Acetylcholinesterase inhibitors and memantine in bipolar disorder: A systematic review and best evidence synthesis of the efficacy and safety for multiple disease dimensions

Acetylcholinesterase inhibitors (Acel) and memantine might prove useful in bipolar disorder (BD) given their neuroprotective and pro-cognitive effects, as highlighted by several case reports. We aimed to systematically review the efficacy and safety of Acel and memantine across multiple outcome dimensions in BD. Systematic PubMed and SCOPUS search until 04/17/2015 without language restrictions. Included were randomized controlled trials (RCTs), open label studies and case series of Acel or memantine in BD patients reporting quantitative data on depression, mania, psychotic symptoms, global functioning, or cognitive performance. We summarized results using a best-evidence based synthesis. Out of 214 hits, 12 studies (RCTs=5, other designs=7, total n=422) were included. Donepezil (studies=5; treated=102 vs. placebo=21): there was strong evidence for no effect on mania and psychotic symptoms; low evidence indicating no effect on depression. Galantamine (studies=3; treated=21 vs. controls=20) (placebo=10, healthy subjects=10): there was strong evidence for no effect on mania; moderate evidence for no effect on depression; low evidence for no effect on global functioning. Memantine (studies=4; treated=152 vs. placebo=88): there was conflicting evidence regarding efficacy for mania, depression and global functioning. Paucity of RCTs; small sample size studies; heterogeneous design, outcome and patient characteristics. There is limited but converging evidence of no effect of Acel in BD, and conflicting evidence about memantine in BD. Too few studies of mostly medium/low quality and lacking sufficient numbers of patients in specific mood states, especially mania, contributed data, focusing solely on short-term/ medium-term treatment, necessitating additional high-quality research to yield more definite results.