Validation study of the early onset schizophrenia diagnosis in the Danish Psychiatric Central Research Register.

The objective of this study is to assess (1) the concordance and validity of schizophrenia register diagnoses among children and adolescents (early onset schizophrenia = EOS) in the Danish Psychiatric Central Research Register (DPCRR), and (2) the validity of clinical record schizophrenia diagnoses. Psychiatric records from 200 patients with a first-time diagnosis of schizophrenia (F20.x) at age < 18 years between 1994 and 2009 in the DPCRR were rated by experienced clinicians according to ICD-10 criteria, using a predefined checklist. We retrieved 178 records, representing 19.6% of all patients diagnosed with EOS from 1994 to 2009. Mean age was 15.2 years and 56.2% were males. The register-based and clinical diagnoses matched in 158 cases (88.8%). Raters' diagnoses confirmed the DPCRR schizophrenia diagnoses in 134 cases, rendering a diagnostic validity of 75.3% of DPCRR schizophrenia, while 149 cases were confirmed as being in the schizophrenia spectrum (83.7%). When removing records with registration errors, 83.5% of cases were confirmed as schizophrenia and 91.8% as being in the schizophrenia spectrum. Interrater reliability was substantial with Cohen's kappa > 0.78-0.83 depending on classification. Compared to diagnoses made in outpatient settings, EOS diagnoses during hospitalizations were more likely to be valid and had fewer registration errors. Diagnosed in inpatient settings, EOS diagnoses are reliable and valid for register-based research. Schizophrenia diagnosed in children and adolescents in outpatient settings were found to have a high number of false-positives, both due to registration errors and diagnostic practice. Utilizing this knowledge, it is possible to reduce the number of false-positives in register-based research of EOS.

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.

Acute Antipsychotic Treatment of Children and Adolescents With Schizophrenia-Spectrum Disorders: A Systematic Review and Network Meta-Analysis.

OBJECTIVE: To determine the comparative efficacy and safety of antipsychotics for youth with early-onset schizophrenia using network meta-analytic methods combining direct and indirect trial data. METHOD: The authors systematically searched MEDLINE, the Cochrane Library, and clinicaltrials.gov and selected randomized controlled trials allocating youth with schizophrenia spectrum disorders to a (non-clozapine) antipsychotic versus placebo or another antipsychotic. Major efficacy outcomes were Positive and Negative Syndrome Scale (PANSS) total and positive symptoms. Major safety outcomes were weight, plasma triglyceride levels, extrapyramidal symptoms, akathisia, and all-cause discontinuation. Sixteen additional outcomes were analyzed. A random-effects arm-based network meta-analysis was applied, and consistency was assessed by pairwise meta-analysis. Confidence in PANSS total estimates was assessed by applying the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: Twelve 6- to 12-week trials (N = 2,158; 8-19 years old; 61% boys) involving 8 antipsychotics (aripiprazole, asenapine, paliperidone, risperidone, quetiapine, olanzapine, molindone, and ziprasidone) were analyzed. PANSS total symptom change was comparable among antipsychotics (low- to moderate-quality evidence), except ziprasidone (very low- to low-quality evidence), and all antipsychotics were superior to placebo (low- to high-quality evidence), except ziprasidone and asenapine (low- to moderate-quality evidence). PANSS positive changes and additional efficacy outcomes were comparable among antipsychotics. Weight gain was primarily associated with olanzapine; extrapyramidal symptoms and akathisia were associated with molindone; and prolactin increased with risperidone, paliperidone, and olanzapine. Serious adverse events, discontinuation of treatment, sedation, insomnia, or change in triglycerides did not differ among antipsychotics. CONCLUSION: This network meta-analysis showed comparable efficacy among antipsychotics for early-onset schizophrenia, except that efficacy appeared inferior for ziprasidone and unclear for asenapine. Adverse reaction profiles varied substantially among the investigated antipsychotics and were largely consistent with prior findings in adults. Protocol registration information-Antipsychotic Treatment for Children With Schizophrenia Spectrum Disorders: Network Meta-Analysis of Randomised Trials; https://www.crd.york.ac.uk/PROSPERO/; CRD42013006676.

Development of Metabolic Syndrome in Drug-Naive Adolescents After 12 Months of Second-Generation Antipsychotic Treatment.

