First- and Second-generation Antipsychotic Medication and Cognitive Processing in Schizophrenia Thomas W. Weickert, PhD and Terry E. Goldberg, PhD* Address *Clinical Brain Disorders Branch, Genes, Cognition, and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. E-mail: goldbert@mail.nih.gov Current Psychiatry Reports 2005, 7:304–310 Current Science Inc. ISSN 1523-3812 Copyright © 2005 by Current Science Inc. Introduction Although antipsychotic medications generally reduce the psychotic symptoms of schizophrenia, their effects on cogni- tive abilities have been somewhat equivocal. The aim of this review is to succinctly describe the cognitive deficits frequently observed in patients with schizophrenia, discuss evidence from previous studies supporting the positive or negative influence of first- and second-generation anti- psychotic medication on cognitive abilities, highlight results from studies of direct comparisons between second-genera- tion and low doses of first-generation antipsychotic medica- tion on cognitive abilities, outline some of the most promising hypotheses regarding the mechanism of anti- psychotic treatment effects on cognitive abilities, and report the results of recent studies examining the interaction among antipsychotic medication treatment and genetic influences on cognitive abilities in patients with schizophrenia. We suggest that future studies of the effects of antipsychotic treat- ment on cognition in patients with schizophrenia will pro- vide a better understanding of the mechanism underlying the antipsychotic-cognition interaction if genetic mecha- nisms are concurrently taken into account. Schizophrenia and Cognition Schizophrenia is a debilitating neuropsychiatric illness that typically is manifest during late adolescence or early adult- hood and is characterized by various combinations of the following symptoms: hallucinations, delusions, flat or inappropriate affect, avolition, alogia, disorganized or cata- tonic behavior, and disorganized speech. In addition to these clinically described symptoms, schizophrenia also has been characterized by numerous cognitive abnormalities includ- ing impairment of executive function (planning, problem solving, and other higher level thought processing), atten- tion, working memory, episodic memory, language, percep- tion, and motor processes. Although some studies have shown evidence for a broad range of cognitive deficits across all cognitive domains assessed [1–12], other studies have provided evidence for limited cognitive impairment gener- ally restricted to deficits in the domain of executive function [13–18]. In a relatively large sample of 117 inpatients with chronic schizophrenia, Weickert et al. [19] showed that approximately 25% of the patients with schizophrenia had cognitive deficits across all domains assessed. In addition, approximately 50% of the patients from the same sample Schizophrenia has been consistently characterized by deficits in the cognitive domains of executive function, working memory, attention, and episodic memory. Although some cognitive abnormalities, such as motor slowing, may be associated with antipsychotic medication administration, generally the cognitive deficits shown by patients with schizophrenia can be attributed at least in part to the disease process. Modulation of the dopamine neurotransmitter system, notably through D2 receptor blockade, has been associated with psychotic symptom reduction and cognitive performance improvements in patients with schizophrenia. Although first-generation antipsychotic medication treatment initially was thought not to result in cognitive improvement, recent studies comparing second-generation antipsychotics to low doses of first-generation antipsychotic medication showed cognitive benefits for first-generation drugs, although perhaps not as great as that found after treatment with second-generation medication. Cognitive improvement associated with administration of antipsychotic medication may be a manifestation of improvement in general cortical information processing. Recent work has shown that specific genetic polymorphisms may interact with anti- psychotic medication treatment to influence the degree to which cognitive abilities display improvement after treatment. In particular, the catechol-O-methyltransferase val108/158met polymorphism has been shown to predict working memory improvement after administration of antipsychotic medication to patients with schizophrenia.