Background: Antipsychotic-related weight gain is a common clinically relevant side effect when treating psychotic disorders in pediatric populations, yet few predictors and no moderators of antipsychotic-related weight gain are known. Methods: The Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS) study randomized 119 youths (age 8-19 years) with schizophrenia or schizoaffective disorder to 8 weeks of antipsychotic treatment with molindone, risperidone, or olanzapine and assessed treatment response and side effects. In this secondary analysis, we used multivariable linear regression and receiver operating characteristic analysis to investigate predictors and moderators of weight change and percent weight change from baseline to week 8. Results: Treatment assignment was the most discriminant predictor of weight change [F(2, 66)=17.00, p<0.001] and percent weight change [F(2, 66)=16.85, p<0.001]. Mean weight gain was 0.74 (standard deviation 3.51) kg for molindone, 4.13 +/- 3.79kg for risperidone, and 7.29 +/- 3.44kg for olanzapine. After adjusting for treatment assignment, lower pretreatment hemoglobin A1C (HgbA1C) predicted more weight gain [F(1, 55)=4.71, p=0.03]. Diagnosis (schizoaffective vs. schizophrenia) moderated weight change [F(2, 63)=6.02, p=0.004] and percent weight change [F(2, 63)=5.26, p=0.008] such that schizoaffective diagnosis predicted larger weight gain for youths in the risperidone treatment arm. Age, sex, family income, baseline weight, and symptoms neither predicted nor moderated weight change or percent weight change. Conclusion: We identified prognostic subgroups and novel risk factors for antipsychotic-related weight gain. We confirmed that antipsychotic choice is extremely important for predicting future weight gain. We also found that younger age did not predict greater weight gain, in contrast to prior studies. Our findings require replication in an independent sample because we did not adjust for multiple comparisons to minimize false negatives. ClinicalTrials.gov Identifier: NCT00053703

Background: Antipsychotic-induced metabolic dysfunction is problematic in youths with psychosis. We used limited-access data from the NIH-funded Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS) study to identify risk factors for neuroleptic-associated metabolic dysfunction. Methods: TEOSS randomized 119 youths with schizophrenia and schizoaffective disorder to 8 weeks of treatment with olanzapine, risperidone or molindone and monitored their response to medication as well as metabolic side effects throughout the trial. TEOSS demonstrated no differences in response rates by antipsychotic agent. In this secondary analysis we used stepwise linear regression and receiver operating characteristics (ROC) to identify baseline predictors associated with changes in weight, fasting glucose, fasting insulin and total cholesterol at week 8 in TEOSS. Results: Randomized assignment to olanzapine (parameter estimate (PE) = 2.88, SE = 1.08, P = .01) and living at home (vs institutionalization) (PE = 2.62, SE = 1.08, P = .02) associated with increased weight gain. Randomized assignment to molindone (PE = −3.45, SE = 0.97, P = .0007) associated with less weight gain. Greater increase in fasting glucose levels associated with randomization to olanzapine (PE = 18.56, SE = 7.33, P = .01) and the absence of a family history of depression (PE = −6.40, SE = 2.82, P = .03). Greater increase in fasting insulin levels associated with randomization to olanzapine (PE = 17.05, SE = 6.39, P = .01), greater number of past psychiatric hospitalizations (PE = 11.81, SE = 2.54, P < .0001), not taking an antipsychotic prior to study entry (PE = −20.35, SE = 6.50, P = .003) and the absence of a family history of depression (PE=−5.33, SE = 2.46, P = .03). Randomization to olanzapine (PE = 26.78, SE = 6.02, P < .0001), congenital heart disease (PE = 45.61, SE = 13.29, P = .0009) and legal difficulties (arrests) (PE= 17.39, SE = 7.64, P = .03) predicted greater increase in cholesterol levels. ROC analysis identified randomization to olanzapine as the most discriminative predictor of >4 kg weight gain. Conclusion: This data-driven moderator analysis confirms secondary findings of the original TEOSS study that demonstrated that metabolic outcomes, particularly weight gain is strongly determined by choice of antipsychotic agent with poor metabolic outcomes associated with olanzapine (weight, glucose, insulin and cholesterol) and better metabolic outcome associated with molindone (weight). Data-driven analysis demonstrated several other predictors of metabolic outcomes that are worthy of further replication. This research was funded by the American Academy of Child and Adolescent Psychiatry Pilot Award.

The Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS) compared the efficacy of risperidone, olanzapine, and molindone over 8 weeks in 119 youths age 8-19 years with early-onset schizophrenia or schizoaffective disorder. From this large dataset, we examined predictors of treatment response and drop out using stepwise regression and receiver operating characteristics curve (ROC) analysis. Treatment response was defined as having both a ≥ 20% improvement in Positive and Negative Syndrome Scale (PANSS) score and a Clinical Global Impression-Improvement (CGI-I) score < 3. More severe baseline symptoms, having a history of being in an early education program, and previous prescription of a mood stabilizer increased the likelihood of responding to treatment. Anhedonia and poor community functioning predicted a reduction in symptom severity on the PANSS. Random assignment to different antipsychotic treatment was not predictive of outcome. Parental report of aggressive behaviors at baseline and being African American were associated with a greater likelihood of drop out. Our results suggest youth with more severe psychotic symptoms are most likely to benefit from treatment with antipsychotics and that aggressive youth may require additional support to improve treatment adherence. Further investigation is needed to understand potentially modifiable predictors of response like early education programs.

Many patients with social anxiety disorder (SAD) experience inadequate symptom relief from available treatments. Ketamine is a potent N-methyl-D-aspartate receptor antagonist with a potentially novel mechanism of action for the treatment of anxiety disorders. Therefore, we conducted a double-blind, randomized, placebo-controlled crossover trial in 18 adults with DSM-5 SAD and compared the effects between intravenous ketamine (0.5 mg/kg over 40 min) and placebo (normal saline) on social phobia symptoms. Ketamine and placebo infusions were administered in a random order with a 28-day washout period between infusions. Ratings of anxiety were assessed 3-h post-infusion and followed for 14 days. We used linear mixed models to assess the impact of ketamine and placebo on anxiety symptoms. Outcomes were blinded ratings on the Liebowitz Social Anxiety Scale (LSAS) and self-reported anxiety on a visual analog scale (VAS-Anxiety). We also used the Wilcoxon signed-rank test to compare the proportion of treatment responders. Based on prior studies, we defined response as a greater than 35% LSAS reduction and 50% VAS-Anxiety reduction. We found ketamine resulted in a significantly greater reduction in anxiety relative to placebo on the LSAS (Time × Treatment: F9,115=2.6, p=0.01) but not the VAS-Anxiety (Time × Treatment: F10,141=0.4, p=0.95). Participants were significantly more likely to exhibit a treatment response after ketamine infusion relative to placebo in the first 2 weeks following infusion measured on the LSAS (33.33% response ketamine vs 0% response placebo, Wilcoxon signed-rank test z=2.24, p=0.025) and VAS (88.89% response ketamine vs 52.94% response placebo, Wilcoxon signed-rank test z=2.12, p=0.034). In conclusion, this proof-of-concept trial provides initial evidence that ketamine may be effective in reducing anxiety.