Comparative Tolerability of Dopamine D2/3 Receptor Partial Agonists for Schizophrenia

Aripiprazole, brexpiprazole and cariprazine differ from all other second-generation antipsychotics due to partial agonism at the dopamine D2 and D3 receptors. In contrast to aripiprazole, brexpiprazole has lower intrinsic dopamine D2 activity and higher affinity for the serotonin 5-HT1A and 5-HT2A receptors, while cariprazine has the highest affinity for the dopamine D3 receptor, and the longest half-life. The main adverse effect of dopamine receptor partial agonists (DRPAs) is akathisia of low-to-moderate severity, which occurs in a small proportion of patients, usually in the first few weeks of treatment. While definitive conclusions concerning differences between the DRPAs require head-to-head comparison studies, on the available evidence, akathisia is probably least likely to occur with brexpiprazole and most likely with cariprazine; the risk of akathisia with aripiprazole lies in between. Weight-gain risk is low with aripiprazole and cariprazine, but moderate with brexpiprazole. Risk of sedation is low with DRPAs, as is risk of insomnia and nausea. Partial dopamine agonism leads to a low risk for hyperprolactinaemia (and probably a low risk of sexual dysfunction). Prolactin concentrations fall in some patients (particularly those with elevated levels prior to initiating the drugs). Rates of discontinuation due to adverse effects in pivotal studies were low, and on the whole, DRPAs are well tolerated. Aripiprazole has been implicated in pathological gambling and other impulse control behaviours, likely due to partial dopamine agonist activity (there have been no reports with brexpiprazole and cariprazine). The risks for diabetes and tardive dyskinesia with DRPAs are unknown, but are likely to be low. On the basis of tolerability, DRPAs should be considered as first-line treatment options, particularly in patients with early schizophrenia.