Anticholinergic Burden in Schizophrenia

Anticholinergic antiparkinsonian agents (AAAs) are frequently prescribed in patients with a primary psychotic disorder either to treat or prevent the emergence of antipsychotic induced extrapyramidal symptoms (EPS). Second generation antipsychotics (SGAs) are by definition associated with fewer neurological side effects. This would be expected to be associated with a lower use of AAAs. However, in a recent prescription survey, Park and colleagues found that while the rate of concomitant use of antiparkinsonian agents dropped by 9.2% in patients with schizophrenia after changing their antipsychotic from typical antipsychotics to SGAs, 30% of prescriptions for SGAs included a concomitant antiparkinsonian agent. This is consistent with the results of other cross-sectional surveys demonstrating anticholinergic co-prescription rates of 12 - 65% in patients treated with SGA. These high rates are remarkable especially when one considers that the incidence of EPS reported in past clinical trials using SGAs (3 - 20%) is much lower than this reported co-prescription rate. This apparent discrepancy is likely explained, in part, by the established tradition of prophylactic (or routine) use of AAAs for patients starting antipsychotic drugs.

The adverse effects of AAAs are well known, and are particularly significant clinically in the elderly, who are at high risk of cognitive impairment with AAAs. Anticholigergic effects have been reported to impair cognitive function both globally as well as in specific domains, including memory and executive functioning. The association between anticholinergic activity and cognitive performance are also strongly supported by recent studies measuring serum anticholinergic activity (SAA).

Furthermore, in addition to their well-known side effects such as dry mouth, blurred vision, and constipation, they have also been reported to increase the risk of tardive kinesia and have been claimed to have a negative impact on the clinical efficacy of antipsychotic drugs.

In view of these adverse effects, the World Health Organization has discouraged the prophylactic use of AAAs, and a careful risk-benefit analysis is necessary for each individual patient. Since most cases of antipsychotic-induced EPS present within 11 weeks of initiation of antipsychotic treatment or a dosage increase, a trial of AAA taper and discontinuation has been recommended following 3 months of regular AAA treatment. These recommendations emerged prior to the widespread use of SGAs, and one might expect that successful discontinuation of concomitant AAAs would be higher for SGAs than conventional antipsychotics. AAA discontinuation trials for conventional antipsychotics have been inconsistent, with some studies reporting favorable outcomes and others reporting re-emergence of EPS. More recently Mori et al reported a favorable outcome following AAA discontinuation for both cognition and EPS in patients maintained on chlorpromazine, risperidone, or haloperidol in mixed age population with schizophrenia.

The only study of AAA discontinuation in older patients with schizophrenia also reported improved cognitive function in a sample of 21 elderly inpatients with schizophrenia. However, this study did not include extrapyramidal symptoms, psychopathology, or other side effects from AAAs as outcome measures. Furthermore, improvement in cognitive function reported in this study could be attributed to practice effects: the Alzheimer's Disease Assessment Scale-Cognitive subscale was administered at intervals of 10 days - though the learning effects of this scale have not been studied in patients with schizophrenia.