Pervasive Refusal Syndrome : Three Case Reports - Autism as a Predisposing Factor and Gentle Coercion to Shorten Duration of Disorder?

Background. Pervasive refusal syndrome (PRS) is a severe child psychiatric syndrome not yet included in the international classification and mostly affecting girls aged 7-15 years. Hospital admission and severe loss of function extend for many months and years but most recover. Autism has been suggested as a predisposing factor but largely lacks support for typical cases of PRS. Treatment is not evidence-based and described as requiring a lengthy inpatient stay with a very gradual and sensitive rehabilitation program. Case Presentations. Three cases of pervasive refusal syndrome (PRS) in girls aged 9-16 years are presented to report autism as a predisposing factor and to discuss gentle coercion as part of the management strategy to speed up the lengthy recovery. The cases, which met the proposed criteria and typical background characteristics, were noted with the addition of undiagnosed autism in two cases. The duration of inpatient admission was 8-14 months. Disease duration was 15-36 months. An adequate but negative lorazepam trial to rule out catatonia was carried out. Treatment was in one case successfully expedited with gentle coercion within a transparent management plan. Rehabilitation was slower in PRS with comorbid autism; additionally, accommodations to school and living support needed to be put in place. Conclusions. PRS is a useful clinical entity and best perceived as a primitive reaction to overwhelming stress rather than as catatonia. Autism might be another predisposing factor and needs to be assessed. A psychoeducational approach and a clear management plan support rehabilitation. A gentle coercion might hasten recovery

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 quetiapineER (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.National Research Council for Health and Disease Foundation for Health Promotion; AP Moller Foundation; Rosalie Petersens Foundation; Stevn and Rindom Foundation; Foundation for the Promotion of Medical Science; Capital Region Psychiatric Research Foundation; Tryg Foundation; Region of Southern Denmark Research Foundation; Danish Psychiatric Research Educational Fund; Psychiatry Foundation; Psychiatric Research Foundation Region Zealand; Capital Region Strategic Research Foundation; Knud og Dagny Andresens Foundation; Psychiatric Research Foundation; Capital Region Research Foundation; Dr Sofus Carl Emil Friis and Hustru Olga Friis Scholarship; Tomrerhandler 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; Tomrermester Jorgen Holm and wife Elisas Scholarship; Foundation of 17-12-1981SCI(E)SSCIARTICLE8605-618

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: NCT0111901