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A double-blind, placebo-controlled trial of adjunctive donepezil in treatment-resistant mania

Authors

  • A. Eden Evins,

    1. Harvard Bipolar Research Program and Department of Psychiatry of the Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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  • Christina Demopulos,

    1. Harvard Bipolar Research Program and Department of Psychiatry of the Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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  • Andrew Nierenberg,

    1. Harvard Bipolar Research Program and Department of Psychiatry of the Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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  • Melissa A. Culhane,

    1. Harvard Bipolar Research Program and Department of Psychiatry of the Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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  • Lori Eisner,

    1. Harvard Bipolar Research Program and Department of Psychiatry of the Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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  • Gary Sachs

    1. Harvard Bipolar Research Program and Department of Psychiatry of the Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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  • The authors report these commercial associations that may pose a conflict of interest in connection with this manuscript: AEE has received grant support from Pfizer GsK, Janssen; AN has received grant support from Eli Lilly & Co., Wyeth, GlaxoSmithKline, BMS, Cyberonics, Lichtwer, Pfizer, Cederroth, Forest Laboratories, Janssen; consultant for Eli Lilly & Co., Shire, GlaxoSmithKline, Innapharma, Genaissance, Sepracor; and has received honoraria from Eli Lilly & Co., Wyeth, GlaxoSmithKline. GS has commercial associations with Abbott Laboratories, AstraZeneca, GlaxoSmithKline, Janssen, Eli Lilly & Co., Pfizer and Wyeth. CD, MC and LE have no reported conflict of interest.

A. Eden Evins, MD, MGH Schizophrenia Research Program, Freedom Trail Clinic, Erich Lindemann Mental Health Center, 25 Staniford Street, Boston, MA 02114, USA. Fax: 617 723 3919; e-mail: a_eden_evins@hms.harvard.edu

Abstract

Introduction:  Because there is a high rate of partial response to standard thymoleptic medication, novel augmentation strategies for treatment-resistant bipolar disorder are needed. In an open trial, donepezil augmentation was associated with improvement in manic symptoms in 9 of 11 subjects.

Method:  We conducted a 6-week, double-blind, placebo-controlled trial of donepezil for treatment-resistant bipolar mania. Eligible subjects had a Young Mania Rating Scale (YMRS) score of at least 15 despite two or more weeks of proven therapeutic levels of lithium or valproate. Subjects who completed the trial were eligible for an 8-week open trial of donepezil. Subjects were started on donepezil 5 mg/day and were eligible for dose increase to 10 mg/day after 4 weeks.

Results:  Twelve subjects were enrolled. Eleven subjects received at least 1 week of study medication and were included in the analysis. No subjects in the donepezil group (0/6) and 60% (3/5) in the placebo group met response criteria of >30% reduction in YMRS score (Fisher's Exact p = 0.061). YMRS scores were higher at trial endpoint in the donepezil group 20.17 (3.66) compared with the placebo group [11.20 (4.60), Z = −2.476, p = 0.01]. There were no differences at trial endpoint in Hamilton Rating Scale for Depression (HAM-D) or Brief Psychiatric Rating Scale (BPRS) scores in either the intent-to-treat or the completer analyses.

Conclusions:  Donepezil does not appear to be an effective adjunctive treatment for refractory manic symptoms. The strength of the conclusion of this trial is limited by the possibility of a false-negative result due to the small sample.

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