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.

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.

Differential effects of age at illness onset on verbal memory functions in antipsychotic-naïve schizophrenia patients aged 12-43 years.

BACKGROUND: The typical onset of schizophrenia coincides with the maturational peak in cognition; however, for a significant proportion of patients the onset is before age 18 and after age 30 years. While cognitive deficits are considered core features of schizophrenia, few studies have directly examined the impact of age of illness onset on cognition. METHODS: The aim of the study was to examine if the effects of age on cognition differ between healthy controls (HCs) and patients with schizophrenia at illness onset. We examined 156 first-episode antipsychotic-naïve patients across a wide age span (12-43 years), and 161 age- and sex-matched HCs. Diagnoses were made according to ICD-10 criteria. Cognition was assessed using the Brief Assessment of Cognition in Schizophrenia (BACS), and IQ was estimated using subtests from the Wechsler adult- or child-intelligence scales. Multivariate analysis of covariance (MANCOVA) was used to examine linear and quadratic effects of age on cognitive scores and interactions by group, including sex and parental socioeconomic status as covariates. RESULTS: There was a significant overall effect of age on BACS and IQ (p < 0.001). Significant group-by-age interactions for verbal memory (for age-squared, p = 0.009), and digit sequencing (for age, p = 0.01; age-squared, p < 0.001), indicated differential age-related trajectories between patients and HCs. CONCLUSIONS: Cognitive functions showing protracted maturation into adulthood, such as verbal memory and verbal working memory, may be particularly impaired in both early- and late-schizophrenia onset. Our findings indicate a potential interaction between the timing of neurodevelopmental maturation and a possible premature age effect in late-onset schizophrenia.

Measuring movements in adolescents with psychosis using the Microsoft Kinect sensor: a pilot study exploring a new tool for assessing aspects of antipsychotic-induced parkinsonism.

BACKGROUND: The assessment of motor disturbances in antipsychotic-treated adolescent patients is often limited to the use of observer-based rating scales with interobserver variability. The objectives of this pilot study were to measure movement patterns associated with antipsychotic-induced parkinsonism in young patients with psychosis and initiating/treated with antipsychotics, using a computer application connected with the Microsoft Kinect sensor (Motorgame). METHOD: All participants were assessed by neurological examination, clinical side effect rating scales (Udvalg for Kliniske Undersøgelser Side Effect Rating Scale, Barnes Akathisia Rating Scale, Simpson Angus Scale (SAS), and Abnormal Involuntary Movement Scale), and the Motorgame. Furthermore, speed of information processing and motor speed with subtests from the Brief Assessment of Cognition in Schizophrenia test battery was assessed. RESULTS: We included 21 adolescents with first-episode psychosis (62% treated with antipsychotics; males 38%; mean age 16 ± 1.4 years) and 69 healthy controls (males 36%; mean age 16 ± 1.5 years). Prolonged time of motor performance (TOMP) in the Motorgame was associated with higher SAS scores for arm dropping (p = .009). A consistent practice effect was detected (p < .001). We found no significant associations between TOMP and age, height, body weight, sex, antipsychotic dosage, or information processing speed. CONCLUSIONS: We found an uncorrected significant association between prolonged TOMP and shoulder bradykinesia. The Motorgame was found useful in assessing parkinsonian symptoms in early-onset psychosis and accepted by participants. Future studies of larger cohorts, including patients with high scores in clinical motor side effect scales, are required to establish solid validity of the novel test.

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.

Change and dispersion of QT interval during treatment with quetiapine extended release versus aripiprazole in children and adolescents with first-episode psychosis: results from the TEA trial.

