Possible Dose-Side Effect Relationship of Antipsychotic Drugs: Relevance to Cognitive Function in Schizophrenia

Tomiki Sumiyoshi


Expert Rev Clin Pharmacol. 2008;1(6):791-802. 

In This Article

Dose-dependent Effect of Antipsychotic Drugs on Cognition in Schizophrenia

The cognitive benefits of antipsychotic drugs in schizophrenia depend on various factors, such as type of antipsychotic (typical or atypical), cognitive domain, stage of schizophrenia (first episode patients or chronic patients) and dose. For example, risperidone has been considered to be effective in alleviating working memory,[76] while relatively short-term treatment with clozapine was associated with deterioration of this cognitive domain both in neuroleptic-resistant[77] and -responsive[78] patients. However, recent studies have reported risperidone specifically worsens working memory in first-episode schizophrenia,[79,80] suggesting a need for caution in the choice of medication for the treatment of early-stage schizophrenia.[81]

While information regarding the dose–effect relationship for cognitive enhancement by antipsychotic drugs may be relatively scarce, a recent meta-analysis of cognitive change with haloperidol in clinical trials of atypical antipsychotics successfully answered several critical questions.[82] Thus, Woodward et al. found first, that overall cognitive performance improves while on haloperidol, and second that studies using a low dose of haloperidol (<10 mg) did not yield larger effect sizes for overall cognitive function or specific neuropsychological measures than studies that used a high dose (>10 mg) Figure 5.[82] These findings provide a valid challenge against the suggestion that the cognitive improvements observed with atypical antipsychotics reflect an avoidance of a deleterious effect of haloperidol on cognitive function that might be dose related.[82]

Cognitive changes with haloperidol in clinical trials of atypical antipsychotic drugs. Meta-analysis of within-group change on several neuropsychological tests with haloperidol from atypical versus haloperidol randomized clinical trials. ES: Effect size; VLLi: Verbal Learning List–Immediate Recall; VLLd: Verbal Learning List–Delayed Recall. WCST: Wisconsin Card Sorting Test. Redrawn with permission from.[82,87]