PMC:3649690 / 9044-11929
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/3649690","sourcedb":"PMC","sourceid":"3649690","source_url":"http://www.ncbi.nlm.nih.gov/pmc/3649690","text":"5. Monoamine Theory of Depression\nMuch of the current understanding of depression has been built upon the serendipitous discovery of the mood-elevating effects of iproniazid, a monoamine oxidase inhibitor (MAOI), during clinical trials for antituberculosis agents in the early 1950s [43, 44]. Around the same time the first tricyclic antidepressant (TCA), imipramine, a drug also known to modulate monoaminergic neurotransmission, was discovered to relieve depressive symptoms [45]. Both compounds enhance monoaminergic neurotransmitters (primarily serotonin and norepinephrine) function in the synapse and therefore acted as a springboard for the rational design of drugs which specifically enhance the transmission of these neuromodulators. Further, these findings resulted in the development of the monoamine hypothesis of depression [46, 47]. The monoamine hypothesis of depression postulates that the pathophysiological basis of depression is due to the deficient activity of monoamines in the central nervous system [48]. \nWhile first generation antidepressant drugs can indeed be effective, remission rates still typically remain below 60%, and treatment is associated with potentially severe side effects, causing a third of patients to discontinue treatment [49, 50]. Thus new drugs, such as selective serotonin reuptake inhibitors (SSRIs), have been developed in an attempt to enhance efficacy and reduce the side effects observed with the broader-acting first generation compounds. However, the ability of these newer drugs to alleviate depression is, unfortunately, typically lower than that of MAOIs and TCAs [50]. SSRIs are the primary first line treatment for patients with major depressive disorder (MDD), yet only a third of patients will respond to these drugs following initial treatment [41]. Even in patients that are initially responsive to treatment, up to 57% will have depressive symptoms return due to a loss of drug efficacy [40]. \nWhile it is known that antidepressants modify monoaminergic neurotransmission, it is not known how antidepressants exert their therapeutic effects, as the influence on monoamines occurs within hours of treatment, but alleviation of depressive symptoms requires weeks of exposure [51–54]. The monoamine theory explains this delayed efficacy of treatment as the time required for the 5-HT1A serotonin autoreceptor to sensitize and normalize serotonergic tone at the synapse [42, 55, 56]. However, disrupting or ablating portions of the serotonergic system fails to induce a depressive phenotype [57], suggesting that the dysregulation of serotonergic neurotransmission is not the only underlying factor in depression. Given the prevalence of treatment-resistant forms of depression and the limited long-term efficacy of current drugs, novel targets are needed for the development of more efficacious pharmacological 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