Psychiatry

Long-term actigraphy metrics predict depressive relapse in remitted MDD

Adults with remitted major depression wore actigraphs for 1–2 years, yielding about 32,000 complete days of recording. Baseline lower sleep regularity, lower relative amplitude, and lower sleep efficiency were associated with higher relapse risk in adjusted Cox models. Higher wake after sleep onset and higher nighttime activity also predicted relapse, indicating clinically relevant sleep fragmentation and nocturnal activation. Time-varying analyses showed that greater sleep phase variability and persistently low daily activity amplitude tracked impending relapse, even after controlling for MADRS scores. Actigraphy distinguished relapsing patients from both ultrastable and subthreshold-fluctuating courses, suggesting utility as an objective relapse-risk biomarker. 1

FAAH inhibition fails to augment exposure therapy or alter neural signatures in PTSD

In a randomized clinical trial of 100 PTSD patients receiving exposure-based psychotherapy, a FAAH inhibitor showed no clinical advantage over placebo. Functional MRI in 76 participants found that symptom improvement related to lower vmPFC–right dlPFC connectivity and reduced right dlPFC activation, regardless of treatment arm. Concurrently, higher current PTSD symptoms correlated with increased vmPFC and amygdala connectivity to broader cortical regions, especially ventral attention and sensorimotor networks. Despite significantly increasing circulating anandamide after 4 weeks, FAAH inhibition did not change resting connectivity or emotional task activation versus placebo. These results argue against FAAH inhibition as a practical pharmacologic augment for PTSD exposure therapy and highlight dlPFC circuitry as a trans-treatment response marker. 2

Polygenic scores do not meaningfully predict methylphenidate response in ADHD

This multi-cohort meta-analysis pooled 1000 real-world ADHD cases from Norway, Brazil, and Spain treated with methylphenidate. Polygenic scores for ADHD, other psychiatric disorders, neuroticism, and educational attainment were tested as predictors of responder versus non-responder status. No polygenic score showed a significant association with methylphenidate response, and effect sizes were uniformly small with minimal heterogeneity. Results were robust to sensitivity analyses adjusting for clinical and treatment-related covariates across cohorts. Current susceptibility-based polygenic scores therefore lack clinical utility for stimulant selection and should not guide methylphenidate prescribing decisions. 3

Psychedelic medicine: converging mechanisms, emerging indications, and unresolved clinical challenges

This state-of-the-art review synthesizes cellular, systems, and clinical data on classic psychedelics acting mainly at 5-HT2A receptors. Preclinical and human evidence converge on acute neural desynchronization followed by a subacute window of enhanced neuroplasticity supporting psychological change. Clinical trials across several neuropsychiatric indications show therapeutic signal, but optimal diagnoses, comparators, and durability remain uncertain. The review emphasizes tensions between non-hallucinogenic analogs that engage putative mechanisms and clinical findings linking subjective experiences to benefit. It highlights safety risks, trial-design complexities, scalability barriers, and regulatory uncertainties that must be addressed before broad clinical integration. 4