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Hi. Jim Phelps here with another issue of Quick Takes for the Psychopharmacology Institute.
First, let’s have a look at a new randomized trial for cariprazine in the treatment of bipolar depression. It’s sold under the names Vraylar and Reagila in Europe. We’re going to look here at a new trial in bipolar depression after its previous positive trials in schizophrenia and mania.
So, we have some generic medications in this niche, notably quetiapine. So, to consider cariprazine in this role, we’d want to see both efficacy and have some data on risk. Let’s take a look. The efficacy data in this new study roughly match those in the previous phase 2 trial. We’re looking at doses of 1.5 mg and 3 mg. They tend to beat placebo or close in the earlier trial, which was the phase 2 trial. The 3 mg was not better than a placebo after adjusting for the multiple statistical comparisons, but that was in large part because the dropout rate in the 3 mg group was larger, and they speculated that maybe they went up too fast. So, in this new study, the dosing was increasing at Day 15 to 3 mg as before, but they started out everyone at 1.5 mg. So, patients actually had 2 weeks at 1.5 mg, whereas in the earlier study, they were titrating up to 1.5 mg. So, the bottom line here is, if you go up slower, you’re less likely to run into the side effects that make people want to stop. And in this case, it leaves the 3 mg dose looking as strong as the 1.5 mg dose in this new study. And overall, the response and remission rates were modest but in the same ballpark as we’ve seen with other atypical antipsychotics for bipolar depression. Number needed to treat 6 or 7, that’s about the same as with quetiapine and with lurasidone.
Why would you consider cariprazine when you have a generic quetiapine and a better-known trade name medication in lurasidone? Well, obviously, we’re all looking for the holy grail of an atypical antipsychotic or any medication that can treat bipolar depression, not induce manic symptoms and not induce weight gain. Let’s look at the weight, and then we’ll look at the treatment-induced mania. On the weight side, we are going to need to watch longer because this was a 6-week trial. The previous one was 8 weeks, but there is a 16-week open trial. And in that study, a body weight increase of greater than 7% was reported in almost 10% of patients. There were 3.5% that lost weight. And in that study, much bigger doses were allowed. So, maybe 1.5 mg to 3 mg will keep the risk of weight gain lower.
In this new study, the rate of weight gain was about the same as with placebo. There were a few patients who had a significant weight increase. The problem is in both of these studies, patients are starting out with a BMI around 30. So, we have to be careful when we think about comparing this to patients whom we might treat who are starting out with a BMI of 20 or 24. It will probably be a different story then, and we’ll have to learn from experience.
Lastly, what about treatment-emergent manic symptoms? Since we’re treating bipolar depression, we have to worry about inducing mania if there is an effective antidepressant effect going on here. This has been a problem with aripiprazole, for example, with induced hypersexuality and gambling and recently a new report of induced mania with lurasidone, which was reassuring because I thought I’d seen that in my own clinical experience as well. Well, let’s take a look at cariprazine. The authors say that, in this study, the incidence of treatment-emergent mania was low in placebo and cariprazine groups. And they concluded that cariprazine is “not associated with mood destabilization or manic switching in patients with bipolar I.” Well, in the open trial, there were about 9 of 350 or so patients who had a worsening of mania, and 3 of them were judged to be related to treatment for maybe about 1% then. So, I think cariprazine is not out of the woods here. The rate is nothing like akathisia, which was seen in 37%, although only 4% stopped for akathisia. But this treatment-emergent mania, you’ll have to keep your eye on that too.
In summary, cariprazine appears to be effective for bipolar depression in the ballpark of quetiapine and lurasidone. We’ll need to watch more closely for weight gain in routine populations. In using it, you’ll see akathisia, but keep an eye out for induced manic symptoms as well.
Clarifying an earlier version of this Quick Take. I earlier reported that cariprazine has caused akathisia in 37% of patients but that was an error. It was 33% in a trial of cariprazine for inpatient mania. As the manufacturer has requested, I make clear in the outpatient bipolar depression study I’m reviewing here the rate of akathisia was 6.4% versus 3.2% on placebo. The difference, 6.4% versus 33%, is likely due to the titration rates which were far faster in the inpatient study.
Abstract
Cariprazine Treatment of Bipolar Depression: A Randomized Double-Blind Placebo-Controlled Phase 3 Study
Willie Earley, M.D., Maria Victoria Burgess, M.D., Ludmyla Rekeda, Ph.D., Regan Dickinson, M.A., Balázs Szatmári, Ph.D., György Németh, M.D., Ph.D., Roger S. McIntyre, M.D., F.R.C.P.C., Gary S. Sachs, M.D., Lakshmi N. Yatham, M.B.B.S., F.R.C.P.C.
Objective: Cariprazine, a dopamine D3/D2 and 5-HT1A receptor partial agonist, was found to be effective in treating bipolar I depression in a previous phase 2 study. This phase 3 study further assessed the efficacy, safety, and tolerability of cariprazine in bipolar I depression.
Methods: In a double-blind placebo-controlled study, adult participants (18–65 years old) who met DSM-5 criteria for bipolar I disorder and a current depressive episode were randomly assigned to receive placebo (N=158) or cariprazine at 1.5 mg/day (N=157) or 3.0 mg/day (N=165). The primary and secondary efficacy parameters were changes from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) score and Clinical Global Impressions severity (CGI-S) score, respectively. Least squares mean differences were estimated using a mixed model for repeated measures, and p values were adjusted for multiplicity.
Results: Both dosages of cariprazine were significantly more effective than placebo in improving depressive symptoms (reducing MADRS total score); the least squares mean differences were −2.5 (95% CI=−4.6, −0.4) for cariprazine at 1.5 mg/day and −3.0 (95% CI=−5.1, −0.9) for cariprazine at 3.0 mg/day. Both cariprazine dosages were associated with lower CGI-S scores compared with placebo, but the differences did not reach statistical significance after adjustment for multiplicity (least squares mean difference, −0.2 [95% CI=−0.5, 0.0] for the 1.5 mg/day group and −0.3 [95% CI=−0.5, 0.0] for the 3.0 mg/day group). Common treatment-emergent adverse events (in at least 5% of participants in either cariprazine treatment group and twice the rate of the placebo group) were nausea, akathisia, dizziness, and sedation. Mean changes in weight and metabolic parameters were relatively small and comparable across groups.
Conclusions: Cariprazine, at both 1.5 mg/day and 3.0 mg/day, was effective, generally well tolerated, and relatively safe in reducing depressive symptoms in adults with bipolar I depression.
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Reference
Earley, W., Burgess, M. V., Rekeda, L., Dickinson, R., Szatmári, B., Németh, G., McIntyre, R. S., Sachs, G. S., & Yatham, L. N. (2019). Cariprazine treatment of bipolar depression: A randomized double-blind placebo-controlled phase 3 study. American Journal of Psychiatry, 176(6), 439-448.
