Nearly 1 in 5 people will experience a major depressive episode at some point in their lives.1 In this review, we discuss data describing how genes, psychosocial adversity in childhood, and ongoing or recent psychosocial stress may impact multiple neurobiological systems relevant to major depressive disorder. Major depressive disorder may be caused by the cumulative effects of these 3 factors on the brain.2
A major depressive episode is characterized by a low mood or an inability to experience pleasure (anhedonia), or both, for more than 2 weeks, combined with several cognitive and vegetative symptoms and the occurrence of distress or impairment.3 A diagnosis of major depressive disorder can be made if a person suffers at least 1 such episode (without ever experiencing mania). However, most people with major depressive disorder have multiple episodes. Importantly, several medical illnesses such as diabetes, heart disease, autoimmune disorders and pain are common comorbid diagnoses.4,5 The relation between major depressive disorder and these chronic and disabling conditions appears to be bidirectional because one may influence the prognosis of the other.
Investigations into the neurobiology of major depressive disorder have traditionally focused on the monoamine neurotransmitters serotonin and norepinephrine. The monoamine hypothesis initially posited that depressed individuals are likely to have low levels of these neurotransmitters because various antidepressant drugs acutely increase their levels.6 However, even though monoaminergic antidepressants are generally used for first-line treatment, they do not exert their clinical benefit immediately and for some people they do not provide any benefit at all. We review the neurobiological research that may help explain this.