OBJECTIVE: The aim of this study was to compare the effect of quetiapine extended release (ER) versus aripiprazole on corrected QT interval (QTc) and QT dispersion (QTd) in youths with first-episode psychosis. METHODS: Youths 12-17 years were randomized to quetiapine ER (daily dose range = 50 to 800 mg) or aripiprazole (daily dose range = 2.5 to 30 mg) in a 12-week double-blinded trial and examined at weeks 0, 4, and 12. Primary outcome was QTc change using Hodges formula (QTcH); secondary outcomes included QTcH > 450 ms, QTcH > 500 ms, QTcH change > 60 ms, QTd, and heart rate (HR). RESULTS: Among 113 randomized youths, follow-up ECG was available for 93 patients (82.3%) (age = 15.8 ± 1.3 years, males = 34.4%, schizophrenia = 67.7%). Quetiapine ER treatment (n = 47) was associated with a significant increase in QTcH of + 6.8 ± 20.2 ms (p = 0.025), while the change from baseline in patients receiving aripiprazole (n = 46) was non-significant (- 3.4 ± 18.9 ms, p = 0.225). One patient in the quetiapine ER group had a QTcH change of + 62.3 ms. Age, sex, smoking, body mass index, and concomitant medication were not significantly associated with QTcH change, but higher baseline potassium was correlated to higher QTcH change in the quetiapine ER group. The HR increased significantly with quetiapine ER (+ 11.0 ± 14.2 bpm, p < 0.001) but not with aripiprazole (- 0.8 ± 12.0 bpm, p = 0.643). QTd did not significantly change with quetiapine ER or aripiprazole. CONCLUSION: QTcH and HR increased significantly with quetiapine ER, although changes were small and likely not clinically significant in otherwise healthy patients. QTcH and HR were unchanged with aripiprazole. No significant change in QTd was seen. ClinicalTrials.gov: NCT01119014, EudraCT: 2009-016715-38.

Quetiapine extended release versus aripiprazole in children and adolescents with first-episode psychosis: the multicentre, double-blind, randomised tolerability and efficacy of antipsychotics (TEA) trial.

BACKGROUND: Head-to-head trials to guide antipsychotic treatment choices for paediatric psychosis are urgently needed because extrapolations from adult studies might not be implementable. In this superiority trial with two-sided significance testing, we aimed to compare the efficacy and safety of quetiapine-extended release (quetiapine-ER) versus aripiprazole in children and adolescents with first-episode psychosis, to determine whether differences between the two treatments were sufficient to guide clinicians in their choice of one drug over the other. METHODS: In this multicentre, double-blind, randomised trial in seven Danish university clinics, we recruited children and adolescents aged 12-17 years with a diagnosis of ICD-10 schizophrenia-spectrum disorder, delusional disorder, or affective-spectrum psychotic disorder, and psychotic symptoms scoring at least 4 on at least one of the following Positive and Negative Syndrome Scale (PANSS) items: P1 (delusions), P2 (conceptual disorganisation), P3 (hallucinations), P5 (grandiosity), P6 (suspiciousness/persecution), and G9 (unusual thought content), and a total PANSS score greater than 60. Patients were randomly assigned (1:1) to 12 weeks of treatment with target doses of 600 mg/day of quetiapine-ER (starting from 50 mg/day) or 20 mg/day of aripiprazole (starting from 2·5 mg/day). The assigned drug was titrated over five levels, with 2 days at each dose, and the final dose achieved on day 9. Randomisation was done using a computer-generated concealed sequence with a block size of 8, and stratified by baseline PANSS positive score (≤20 points or >20 points) and age (12-14 years or 15-17 years). Study drugs were administered in identical capsules, and interventions, assessments, and data analysis were done masked. The primary outcome was PANSS positive score. Key adverse outcomes were bodyweight, homoeostatic model of insulin resistance (HOMA-IR), akathisia, and sedation. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01119014. FINDINGS: Between June 10, 2010, and Jan 29, 2014, 231 participants were assessed for elegibility, of whom 113 were randomly assigned to quetiapine-ER (n=55) or aripiprazole (n=58). PANSS positive score did not differ between groups after 12 weeks (adjusted mean change -5·05 [5·46] for quetiapine-ER, -6·21 [5·42] for aripiprazole; p=0·98), but decreased over time in both groups (p<0·0001). Weight gain was more rapid with quetiapine-ER (p=0·0008), with an adjusted mean weight group difference at week 12 of 3·33 kg (SD 7·23; effect size 0·64; p<0·0001). The HOMA-IR group difference at week 12 favoured aripiprazole (adjusted mean log-transformed group difference 0·259 [SD 0·906]; effect size 0·35; p=0·0060). Akathisia was more common with aripiprazole at week 2 (observed in 34 [60%] of 57 patients; estimated 63·5%) than with quetiapine-ER (15 [30%] of 50; estimated 31·3%; p=0·0021), but not at other timepoints. Sedation proportions did not change significantly over time with either intervention (observed at weeks 2, 4, and 12, respectively, for quetiapine-ER in 43 [83%] of 52, 40 [83%] of 48, and 34 [72%] of 47 patients and for aripiprazole in 49 [89%] of 55, 52 [96%] of 54, and 44 [92%] of 48 patients), and the overall estimated probability combining all timepoints was significantly higher for aripiprazole (97·1%) than for quetiapine-ER (89·2%; p=0·012). In addition to sedation and akathisia, the most common adverse events were tremor (42 [79%] patients in the quetiapine-ER group vs 52 [91%] patients in the aripiprazole group), increased duration of sleep (47 [92%] vs 39 [71%]), orthostatic dizziness (42 [78%] vs 46 [81%]), depression (43 [80%] vs 44 [77%]), tension/inner unrest (37 [69%] vs 50 [88%]), failing memory (41 [76%] vs 44 [77%]), and weight gain (46 [87%] vs 38 [68%]). INTERPRETATION: This first head-to-head comparison of quetiapine-ER versus aripiprazole in early-onset psychosis showed no significant group differences in severity of psychopathology after 12 weeks of treatment. Quetiapine-ER was associated with more metabolic adverse events and aripiprazole with more initial akathisia and, unexpectedly, more sedation. The limited antipsychotic efficacy and high level of adverse events were noticeable. This trial provides novel information for the treatment of early-onset psychosis and highlights the importance of adverse event profiles when choosing among antipsychotics for children and adolescents who often require chronic treatment. FUNDING: The National Research Council for Health and Disease Foundation for Health Promotion, AP Møller Foundation, Rosalie Petersens Foundation, Stevn and Rindom Foundation, Foundation for the Promotion of Medical Science, The Capital Region Psychiatric Research Foundation, Tryg Foundation, Region of Southern Denmark Research Foundation, Danish Psychiatric Research Educational Fund, Psychiatry Foundation, Foundation of 17-12-1981, Psychiatric Research Foundation Region Zealand, Capital Region Strategic Research Foundation, Knud og Dagny Andresens Foundation, Psychiatric Research Foundation of 1967, The Capital Region Research Foundation, Dr Sofus Carl Emil Friis and Hustru Olga Friis Scholarship, Tømrerhandler Johannes Fogs Foundation, Brdr Hartmanns Foundation DKK, Aase and Ejnar Danielsens Foundation, Jacob Madsen and wife Olga Madsens Foundation, CC Klestrup and wife Scholarship, Lundbeck Foundation Scholarship, and Tømrermester Jørgen Holm and wife Elisas Scholarship.

Corrected QT changes during antipsychotic treatment of children and adolescents: a systematic review and meta-analysis of clinical trials.

