The introduction of chlorpromazine a half century ago clearly revolutionized the treatment of schizophrenia and other psychotic disorders. Unfortunately, neither this drug nor other typical antipsychotic medications are uniformly or optimally effective in the treatment of individuals with schizophrenia. These agents do not reduce psychotic symptoms in all patients and have limited efficacy against other clinical features of the illness (e.g., negative symptoms and cognitive deficits). In addition, the different side effects associated with these medications have both contributed to problems with compliance and introduced additional sources of morbidity. The availability of atypical agents, such as clozapine, olanzapine, and risperidone, promised advantages in both efficacy and tolerance but raised very important questions, such as, 1) Which antipsychotic medication is best for a given profile of symptoms? and 2) Just how much advantage in treatment efficacy, especially for negative symptoms, do the newer atypical medications actually provide?
Clear answers to these questions have been difficult to obtain from the existing literature because the available studies evaluated only a subset of the medications of interest, used different experimental designs and outcome measures that hinder comparisons across studies, and examined primarily acutely ill subjects, making it difficult to determine whether clinical improvement reflected reductions in not only secondary but also primary negative symptoms. In addition, a number of the comparative studies that have been published were developed and sponsored by the pharmaceutical companies whose medications were being evaluated, raising concerns about potential sources of bias in experimental design or interpretation of outcomes.
The study by Volavka and colleagues published in this month’s issue of the Journal provides compelling new data that address these important issues. These investigators recruited 157 inpatients who had a diagnosis of chronic schizophrenia or schizoaffective disorder and a history of suboptimal treatment response to adequate duration and doses of one or more typical antipsychotics. The patients were randomly assigned to receive clozapine, olanzapine, risperidone, or haloperidol in a 14-week, double-blind trial. Total Positive and Negative Syndrome Scale scores were significantly improved for all three patient groups treated with atypical agents but were unchanged for the haloperidol-treated group. This finding would be expected for individuals who were selected for study because 1) they had not responded adequately to previous treatment with typical antipsychotics and 2) they had not failed previously to respond to treatment with atypical agents. When compared with haloperidol treatment (with conservative corrections for the performance of multiple statistical tests), only clozapine and olanzapine demonstrated statistically significant improvement in negative symptoms. In addition, none of the three atypical antipsychotics produced a statistically significant improvement in positive symptoms or general psychopathology compared with haloperidol.
In considering the significance of these findings, several aspects of this study are worthy of note. First, the importance of such double-blind direct comparisons of therapeutic agents is rivaled by the difficulties involved in conducting such studies. For example, achieving the optimal dose for each agent can be a major challenge; as noted by the authors, the dose of risperidone was probably too high, presenting one limitation to the study. In addition to the complexity involved and time required to conduct these types of studies, the staged introduction of new medications produces problems in making direct comparisons across medications. In the study by Volavka et al., the comparison of haloperidol, clozapine, and risperidone was designed and implemented before 1996, when olanzapine became available commercially. To enhance the relevance of their study to clinical practice, the investigators subsequently added an olanzapine treatment arm. However, the later addition of olanzapine-treated subjects meant that assignment to treatment with olanzapine was not completely random with the other three medications, creating the possibility of a cohort effect. This raises the question of whether subjects who entered the study later, and received olanzapine, were somehow different from the subjects who entered the study earlier, and received the other drugs, in a way that would account for any differential response (or lack thereof) to a given treatment. The authors have thoughtfully addressed this question and provide reasonable arguments for the absence of such a cohort effect, but they acknowledge that the possibility cannot be completely excluded.
Second, the study was supported by a grant from the National Institute of Mental Health (NIMH), contributions of medications from four pharmaceutical corporations, and supplemental funding for the olanzapine arm (equal to about 18% of the total cost of the project) from Eli Lilly and Company, the manufacturer of olanzapine. This arrangement, a realistic compromise that made possible the direct comparison of four drugs, nonetheless raises concerns about potential bias, given that olanzapine proved to be more effective than other drugs on some measures. However, in contrast to investigations that are initiated and controlled by industry, the authors had complete independence in the design, conduct, analysis, and interpretation of the study. In some ways, this study may represent a model approach for the support of clinical trials; that is, the study was designed and conducted by independent investigators, principally funded by the federal government, and supplemented by contributions from, but without undue influence by, the pharmaceutical industry. Indeed, such government/private collaborations for investigator-initiated research have been encouraged by NIMH.
Third, despite achieving statistical significance, the differences in efficacy across the medications examined in this study were, as noted by the authors, "modest and their clinical significance limited." Thus, the disappointingly small "added value" of atypical antipsychotics in this patient population clearly underscores the need for the identification of more effective treatments. In this regard, the study by Leucht et al. in this month’s Journal provides an informative lesson. These authors conducted a meta-analysis of amisulpride, an "atypical atypical" antipsychotic that has been used clinically in France for the past decade. Leucht et al. found that amisulpride was superior to typical antipsychotics in improving global symptoms and negative symptoms in acutely ill patients with schizophrenia and more effective than placebo (but not than typical antipsychotics) in patients with predominantly negative symptoms. However, as in the study by Volavka et al., the additional improvement provided by amisulpride was relatively small. For example, the mean effect size was 0.11 in acutely ill patients, indicating 11 percentage points more improvement in Brief Psychiatric Rating Scale total score with amisulpride than with typical antipsychotic medications.
In addition to clarifying the clinical efficacy of amisulpride, the findings of Leucht and colleagues are informative regarding the pharmacological basis for the "atypicality" of antipsychotic medications. Although it shares the clinical properties (e.g., reduced extrapyramidal symptoms at therapeutic doses) that characterize other atypical agents, amisulpride is unusual in that it lacks the combination of activity at dopamine D2 and serotonin 5-HT2 receptors that has been proposed to account for the efficacy and side effect profile of atypical antipsychotics (1). In contrast, amisulpride is a highly selective antagonist of dopamine D2/D3 receptors. Thus, the superiority of amisulpride in terms of clinical response and reduced extrapyramidal symptoms suggests that activity at the serotonin 5-HT2 receptor is not required for "atypicality." As a consequence, these findings may indirectly support the hypothesis of Kapur and Seeman (2), published last year in the Journal, that fast dissociation from the dopamine D2 receptor accounts for the distinctive features of atypical antipsychotic medications.
The findings of both studies in this month’s Journal may further enhance the ability of clinicians to make informed, evidence-based decisions regarding the antipsychotic medication that is most likely to be effective in individual patients. However, the modest differences in clinical efficacy of a given atypical medication relative to typical antipsychotics, and especially in comparison with other atypical antipsychotics, both warrant caution in the face of marketing claims of superiority for a given drug and underscore the continued need for the types of basic research that can contribute to the development of novel and more effective medications for the treatment of schizophrenia.
Address reprint requests to Dr. Lewis, Department of Psychiatry, University of Pittsburgh, 3811 O’Hara St., W1651 BST, Pittsburgh, PA 15213; firstname.lastname@example.org (e-mail).