Sara Griffin, Mercer University College of Pharmacy
Bipolar disorder’s most distinctive clinical feature is an elevated mood; however, the majority of patients spend more time in depressive moods. The pharmacologic treatment typically consists of at least two drugs, including mood stabilizers, atypical antipsychotics, and antidepressants. Unfortunately, there are several guidelines for bipolar disorder and recommended treatments can differ from one guideline to the next. Although the guidelines do not recommend the use of antidepressants as maintenance therapy, long-term treatment is strongly recommended.1
The United States Food and Drug Administration (FDA) approved Vraylar™ (cariprazine) on September 17, 2015 for the treatment of bipolar disorder and schizophrenia. Schizophrenia and bipolar disorder are noted to be brain disorders that can negatively impact a person’s quality of life by interfering with day-to-day activities. Three 3-week clinical trials of more than 1,000 participants demonstrated the efficacy of cariprazine in treating bipolar disorder and a review of one of these clinical trials is analyzed in the table below.2, 3
|Title: Efficacy and safety of low- and high-dose cariprazine in acute and mixed mania associated with bipolar I disorder: a double-blind, placebo-controlled study3|
|Design||Multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed/flexible-dose study; N = 497|
|Objective||To evaluate the efficacy, safety, and tolerability of low- and high-dose cariprazine in patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for acute manic or mixed episodes associated with bipolar I disorder|
|Study Groups||Placebo (n = 161), cariprazine 3-6 mg/day (n = 167), or cariprazine 6-12 mg/day (n = 169)|
|Methods||Study comprised of a no-drug washout period of up to 7 days, 3 weeks of double-blind treatment, and a 2-week safety follow-up. Patients were randomly assigned (1:1:1) to placebo, cariprazine 3-6 mg/day (low dose), or cariprazine 6-12 mg/day (high dose). Efficacy evaluations included the YMRS and CGI-S (screening, baseline, and days 3, 5, 7, 10, 14, and 21), CGI-I scale (days 3, 5, 7, 10, 14, and 21), MADRS (screening, baseline, and days 0, 7, 14, and 21), and PANSS (baseline and days 0, 7, 14 and 21). Safety was assessed by TEAEs, clinical laboratory evaluations, vital signs, electrocardiograms, EPS scales (BARS, SAS, and AIMS), and C-SSRS.|
|Duration||February 2010 to December 2011|
|Primary Outcome Measure||Change from baseline to week 3 in Young Mania Rating Scale (YMRS) total score|
|Baseline Characteristics||Patients had baseline YMRS total score > 20, score > 4 on at least two of four YMRS items (irritability, speech, content, disruptive/aggressive behavior), and MADRS total score < 18.|
|Demographics||Placebo||Cariprazine 3-6 mg/d||Cariprazine 6-12 mg/d|
|Age, mean (SD), years||41.5 (11.4)||43.1 (12.2)||41.2 (11.3)|
|Men, n (%)||89 (55.3)||90 (53.9)||85 (50.3)|
|White, n (%)||114 (70.8)||117 (70.1)||114 (67.5)|
|Results||YMRS total score||Placebo
(n = 160)
|Cariprazine 3-6 mg/d (n = 165)||Cariprazine 6-12 mg/d (n = 167)|
|Baseline, mean (SD)||32.6 (5.8)||33.2 (5.6)||32.9 (4.7)|
|LS mean (SE) change at week 3||-12.5 (0.8)||-18.6 (0.8)||-18.5 (0.8)|
|LSMD* (95% CI)||————–||-6.1 (-8.4 to -3.8)||-5.9 (-8.2 to -3.6)|
|p-value**||< 0.001||< 0.001|
|Adverse Events||Common Adverse Events:
Cariprazine, both groups: Akathisia
Cariprazine, 6-12 mg/day: Nausea, constipation and tremor
|Serious Adverse Events (SAEs):
Placebo: All three SAEs (mania, bipolar disorder, and bipolar I disorder) reported were associated with worsening of mania or bipolar disorder.
Cariprazine, 3-6 mg/day: Four of the seven SAEs (mania , bipolar disorder, aggression) reported were associated with worsening of mania or bipolar disorder. The specific SAEs of the remaining three were not reported.
Cariprazine, 6-12 mg/day: None reported
|Percentage that Discontinued due to Adverse Events:
Cariprazine, 3-6 mg/day: 9%
Cariprazine, 6-12 mg/day: 14.8%
|Study Author Conclusions||Results of this study demonstrated that both low- and high-dose cariprazine were more effective than placebo in the treatment of acute manic or mixed episodes associated with bipolar I disorder. Cariprazine was generally well tolerated, although the incidence of akathisia was greater with cariprazine than with placebo.|
YMRS: Young Mania Rating Scale; MADRS: Montgomery-Asberg Depression Rating Scale; CGI-S: Clinical Global Impressions-Severity of Illness; CGI-I: Clinical Global Impressions-Improvement; PANSS: Positive and Negative Syndrome Scale; TEAEs: treatment-emergent adverse events; EPS: extrapyramidal symptoms; BARS: Barnes Akathisia Rating Scale; SAS: Simpson-Angus Scale; AIMS: Abnormal Involuntary Movement Scale; C-SSRS: Columbia-Suicide Severity Rating Scale; SD: standard deviation; SE: standard error of the mean
*LSMD from placebo
**p-values for primary efficacy analysis were adjusted for multiple comparisons
The short duration of the study limits the use of the results to only short-term outcomes. The flexible-dose design and the lack of power to detect differences between cariprazine dose groups make it difficult for determining the risk and/or benefit profile of the different cariprazine doses. Clinicians should determine the appropriate course of treatment by taking into account patient-specific factors, such as pregnancy and elderly patients with dementia.3,4
Vraylar™ is an atypical antipsychotic indicated for the acute treatment of manic or mixed episodes with bipolar I disorder. The starting dose for bipolar mania is 1.5 mg/day and has a recommended dose of 3 mg to 6 mg/day and may be taken with or without food. Doses above 6 mg daily do not confer significant benefit and increases the risk of dose-related adverse effects. Common adverse reactions include extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness.4
- Vieta E, Valentí M. Pharmacological management of bipolar depression: acute treatment, maintenance, and prophylaxis. CNS Drugs. 2013;27(7):515-29.
- FDA approves new drug to treat schizophrenia and bipolar disorder. United States Food and Drug Administration. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm463103.htm. Published September 17, 2015. Accessed September 23, 2015.
- Calabrese JR, Keck PE, Starace A, et al. Efficacy and safety of low- and high-dose cariprazine in acute and mixed mania associated with bipolar I disorder: a double-blind, placebo-controlled study. J Clin Psychiatry. 2015;76(3):284-92.
- Vraylar™ [Prescribing Information]. Parsippany, NJ: Actavis Pharma, Inc.; 2015.