It would be appealing to attempt to categorize depression
in terms of monoamine-depletion formsfrom 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.
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