On September 17, 2015, the US Food and Drug Administration (FDA) has approved the new antipsychotic cariprazine for the treatment of schizophrenia and manic or mixed episodes associated with bipolar disorder.
Copyright: M. Großmann / www.pixelio.de
Cariprazine was developed by the Hungarian company Gedeon Richter Plc. (Budapest) and licensed to the American Forest Laboratories (Jersey City, NJ) for the USA and Canada. Cariprazine is distributed as Vraylar® by Actavis Pharmaceuticals (Parsippany, NJ).
Forest had submitted an application for approval already in November 2012 to the FDA. In November 2013, the FDA rejected approval by pointing to the need for further data, in particular with regard to the correct dosages. In January 2015, the companies involved had submitted their application for approval again. This application has now received a positive response.
I have published a review on cariprazine in 2010 (Gründer, 2010), and in 2013 Tanja Veselinović, Michael Paulzen and myself provided an update of that review (Veselinović et al., 2013). Here we summarize the pharmacology, the preclinical and the clinical data. Unfortunately, these papers are not publicly available, but PDFs can be requested from me by email.
Cariprazine is a high affinity partial agonist at D2 and D3 dopamine receptors, with the binding to D3 receptors being three- to tenfold higher than to D2 receptors. This is a major difference of the compound to aripiprazole. Cariprazine also seems to have a somewhat lower intrinsic activity at D2 receptors compared to aripiprazole, i.e., under conditions of increased dopamine activity the compound exerts stronger antagonistic activity than aripiprazole. At D3 receptors, the compound has a higher intrinsic activity than aripiprazole, which has been claimed to explain the pro-cognitive effects in animal models. Cariprazine is also a high-affinity partial agonist at 5-HT1A serotonin receptors and an antagonist at 5-HT2B receptors. The elimination half-life is very long (2-5 days), the drug is metabolized primarily via CYP3A4 and to a lesser extent also via CYP2D6. Metabolism creates two active metabolites, their elimination is even slower than that of the parent drug. It is recommended to halve the dose in combination with CYP3A4 inhibitors.
The approval of cariprazine for the treatment of schizophrenia and bipolar disorder (mania and mixed episodes) is based on evidence of the superiority of the compound compared to placebo in three double-blind randomized trials in each indication (schizophrenia: three studies over six weeks with a total of 1754 patients, bipolar disorder: three studies over three weeks with a total of 1037 patients). The most prevalent adverse events reported in the studies were extrapyramidal disorders (dyskinesia, akathisia), dyspepsia, nausea and vomiting, drowsiness and restlessness. Recommended starting dose is 1.5 mg daily (in a single dose), maintenance doses of between 1.5 mg and 6 mg are recommended for the treatment of schizophrenic disorders, 3 mg to 6 mg for the treatment of bipolar disorders. In the United States tablets of 1.5 mg, 3 mg, 4.5 mg and 6 mg are available. In the clinical studies, the highest administered dose was 12.5 mg. Doses higher than 6 mg, however, are not usually associated with better efficacy, but the rate of adverse effects increases. Like all other antipsychotics the package insert contains a black-box warning, pointing to the increased mortality in patients with dementia-related psychosis. Cariprazine is not approved for the treatment dementia-related psychosis.
In a press release on the approval of cariprazine the FDA announced: „It is important to have a variety of treatment options available to patients with mental illnesses so that treatment plans can be tailored to meet a patient’s individual needs.“ Exactly this reasoning was put forward by the German Psychiatric Association (DGPPN) in the context of the AMNOG process in its expert opinions on lurasidone and vortioxetine. The G-BA did not follow this rationale and denied any so called “additional benefit” of these two drugs. I am very certain that, according to current data, the IQWiG would also deny any additional benefit for cariprazine. Cariprazine has been tested primarily against risperidone, and in these studies – according to the criteria of the IQWiG – an advantage of the new substance was not unequivocally demonstrated. In preclinical studies, there is indeed evidence of pro-cognitive effects of cariprazine, but data in patients are completely lacking thus far. If the manufacturers do not provide data, which convince the IQWiG and the G-BA of a certain advantage of the new over commercially available drugs, this interesting compound will not survive the assessment of the critical German authorities.
This post is also available in: German