CYP2D6 Genotyping and Antipsychotic-Associated Extrapyramidal Adverse Effects in a Randomized Trial of Aripiprazole Versus Quetiapine Extended Release in Children and Adolescents, Aged 12-17 Years, With First Episode Psychosis.

PURPOSE/BACKGROUND: The aim of this study was to examine the association between genetically predicted CYP2D6 phenotypes and extrapyramidal symptoms (EPSs). METHODS/PROCEDURES: Data from the Tolerability and Efficacy of Antipsychotics trial of adolescents with first-episode psychosis randomized to aripiprazole versus quetiapine extended release were studied. Extrapyramidal symptom assessments included the Simpson-Angus Scale and the Barnes Akathisia Rating Scale. Patients were CYP2D6 genotyped. Plasma concentrations of antipsychotics and antidepressants were analyzed. FINDINGS/RESULTS: One hundred thirteen youths (age, 12-17 years; males, 30%; antipsychotic naive, 51%) were enrolled. Poor metabolizers had a significantly higher dose-adjusted aripiprazole plasma concentration (±SD) compared with normal metabolizers at week 4 (24.30 ± 6.40 ng/mL per milligram vs 14.85 ± 6.15 ng/mL per milligram; P = 0.019), but not at week 12 (22.15 ± 11.04 ng/mL per milligram vs 14.32 ± 4.52 ng/mL per milligram; P = 0.067). This association was not found in the quetiapine extended release group. No association between CYP2D6 genotype groups and global Barnes Akathisia Rating Scale score or Simpson-Angus Scale score was found in any of the treatment arms. IMPLICATIONS/CONCLUSIONS: Our results do not support routine use of CYP2D6 testing as a predictor of drug-induced parkinsonism or akathisia risk in clinical settings. Further studies with larger samples of CYP2D6 poor metabolizers are needed.

Early Antipsychotic Nonresponse as a Predictor of Nonresponse and Nonremission in Adolescents With Psychosis Treated With Aripiprazole or Quetiapine: Results From the TEA Trial.

OBJECTIVE: To evaluate 1) whether early nonresponse to antipsychotics predicts nonresponse and nonremission, 2) patient and illness characteristics as outcome predictors, and 3) response prediction of 30-item Positive and Negative Syndrome Scale (PANSS-30) compared with 6-item PANSS (PANSS-6) and Clinical Global Impressions-Improvement Scale (CGI-I) in youths with first-episode psychosis. METHOD: Post hoc analysis from a 12-week, double-blinded, randomized trial of aripiprazole vs extended-release quetiapine in adolescents (age 12-17 years) with first-episode psychosis was performed. Early nonresponse (week 2 or week 4) was defined as <20% symptom reduction (PANSS-30) (or <20% symptom reduction [PANSS-6] or CGI-I score 4-7 [less than "minimally improved"]). Nonresponse (week 12) was defined as <50% symptom reduction (PANSS-30). Nonremission (week 12) was defined as a score of >3 on 8 selected PANSS-items. Positive/negative predictive values (PPV/NPV) and receiver operating characteristics, binary logistic regression models, and PPV/NPV using PANSS-6 and CGI-I were analyzed. RESULTS: Of 113 randomized patients, 84 were included in post hoc analysis (mean [SD] age = 15.7 [1.3] years; 28.6% male). The 12-week symptom decrease was 31.9% [27.9%], most pronounced within the first 2 weeks (61.1% of total PANSS reduction). Response (27.4%) and remission (22.6%) rates were low. Results indicated that early nonresponse reliably predicted 12-week nonresponse (PPV: week 2, 82.2%; week 4, 90.0%) and nonremission (PPV: week 2, 80.0%; week 4, 90.0%); early nonresponse at week 4 was a statistically significant baseline predictor for 12-week nonresponse; and PANSS-6 had similar predictive significance as PANSS-30. However, outcomes were heterogeneous using CGI-I. CONCLUSION: In youths with first-episode psychosis showing early nonresponse to aripiprazole or extended-release quetiapine, switching antipsychotic drug should be considered. PANSS-6 is a feasible and clinically relevant alternative to PANSS-30 to predict 12-week nonresponse/nonremission. CLINICAL TRIAL REGISTRATION INFORMATION: Tolerance and Effect of Antipsychotics in Children and Adolescents With Psychosis; https://www. CLINICALTRIALS: gov/; NCT01119014.

Cardiometabolic Adverse Effects and Its Predictors in Children and Adolescents With First-Episode Psychosis During Treatment With Quetiapine-Extended Release Versus Aripiprazole: 12-Week Results From the Tolerance and Effect of Antipsychotics in Children and Adolescents With Psychosis (TEA) Trial.

OBJECTIVE: To investigate cardiometabolic effects and their predictors in youths with first-episode psychosis (FEP) treated with quetiapine-extended release (ER) versus aripiprazole. METHOD: Youths with FEP who were 12 to 17 years of age were randomized to quetiapine-ER or aripiprazole in the 12-week, double-blinded, Tolerability and Efficacy of Antipsychotics (TEA) trial. Primary outcome was change in body weight; secondary outcomes were changes in body mass index (BMI) and waist circumference (WC), blood pressure (BP), heart rate, and lipid and glucose metabolism parameters. Possible predictors of cardiometabolic changes were examined. RESULTS: Altogether, 113 patients (schizophrenia-spectrum disorders = 93%; age [mean ± SD] = 15.7 ± 1.4 years; male participants = 30.1%) were randomized to quetiapine-ER (n = 55) or aripiprazole (n = 58). Quetiapine-ER led to significant increases in body weight (4.88 kg, 95% CI = 3.92-5.83, p < .0001), BMI z-score (0.43, 95% CI = 0.33-0.53, p < .0001), and WC z-score (0.97, CI = 0.7-1.23, p < .0001). Changes were significantly smaller with aripiprazole (all between-group p values <.0001): body weight: 1.97 kg (CI = 0.97-2.97, p = .0001), BMI z-score: 0.10 (CI = -0.01 to 0.20, p = .0646), and WC z-score: 0.18 (CI = -0.09 to 0.45, p = .1968). Lipid and glucose metabolism parameters increased significantly at week 4 and week 12 only with quetiapine-ER (p range = 0.0001-0.037). Quetiapine-ER was associated with an increased occurrence of obesity, elevated blood lipids and hyperinsulinemia (p range = 0.004-0.039). Early weight gain, obesity, or type 2 diabetes in the family significantly predicted weight and BMI gain at week 12. CONCLUSION: In youths with FEP, quetiapine-ER was associated with significantly greater weight gain and adverse changes in metabolic outcomes than was aripiprazole. Early weight gain must be addressed and family lifestyle factors taken into consideration when treating youths with antipsychotics. CLINICAL TRIAL REGISTRATION INFORMATION: Tolerance and Effect of Antipsychotics in Children and Adolescents With Psychosis (TEA); https://clinicaltrials.gov; NCT01119014.