Cariprazine for Schizophrenia and Bipolar I Disorder
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Out of the Pipeline Cariprazine for schizophrenia and bipolar I disorder Gregory Mattingly, MD, and Richard Anderson, MD, PhD ariprazine is a newly approved Table 1 As a dopamine (September 2015) dopamine D3/D2 Fast facts about cariprazine D3-preferring D3/ receptor partial agonist with higher C Brand name: Vraylar D2 partial agonist, affinity for the D3 receptor than for D2. Class: Atypical antipsychotic cariprazine offers The drug is FDA-indicated for treating Indications: Schizophrenia, bipolar I disorder an alternative to schizophrenia and bipolar I disorder (BD I)1,2 FDA approval date: September 17, 2015 antipsychotics (Table 1). In clinical trials, cariprazine alle- Availability date: First quarter of 2016 viated symptoms of schizophrenia and that preferentially Manufacturer: Allergan mixed and manic symptoms of BD I, with modulate D2 Dosing forms: 1.5 mg, 3 mg, 4.5 mg, minimal effect on metabolic parameters, and 6 mg capsules receptors the prolactin level, and cardiac conduction. Recommended dosage: 1.5 to 6 mg/d (schizophrenia); 3 to 6 mg/d (bipolar I disorder) Clinical implications Despite numerous developments in phar- macotherapeutics, people with schizo- Use in schizophrenia. Recommended dos- phrenia or bipolar disorder continue to age range is 1.5 to 6 mg/d. In Phase-III clini- struggle with residual symptoms or endure cal trials, dosages of 3 to 9 mg/d produced treatments that produce adverse effects significant improvement on the Positive (AEs). In particular, metabolic issues, seda- and Negative Symptom Scale (PANSS) and tion, and cognitive impairment plague on the Clinical Global Impression scale. many current treatment options for these Higher dosages (6 to 9 mg/d) showed early disorders. separation from placebo—by the end of Week 1—but carried a dosage-related risk Receptor blocking. As a dopamine of AEs, leading the FDA to recommend D3-preferring D3/D2 partial agonist, carip- 6 mg/d as the maximum dosage.1,6-8 razine offers an alternative to antipsychotics that preferentially modulate D2 receptors. Use in manic or mixed episodes of BD I. First-generation (typical) antipsychotics Recommended dosage range is 3 to 6 mg/d. block D2 receptors; atypical antipsychotics In clinical trials, dosages in the range of block D2 receptors and 5-HT2A receptors. Discuss this article at Dopamine partial agonists aripiprazole and Dr. Mattingly is Associate Clinical Professor and Psychopharmacology brexpiprazole are D2-preferring, with mini- Instructor, Washington University in St. Louis, St. Louis, Missouri, and www.facebook.com/ CurrentPsychiatry mal D3 effects. In contrast, cariprazine has a Founding Partner, Midwest Research Group, St. Charles, Missouri. Dr. Anderson is Clinical Instructor, Department of Psychiatry, 6-fold to 8-fold higher affinity for D3 recep- Washington University in St. Louis, St. Louis, Missouri, and Founding tors than for D2 receptors, and has specific- Partner, Midwest Research Group, St. Charles, Missouri. ity for the D3 receptor that is 3 to 10 times Disclosures The authors report no financial relationships with any company higher than what aripiprazole has for the D3 whose products are mentioned in this article or with manufacturers Current Psychiatry receptor3-5 (Table 2, page 37). of competing products. Vol. 15, No. 1 e1 Out of the Pipeline 3 to 12 mg/d were effective for acute manic and 5-HT7 receptors. Cariprazine has little or mixed symptoms; significant improve- or no affinity for adrenergic or cholinergic ment in the Young Mania Rating Scale receptors.14 (YMRS) score was seen as early as Day 4. In patients with schizophrenia, as Dosages >6 mg/d yielded no additional measured on PET scanning, a dosage of benefit and were associated with increased 1.5 mg/d yielded 69% to 75% D2/D3 risk of AEs.9-12 receptor occupancy. A dosage of 3 mg/d yielded >90% occupancy. Pharmacologic profile, adverse effects. Cariprazine has a pharmacologic profile Search for an understanding of action consistent with the generally favorable continues. The relative contribution of D3 metabolic profile and lack of anticholiner- partial agonism, compared with D2 partial Clinical Point gic effects seen in clinical trials. In short- agonism, is a subject of ongoing basic sci- Across clinical and long-term trials, the drug had minimal entific and clinical research. D3 is an auto- effects on prolactin, blood pressure, and receptor that (1) controls phasic, but not trials for both cardiac conduction.13 tonic, activity of dopamine nerve cells and disorders, akathisia Across clinical trials for both disorders, (2) mediates behavioral abnormalities and parkinsonism akathisia and parkinsonism were among induced by glutamate and N-methyl-d- were among more more common AEs of cariprazine. Both AEs aspartate receptor