Monoamine Dysfunction and the Pathophysiology and Treatment of Depression

Alterations in noradrenergic and serotonergic function in the central nervous system (CNS) havebeen implicated in the pathophysiology of depression and the mechanism of action of antidepressantdrugs. Based on changes in norepinephrine and serotonin metabolism in the CNS, it has been postulatedthat subgroups of patients with differential responses to norepinephrine and serotonin reuptakeinhibitors may exist. α-Methylparatyrosine (AMPT), which causes rapid depletion of brain catecholamines,has been used as a noradrenergic probe to test the hypothesis that changes in neurotransmissionthrough the catecholamine system may underlie the therapeutic response to norepinephrinereuptake inhibitors. Brain serotonin is dependent on plasma levels of the essential amino acid tryptophan.Rapid tryptophan depletion, in the form of a tryptophan-free amino acid drink, has been used asa serotonergic probe to identify therapeutically responsive subsets of patients. Using these probes, wehave recently examined the behavioral effects of reduced concentrations of brain monoamines on depressedpatients treated with a variety of serotonin selective reuptake inhibitors (SSRIs) or the relativelynorepinephrine-selective antidepressant desipramine, during 3 different states: drug-free anddepressed; in remission on antidepressant drugs; and drug-free in remission. The results of a series ofinvestigations confirm the importance of monoamines in the mediation of depressed mood, but alsosuggest that other brain neural systems may have more of a primary role than previously thought inthe pathophysiology of depression. Noradrenergic and serotonergic probes may be used in time toidentify subsets of depressed patients to determine which patients might respond differentially to thenew selective norepinephrine reuptake inhibitors or SSRIs.