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

Five-year View

Increasing attention and efforts are now directed to the development of pharmacotherapy to intervene into the early stage of psychosis.[81] Preventive treatment with risperidone[97] or olanzapine[98] has been shown to reduce the risk of transition to psychosis in subjects with prodromal symptoms of schizophrenia. However, attention should be paid to evidence that these compounds, particularly risperidone, may be associated with deterioration of working memory in patients with first-episode psychosis.[79,80] Moreover, as discussed earlier, atypical antipsychotic drugs in general have metabolic side effects, (e.g., increased incidence of DM and weight gain),[32,33] underscoring the need for risk–benefit considerations before using these drugs to intervene with people who do not elicit overt psychotic symptoms.[81,99,100]

In spite of strenuous efforts to identify pharmacotherapy to tackle cognitive disturbances of schizophrenia,[101] there are several cognitive domains that are less likely to respond than others. In particular, impairment of executive function, as measured by the Wisconsin Card Sorting Test, is treatable only by a limited number of antipsychotics, such as melperone,[29] which, similar to clozapine, is one of the prototypical atypical antipsychotic drugs.[30,102] As to attention/vigilance, a recent study of the effect of blonanserin, a novel antipsychotic drug Figure 2 and risperidone as a comparator found the ability of blonanserin to specifically ameliorate attention/information processing in patients with schizophrenia.[103]

Prompted by our discovery that 5-HT1A receptors are promising targets in the management of cognitive disturbances of schizophrenia,[72–74,91,92] research is now focused on developing 'third-generation' antipsychotics that combine antagonism or partial agonism at dopamine D2-like receptors with agonism at serotonin 5-HT1A receptors.[14] Thus, preclinical and clinical studies of novel antipsychotics with 5-HT1A agonist actions (e.g., bifeprunox, SLV313, SSR181507 and lurasidone) are currently in progress.[14,104–106] Optimizing the balance of actions on various neurotransmitter systems may be beneficial for the purpose of the development of a series of pharmacotherapies that are both efficacious and accompanied with minimal incidence of adverse effects.