Psychiatry

Combined psychotherapy plus antidepressants outperforms pharmacotherapy alone for adult depression, without identifiable patient-level modifiers

Across 31 randomized trials with 3703 adults, combined psychotherapy plus pharmacotherapy reduced depressive symptoms more than medication alone at post-treatment and follow-up. Effect sizes were moderate at post-treatment and six months and remained favorable, though smaller, at twelve months. No individual patient-level effect modifiers were identified, suggesting benefits across demographic and clinical subgroups. Study-level features, including SSRI use and adequacy of pharmacotherapy, showed inconsistent moderating effects and were not robust in sensitivity analyses. Because only 41% of eligible trials provided individual data, generalizability is somewhat limited but still supports broad combined-treatment use. 1

DNA methylation plus clinical data strongly predicts ketamine response in PTSD

In the CAP-ketamine PTSD trial, pretreatment blood DNA methylation and clinical variables were used to predict ketamine response. A model based on 1208 methylation sites outperformed models using clinical features alone. Combining methylation with clinical data further improved prediction, and a methylation-derived score identified responders with 92.9% accuracy. Predictive CpGs clustered near genes involved in glutamatergic signaling, immune regulation, and known PTSD risk loci. These findings suggest a feasible blood-based biomarker approach to select PTSD patients more likely to benefit from ketamine. 2

Mindfulness-based interventions yield small–moderate reductions in adolescent substance use

This systematic review included 21 randomized trials (23 studies; 2297 participants) of mindfulness-based interventions for youth aged 12–21 who use substances. Over two-thirds of trials reported better postintervention substance use outcomes with mindfulness interventions versus comparators. Pooled analyses suggested small to moderate reductions in alcohol and drug use and improvements in impulsivity and stress reactivity. Preliminary data indicate that changes in impulsivity and responses to stress and craving may mediate substance use reductions. Heterogeneous interventions, outcomes, and limited data on illicit substances constrain generalizability and specific protocol recommendations. 3

GLP-1 receptor agonists show early promise for substance use disorders without clear psychiatric harms

This narrative review summarizes preclinical, observational, and early clinical data on GLP-1 receptor agonists for alcohol and other substance use disorders. Preclinical models across species consistently show GLP-1 agonists reduce drug intake and other addiction-like behaviors. Electronic health record cohorts suggest improved substance-related outcomes among patients receiving GLP-1 drugs for metabolic indications. Randomized clinical trials in addiction populations remain few with mixed but generally encouraging signals, and several trials are ongoing. Current evidence does not support increased depression or suicidality risk and hints at possible mental health benefits, but key questions about dosing, duration, and access remain. 4