The State of Our Understanding of the Pathophysiology and Optimal Treatment of Depression: Glass Half Full or Half Empty?

Major depressive disorder is a remarkably common and often severe psychiatric disorder associated with high levels of morbidity and mortality. Patients with major depression are prone to several comorbid psychiatric conditions, including posttraumatic stress disorder, anxiety disorders, obsessive-compulsive disorder, and substance use disorders, and medical conditions, including cardiovascular disease, diabetes, stroke, cancer, which, coupled with the risk of suicide, result in a shortened life expectancy. The goal of this review is to provide an overview of our current understanding of major depression, from pathophysiology to treatment. In spite of decades of research, relatively little is known about its pathogenesis, other than that risk is largely defined by a combination of ill-defined genetic and environmental factors. Although we know that female sex, a history of childhood maltreatment, and family history as well as more recent stressors are risk factors, precisely how these environmental influences interact with genetic vulnerability remains obscure. In recent years, considerable advances have been made in beginning to understand the genetic substrates that underlie disease vulnerability, and the interaction of genes, early-life adversity, and the epigenome in influencing gene expression is now being intensively studied. The role of inflammation and other immune system dysfunction in the pathogenesis of major depression is also being intensively investigated. Brain imaging studies have provided a firmer understanding of the circuitry involved in major depression, providing potential new therapeutic targets. Despite a broad armamentarium for major depression, including antidepressants, evidence-based psychotherapies, nonpharmacological somatic treatments, and a host of augmentation strategies, a sizable percentage of patients remain nonresponsive or poorly responsive to available treatments. Investigational agents with novel mechanisms of action are under active study. Personalized medicine in psychiatry provides the hope of escape from the current standard trial-and-error approach to treatment, moving to a more refined method that augurs a new era for patients and clinicians alike.