The Neurobiology of Depression: Inroads to Treatment and New Drug Discovery

The underlying causes of most mood and anxiety disorders remain unknown. There is a strongheritable component to psychiatric illnesses that, when coupled with environmental influences, resultsin increased vulnerability. Intensive research efforts have been expended to better characterize thegenetic underpinnings of mental illness. However, most psychiatric disorders, including mood andanxiety disorders, are polygenetic in nature rather than determined by traditional autosomal-dominantMendelian genetics. Recent technological advances, including the completion of the human genomeinventory, chromosome mapping, high throughput DNA sequencing, and others, offer the promise ofsomeday identifying the genetic basis of mental illnesses. In parallel, tremendous inroads have beenmade into understanding the neurobiological basis of mood and anxiety disorders and the influenceof life events on risk and resilience. Evidence from preclinical, epidemiologic, and clinical studies hasconverged to convincingly demonstrate that stressful or traumatic events occurring in early life significantlyincrease the risk for depression and other psychiatric illnesses in adulthood. Neural circuitscontaining corticotropin-releasing factor (CRF) have been identified as an important mediator ofthe stress response. Early-life adversity, such as physical or sexual abuse during childhood, results inlong-lasting changes in the CRF-mediated stress response and a greatly increased risk of depression ingenetically predisposed persons. Identification and cloning of CRF receptors and characterization oftheir role in the stress response have enabled a better understanding of maladaptive responses to early-lifeadversity. In addition, studies of the CRF system have suggested molecular targets for new drugdevelopment, biological risk factors, and predictors of treatment response.