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Commentaries

Cariprazine in Bipolar Disorders

See Article by Calabrese et al.

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Cariprazine in Bipolar Disorders

This issue of JCP includes a report on the efficacy and safety of cariprazine for the treatment of bipolar mania from Calabrese and colleagues.1

Key Study Findings

The authors report a multicenter (N = 497), randomized, double-blind, placebo-controlled study (NCT01058668). Patients were randomly assigned to placebo, cariprazine 3-6 mg/d, or cariprazine 6-12 mg/d for 3 weeks. The primary outcome was change from baseline to week 3 utilizing the Young Mania Rating Scale (YMRS). Both cariprazine groups were statistically significantly superior to placebo on the primary outcome, all 11 YMRS single items, and Clinical Global Impressions-Severity of Illness scores. The most common (≥ 5% and twice the rate of placebo) treatment-related adverse events for cariprazine were akathisia (both groups) and nausea, constipation, and tremor (6-12 mg/d only).

Other Controlled Studies of Cariprazine for Acute Mania

Including the current study, 3 placebo-controlled studies utilizing cariprazine in the treatment of acute mania have been conducted (NCT01058668, NCT00488618, NCT01058096),1-3 and all show significantly higher efficacy for cariprazine compared to placebo. Pooled analysis of the 3 trials (N = 1,037) on the primary outcome scale (YMRS), recently presented at a scientific meeting,4 showed significance in all items favoring cariprazine, with moderate effect sizes (Cohen d) on YMRS items ranging from −0.31 (increased motor activity) to −0.55 (irritability). Pooled safety and tolerability analyses of the 3 trials (N = 1,065), also presented at a scientific meeting,5 reported treatment-emergent adverse events (5% and twice placebo) including akathisia (placebo, 5%; cariprazine, 20%), extrapyramidal symptoms (5%/13%), restlessness (2%/6%), and vomiting (4%/9%), with a small amount of weight gain (placebo, 0.17 kg; cariprazine, 0.54 kg).

How Does Cariprazine EfficacyCompare to That of Other Agents?

The design of Calabrese and colleagues’ study1 is similar to those of previous clinical trials with other compounds explored for the treatment of mania. This includes the duration (3 weeks) and the minimum YMRS severity score (> 20), although a minimum severity score for the Montgomery-Asberg Depression Rating Scale total score < 18 may limit the generalizability of findings in patients with mixed features. Exclusion criteria were similar to those of previous clinical trials as well.6

Yildiz et al7 recently published a network meta-analysis, with a Bayesian framework, comparing 18 active treatments against placebo including the current cariprazine study (NCT01058668)1 from data available from meeting abstracts.8 Cariprazine appears to compare well with other treatments, with an effect size of 0.62 and a number needed to treat (NNT) of 5 for response and 7 for remission. Yildiz and colleagues’ 7 effect size estimations put cariprazine toward the top: only topiramate, risperidone, and olanzapine had larger effect size estimations. A limitation of these comparisons across studies is of course that their populations may be quite diverse in terms of demographics and inclusion and exclusion criteria. In addition, the NNT of 5 for remission in this study1 compares favorably to a pooled NNT of 8 for all atypical agents estimated by another meta-analysis conducted by Tamayo et al.9

Furthermore, Citrome10 recently reported effect size metrics of different atypical antipsychotics compared to cariprazine with NNT values versus placebo for response and remission. The NNTs for response of 5 in this trial and 7 in a phase 2 study3 are similar to those observed with other compounds including lithium (NNT = 4), divalproex extended release (NNT = 7), carbamazepine extended release (NNT = 4), olanzapine (NNT = 5), risperidone (NNT = 4), quetiapine extended release (NNT = 6), ziprasidone (NNT = 7), aripiprazole (NNT = 5), and asenapine (NNT = 8).10 Citrome also noted that number needed to harm values regarding akathisia for cariprazine versus placebo are approximately the same as the NNT for response. A remission NNT of 5 appears good. However, Calabrese et al1 also estimated remission rates using a definition recommended by the International Society for Bipolar Disorders11 of YMRS score < 8, and the results were quite modest, with only 25% of patients achieving remission. In other words, the vast majority of patients in this study either did not remit or achieved only partial remission and remained in a subsyndromic manic state. Data have shown that when patients achieve only partial remission, the risk of relapse is higher compared to those who achieve full remission.12

Other Studies of Cariprazine in Mood Disorders

Positive results have been presented at scientific meetings on the efficacy of cariprazine in phase 2 studies (NCT01396447) for bipolar depression13 and as an adjunctive treatment in patients with inadequate response to standard antidepressant therapy (NCT01469377).14

Do We Need Another Molecule to Treat Mania?

