A meta-analysis of deep brain structural shape and asymmetry abnormalities in 2,833 individuals with schizophrenia compared with 3,929 healthy volunteers via the ENIGMA Consortium.

Schizophrenia is associated with widespread alterations in subcortical brain structure. While analytic methods have enabled more detailed morphometric characterization, findings are often equivocal. In this meta-analysis, we employed the harmonized ENIGMA shape analysis protocols to collaboratively investigate subcortical brain structure shape differences between individuals with schizophrenia and healthy control participants. The study analyzed data from 2,833 individuals with schizophrenia and 3,929 healthy control participants contributed by 21 worldwide research groups participating in the ENIGMA Schizophrenia Working Group. Harmonized shape analysis protocols were applied to each site's data independently for bilateral hippocampus, amygdala, caudate, accumbens, putamen, pallidum, and thalamus obtained from T1-weighted structural MRI scans. Mass univariate meta-analyses revealed more-concave-than-convex shape differences in the hippocampus, amygdala, accumbens, and thalamus in individuals with schizophrenia compared with control participants, more-convex-than-concave shape differences in the putamen and pallidum, and both concave and convex shape differences in the caudate. Patterns of exaggerated asymmetry were observed across the hippocampus, amygdala, and thalamus in individuals with schizophrenia compared to control participants, while diminished asymmetry encompassed ventral striatum and ventral and dorsal thalamus. Our analyses also revealed that higher chlorpromazine dose equivalents and increased positive symptom levels were associated with patterns of contiguous convex shape differences across multiple subcortical structures. Findings from our shape meta-analysis suggest that common neurobiological mechanisms may contribute to gray matter reduction across multiple subcortical regions, thus enhancing our understanding of the nature of network disorganization in schizophrenia.

Rapid and sustained antidepressant response with sleep deprivation and chronotherapy in bipolar disorder.

BACKGROUND: The development of a rapid-acting and sustainable treatment for bipolar disorder (BPD) depression has been a goal for decades. The most widely documented rapid-onset antidepressant therapy is sleep deprivation (SD), which acts within 24-48 hours in 40%-60% of depressed patients. Conventional antidepressants usually require 2-8 weeks to meet response criteria. The delay, which may prolong suffering and increase suicidal risk, underlines the urgency of alternative treatment strategies. This study evaluates the combined efficacy of three established circadian-related treatments (SD, bright light [BL]), sleep phase advance [SPA]) as adjunctive treatment to lithium and antidepressants. METHODS: Forty-nine BPD patients were randomly assigned to a chronotherapeutic augmentation (CAT; SD+ BL+ SPA) or to a medication-only (MED) group. Clinical outcome was assessed using the Hamilton Rating Scale for Depression. RESULTS: Significant decreases in depression in the CAT versus MED patients were seen within 48 hours of SD and were sustained over a 7-week period. CONCLUSIONS: This is the first study to demonstrate the benefit of adding three noninvasive circadian-related interventions to SD in medicated patients to accelerate and sustain antidepressant responses and provides a strategy for the safe, fast-acting, and sustainable treatment of BPD.

Circadian abnormalities, molecular clock genes and chronobiological treatments in depression.

BACKGROUND: A long-standing challenge in the treatment of depression is the development of a rapidly acting antidepressant. Conventional antidepressants typically require 2-8 weeks for clinical remission. In contrast, chronobiological interventions such as sleep deprivation treatment dramatically reduce depressive symptoms within 24-48 h in 40-60% of depressed subjects. It is hypothesized that fast-acting treatments for depression may alter circadian rhythms through chronobiological mechanisms relevant to clock gene function. SOURCES OF DATA: A bibliographic review using Entrez PubMed with Boolean search terms 'circadian' and 'depressive' identified more than 1000 clinical papers published over a 40-year period (1966-present). AREAS OF AGREEMENT: A large body of clinical data reports that sleep, temperature, hormone and mood changes in depression are consistent with disturbances in circadian-related processes. AREAS OF CONTROVERSY: Consensus has not been achieved in terms of defining underlying chronobiological mechanisms for optimal methods to produce rapid and sustained antidepressant responses to circadian interventions. GROWING POINTS: Chronobiological augmentation using combinations of sleep deprivation with light therapy and/or sleep phase advance in medicated patients supports a clinical strategy for accelerating and sustaining antidepressant responses. AREAS TIMELY FOR DEVELOPING RESEARCH: Advances in technology including improved assays for clock gene expression will facilitate exploring the role of clock genes and may lead to new rapidly acting antidepressant strategies and potential novel drug targets.