To the Editor: We agree with Dr. Waugaman that there is an increasing lack of familiarity with first-generation antipsychotics and that these agents can provide advantages to many patients, particularly pediatric patients. Indeed, this was the primary message of the TEOSS study. Unfortunately, there is very little evidence directly comparing the efficacy and tolerability of different antipsychotics with one another, particularly for the treatment of early-onset schizophrenia. At the time we designed the TEOSS study, there was considerable evidence from treatment studies of adults with schizophrenia that second-generation antipsychotics had greater efficacy than haloperidol and other first-generation antipsychotics used as active comparators. Haloperidol was the most frequently used first-generation antipsychotic in these studies, since it was generally thought to be the most efficacious. However, pilot work in early-onset psychosis (1) demonstrated that haloperidol caused significant weight gain in youths and raised the possibility that it was not as effective as risperidone or olanzapine. In designing the TEOSS study, we felt that it was essential that the first-generation antipsychotic comparator we chose provide some potential advantage over the newer agents. Given that children and adolescents are extremely vulnerable to antipsychotic-associated weight gain and its subsequent long-term health consequences, we chose molindone, which has minimal potential for causing weight gain, as noted by both Dr. Waugaman and a recent meta-analysis exploring molindone’s efficacy and adverse-event profile relative to other antipsychotics (2). Further, the limited empirical evidence available has suggested that molindone possesses an efficacy that is equivalent to other antipsychotics (3).

The TEOSS study emphasized the importance of comparative trials and variability in side-effect profiles. Without direct head-to-head comparisons of other mid-potency first-generation antipsychotics with various second-generation antipsychotics, it remains unknown whether any given antipsychotic offers clear advantage over others for the treatment of early-onset schizophrenia. More comparative trials are critically needed to help individuals with serious mental illness and to help those who care for them to make informed treatment decisions.

1.Sikich L, Hamer RM, Bashford RA, Sheitman BB, Lieberman JA: A pilot study of risperidone, olanzapine, and haloperidol in psychotic youth: a double-blind, randomized, 8-week trial. Neuropsychopharmacology 2004; 29:133–1452.Bagnall A, Fenton M, Kleignen J, Lewis R: Molindone for schizophrenia and severe mental illness. Cochrane Database Syst Rev 2007; (1):CD0020833.Bagnall A, Fenton M, Lewis R, Leitner ML, Kleignen J: Molindone for schizophrenia and severe mental illness. Cochrane Database Syst Rev 2000; (2):CD002083

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