I wish the answer were no. However, the available treatments including mood stabilizers are effective and tolerable to only some patients, and in many cases the efficacy is only partial. Currently, we have 11 US Food and Drug Administration (FDA)-approved treatments for acute mania (lithium, valproate, chlorpromazine, and 7 atypical antipsychotics including risperidone, olanzapine, paliperidone, aripiprazole, asenapine, quetiapine, and ziprasidone). Cariprazine appears to be novel: it is a dopamine D3 and D2 receptor partial agonist with preferential binding to D3 receptors, which have been reported to regulate both mood and cognition.15 The unique pharmacologic profile of cariprazine may provide added value to the existing armamentarium for treatment options of acute mania. However, it has not yet been approved by the FDA; according to the manufacturer16 and sources publicly available on the Internet,17 it appears that the agency has requested more clinical data to better define the optimal dosing for its use in schizophrenia and bipolar mania. Assuming regulatory approval is met, cariprazine for the treatment of acute mania may be an additional option. With a number of atypical antipsychotics already available as generic, cost will be a major challenge unless, of course, further studies demonstrate an advantage of cariprazine in head-to-head studies and/or focus on other outcomes such as cognition or functioning.

Areas of Unmet Medical Need in Bipolar Disorder

Our patients have a larger need for more options for bipolar depression and maintenance treatment. As mentioned, 1 trial for bipolar depression has been completed.13 For bipolar depression, the only products approved by the FDA are quetiapine, lurasidone as monotherapy and in combination with lithium or valproate, and the combination of olanzapine and fluoxetine. FDA-approved maintenance treatment for bipolar disorder includes lithium, lamotrigine, olanzapine, quetiapine as monotherapy and in combination with lithium or valproate, aripiprazole, risperidone depot intramuscular, and ziprasidone in combination with lithium or valproate. No controlled maintenance studies for cariprazine are currently listed on the ClinicalTrials.gov website.

Psychopharmacology has not yet reached the state of personalized medicine.18 Currently, we do not even tailor treatment for individual patients on the basis of their clinical characteristics. Even if we did tailor to symptoms, this does not guarantee success. Tailoring to biomarkers, already a reality in oncology, is hopefully coming soon to psychiatry. We also need to “personalize” our outcomes. We currently focus on symptomatic remission, which has been shown in observational studies19,20 to always exceed functional recovery.

To summarize, the additional value of cariprazine to our current treatment armamentarium in bipolar disorder remains to be determined. My hope is that our field will move into personalized medicine with an emphasis in patient-based functional outcomes.

Author affiliations: Department of Psychiatry, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.

Potential conflicts of interest: Dr Tohen was a full-time employee at Eli Lilly (1997-2008). In the past 2 years, he has received grant/research support from American Psychiatric Association, Baptist Health Foundation, Pfizer, Johnson & Johnson, Forest, National Institute of Mental Health, and the Atlas Foundation. He has received honoraria from or consulted for Abbott, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Johnson & Johnson, Otsuka, Merck, Sunovion, Forest, Gedeon Richter, Roche, Elan, Alkermes, Lundbeck, Teva, Pamlab, Wyeth, and Wiley Publishing. His spouse was also a full-time employee at Eli Lilly (1998-2013).

Funding/support: None reported.

REFERENCES

1. 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):284-292.

2. Durgam S, Starace A, Li D, et al. The efficacy and tolerability of cariprazine in acute mania associated with bipolar I disorder: a phase II trial [published online ahead of print July 24, 2014]. Bipolar Disord. PubMed doi:10.1111/bdi.12238

3. Bose A, Starace A, Wang Q, et al. Cariprazine in the treatment of acute mania in bipolar disorder: a double-blind, placebo-controlled, phase III trial. Eur Neuropsychopharm. 2012;22(suppl 2):S285. doi:10.1016/s0924-977x(12)70432-7.

4. Keck PE, Zukin S, Lu K, et al. Cariprazine effects on YMRS items: results of a pooled analysis of 3 randomized, double-blind, placebo-controlled trials in bipolar mania. Presented at the 29th CINP World College of Neuropsychopharmacology; June 22-26, 2014; Vancouver, British Columbia, Canada.

5. Yatham L, Vieta E, Lu K, et al. Safety and tolerability of cariprazine in patients with acute bipolar mania: pooled analysis of 3 phase 11/111 pivotal studies. Presented at the 29th CINP World College of Neuropsychopharmacology; June 22-26, 2014; Vancouver, British Columbia, Canada.

