Dual monoamine modulation for improved treatment of major depressive disorder

J Clin Psychopharmacol. 2003 Feb;23(1):78-86. doi: 10.1097/00004714-200302000-00011.


The worldwide scope of depressive illness and lack of fully effective pharmacotherapy mandates significant improvements in treatment paradigms. Current antidepressant medications remain limited by poor efficacy, slow onset of action, and untoward side effects. While the introduction of serotoninspecific reuptake inhibitors (SSRIs) offered significant improvements in tolerability, no improvements in efficacy or speed of onset have been made relative to the traditional and poorly tolerated tricyclic antidepressants (TCA). The dominant efforts toward improving antidepressant medications are guided by cumulative evidence from neurochemical and clinical studies supporting the therapeutic potential of enhancing monoamine function in depression. A number of novel antidepressant drugs, including mirtazapine, milnacipran, venlafaxine, and duloxetine have been developed based on their interaction with both 5-HT and NE. Current clinical evidence suggests that these new agents may offer improved efficacy and/or faster onset of action compared with SSRIs and an improved side effect profile compared with TCAs. Potential neurobiological substrates mediating the enhanced antidepressant activity of dual reuptake inhibitors are discussed.

Publication types

  • Review

MeSH terms

  • Adrenergic Uptake Inhibitors / therapeutic use
  • Animals
  • Biogenic Monoamines / physiology*
  • Brain Chemistry / drug effects
  • Clinical Trials as Topic
  • Depressive Disorder, Major / drug therapy*
  • Humans
  • Neurotransmitter Uptake Inhibitors / therapeutic use*
  • Selective Serotonin Reuptake Inhibitors / therapeutic use


  • Adrenergic Uptake Inhibitors
  • Biogenic Monoamines
  • Neurotransmitter Uptake Inhibitors
  • Serotonin Uptake Inhibitors