It would be appealing to attempt to categorize depression in terms of monoamine-depletion forms that are perhaps related to genes coding for enzymes involved in neurotransmission and cortisolrelated forms that are characterized by a more long-term course, hippocampal atrophy, and a history of psychosocial stress. However, the clinical data do not fall into such neat categories, since monoamine-based antidepressants are most effective in patients with severe depression when cortisol levels remain high after the administration of dexamethasone. Major depressive disorder is likely to have a number of causes. Middle-aged or elderly patients presenting with depression may have a disorder related to cardiovascular disease and originating from endothelial dysfunction.128 Patients in their late teens or early 20s who have severe depression may have important genetic risk factors and a high risk of manic episodes.8 In patients with an anxious and depressive personality, depression may be due to genetically determined personality factors11 or adverse childhood experiences.129 Avoidance of premature closure on any one scientific theory of the mechanism of depression will best serve the search for new, more effective treatments. It is likely that the pathogenesis of acute depression is different from that of recurrent or chronic depression, which is characterized by long-term declines in function and cognition. Mood can be elevated (by stimulants,46 by brain stimulation,123 or by ketamine94) or depressed (by monoamine depletion19 in recovered patients) for short periods, but longer-term improvement may require reduction of the abnormal glucocorticoid function induced by stress or increases in brain neurotrophic factors.
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