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


METHODS
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.
Eden Evins
A
A
Department of Psychiatry of the Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. a_eden_evins@hms.harvard.edu
Demopulos
Christina
C
Nierenberg
Andrew
A
Culhane
Melissa A
MA
Eisner
Lori
L
Sachs
Gary
G
D000328:Adult; D018692:Antimanic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001714:Bipolar Disorder / Q000188:drug therapy*; D010054:Brief Psychiatric Rating Scale; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D000077265:Donepezil; D004311:Double-Blind Method; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007189:Indans / Q000008:administration & dosage* / Q000009:adverse effects; D018020:Lithium Compounds / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects; D011569:Psychiatric Status Rating Scales; D016896:Treatment Outcome; D014635:Valproic Acid / Q000008:administration & dosage / Q000009:adverse effects
D018692:Antimanic Agents; D002800:Cholinesterase Inhibitors; D007189:Indans; D018020:Lithium Compounds; D010880:Piperidines; D014635:Valproic Acid; D000077265:Donepezil