Cholinesterase inhibitors as adjunctive therapy in patients with schizophrenia and schizoaffective disorder: a review and meta-analysis of the literature.

BACKGROUND Cognitive deficits have been described in patients with schizophrenia from the first descriptions of dementia praecox to current concepts of cognitive dysmetria. Nevertheless, little is known about how to deal with them. In Alzheimer disease, cholinergic deficit is found and cholinesterase inhibitors have been used to delay the progression of memory and cognitive dysfunction. Several lines of evidence suggest that the cholinergic system may be disrupted in schizophrenia. OBJECTIVE To evaluate cognitive and clinical effects of adjunctive cholinesterase inhibitors in patients with schizophrenia and schizoaffective disorder. METHOD We conducted a literature search on PubMed and EMBASE (up to December 2008) for articles that investigated adjunctive cholinesterase inhibitors in patients with schizophrenia. The terms 'schizophrenia', 'acetylcholinesterase inhibitors', 'rivastigmine', 'donepezil', 'galantamine' and 'cognitive deficit' were searched with restriction for English language and without a year limit. All articles that presented original data from randomized, double-blind, placebo-controlled trials with donepezil, rivastigmine or galantamine in patients with schizophrenia or schizoaffective disorder were included in the meta-analysis. Studies were excluded for the following reasons: (i) case study/letter/correspondence/review; (ii) animal study; (iii) molecular/genetic investigation; and (iv) inclusion of patients with schizophrenia and co-morbid dementia. Few appropriate data for meta-analysis were found because of the large heterogeneity of the assessment instruments used. Nevertheless, effects of cholinesterase inhibitors in some cognitive domains (executive function, memory and language), psychopathology (using the Positive and Negative Syndrome Scale) and extrapyramidal symptoms could be analysed. RESULTS Six open-label and 24 double-blind studies were found. In five open-label studies there was an improvement in memory, attention and executive functions. Thirteen double-blind studies (four with rivastigmine, six with donepezil and three with galantamine) contributed to the meta-analysis. Significant improvement was found in this analysis for memory and the Trail Making test part A. CONCLUSIONS The reviewed studies suggest that specific cognitive deficits (memory, and the motor speed and attention part of executive function) of patients with schizophrenia and schizoaffective disorder are responsive to rivastigmine, donepezil and galantamine as adjunctive therapy. Confirmatory studies are needed to determine the clinical utility of this treatment strategy.