Leslie Citrome, MD, MPH Clinical Professor Department of Psychiatry and Behavioral Sciences New York Medical College Valhalla, New York
Disclosure In the past 12 months, Dr. Citrome has served as a consultant to Acadia, Alkermes, Allergan, Intra-Cellular Therapeutics, Janssen, Lundbeck, Merck, Neurocrine, Noven, Otsuka, Pfizer, Shire, Sunovion, Takeda, Teva, and Vanda; and a speaker for Acadia, Alkermes, Allergan, Janssen, Lundbeck, Merck, Neurocrine, Otsuka, Pfizer, Shire, Sunovion, Takeda, Teva, and Vanda.
For MDD, using the definition of response as a ≥50% decrease in MADRS total score, and pooling the results for brexpiprazole 1, 2, and 3 mg/d from the 2 pivotal trials,23,24 23.2% of the patients receiving brexpiprazole were responders, vs 14.5% for placebo, yielding a NNT of 12 (95% CI 8 to 26).22 Including the 1.5-mg/d dose arm and the placebo arm from the phase II study for which results are also available but not included in product labelling, the NNT becomes a slightly more robust 11 (95% CI 8 to 20).22 Although the magnitude of the NNT effect size is stronger for aripiprazole than for brexpiprazole, the 95% CIs do overlap.
The most commonly encountered adverse event in the short-term trials in schizophrenia (incidence ≥4% and at least twice the rate of placebo) was increased weight. The most commonly encountered adverse events in the short-term trials in MDD (incidence ≥5% and at least twice the rate of placebo) were increased weight and akathisia. Rates of discontinuation because of an adverse event were not higher for active medication vs placebo for the schizophrenia studies, suggesting excellent overall tolerability, and for MDD the NNH vs placebo on discontinuation because of an adverse event was 50, representing reasonable overall tolerability for this indication as well (Table 11).
Cariprazine
Cariprazine was launched in the United States in 2015 for 2 indications: schizophrenia, and the acute treatment of manic or mixed episodes associated with bipolar I disorder, both in adults.25 In terms of binding, cariprazine has very high binding affinities to dopamine D3 (0.085 nM), dopamine D2L (0.49 nM), serotonin 5-HT2B (0.58 nM), and dopamine D2S (0.69 nM) receptors, and high binding affinity to serotonin 5-HT1A (2.6 nM) receptors. Cariprazine forms 2 major metabolites, desmethyl cariprazine and didesmethyl cariprazine, that have in vitro receptor binding profiles similar to the parent drug. This latter metabolite, didesmethyl cariprazine, has a half-life of 1 to 3 weeks, and is the active moiety responsible for the majority of cariprazine’s effect when in steady state. Thus, following discontinuation of cariprazine, the decline in plasma concentrations of active drug will be slow.
The starting dose for cariprazine for schizophrenia, 1.5 mg/d, can be therapeutic. The dosage can be increased to 3 mg/d on Day 2. Depending upon clinical response and tolerability, further dose adjustments can be made in 1.5-mg or 3-mg increments to a maximum dose of 6 mg/d. For the treatment of bipolar mania, cariprazine will need to be titrated from the starting dose of 1.5 mg/d to the recommended target dose range of 3 to 6 mg/d; this can be done on Day 2. Cariprazine has been tested in clinical trials at higher doses; however, doses that exceed 6 mg/d did not confer significant additional benefit.25
A more conservative definition of response was used in the reporting of the cariprazine acute schizophrenia studies. This was simply a ≥30% decrease in the PANSS total score, and did not include the option of including patients who scored a 1 or 2 on the CGI-I. For pooled doses of cariprazine 1.5 to 6 mg/d,26-28 the percentage of responders was 31%, compared with 21% for the pooled placebo groups, yielding a NNT of 10 (95% CI 7 to 18).1 Although the magnitude of the NNT effect size is weaker for cariprazine than the other dopamine receptor partial agonists, the 95% CI overlaps with that of aripiprazole and brexpiprazole. An appropriately designed head-to-head trial would be necessary to directly test noninferiority.
