Psychiatry

Complex antidepressant trajectories in MDD signal a more severe, genetically loaded phenotype

In adults with MDD (n=12,074), higher antidepressant treatment complexity correlated with more severe and atypical clinical profiles and greater comorbidity burden. Complex regimens were linked to recurrent MDD, suicidal ideation, smoking, chronic pain, and circadian or atypical depressive subtypes. Higher treatment complexity also associated with elevated polygenic scores for MDD, ADHD, bipolar disorder, and neuroticism, indicating genetically driven treatment resistance risk. About 61% met criteria for sustained use of a single antidepressant for at least 360 days, and these groups showed distinct phenotypic profiles. Genome-wide analyses identified novel loci, including immune-related SLAMF3/LY9 variation, associated with sustained SSRI or SSRI/SNRI use. 1

Youth SGAs track high-risk periods and modestly reduce severe outcomes

In 21,306 Swedish youth starting SGAs, risks of psychiatric hospitalization, self-harm, and violent crime peaked just before initiation. During SGA treatment, these risks declined but generally did not return to pre-escalation baseline, indicating partial stabilization rather than full normalization. In psychosis-related disorders, psychiatric hospitalization and self-harm showed large pre-initiation spikes and marked, though incomplete, reductions after initiation. In neurodevelopmental disorders, SGAs were linked to greater decreases in violent crime, particularly in youth with ADHD. Accidental injury risk showed little evidence of change with SGA treatment, suggesting limited impact on general safety-related behaviors. 2

Moderate-dose antipsychotics, except quetiapine, prevent relapse after cannabis-induced psychosis

This nationwide cohort of 1,772 individuals with first cannabis-induced psychosis examined dose–response relationships of oral antipsychotics for relapse prevention. Antipsychotic polytherapy reduced hospitalization for psychosis across all dose ranges, with hazard ratios around 0.54–0.65 versus no-treatment periods. Clozapine, olanzapine, aripiprazole, risperidone, and other antipsychotics were most effective at 0.6–<1.4 defined daily doses per day. Higher or lower doses generally did not outperform this moderate range, supporting dose optimization to balance efficacy and adverse effects. Quetiapine monotherapy showed no significant benefit for preventing psychosis hospitalization after cannabis-induced psychosis. 3

Psilocybin-assisted therapy shows large antidepressant effects; protocol choices may matter

This meta-analysis of seven RCTs (n=522) found psilocybin-assisted therapy produced large reductions in depressive symptoms versus comparators. Methodological features appeared to influence effect size, though subgroup differences were not statistically definitive. Larger effects were seen in studies using bodyweight-adjusted psilocybin dosing and longer preparation, dosing, and integration sessions. Non-manualized psychotherapy paired with psilocybin was associated with larger antidepressant effects than manualized approaches in exploratory analyses. 4