OBJECTIVE: To evaluate the effect of antipsychotics on the corrected QT (QTc) interval in youth. METHOD: We searched PubMed (http://www.ncbi.nlm.nih.gov/pubmed) for randomized or open clinical trials of antipsychotics in youth <18 years with QTc data, meta-analyzing the results. Meta-regression analyses evaluated the effect of age, sex, dose, and study duration on QTc. Incidences of study-defined QTc prolongation (>440-470 milliseconds), QTc >500 milliseconds, and QTc change >60 milliseconds were also evaluated. RESULTS: A total of 55 studies were meta-analyzed, evaluating 108 treatment arms covering 9 antipsychotics and including 5,423 patients with QTc data (mean age = 12.8 ± 3.6 years, female = 32.1%). Treatments included aripiprazole: studies = 14; n = 814; haloperidol: studies = 1; n = 15; molindone: studies = 3; n = 125; olanzapine: studies = 5; n = 212; paliperidone: studies = 3; n = 177; pimozide: studies = 1; n = 25; quetiapine: studies = 5; n = 336; risperidone: studies = 23; n = 2,234; ziprasidone: studies = 10, n = 523; and placebo: studies = 19, n = 962. Within group, from baseline to endpoint, aripiprazole significantly decreased the QTc interval (-1.44 milliseconds, CI = -2.63 to -0.26, p = .017), whereas risperidone (+1.68, CI = +0.67 to +2.70, p = .001) and especially ziprasidone (+8.74, CI = +5.19 to +12.30, p < .001) significantly increased QTc. Compared to pooled placebo arms, aripiprazole decreased QTc (p = .007), whereas ziprasidone increased QTc (p < .001). Compared to placebo, none of the investigated antipsychotics caused a significant increase in the incidence of the 3 studied QTc prolongation measures, but there was significant reporting bias. CONCLUSION: Based on these data, the risk of pathological QTc prolongation seems low during treatment with the 9 studied antipsychotics in otherwise healthy youth. Nevertheless, because individual risk factors interact with medication-related QTc effects, both medication and patient factors need to be considered when choosing antipsychotic treatment.

Quetiapine versus aripiprazole in children and adolescents with psychosis--protocol for the randomised, blinded clinical Tolerability and Efficacy of Antipsychotics (TEA) trial.

BACKGROUND: The evidence for choices between antipsychotics for children and adolescents with schizophrenia and other psychotic disorders is limited. The main objective of the Tolerability and Efficacy of Antipsychotics (TEA) trial is to compare the benefits and harms of quetiapine versus aripiprazole in children and adolescents with psychosis in order to inform rational, effective and safe treatment selections. METHODS/DESIGN: The TEA trial is a Danish investigator-initiated, independently funded, multi-centre, randomised, blinded clinical trial. Based on sample size estimation, 112 patients aged 12-17 years with psychosis, antipsychotic-naïve or treated for a limited period are, 1:1 randomised to a 12- week, double-blind intervention with quetiapine versus aripiprazole. Effects on psychopathology, cognition, health-related quality of life, and adverse events are assessed 2, 4, and 12 weeks after randomisation. The primary outcome is change in the positive symptom score of the Positive and Negative Syndrome Scale. The recruitment period is 2010-2014. DISCUSSION: Antipsychotics are currently the only available pharmacologic treatments for psychotic disorders. However, information about head-to-head differences in efficacy and tolerability of antipsychotics are scarce in children and adolescents. The TEA trial aims at expanding the evidence base for the use of antipsychotics in early onset psychosis in order to inform more rational treatment decisions in this vulnerable population. Here, we account for the trial design, address methodological challenges, and discuss the estimation of sample size. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01119014.

[Necroticing fasciitis in children]. / Nekrotiserende fasciitis hos børn.

Necrotizing fasciitis (NF) is a serious condition with infection of the muscular fascia causing rapidly spreading necrosis. NF rarely affects children, and we here report two paediatric cases of NF. The first developed NF after a joint puncture, the other after surgical extirpation of a lymph node. Both were treated with antibiotics, human immunoglobulin, hyperbaric oxygen and repeated surgery and survived. In contrast to adults, children with NF often have no underlying chronic illness. The most frequent access point is varicella zoster ulcers.