New approaches to antidepressant drug discovery: beyond monoamines

Nat Rev Neurosci. 2006 Feb;7(2):137-51. doi: 10.1038/nrn1846.


All available antidepressant medications are based on serendipitous discoveries of the clinical efficacy of two classes of antidepressants more than 50 years ago. These tricyclic and monoamine oxidase inhibitor antidepressants were subsequently found to promote serotonin or noradrenaline function in the brain. Newer agents are more specific but have the same core mechanisms of action in promoting these monoamine neurotransmitters. This is unfortunate, because only approximately 50% of individuals with depression show full remission in response to these mechanisms. This review summarizes the obstacles that have hindered the development of non-monoamine-based antidepressants, and provides a progress report on some of the most promising current strategies.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Antidepressive Agents / classification
  • Antidepressive Agents / pharmacology
  • Antidepressive Agents / therapeutic use*
  • Biogenic Monoamines*
  • Brain Chemistry / drug effects
  • Depressive Disorder / drug therapy*
  • Depressive Disorder / metabolism
  • Disease Models, Animal
  • Humans
  • Hypothalamo-Hypophyseal System / drug effects
  • Hypothalamo-Hypophyseal System / metabolism
  • Models, Neurological


  • Antidepressive Agents
  • Biogenic Monoamines