Subject:
Cariprazine (Vraylar): A drug for negative symptoms? Don’t be positive. 

Background:

On September 17, the FDA approved cariprazine (Vraylar) for the treatment of schizophrenia and bipolar disorder. There’s already some buzz about whether this medication has advantages over other atypicals for treating negative symptoms of schizophrenia. Cariprazine has a slightly different mechanism of action than its competitors. Most atypicals appear to work by blocking two types of receptors: dopamine 2 (D2) receptors and serotonin 2A (5HT-2A) receptors. Aripiprazole is somewhat different in that it is a “partial agonist” at D2, meaning it partly blocks the receptor. The advantage is that it allows enough dopamine stimulation to prevent the movement disorders that plague first-generation antipsychotics. Now comes cariprazine. Like aripiprazole, it is a partial D2 agonist, but it is also a partial D3 agonist. Some theorize that D3 modulates mood and cognition more than other dopamine receptors. Hence, so the theory goes, perhaps cariprazine does less to dampen mood and cognition than other antipsychotics. The clinical effect of this would presumably be a patient who has fewer negative symptoms, such as social withdrawal and poor motivation. Let’s take a look at some of the data. 

Schizophrenia data. Three 6-week randomized double-blind controlled trials compared cariprazine to placebo in 1,754 patients with schizophrenia. In two of these studies, some patients were also randomized to active medications—risperidone in one study and aripiprazole in the other. But don’t get too excited. The studies were powered only to compare cariprazine to placebo—the active meds were there for “assay sensitivity.” If neither of those meds ended up separating from placebo, they would have been deemed “failed” studies. 

In all three studies, cariprazine, at doses ranging from 1.5–9 mg/day, beat placebo on standard outcome scales, which measure both positive and negative symptoms. One study reported that cariprazine improved a negative symptoms subscale score, but so did risperidone (Durgam S et al, Schizophrenia Research 2014;152(2–3):450–457). 

More convincing negative symptoms data (not yet published) were presented at the 28th European College of Neuropsychopharmacology (ECNP) Congress in August in Amsterdam. Unlike the other studies, this one recruited 461 patients with primarily negative symptoms. Patients were randomized to receive either cariprazine 4.5 mg/day or risperidone 4 mg/day for 6 months. While patients in both groups improved significantly, those taking cariprazine improved more. From a baseline of about 27 points on the negative symptom scale, there was an 8.9-point reduction with cariprazine vs a 7.4-point reduction with risperidone. The difference was statistically significant, though the clinical significance of this 1.5-point benefit is not entirely clear.

Acute bipolar mania data. Three 3-week randomized double-blind controlled trials compared cariprazine to placebo in 1,037 patients in an acute manic or mixed episode of bipolar disorder. In all three studies, cariprazine, at doses of 3–12 mg/day, was significantly better than placebo (as measured by the Young Mania Rating Scale [YMRS] and the Clinical Global Impression - Severity Scale [CGI-S]). Doses above 6 mg/day did not seem to result in greater efficacy.
Cariprazine is also being studied for use in bipolar depression and as an adjunct in the treatment of major depressive disorder. 

Here are some of the side effects that occurred more commonly with cariprazine than placebo in the studies (listed as the range in schizophrenia and bipolar studies vs placebo): parkinsonism and dystonia (17%–28% cariprazine vs 8%–12% placebo), akathisia (11%–20% vs 4%–5%), vomiting (4%–10% vs 3%–4%), somnolence (5%–7% vs 4%–5%), restlessness (4%–7% vs 2%–3%), and weight gain (8% vs 5% in schizophrenia studies, no weight gain difference in the bipolar studies). What about side effects over the long term? Preliminary data from an open- label 48-week extension study in schizophrenia (n=53 cariprazine, n=25 risperidone, n=15 placebo) list akathisia (17%), insomnia (14%), and weight gain (33%) as the most common long-term side effects of the new medication (Cutler A et al. Safety and tolerability of cariprazine in the long-term treatment of schizophrenia: results from a 48-week extension study. Poster Presented at: American Psychiatric Association Annual Meeting; May 2012; Philadelphia, PA).

Cariprazine will be available as 1.5 mg, 3 mg, 4.5 mg, and 6 mg capsules. The usual therapeutic doses are 1.5–6 mg/day for schizophrenia and 3–6 mg/day for bipolar disorder. The drug has a long half-life (2–4 days for parent drug and 1–3 weeks for active metabolites) and is metabolized by CYP3A4.

TCPR’s Verdict: Cariprazine’s potential claim to fame will be efficacy for negative symptoms, but the data are both preliminary and not stunningly impressive. At this point, we have to say that cariprazine is just the latest in a series of me-too antipsychotics, with a side effect profile notable for EPS and akathisia as well as significant weight gain in one long-term trial. The drug’s marketers have their work cut out for them!