How antidepressants work: cautionary conclusions based on clinical and laboratory studies of the longer-term consequences of antidepressant drug treatment.

Time-dependent alterations in the functional activity of adrenergic and serotonergic neurotransmitter systems and, in particular, a frequently observed down-regulation of brain beta-adrenoceptors have been implicated in antidepressant drug effects. Current studies of catecholamine and serotonin neurotransmitter systems suggest that the net physiological output changes in neuroendocrine responses, blood pressure, sleep and motor activity which follow various antidepressant treatments in psychiatric patients, normal controls and different experimental animals are not indicative of a common response pattern to all therapeutically effective agents. Rather, antidepressant treatment effects differ according to many variables, including the pre-existing state of the organism (e.g. depressed, stressed or normal), the species, the duration of treatment and the particular brain or peripheral circuits investigated. Examples are cited from our studies of the effects of monoamine oxidase inhibitors and other antidepressants on noradrenergic-serotonergic interactions that affect melatonin release and other neuroendocrine responses, on some additional functional end-points, and on depressive mood and other symptoms in patients with depression or other tricyclic-responsive disorders. These examples illustrate the complexity found in attempts to identify a unitary mechanism of antidepressant drug action.