Assessment of safety, tolerability and effectiveness of adjunctive aripiprazole to lithium/valproate in bipolar mania: a 46-week, open-label extension following a 6-week double-blind study

Abstract

Objective:

This study evaluated the long-term tolerability and effectiveness of aripiprazole adjunctive to lithium or valproate in partial responders with bipolar mania.

Methods:

Completers of a 6-week double-blind comparison of adjunctive aripiprazole versus placebo in bipolar mania partially responsive to lithium or valproate monotherapy could enter a 46-week extension treatment with open-label adjunctive aripiprazole plus lithium (ARI + LI) or valproate (ARI + VAL). Safety, efficacy and functioning were assessed.

Clinical trial registration:

CN138-134LT: Study of Aripiprazole in Patients With Bipolar I Disorder; ID number: NCT00257972; registry: www.clinicaltrials.gov

Results:

In total, 283 (ARI + LI n = 108; ARI + VAL n = 175) patients entered and 146 (ARI + LI n = 55; ARI + VAL n = 91) completed the 46-week, open-label extension. Frequently reported adverse events (AEs) that occurred with ARI + LI vs. ARI + VAL were: tremor (17.0% vs. 12.1%), akathisia (6.6% vs. 8.6%), headache (6.6% vs. 4.0%), insomnia (9.4% vs. 10.3%), depression (7.5% vs. 9.2%) and weight increase (11.3% vs. 8.6%). Extrapyramidal symptom-related AEs occurred in 24 (22.6%) ARI + LI- and 38 (21.8%) ARI + VAL-treated patients, with eight discontinuations. The majority of new-onset events of akathisia and insomnia occurred early. Mean (SE) weight change from double-blind endpoint to Week 46 (LOCF) was 2.3 (0.6) kg with ARI + LI and 2.0 (0.4) kg with ARI + VAL. Significant improvements from baseline over the 52 weeks (LOCF) occurred with ARI + LI and ARI + VAL on mean (95%CI) YMRS total score (−16.5 [−18.1; −14.8] and −17.6 [−18.9; −16.3], both p < 0.001 vs. baseline) and MADRS total score (−1.7 [−3.3; −0.1], p < 0.05 vs. baseline vs. −2.7 [−4.0; −1.4], p < 0.001 vs. baseline). Over the 46-week extension, continued aripiprazole provided continued YMRS improvement with ARI + LI (−2.9) and ARI + VAL (−3.3), while mean MADRS total changes were +1.1 and +1.0, respectively, and LIFE-RIFT changes were 0.2 and −0.5, respectively.

Conclusions:

Long-term aripiprazole adjunctive to lithium/valproate in bipolar mania was safe and well tolerated. Improvements in manic symptoms and functioning were maintained. Aripiprazole, adjunctive to either lithium or valproate, appeared to be equally safe and effective combinations for the treatment of bipolar disorder.

Limitations:

As an open-label extension study with a low completion rate, a conservative interpretation of the findings is warranted. Additionally, the study population was not randomly selected but chosen at the discretion of the investigator, and patients did not maintain therapeutic levels of their mood stabiliser consistently.

Key words::

• Bipolar mania
• Long term
• Maintenance
• Monotherapy

Transparency

Declaration of funding

This study was supported by Bristol-Myers Squibb (Princeton, NJ) and Otsuka Pharmaceutical Co., Ltd (Tokyo, Japan).

Declaration of financial/other relationships

R.O., C.B. and R.N.M. are employees of Bristol Myers Squibb. R.D.M. and R.S. are employees of Otsuka Pharmaceutical Development & Commercialization Inc. E.V. has received grants and served as consultant, advisor or speaker for the following entities: Almirall, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest Research Institute, GlaxoSmithKline, Janssen-Cilag, Jazz, Johnson & Johnson, Lundbeck, Merck, Novartis, Organon, Otsuka, Pfizer, Sanofi-Aventis, Servier, Schering-Plough, Solvay, Takeda, the Spanish Ministry of Science and Innovation (CIBERSAM), the Seventh European Framework Programme (ENBREC), the Stanley Medical Research Institute, United Biosource Corporation, and Wyeth.

Peer reviewers may receive honoraria from CMRO for their review work. The peer reviewers have declared no relevant financial relationships.

Acknowledgements

Editorial support for the preparation of this manuscript was provided by Ogilvy Healthworld Medical Education; funding was provided by Bristol-Myers Squibb. Statistical analyses were conducted by the co-author Christine Baudelet of Bristol-Myers Squibb.

Data were previously presented at the European Psychiatric Association (EPA), Munich, Germany, 28 February–2 March 2010. Also presented at the Biennial International Conference on Bipolar Disorder (ICBD), Pittsburgh, PA, USA, 25–27 June 2009.