Cariprazine as a strategy for augmentation of treatment of major depressive disorder: from pharmacological aspects to clinical practice

Major depressive disorder remains the leading cause of disability worldwide, with up to 33% of patients failing to respond to antidepressant therapy. One promising strategy for the treatment of resistant depression is augmentation of antidepressant therapy with atypical antipsychotics. Cariprazine, a third-generation drug with a unique receptor profile, has demonstrated significant superiority over placebo in reducing symptoms of depression, anxiety, and anhedonia. The most optimal dose in most cases is 1.5 mg/day. Higher doses are associated with an increase in adverse drug reactions without enhancing the antidepressant effect. Cariprazine also reduces the frequency of hospitalizations and economic costs of treatment compared with other atypical antipsychotics in the treatment of major depressive disorder. Early administration of cariprazine as a first-line augmentation of antidepressant therapy is associated with better outcomes. The putative mechanism of antidepressant action is modulation of the dopamine and serotonin systems. Cariprazine is metabolized primarily by CYP3A4 to form active metabolites with a long half-life. Therefore, it is undesirable to combine the drug with strong and moderate CYP3A4 inhibitors and inducers. Cariprazine is not a p-glycoprotein substrate, which increases its efficacy and safety in patients — slow transporters. However, it exhibits properties of a weak p-glycoprotein inhibitor. In this regard, additional monitoring of adverse drug reactions may be required when using cariprazine with p-glycoprotein substrates and inhibitors. The most favorable pharmacokinetic interaction is observed in a combination of cariprazine and trazodone. There is currently insufficient information on the ratio of efficacy/tolerability indicators of cariprazine with various antidepressants, which necessitates further studies to clarify the optimal combinations and doses of drugs.