Cellular mechanisms in the vulnerability to depression and response to antidepressants

Major depressive disorder is an enigmatic disorder that has defied three decades of research into its fundamental biological causes; however, a perusal of the signs and symptoms of the disease reveals tantalizing clues. Depressed mood, sleep disturbance, fatigue, loss of pleasure and motivation, appetite and weight changes, rumination, and loss of sexual interest are recognized characteristics of the disorder; however, these features also can be seen as normal reactions to stressful external events. Therefore, the symptoms of the disorder are not abnormal but may represent exaggerated and prolonged forms of stress response. Therefore, major depressive disorder can be formulated as a malady of stress adaptation in the brain.(30,31,37,38,104) Also, cellular mediators of stress response, whether activators or inhibitors, are considered important candidates for investigation. This article focuses on depression as a disorder of stress response and adaptation (sometimes referred to as neural plasticity). It begins with cellular mechanisms related to antidepressant drug actions, including transductional and transcriptional factors, culminating in the regulation of the expression of specific genes related to the stress-response system more broadly.