Question

A patient has tried several different treatments for bipolar disorder without control. Previous therapies include lithium, Depakote, carbamazapine, Saphris, Seroquel, benztropine, diazepam and Latuda. Her doctor is suggesting using Clozaril for her condition. The physician would like a pharmacist consult on Abilify (aripiprazole) for the treatment of refractory bipolar disorder.

Introduction

Refractory bipolar disorder has symptoms that include frequent changes between manic and depressive states (rapid cycling), and suicide attempts, even if treatment with mood stabilizers are maximized. Even without rapid cycling, these patients may suffer from relapses and great difficulties in their social and occupational lives.¹ Patients that have at least four episodes of frequent changes between manic and depressive states in 12-months are classified as “rapid cycling” ²

Bipolar disorder can be caused by dysregulation of catecholamine (e.g., dopamine) and serotonin (5HT). "Although, the exact cause of bipolar disorder is unknown, heredity and fluctuations in the level of brain neurotransmitters may be associated with it. The Best pharmacologic treatment is mood stabilizers”.³ Identifying and treating other medical conditions (e.g., hypothyroidism, alcohol abuse, or drug abuse) is also important as they may contribute to rapid cycling.⁴

Clinical studies validating the use of Clozaril for refractory bipolar disorder

The exact mechanism of Clozaril is unknown. Some clinical trials have been conducted to determine its efficacy in treating bipolar disorder. Calabrese et. al conducted an open uncontrolled study. Twenty five manic patients with bipolar disorder that have been unsuccessful with lithium, anticonvulsants, and narcoleptics were studied. A seven day washout period was allowed, they were then given Clozaril monotherapy. The Young Mania Rating Scale (YMRS) and the Brief Psychiatric Rating Scale (BPRS) were used to evaluate them after 13 weeks. Seventy-two percent of the patients had an improvement on the Young Mania Rating Scale, and thirty-two percent had an improvement on the BPRS. The results indicated that Clozaril can be useful in treatment-resistant bipolar disorder. It showed to be most useful in refractory manic disorders.⁵

Clinical Studies Validating the Use of Abilify for Bipolar

Keck et al. conducted a three week, multicenter, double-blind study. They randomly assigned 262 bipolar disorder patients in a short term manic or mixed episode to abilify (monotherapy) or placebo. Patients were admitted for minimum of two weeks and YMRS was used as a measuring scale. This scale showed a statistical improvement in bipolar symptoms with patients on abilify compared to placebo (-8.2 vs. -3.4, respectively) and they also showed a 40% higher response rate compared to 19% in the placebo group. Adverse effects were not a significant issue, but completion of the study was an issue with a few patients. 42% of patient receiving aripiprazole and 21% patients receiving placebo completed the study. However, the results were statistically significant in favor of Abilify. Abilify was more effective than placebo for the treatment of acute manic or mixed episodes of bipolar disorder. Abilify also proved to be safe and well tolerated.⁶

Conclusion

Both Abilify and Clozaril have been shown to be effective in the treatment of mixed episode bipolar disorder. In addition, Abilify was well tolerated in the study discussed above. Because they are both effective as monotherapies, the patient may be administered an appropriate monotherapy dose of Clozaril for refractory bipolar disorder. Effectiveness and side effects should be closely monitored. If Clozaril is ineffective or significant side effects occur, the patient may be switched to Abilify. Other medical conditions should also be identified and treated as they may also contribute to rapid cycling.

References

1. Cowen M. Combination treatment benefits patients with refractory bipolar disorder. Sept 07, 2010. J Affect Disord 2010; 126: 80–8.

2. Kupka R. Rapid Cycling bipolar disorder: Epidemiology, Pathogenesis, clinical features, and diagnosis. In: UptoDate, Keck P (ED), UpToDate. Waltham, MA, 2012.

3. Coryell, MD et. al. (2009). Merck Manual Index: Bipolar.

4. Bipolar In: Diseadex [database on the internet]. Greenwood Village (CO): Thomson Reuters Micromedex; 1974-2012[cited 04 Oct 2012]

5. Calabrese JR, Kimmel SE, Woyshville MJ, et al. Clozapine for treatment-refractory mania. Am J Psychiatry. 1996;153:759-764.

6. Keck Jr PE, Marcus R, Tourkodimitris S, et al. A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Aripiprazole Study Group. Am J Psychiatry 2003 Sep; 160 (9): 1651-8

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This medication summary is for information only and is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider.