Letter

Classifying Antipsychotics by Likelihood of Metabolic Side-Effects

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.

Acknowledgments and disclosures

The authors report no competing interests.