OBJECTIVES: Mental illness is often accompanied by poor physical health and shorter life expectancy. Second-generation antipsychotics (SGAs) are suspected of increasing cardiovascular risk, possibly through development of metabolic syndrome (MetS), and the risk of adverse outcome is even higher if obesity or metabolic aberration starts in childhood or adolescence. METHODS: Drug-naive adolescents were recruited after contact with an outpatient Psychosis Team. Changes relative to baseline in body mass index (BMI), waist circumference (WC), blood pressure (BP), fasting blood glucose (FBG), triglycerides (TG), and high-density lipoprotein (HDL) cholesterol were determined through regular follow-ups. RESULTS: The sample included 35 SGA-naive patients aged 7-19 (mean: 15.5) with a diagnosis of psychosis. Over 12 months, the overall rate of MetS changed significantly (from 0% to 20% [p < 0.016]). There was a significant increase in BMI (18.4% [p < 0.001]), WC (14.3% [p < 0.001]), TG (25.2% [p = 0.039]), and FBG (3.6% [p = 0.038]), whereas there was a significant decrease in HDL (-11.5% [p < 0.001]). No significant change was found for BP. Compared with the 2014 Danish references BMI-for-age charts, after 12 months the participants' BMI had increased from 0.5 to 1.57 standard deviation (SD) above the 50th percentile for age and gender (p = 0.0001). CONCLUSION: To our knowledge, this is the first study to include all the aspects of MetS in a sample of drug-naive adolescents followed over the first 12 months after starting SGA treatment. A significant shift in all parameters (except BP) toward MetS was found, presumably due to SGA use. Therefore, these adolescents will need proper follow-up, consisting of not only monitoring but also preventive measures to diminish these effects of SGA use.

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.

[Rising incidence rates of schizophrenia among children and adolescents]. / Stigende incidensrate af skizofreni hos børn og unge.

INTRODUCTION: The purpose was to expand the understanding of schizophrenia development in children and adolescents. An age- and gender-specific analysis of children and adolescents diagnosed with schizophrenia (F20.xx) was performed. The analysis included calculation of incidence rates of schizophrenia, schizophrenia subtypes, and an account of occurrence of any registered psychiatric diagnoses prior to first schizophrenia diagnosis. MATERIAL AND METHODS: Patients aged 0-21 years diagnosed with schizophrenia (F20.xx) and registered in the Danish Psychiatric Central Research Register in 1994-2007 were included. RESULTS: The cohort consisted of 3,065 patients aged 6-21 years. Incidence rates vary with age and gender, and have been increasing in recent years. Boys have earlier onset and higher incidence rates than girls. The most common schizophrenia subtypes were paranoid (F20.0; 44.0%) and unspecified (F20.9; 28.7%). Three in every four patients had contact with the psychiatric hospital system prior to first schizophrenia diagnosis. CONCLUSION: Schizophreniform symptomatology tends to overlap with other psychiatric disorders, and diagnostic stability is low. The diagnosis schizophrenia should be systematically included in diagnostic deliberations. Qualitative studies describing and analysing early psychopathology in children and adolescents with schizophrenia will improve the present knowledge.

[Aripiprazole for the treatment of Tourette's syndrome]. / Behandling af Tourettes syndrom med aripiprazol.

Tourette's syndrome (TS) is a motoric disorder characterised by multiple motor and vocal tics. The treatment for patients with moderate to severe TS includes antipsychotic medication. A case report is described in which a 20 year-old male had taken antipsychotic medication since the age of five, due to TS. The initial treatment consisted of pimozide and risperidone, both of which had an unsatisfactorily efficacy on tics and side effects in the form of weight gain and sedation. The patient is now treated with aripiprazole and there is a marked reduction of tics and no side effects.

[Early onset of schizophrenia symptoms in children. A literature review]. / Tidlige skizofreniforme symptomer hos børn. En litteraturgennemgang.

Diagnosing schizophrenia in children is difficult, especially in the early stages, and the diagnosis is rarely made. The explanation could be that our knowledge of schizophrenia symptoms in children is insufficient. Moreover, there are no classification systems designed specifically for diagnosing schizophrenia in children. Perhaps diagnosis is rarely made because the disease is a rarity. This article presents a literature review of the present knowledge of early onset of schizophrenia in children and indicates perspectives for future research in schizophrenia.

[Schizophrenia in a seven year-old boy]. / Skizofreni hos en syvårig dreng.

Diagnosing schizophrenia in children is difficult, especially in the early stages. A possible explanation is that our knowledge of symptoms is insufficient. Moreover, there are no specific classification systems for diagnosing childhood schizophrenia. A seven year-old boy presented with symptoms resulting in differential diagnostic considerations of attention deficit/hyperactivity disorder or a behavioural or emotional disorder. The boy had auditory hallucinations, was socially dysfunctional and had emotional contact disturbances, leading to the schizophrenia diagnosis.