antagonists.5,12 In animal were usually mild, resulting in relatively studies, D3-preferring agents have been common AEs of few premature discontinuations from trials. shown to exert pro-cognitive effects and cariprazine Parkinsonism appeared somewhat dosage- improve anhedonic symptoms. related; akathisia had no clear relationship to dosage. Pharmacokinetics Cariprazine is a once-daily medication How it works with a relatively long half-life that can The theory behind the use of partial ago- be taken with or without food. Dosages nists, including cariprazine, is that these of 3 to 12 mg/d yield a fairly linear, dose- agents restore homeostatic balance to neu- proportional increase in plasma concen- rochemical circuits by: tration. The peak serum concentration • decreasing the effects of endogenous for cariprazine is 3 to 4 hours under fast- neurotransmitters (dopamine tone) in ing conditions; taking the drug with food regions of the brain where their trans- causes a slight delay in absorption but mission is excessive, such as mesolimbic does not have a significant effect on the regions in schizophrenia or mania area under the curve. Mean half-life for • simultaneously increasing neurotrans- cariprazine is 2 to 5 days over a dosage mission in regions where transmission of range of 1.5 to 12.5 mg/d in otherwise endogenous neurotransmitters is low, such healthy adults with schizophrenia.1 as the prefrontal cortex in schizophrenia Cariprazine is metabolized primarily by • exerting little effect in regions where cytochrome P450 (CYP) 3A4. It is a weak neurotransmitter activity is normal, such as inhibitor of CYP2D6 and CYP3A4.1 Hepatic the pituitary gland. metabolism of cariprazine produces 2 active Cariprazine has higher binding affinity metabolites: desmethyl-cariprazine (DCAR) for dopamine D3 receptors (Ki 0.085 nM) and didesmethyl-cariprazine (DDCAR), than for D2L receptors (Ki 0.49 nM) and both of which are equipotent to caripra- D2S receptors (Ki 0.69 nM). The drug also zine. After multiple dose administration, has strong affinity for serotonin receptor mean cariprazine and DCAR levels reach 5-HT2B; moderate affinity for 5-HT1A; and steady state in 1 to 2 weeks; DDCAR, in 4 to Current Psychiatry e2 January 2016 lower affinity for 5-HT2A, histamine H1, 8 weeks. The systemic exposure and serum Out of the Pipeline levels of DDCAR are roughly 3-fold greater ages ranging from 1.5 to 9 mg/d. Although than cariprazine because of the longer elimi- there was a modest trend toward higher nation half-life of DDCAR.1 efficacy at higher dosages, there was a dose- related increase in certain adverse reactions Efficacy in schizophrenia (extrapyramidal symptoms [EPS]) at dos- The efficacy of cariprazine in schizophrenia ages >6 mg/d.1 was established by 3 six-week, randomized, placebo-controlled trials. Two trials were Efficacy in bipolar disorder fixed-dosage; a third used 2 flexible dos- The efficacy of cariprazine for acute treat- age ranges. The primary efficacy measure ment of manic or mixed episodes of BD I was change from baseline in the total score was established in 3 randomized, placebo- of the PANSS at the end of Week 6, com- controlled, flexibly dosed 3-week trials. In pared with placebo. In all trials, patients all trials, patients were adults (age 18 to 65) Clinical Point were adults (age 18 to 60) who met DSM- who met DSM-IV-TR criteria for BD I with Cariprazine is IV-TR criteria for schizophrenia and had a manic or mixed episodes and with or with- PANSS score between 80 and 120 at screen- out psychotic features (YMRS score, ≥20). The metabolized ing and baseline. primary efficacy measure in the 3 trials was a primarily by CYP3A4; change from baseline in the total YMRS score it is a weak inhibitor Study 1 (n = 711) compared dosages of at the end of Week 3, compared with placebo. of CYP2D6 and 1.5 mg/d, 3 mg/d, and 4.5 mg/d with CYP3A4 placebo.7 All cariprazine dosages and an Study 1 (n = 492) compared 2 flexibly dosed active control (risperdone) were superior to ranges of cariprazine (3 to 6 mg/d and placebo in reducing symptoms of schizo- 6 to 12 mg/d) with placebo.10 Both dosage phrenia, as measured by the PANSS. The ranges were superior to placebo in reduc- placebo-subtracted differences on PANSS ing mixed and manic symptoms, as mea- score at 6 weeks for dosages of 1.5 mg/d, sured by reduction in the total YMRS score. 3 mg/d, and 4.5 mg/d were –7.6, –8.8, –10.4, Placebo-subtracted differences in YMRS respectively (significant at 95% CI). scores from placebo at Week 3 for caripra- zine 3 to 6 mg/d and 6 to 12 mg/d were Study 2 (n = 151) compared 3 mg/d and –6.1, –5.9, respectively (significant at 95% 6 mg/d dosages of cariprazine with pla- CI). The higher range offered no additional cebo.1 Both dosages and an active control advantage over the lower range. (aripiprazole) were superior to placebo in reducing PANSS scores.