The neurobiology of depression: inroads to treatment and new drug discovery

Abstract

The underlying causes of most mood and anxiety disorders remain unknown. There is a strong heritable component to psychiatric illnesses that, when coupled with environmental influences, results in increased vulnerability. Intensive research efforts have been expended to better characterize the genetic underpinnings of mental illness. However, most psychiatric disorders, including mood and anxiety disorders, are polygenetic in nature rather than determined by traditional autosomal-dominant Mendelian genetics. Recent technological advances, including the completion of the human genome inventory, chromosome mapping, high throughput DNA sequencing, and others, offer the promise of someday identifying the genetic basis of mental illnesses. In parallel, tremendous inroads have been made into understanding the neurobiological basis of mood and anxiety disorders and the influence of life events on risk and resilience. Evidence from preclinical, epidemiologic, and clinical studies has converged to convincingly demonstrate that stressful or traumatic events occurring in early life significantly increase the risk for depression and other psychiatric illnesses in adulthood. Neural circuits containing corticotropin-releasing factor (CRF) have been identified as an important mediator of the stress response. Early-life adversity, such as physical or sexual abuse during childhood, results in long-lasting changes in the CRF-mediated stress response and a greatly increased risk of depression in genetically predisposed persons. Identification and cloning of CRF receptors and characterization of their role in the stress response have enabled a better understanding of maladaptive responses to early-life adversity. In addition, studies of the CRF system have suggested molecular targets for new drug development, biological risk factors, and predictors of treatment response.