Drug treatment for schizophrenia has relied for many years on antipsychotics such as chlorpromazine and haloperidol, but side-effects limited their usefulness, particularly in terms of compliance
Schizophrenia can cause a total breakdown in mental processes. Positive symptoms include delusions, bizarre thoughts, irrational fears, and auditory hallucinations. Negative symptoms include apathy, social withdrawal, and a lack of both energy and motivation. For many years, drug treatment relied on antipsychotics such as chlorpromazine and haloperidol, but side-effects limited their usefulness, particularly in terms of compliance. Modern atypical antipsychotics have reduced side-effect profiles, improving compliance, but even so, perhaps a third of schizophrenics continue to experience severe symptoms.
The novel antipsychotic cariprazine, developed by Gedeon Richter and Actavis, acts as a partial agonist at dopamine D3/D2 receptors, with a preference for D3. This is in contrast to the majority of atypical antipsychotics, which are D2 and 5-HT2A receptor antagonists. It was discovered by chance as a by-product in the synthesis of another dopamine-acting compound.1 It has good absorption and excellent brain penetration.
In a double blind, randomised, placebo- and active-controlled fixed dose trial, 732 patients with acute exacerbations of schizophrenia were given 1.5, 3.0 or 4.5mg cariprazine, 4.0mg risperidone or placebo for six weeks of treatment plus a further two weeks of safety follow up.2 Almost two-thirds completed the study. The Positive and Negative Syndrome Scale (PANSS) total score improvement after six weeks was statistically significant for all doses compared with placebo. The most frequent adverse events resulting from cariprazine treatment were insomnia, extrapyramidal disorder, akathisia, sedation, dizziness, nausea and constipation.
Its potential in bipolar disorder is also being evaluated. In a randomised, double blind, placebo-controlled, flexible dose Phase II trial, patients with acute manic or mixed episodes associated with bipolar I disorder were given doses of 3–12mg of the drug or placebo for three weeks following a washout period.3 Again, almost two-thirds completed the study, and the overall mean daily dose was 8.8mg. At week three, cariprazine significantly reduced scores on the Young Mania Rating Scale, and the Clinical Global Impressions – Severity scores, and the changes were significantly greater than those for placebo-treated subjects. Akathisia and extrapyramidal symptoms were experienced by 22% and 16% of those given cariprazine respectively.
A randomised, double blind, placebo-controlled, flexible dose Phase III trial has also been carried out in bipolar patients.4 A total of 312 patients were randomised to three weeks of double blind treatment with cariprazine, again in doses of 3–12mg/day, or placebo. Again, a significant improvement in YMRS was seen with treatment, with 59% experiencing at least a 50% improvement, and 52% remission, compared with 44% and 35% respectively for placebo.
The US FDA has now approved Vraylar (cariprazine) capsules to treat schizophrenia and bipolar disorder in adults.
1. E. Agai-Csongor et al. Bioorg. Med. Chem. Lett. 2012, 22, 3437
2. S. Durgam et al. Schizophr. Res. 2014, 152, 450
3. S. Durgam et al. Bipolar Disord. 2015, 17, 63
4. G.S. Sachs et al. J. Affect. Disord. 2015, 174, 296