Pharmacologic Treatment of Schizophrenia John M Kane The pharmacologic treatment of schizophrenia remains a critical component in the short and long term management of this disease Considerable progress has been made in delineating different domains of this illness ranging from positive and negative symptoms to cognitive dysfunction and psychosocial vulnerabilities Increasingly treatments are being studied in relation to a variety of different outcome measures with functional ability and quality of life achieving appropriate emphasis The introduction of a new generation of antipsychotic drugs has helped to raise optimism and expectations Overall second generation drugs do provide clear advantages in terms of reducing adverse effects particularly drug induced Parkinsonism akathesia and hopefully tardive dyskinesia Advantages in alleviating refractory symptoms negative symptoms depression and suicidal behavior are found in some reports however much remains to be done methodologically in establishing the relative merits of specific drugs in the multiple domains of interest Biol Psychiatry 1999 46 1396 1408 1999 Society of Biological Psychiatry Key Words Schizophrenia treatment psychopharmacology antipsychotic medication Introduction T he modern age of pharmacologic treatment of schizophrenia began in the mid 1950s with the development of chlorpromazine Subsequent to that development a number of different chemical classes of antipsychotic drugs were introduced into clinical practice Over the next three decades considerable progress was made in several areas which influenced subsequent development and utilization of antipsychotic drugs as well the over all care of patients suffering from schizophrenia The observations that antipsychotic drugs were associated with a variety of neurologic side effects most commonly drug induced Parkinsonism but also tardive dyskinesia and tardive dystonia helped contribute support From the Department of Psychiatry Hillside Hospital Division of Long Island Jewish Medical Center Glen Oaks New York and Department of Psychiatry and Neuroscience Albert Einstein College of Medicine Bronx New York Address reprint requests to John M Kane MD Hillside Hospital 75 59 263rd Street Glen Oaks NY 11004 Received October 12 1998 revised February 17 1999 accepted March 5 1999 1999 Society of Biological Psychiatry for a dopamine hypothesis of antipsychotic drug activity and in turn a dopamine hypothesis of schizophrenia At the same time further developments in establishing the validity and reliability of psychiatric diagnosis resulted in a narrowing of the diagnosis of schizophrenia and to some extent a reevaluation of drug efficacy in more selectively defined patient populations It took many years after the introduction of antipsychotics to begin to establish the role of these medications in long term treatment with the intention initially of reducing rates of relapse and rehospitalization Even after relevant studies began to be conducted very few lasted more than 1 year and they tended to involve multi episode or chronically ill patients At the same time that more and more data emerged supporting the value of maintenance treatment Davis 1975 increasing knowledge and concern was developing regarding the long term risks associated with antipsychotic drug treatment Kane and Smith 1982 Not surprisingly outcome measures in clinical trials of antipsychotic drugs initially tended to focus more on positive symptoms than negative symptoms Positive symptoms were more likely to be associated with disruptive or troublesome behavior more likely to result in hospitalization the focus for most initial clinical trials of drug efficacy and to some extent were felt to be easier to measure With this background for the first two decades of widespread clinical use of antipsychotic medication it was generally accepted that among available agents there were no significant differences in clinical efficacy In 100 comparisons of different conventional antipsychotic drugs only one study reported a significant difference Klein and Davis 1969 Janicak et al 1993 This result did not necessarily mean that an individual patient was equally likely to respond to any drug but rather in group comparisons similar proportions of patients responded regardless of which drug was involved The notion that if a particular patient did not respond to one drug then he or she might respond to another was widely assumed however as we will discuss below rarely tested The discovery that enormous variations in bioavailability and metabolism occurred with these drugs led to renewed hope that outcome could be improved substantially by measuring blood levels following the develop0006 3223 99 20 00 PII S0006 3223 99 00059 1 Pharmacologic Treatment of Schizophrenia ment of steady state and adjusting them up or down accordingly Kane et al 1976 Despite a fairly extensive literature suggesting relationships between blood levels and clinical response very few studies confirmed the value of these measures by subsequently manipulating blood levels into a putative therapeutic range under controlled conditions and demonstrating a clinically and statistically significant effect Volavka et al 1992 The reality is that blood levels have not come to be used routinely as a reliable and valued guide to clinical management Whether this is the consequence of lack of knowledge transfer impediments related to cost and feasibility or an insufficiently compelling data base could be debated Another important development in the pharmacologic treatment of schizophrenia was the introduction of longacting injectable depot medications Compliance in oral medication taking over long periods of time is an enormous problem Kane 1985 Initially the mirror image and controlled trials with these medications led to considerable enthusiasm regarding their potential to improve long term outcomes by reducing rates of relapse and rehospitalization Interestingly a number of trials comparing oral and depot medication were not successful in demonstrating as significant a reduction in rates of relapse as expected Glazer and Kane 1992 We have argued elsewhere Kane and Borenstein 1985 that to some extent this is likely a result of the methodology employed in these trials Specifically relatively compliant patients were selected given the nature of the study design double blind oral and depot drug frequent assessments need for consent etc Perhaps most importantly almost