High-throughput screening of glucocorticoid-induced enhancer activity reveals mechanisms of stress-related psychiatric disorders.

Exposure to stressful life events increases the risk for psychiatric disorders. Mechanistic insight into the genetic factors moderating the impact of stress can increase our understanding of disease processes. Here, we test 3,662 single nucleotide polymorphisms (SNPs) from preselected expression quantitative trait loci in massively parallel reporter assays to identify genetic variants that modulate the activity of regulatory elements sensitive to glucocorticoids, important mediators of the stress response. Of the tested SNP sequences, 547 were located in glucocorticoid-responsive regulatory elements of which 233 showed allele-dependent activity. Transcripts regulated by these functional variants were enriched for those differentially expressed in psychiatric disorders in the postmortem brain. Phenome-wide Mendelian randomization analysis in 4,439 phenotypes revealed potentially causal associations specifically in neurobehavioral traits, including major depression and other psychiatric disorders. Finally, a functional gene score derived from these variants was significantly associated with differences in the physiological stress response, suggesting that these variants may alter disease risk by moderating the individual set point of the stress response.

Effectiveness of Schema Therapy versus Cognitive Behavioral Therapy versus Supportive Therapy for Depression in Inpatient and Day Clinic Settings: A Randomized Clinical Trial.

INTRODUCTION: Schema therapy (ST) reduces depressive symptoms, but clinical trials have not investigated its effectiveness for patients suffering from severe forms of depression and high rates of comorbidities. There is high demand for exploring and improving treatments for this patient group. The objective of the current study was to evaluate whether ST is more effective than individual supportive therapy (IST) and noninferior compared with cognitive behavioral therapy (CBT) in treating depression. METHODS: For this clinical trial, medicated patients were recruited in inpatient and day clinic settings. The major inclusion criteria were age between 18 and 75 years and primary diagnosis of depression without psychotic symptoms. A total of 292 participants were randomized to ST, CBT, or IST and received 7 weeks of psychotherapy (up to 14 individual and 14 group sessions). The primary outcome was change in depression severity after treatment measured by Beck Depression Inventory-II. Primary test for efficacy was superiority of ST over IST. Secondary test was noninferiority of ST compared with CBT. Multilevel modeling was conducted. The results at 6-month follow-up were explored. RESULTS: Across treatment, ST was not superior to IST. Secondary outcome analyses and completer analyses showed similar results. However, ST showed clinically relevant noninferiority compared with CBT. CONCLUSION: ST for depression as part of a psychiatric care program showed clinical noninferiority compared to CBT, without being superior to IST. ST represents a potentially useful addition to the therapeutic repertoire for the treatment of depression but its efficacy, including long-term efficacy, should be evaluated further.

Human cortical neurogenesis is altered via glucocorticoid-mediated regulation of ZBTB16 expression.

Glucocorticoids are important for proper organ maturation, and their levels are tightly regulated during development. Here, we use human cerebral organoids and mice to study the cell-type-specific effects of glucocorticoids on neurogenesis. We show that glucocorticoids increase a specific type of basal progenitors (co-expressing PAX6 and EOMES) that has been shown to contribute to cortical expansion in gyrified species. This effect is mediated via the transcription factor ZBTB16 and leads to increased production of neurons. A phenome-wide Mendelian randomization analysis of an enhancer variant that moderates glucocorticoid-induced ZBTB16 levels reveals causal relationships with higher educational attainment and altered brain structure. The relationship with postnatal cognition is also supported by data from a prospective pregnancy cohort study. This work provides a cellular and molecular pathway for the effects of glucocorticoids on human neurogenesis that relates to lasting postnatal phenotypes.