but 7.2% THC reduced alcohol urge immediately after smoking. Participants consumed significantly less alcohol after smoking cannabis with 3.1% THC and 7.2% THC, reducing consumption by 19% and 27%, respectively. CONCLUSIONS: Following overnight cannabis abstinence, smoking cannabis acutely decreased alcohol consumption compared to placebo. Further controlled research on a variety of cannabinoids is needed to inform clinical alcohol treatment guidelines.
Gober Dykan CD, Levinstein Y, Tetse-Laur L
… +5 more, Ben-Yehuda A, Rotschield J, Pine DS, Bliese PD, Bar-Haim Y
Am J Psychiatry
· 2026 Mar · PMID 41254848
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OBJECTIVE: Evidence suggests that attentional threat avoidance is associated with increased risk for posttraumatic stress disorder (PTSD). This study evaluated the efficacy of two attention bias modification (ABM) protoc...OBJECTIVE: Evidence suggests that attentional threat avoidance is associated with increased risk for posttraumatic stress disorder (PTSD). This study evaluated the efficacy of two attention bias modification (ABM) protocols designed to enhance attention toward threats as a primary prevention of PTSD. METHODS: The efficacy of the two ABM protocols was assessed using a three-arm randomized controlled trial in 501 male combat-bound soldiers. One protocol used response-time (RT)-based ABM to train attention toward threat over neutral stimuli (dot-probe task); the other used an eye-tracking-based ABM employing instrumental reward to enhance sustained attention to threat over neutral stimuli. Each intervention was compared to a sham RT-based task (dot-probe) presenting only neutral stimuli. Participants underwent four sessions of active or sham training. Threat-related attention was measured before and after training. Self-reported symptoms of PTSD (primary outcome) and of depression and anxiety (secondary outcomes), were assessed at baseline and postcombat 1 year later. RESULTS: RT-based ABM delivered prior to combat exposure was associated with lower symptom severity and lower prevalence of probable PTSD postcombat relative to sham training (number needed to treat=22.7). A significant association was noted between training-induced threat attention and postcombat PTSD symptom severity in the RT-based ABM group. Eye-tracking-based ABM was not effective as a primary prevention protocol for PTSD symptoms. CONCLUSIONS: Consistent with a previous randomized controlled trial, RT-based ABM reduced risk for PTSD relative to sham ABM when implemented prior to combat exposure. These findings support the integration of RT-based ABM into resilience-building programs in military settings.
Kantrowitz JT, Mayer MR, Choo TH
… +4 more, Liu K, Govani V, Francis S, Javitt DC
Am J Psychiatry
· 2026 Mar · PMID 41254842
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OBJECTIVE: Meta-analytic evidence supports the effectiveness of several mechanisms of action adjunctive to antipsychotics for the treatment of negative symptoms in schizophrenia. Nevertheless, the results have not been r...OBJECTIVE: Meta-analytic evidence supports the effectiveness of several mechanisms of action adjunctive to antipsychotics for the treatment of negative symptoms in schizophrenia. Nevertheless, the results have not been replicated consistently in multicenter randomized clinical trials. The authors' primary objective in this study was to assess whether differential scaling of response in the placebo arm by sample size could account for the discrepant results between smaller- and larger-scale trials. METHODS: The authors conducted a meta-analysis and meta-regression of the potential contribution of differential scaling by sample size, site number, and other potential moderators in randomized clinical trials of adjunctive mechanisms of action in schizophrenia that included negative symptom outcomes. RESULTS: Eight mechanisms of action were identified across 159 active-placebo comparisons with 13,020 unique participants (59.2% male [SD=26.8]; 57.2% multicenter studies). Between-group differences in negative symptoms were observed for four mechanisms of action. The size of the between-group treatment effects decreased significantly with increasing sample size (b=-0.60) and site number (b=-0.33). This was attributable primarily to significantly greater improvement in the placebo arm (b=-0.45, SE=0.21), but not the active treatment arm (b=0.14, SE=0.21). Consequently, significant between-group effects were observed preferentially in studies with ≤150 participants and ≤10 sites, along with a mean of >20 participants per site ("recruitment density") (b=-0.52). CONCLUSIONS: This differential placebo-active scaling with increased sample size is unlikely to be of physiological origin and may indicate that site management issues contribute to negative clinical results in large-scale trials for the negative symptoms of schizophrenia. Current power analytic approaches do not adequately consider the consequences of sample size-dependent effect size deflation, leading to excessive risk of type II error with increasing sample size or site numbers and decreasing recruitment density.