Review of the Safety of Second-Generation Antipsychotics: Are They Really “Atypically” Safe for Youth and Adults?

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Objective: There is general consensus that second-generation antipsychotics are at least as effective as and more tolerable than first-generation antipsychotics. We address questions of safety and tolerability in both the short-term and long-term use of these medications by reviewing the existing literature in youth and adults.

Data Sources: A MEDLINE search was conducted via PubMed using the following keywords (in various combinations): typical antipsychotics, atypical antipsychotics, children, adolescents, side effects, weight gain, diabetes, metformin, metabolic syndrome, and CATIE. Only English-language articles published from 2000–2010 were included. The bibliographies of papers identified through MEDLINE searches were also reviewed.

Results: Six adult studies were analyzed in detail. A summary of the data suggests that there may be a lower association of weight gain and diabetes with ziprasidone, aripiprazole, and haloperidol, while olanzapine, clozapine, quetiapine, and risperidone appear to be more highly associated. There may be less difference than originally thought concerning frequency of extrapyramidal side effects among these medications. All of these antipsychotics, including perphenazine, are similarly efficacious in treating psychosis, with the exception of clozapine, which demonstrates significantly more effectiveness. Although the studies on youth tend to be small (few subjects with large age ranges of 4 to 19 years) and short term in comparison to the adult studies, the data reviewed from 5 studies suggest that, in youth, olanzapine may be associated with the greatest weight gain, extrapyramidal side effects and metabolic changes are quite prevalent, and the antipsychotics studied seem to be similarly effective.

Conclusions: Considering effectiveness, safety, and tolerability, this literature review suggests that in adults there may be a lower association of weight gain and diabetes with ziprasidone, aripiprazole, and haloperidol as compared with olanzapine, clozapine, quetiapine, and risperidone. Youth may be particularly sensitive to weight gain, especially with olanzapine, as well as extrapyramidal side effects and metabolic changes. The literature suggests similar effectiveness among the antipsychotics, perhaps with the exception of clozapine having greater effectiveness, at least in adults.

Prim Care Companion CNS Disord 2012;14(3):doi:10.4088/PCC.11r01298

Submitted: September 9, 2011; accepted January 17, 2012.

Published online: June 7, 2012.

Corresponding author: John J. Briles, MD, Henry Ford Health System, Clinton Oaks, 42633 Garfield, Ste #314, Clinton Township, MI 48038 (

Prim Care Companion CNS Disord 2012;14(3):doi:10.4088/PCC.11r01298