Double-blind comparison of first- and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: findings from the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study

Abstract

Objective: Atypical (second-generation) antipsychotics are considered standard treatment for children and adolescents with early-onset schizophrenia and schizoaffective disorder. However, the superiority of second-generation antipsychotics over first-generation antipsychotics has not been demonstrated. This study compared the efficacy and safety of two second-generation antipsychotics (olanzapine and risperidone) with a first-generation antipsychotic (molindone) in the treatment of early-onset schizophrenia and schizoaffective disorder.

Method: This double-blind multisite trial randomly assigned pediatric patients with early-onset schizophrenia and schizoaffective disorder to treatment with either olanzapine (2.5-20 mg/day), risperidone (0.5-6 mg/day), or molindone (10-140 mg/day, plus 1 mg/day of benztropine) for 8 weeks. The primary outcome was response to treatment, defined as a Clinical Global Impression (CGI) improvement score of 1 or 2 and >or=20% reduction in Positive and Negative Syndrome Scale (PANSS) total score after 8 weeks of treatment.

Results: In total, 119 youth were randomly assigned to treatment. Of these subjects, 116 received at least one dose of treatment and thus were available for analysis. No significant differences were found among treatment groups in response rates (molindone: 50%; olanzapine: 34%; risperidone: 46%) or magnitude of symptom reduction. Olanzapine and risperidone were associated with significantly greater weight gain. Olanzapine showed the greatest risk of weight gain and significant increases in fasting cholesterol, low density lipoprotein, insulin, and liver transaminase levels. Molindone led to more self-reports of akathisia.

Conclusions: Risperidone and olanzapine did not demonstrate superior efficacy over molindone for treating early-onset schizophrenia and schizoaffective disorder. Adverse effects were frequent but differed among medications. The results question the nearly exclusive use of second-generation antipsychotics to treat early-onset schizophrenia and schizoaffective disorder. The safety findings related to weight gain and metabolic problems raise important public health concerns, given the widespread use of second-generation antipsychotics in youth for nonpsychotic disorders.

Trial registration: ClinicalTrials.gov NCT00053703.

Figure 1. Enrollment and Outcomes

The majority of those who expressed interest in the study but did not enroll did not meet inclusion or exclusion criteria because of diagnosis, prior treatment exposure or age. The primary adverse event leading to withdrawal from the study is listed, however often subjects who withdrew experienced multiple adverse effects.

Figure 2. Time Course of Key Outcomes

Figure 2a shows the proportion of each group continuing to take the randomized medication during each week of the trial is shown. Figure 2b presents the mean PANSS total score of observed cases during each week of the trial. The number of subjects in each treatment group with PANSS assessments at the given timepoint is shown below the X axis. The minimal possible score on the PANSS is 30; scores above 60 are typically viewed as problematic.

Figure 3. Adverse Effects Observed with Antipsychotic Treatment

Figure 3a presents each individual participant’s BMI percentile change to demonstrate the variability of changes within each treatment. Children continuing on their growth trajectory would be expected to show no change in BMI percentile. The mean BMI percentile change in the molindone group was -2.3 (8.0), in the olanzapine group 10.8 (14.4), and in the risperidone group 6.8 (10.3), which were statistically different between groups at the p<0.0001 level. Figure 3 focuses on weight changes and metabolic adverse effects. The significance of three way comparisons is shown above the observed values in the category. Significant pairwise comparisons are represented just above the category labels with “O” representing olanzapine, “R” representing risperidone, and “M” representing molindone. Only participants with paired fasting laboratory values of the lipids and insulin were included in the analysis. BMI is body mass index, Tot Chol is total cholesterol, LDL is low density lipoprotein cholesterol, TRIG is triglycerides, AST is aspartate aminotransferase, ALT is alanine aminotransferase. Figure 3c focuses on neurologic adverse effects. All youth on molindone received 1mg/day benztropine in addition to any added benztropine. Simpson Angus scores reflect Parkinsonian symptoms and dystonia. Akathisia ratings are from item 4 of the Barnes Akathisia Scale. Tardive Dyskinesia (TD) is assessed with the AIMS. AIMS ratings of 2 or above indicate at least two questionable movements.