Receptor targets for antidepressant therapy in bipolar disorder: an overview

J Affect Disord. 2012 May;138(3):222-38. doi: 10.1016/j.jad.2011.04.043. Epub 2011 May 20.


The treatment of bipolar depression is one of the most challenging issues in contemporary psychiatry. Currently only quetiapine and the olanzapine-fluoxetine combination are officially approved by the FDA against this condition. The neurobiology of bipolar depression and the possible targets of bipolar antidepressant therapy remain relatively elusive. We performed a complete and systematic review to identify agents with definite positive or negative results concerning efficacy followed by a second systematic review to identify the pharmacodynamic properties of these agents. The comparison of properties suggests that the stronger predictors for antidepressant efficacy in bipolar depression were norepinephrine alpha-1, dopamine D1 and histamine antagonism, followed by 5-HT2A, muscarinic and dopamine D2 and D3 antagonism and eventually by norepinephrine reuptake inhibition and 5HT-1A agonism. Serotonin reuptake which constitutes the cornerstone in unipolar depression treatment does not seem to play a significant role for bipolar depression. Our exhaustive review is compatible with a complex model with multiple levels of interaction between the major neurotransmitter systems without a single target being either necessary or sufficient to elicit the antidepressant effect in bipolar depression.

Publication types

  • Review
  • Systematic Review

MeSH terms

  • Antidepressive Agents / pharmacology*
  • Antidepressive Agents / therapeutic use
  • Bipolar Disorder / drug therapy*
  • Bipolar Disorder / physiopathology*
  • Humans


  • Antidepressive Agents