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

Side Effects of Antipsychotics

Treatment with antipsychotic drugs, whether typical or atypical agents, is associated with various adverse effects, including acute EPS (dystonia, parkinsonism and akathisia), chronic EPS (tardive dyskinesia), neuroleptic malignant syndrome, weight gain, glucose intolerance (diabetes mellitus [DM]), metabolic syndrome and elevation of plasma prolactin levels.[1–3,32,33] Several of these side effects are known to be related to distinct pharmacological profiles of the antipsychotic agents. For example, parkinsonisms, tardive dyskinesia, neuroleptic malignant syndrome and hyperprolactinemia are considered to be a result of acute or chronic blockade of DA receptors, while histamine-H1 and 5-HT2Creceptors may contribute to antipsychotic-induced weight gain.[1–3,32,33]

A summary of side effect-inducing potentials of widely used antipsychotic drugs is shown in Table 1 . By definition, typical antipsychotic drugs (first-generation antipsychotics) are prone to induce EPS; whereas atypical compounds are less likely to cause EPS and tardive dyskinesia, but some atypicals are more frequently associated with metabolic side effects, such as DM and weight gain. However, recent large-scale studies, particularly the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE)[34] and the European First Episode Schizophrenia Trial (EUFEST),[35] did not find a significant difference in the incidence of the development of antipsychotic-induced DM among typical and atypical antipsychotic drugs.

The CATIE (Phase I) and EUFEST studies were multicenter, active-control, randomized trials that were designed to compare the effectiveness of atypical and typical antipsychotic drugs.[34,35] The side-effect profiles of antipsychotic drugs, as revealed in these studies, are summarized in Table 2 . Olanzapine, quetiapine and ziprasidone were tested as atypical antipsychotic drugs in both trials, while the EUFEST study used amisulpiride instead of risperidone, which was included in the CATIE study. The most substantial difference between the two studies was the type of typical antipsychotic drug as a comparator, such as perphenazine, a low-potency drug, in the CATIE study versus haloperidol, a high-potency and one of the most commonly used typical drugs, in the EUFEST study. Risperidone was found to show the lowest treatment discontinuation rate due to side effects overall in the CATIE study, while olanzapine and quetiapine were superior to haloperidol in the EUFEST study. It is noteworthy that the incidence of neurologic side effects, such as EPS and akathisia, did not differ between atypical drugs across the two studies, while the typical compound haloperidol elicited the greatest incidence of parkinsonism.

Olanzapine yielded the greatest degree of weight gain, whereas it did not differ from other atypical or typical antipsychotic drugs in terms of the DM-inducing potential Table 2 .[34,35] This may not be in agreement with the traditional notion that patients taking olanzapine have an increased risk of developing DM than those taking typical antipsychotics,[36] but indeed confirms the results of head-to-head comparisons of the incidence of DM between clozapine, olanzapine, risperidone and quetiapine.[32,33] These studies provided the first data showing that olanzapine did not differentiate from risperidone with regard to the risk of developing DM, similar to the result of a retrospective study.[37] Only the CATIE study reports a significant difference in the incidence of plasma lipid elevation between olanzapine and other atypical or typical drugs. On the other hand, risperidone and amisulpiride showed the greatest risk of plasma prolactin elevation in the respective studies Table 2 .[34,35]