Antipsychotic Study in Early-Onset Schizophrenia Really Begs a Different Study

Approximately one third of individuals with schizophrenia will develop so-called positive psychiatric symptoms (eg, auditory hallucinations, delusional thinking) before the age of 18 years. The prognosis of early-onset disease is typically poorer than that of adult-onset schizophrenia, and studies suggest that adults with earlier-onset symptoms are less responsive to first-generation antipsychotics (FGAs).

The rationale for using atypical, or second-generation, antipsychotics (SGAs) in teenage patients with schizophrenia is based primarily on adult data, given the efficacy of SGAs to reduce positive and negative psychiatric symptoms and the relatively lower risks of extrapyramidal side effects and irreversible tardive dyskinesia with SGAs. Of the few studies that have compared an SGA with an FGA in early-onset schizophrenia (EOS), most (if not all) have used haloperidol (Haldol) as the comparator FGA. These studies have also been of relatively brief duration (6-8 weeks).

Now come results of another short (8-week), double-blind study, which was funded by the NIMH and published online yesterday in the American Journal of Psychiatry. A total of 116 individuals with EOS or early-onset schizoaffective disorder (age range, 8-19 years) received at least one dose of randomly assigned olanzapine (Eli Lilly's Zyprexa—the biggest weight-gain and metabolic offender of the SGAs); risperidone (JNJ's Risperdal—another SGA with a not-inconsequential risk of weight gain); or the FGA molindone (Moban—which has been associated with weight loss in adults; see Allison DB et al. Am J Psychiatry. 1999;156:1686-1696). Molindone was administered with benztropine 1 mg/d, to reduce the risk of FGA-associated extrapyramidal effects.

On the basis of the Clinical Global Impression (CGI) scale and the Positive and Negative Syndrome Scale (PANSS), psychiatric improvement was noted in 50%, 46%, and 34% of molindone-, risperidone-, and olanzapine-treated children, respectively, at 8 weeks. These improvement rates were not statistically significantly different. However, responses were seen earlier (at 2 weeks) with olanzapine and risperidone than with molindone (at 3 weeks).

Subjects receiving olanzapine or risperidone, not surprisingly, experienced significant weight gain, while those taking molindone did not gain weight. In addition, olanzapine-treated patients demonstrated significantly increased fasting levels of cholesterol, LDL, insulin, and hepatic transaminases.

Given that these study results are not particularly surprising (see another EOS study of olanzapine, risperidone, and haloperidol by the same lead author, Sikich, for example), a more useful study would have compared an FGA with SGAs that are less likely to be associated with significant weight gain (eg, aripiprazole [Abilify*; BMS]). Also longer-term studies are warranted in EOS to evaluate, not only the risk of FGA-associated movement disorders, but also sexual maturity in the setting of antipsychotic-induced hyperprolactinemia.

Randomish side note: Katrina Megget, over at PharmaTimes, reported that shares of Eli Lilly and JNJ dropped more than 1% yesterday on the news of the NIMH study results—which is relatively terrific, because THE DOW DROPPED BELOW ELEVEN-FREAKING-THOUSAND yesterday, Katrina.

* Which has to be one of the dumbest drug trade names ever. Think George W. Bush saying, "We're going to abilify our troops in Iraq."