To the Editor: Recent studies demonstrate relatively small differences in efficacy among most antipsychotics. Leucht and colleagues (1) recently concluded "because the second-generation antipsychotic drugs differ in many respects, including efficacy, side-effects, cost (some are now generic), and pharmacology …, they do not form a homogenous class and neither do first-generation drugs." Among antipsychotics, differences in efficacy are greatly outweighed by different propensities to cause side effects, such as metabolic effects (weight gain, hyperlipidemia, hyperglycemia, and diabetes), extrapyramidal symptoms and tardive dyskinesia, sedation, and hyperprolactinemia. In view of this, classifying antipsychotic medications according to the likelihood of patients' developing certain side effects may be more useful to clinicians than current classifications.
Metabolic effects appear to be the most frequently occurring antipsychotic side effect likely to cause substantial harm. Metabolic syndrome is more prevalent among patients with schizophrenia than in the general population (2). Use of both first- and second-generation antipsychotics has been associated with weight gain and with increased risk of diabetes (3).
We propose an alternate classification for antipsychotic drugs based on metabolic risk. On the basis of the work of Allison and colleagues (4) and Leucht and colleagues (1), we suggest that "higher metabolic risk" (HMR) antipsychotic medications include clozapine, olanzapine, thioridazine or mesoridazine, sertindole, risperidone, quetiapine, and by extension, other low-potency older antipsychotics. "Lower metabolic risk" (LMR) antipsychotic medications would include molindone, ziprasidone, fluphenazine, haloperidol, aripiprazole, and by extension, other high- and middle-potency older antipsychotics.
Other kinds of side effects, such as neurological effects, might be considered. In this case, all antipsychotic drugs, except possibly clozapine, can cause extrapyramidal symptoms and tardive dyskinesia—risks that depend as much on dosage and duration of treatment as they do on choice of medication. The risk of QTc prolongation might be considered, but it is relatively rare, and the risk of sudden cardiac death has been shown to be distributed more or less evenly among all antipsychotic drugs (5). We believe that using metabolic risk captures the primary set of choices a clinician and patient need to make in selecting a specific antipsychotic medication.
Treatment with antipsychotic medications must be individualized. Although differences in efficacy are important, they may legitimately be outweighed by the patient's previous positive response to a drug and the risks that probable side effects pose to the patient's overall health. Our proposed categorization would help draw the attention of clinicians to this very important risk.
The authors are affiliated with Care Management Technologies, White Plains, New York. Dr. Carmel is also with the Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina.
The authors report no competing interests.
Leucht S, Corves C, Arbter D, et al: Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 373:31–41, 2009
McEvoy JP, Meyer JM, Goff DC: Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES IIII. Schizophrenia Research 80:19–32, 2005
Dixon L, Weiden P, Delahanty J, et al: Prevalence and correlates of diabetes in national schizophrenia samples. Schizophrenia Bulletin 26:903–912, 2000
Allison DB, Mentore JL, Heo M, et al: Antipsychotic-induced weight gain: a comprehensive research synthesis. American Journal of Psychiatry 156:1686–1696, 1999
Ray WA, Chung CP, Murray KT, et al: Atypical antipsychotic drugs and the risk of sudden cardiac death. New England Journal of Medicine 360:225–235, 2009