Antidepressant efficacy of cariprazine in bipolar disorder and the role of its pharmacodynamic properties: A hypothesis based on data

The treatment of bipolar depression is one of the most challenging needs in contemporary psychiatry. Currently, only quetiapine, olanzapine-fluoxetine combination, lurasidone, cariprazine, and recently lumateperone have been FDA-approved to treat this condition. The neurobiology of bipolar depression and the possible targets of bipolar antidepressant therapy remain elusive. The current study investigated whether the pharmacodynamic properties of cariprazine fit into a previously developed model which was the first to be derived based on the strict combination of clinical and preclinical data. The authors performed a systematic review of the literature to identify the pharmacodynamic properties of cariprazine. The original model suggests that a constellation of effects on different receptors is necessary and that serotonin reuptake inhibition does not appear to play a significant role in acute bipolar depression. On the contrary, norepinephrine activity seems to be necessary. Probably the early antidepressant effect can be achieved through an agonistic activity at 5HT-1A and antagonism at alpha1 noradrenergic and 5-HT2A receptors, but the presence of a norepinephrine reuptake inhibition appears essential to sustain it. Overall, the properties of cariprazine fit well the proposed model and add to its validity. A point that needs further clarification is norepinephrine reuptake inhibition which is not yet fully studied for cariprazine.