Serotonin and beyond: therapeutics for major depression

Philos Trans R Soc Lond B Biol Sci. 2013 Feb 25;368(1615):20120536. doi: 10.1098/rstb.2012.0536. Print 2013.

Abstract

The serotonin (5-HT, 5-hydroxytryptamine) system has been implicated in the pathogenesis of major depressive disorder (MDD). The case for its contribution to the therapeutic efficacy of a wide variety of antidepressant treatments is, however, much stronger. All antidepressant strategies have been shown to enhance 5-HT transmission in the brain of laboratory animals. Catecholamines, norepinephrine (NE) and dopamine (DA) can also play a pivotal role in the mechanism of action of certain antidepressant strategies. The enhancement of 5-HT transmission by selective serotonin reuptake inhibitors, which leads to a dampening of the activity of NE and DA neurons, may account in part for the low remission rate achieved with these medications and/or the residuals symptoms after remission is achieved. The functional connectivity between the 5-HT, NE and DA systems can be used to understand the mechanism of action of a wide variety of augmentation strategies in treatment-resistant MDD. Proof-of-concept studies have shown that antidepressant medications with complementary mechanisms of action on monoaminergic systems can double the remission rate achieved in a trial of standard duration. Novel approaches are also being used to treat MDD, which also appear to involve the monoaminergic system(s) to a varying extent.

Publication types

  • Review

MeSH terms

  • Animals
  • Antidepressive Agents / therapeutic use
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / pathology
  • Dopamine Agonists / therapeutic use
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / pathology
  • Electrophysiological Phenomena
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Norepinephrine / metabolism
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Serotonergic Neurons / drug effects
  • Serotonergic Neurons / metabolism
  • Serotonergic Neurons / pathology
  • Serotonin / genetics
  • Serotonin / metabolism*
  • Serotonin Uptake Inhibitors / therapeutic use
  • Synaptic Transmission

Substances

  • Antidepressive Agents
  • Dopamine Agonists
  • Serotonin Uptake Inhibitors
  • Receptor, Serotonin, 5-HT1A
  • Serotonin
  • Norepinephrine