Pharmacology Update

Aripiprazole Tablets (Abilify—Bristol-Myers Squibb)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

Aripiprazole is a new antipsychotic agent approved for the treatment of schizophrenia. This atypical agent is a quinolinone that has partial agonist activity at dopamine D2 receptors. The drug will be marketed as being better tolerated and safer than other atypical agents, as well as being dosed once a day. Aripiprazole is manufactured by Otsuka Pharmaceutical Company in Japan and is marketed by Bristol-Myers Squibb and Otsuka America Pharmaceutical Inc. under the rather unique tradename "Abilify."

Indications

Aripiprazole is indicated for the treatment of schizophrenia.1

Dosage

The recommended starting dose and target dose is 10 or 15 mg once daily. The drug may be taken without regard to meals, and dosage adjustments are not needed for renal or hepatic impairment. The dose should be reduced by 50% if administered concomitantly with drugs that inhibit 2D6 or 3A4 isoenzymes. The dose should be doubled if administered concomitantly with 3A4 inducers.1 Aripiprazole is available as 2-mg, 5-mg, 10-mg, 15-mg, 20-mg, and 30-mg tablets.

Potential Advantages

Aripiprazole does not appear to cause prolactino ma, extrapyramidal effects, or prolongation of QT interval.2,3 It also has minimal effect on weight gain and no effects on plasma triglyceride and glucose levels.4 Aripiprazole also has the lowest affinity among the atypical antipsychotics alpha-1 adrenergic receptors, histamine-1 and muscarinic receptors.5

Potential Disadvantages

Common side effects of nausea, postural dizziness, and somnolence were moderate in severity.2 Aripiprazole is extensively metabolized by cytochrome P450 isoenzymes 2D6 and 3A4. Dosage adjustment is recommended when aripiprazole is co-administered with inhibitors of 2D6 or 3A4 or inducers of 3A4.1

Comments

Aripiprazole’s pharmacology differs from other atypical antipsychotics. It is a partial agonist at dopamine D2 and serotonin 5-HT1A receptors and may be considered as the first dopamine-serotonin system stabilizer.8,9 It is also an antagonist at 5-HT2A.4 Efficacy was demonstrated in 3 out of 4 short-term studies (4-6 weeks) involving patients with a primary diagnosis of schizophrenia or schizoeffective disorder.

The efficacy measures include the Positive and Negative Syndrome Scale (PANSS) total, PANSS- positive subscale, PANSS negative subscale, PANSS-derived Brief Psychiatric Rating Scale (BPRS) score, and clinical global impression (CGI). In general, aripiprazole was superior to placebo in PANSS total and PANSS positive and negative subscales in all 3 studies and CGI in 2 of 3.1,6 In the 4th study (n = 103) aripiprazole was superior to placebo in the BPRS. Two of the studies had an active control (haloperidol 10 mg/d or risperidone 6 mg/d) but these studies were not designed to compare active treatments. Aripiprazole appears to be well tolerated. In an unpublished 52-week study, aripiprazole 30 mg appeared to be comparable to haloperidol in patients with an acute relapse of chronic schizophrenia.4,7 In this study, 8% of patients had a weight gain of > 7% of body weight. The weight gains were related to BMI with 30% weight gain of those with BMI < 23 and 19% in those with BMI between 23 and 27.1 The wholesale cost for aripiprazole (10 mg or 15 mg per day) is about $250 per month.

Clinical Implications

Aripiprazole offers another atypical antipsychotic that appears to be effective and well tolerated. Currently available drugs have some drawbacks. Clozaril requires periodic blood testing for agranulocytosis, ziprasidone increases QT interval, olanzapine causes weight gain, and risperidone causes prolactinoma.10-12 Broader clinical experience or comparative studies between aripiprazole and other atypical antipsychotics will determine the future role of this agent.

References

1. Abilify Product Information. Bristol-Myers Squibb. November 2002.

2. Kelleher JP, et al. CNS Drugs. 2002;16(4):249-261.

3. Taylor DM. Int J Clin Pract. 2003;57(1):49-54.

4. Anonymous. Med Lett Drugs Ther. 2003;45:15-16.

5. Goodnick PJ, Jerry JM. Expert Opin Pharmacother. 2002;2(12):1773-1781.

6. Kane JM, et al. J Clin Psychiatry. 2002;63(9):763-771.

7. McGavin JK, Goa KL. CNS Drugs. 2002;16(11):779-786.

8. Jordan S, et al. Eur J Pharmacol. 2002;441(3):137-140.

9. Burris KD, et al. J Pharmacol Exp Ther. 2002;302(1):381-339.

10. Taylor D. CNS Drugs. 2003;17(6):423-430.

11. Bobes J, et al. Schizophr Res. 2003;62(1-2):77-88.

12. Goodnick PJ et al. Expert Opin Pharmacother. 2002;3(10):1381-1391.

Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California-San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Both are Associate Editors of Internal Medicine Alert.