6. Ketter TA, Wang PW. Overview of pharmacotherapy for bipolar disorders. In: Ketter TA, ed. Handbook of Diagnosis and Treatment of Bipolar Disorder. Washington, DC: American Psychiatric Publishing, Inc; 2010:83-106.

7. Yildiz A, Nikodem M, Vieta E, et al. A network meta-analysis on comparative efficacy and all-cause discontinuation of antimanic treatments in acute bipolar mania [published online ahead of print July 18, 2014]. Psychol Med. PubMed doi:101017/S0033291714001305

8. Calabrese JR, Keck PE Jr, Starace A, et al. Efficacy and safety of low- and high-dose cariprazine in patients with acute mania associated with bipolar I disorder. Eur Neuropsychopharmacol. 2013;23(suppl. 2):S378-S379. doi:10.1016/S0924-977X(13)70597-2

9. Tamayo JM, Zarate CA, Vieta E, et al. Level of response and safety of pharmacological monotherapy in the treatment of acute bipolar I disorder phases: a systematic review and meta-analysis. Int J Neuropsychopharmacol. 2010;13(6):813-832. PubMed doi:10.1017/S1461145709991246

10. Citrome L. Cariprazine in bipolar disorder: clinical efficacy, tolerability, and place in therapy. Adv Ther. 2013;30(2):102-113. PubMed doi:10.1007/s12325-013-0004-9

11. Tohen M, Frank E, Bowden CL, et al. The International Society for Bipolar Disorders (ISBD) Task Force report on the nomenclature of course and outcome in bipolar disorders. Bipolar Disord. 2009;11(5):453-473. PubMed doi:10.1111/j.1399-5618.2009.00726.x

12. Tohen M, Bowden CL, Calabrese JR, et al. Influence of sub-syndromal symptoms after remission from manic or mixed episodes. Br J Psychiatry. 2006;189(6):515-519. PubMed doi:10.1192/bjp.bp.105.020321

13. Durgam S, Lipschitz A, Guo H, et al. Cariprazine monotherapy in the treatment of bipolar depression: a double-blind, placebo-controlled study. Presented at the 29th CINP World College of Neuropsychopharmacology; June 22-26, 2014; Vancouver, British Columbia, Canada.

14. Durgam S, Németh G, Mergel V, et al. Cariprazine as adjunctive treatment in major depressive disorder; a double blind placebo controlled study. Presented at the 29th CINP World College of Neuropsychopharmacology; June 22-26, 2014; Vancouver, British Columbia, Canada.

15. Cho DI, Zheng M, Kim KM. Current perspectives on the selective regulation of dopamine D₂ and D₃ receptors. Arch Pharm Res. 2010;33(10):1521-1538. PubMed doi:10.1007/s12272-010-1005-8

16. Forest Laboratories and Gedeon Richter receive complete response letter for cariprazine. Forest Laboratories website. http://investor.frx.com/press-release/r-and-d-news/forest-laboratories-and-gedeon-richter-receive-complete-response-letter-c. Updated November 21, 2013. Accessed October 22, 2014.

17. Dennis M. FirstWordPharma: FDA declines to approve Forest, Gedeon Richter’s antipsychotic cariprazine, seeks more clinical data. http://www.firstwordpharma.com/node/1165110#axzz3G99XeU2c. Updated November 21, 2013. Accessed October 22, 2014.

18. Hayes DF, Markus HS, Leslie RD, et al. Personalized medicine: risk prediction, targeted therapies and mobile health technology. BMC Med. 2014;12(1):37. PubMed doi:10.1186/1741-7015-12-37

19. Tohen M, Waternaux CM, Tsuang MT. Outcome in mania: a 4-year prospective follow-up of 75 patients utilizing survival analysis. Arch Gen Psychiatry. 1990;47(12):1106-1111. PubMed doi:10.1001/archpsyc.1990.01810240026005

20. Tohen M, Zarate CA Jr, Hennen J, et al. The McLean-Harvard First-Episode Mania Study: prediction of recovery and first recurrence. Am J Psychiatry. 2003;160(12):2099-2107. PubMed doi:10.1176/appi.ajp.160.12.2099

Submitted: October 21, 2014; accepted October 21, 2014.

Corresponding author: Mauricio Tohen, MD, DrPH, MBA, Department of Psychiatry, University of New Mexico Health Sciences Center, Albuquerque, NM (mtohen@gmail.com).

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