Receptor targets for antidepressant therapy in bipolar disorder: an overview

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.