The short-term and long-term adverse effects of melatonin treatment in children and adolescents: a systematic review and GRADE assessment.

Background: Currently, melatonin is used to treat children and adolescents with insomnia without knowing the full extent of the short-term and long-term consequences. Our aim was to provide clinicians and guideline panels with a systematic assessment of serious-and non-serious adverse events seen in continuation of melatonin treatment and the impact on pubertal development and bone health following long-term administration in children and adolescents with chronic insomnia. Methods: We searched PubMed, Embase, Cinahl and PsycINFO via Ovid, up to March 17, 2023, for studies on melatonin treatment among children and adolescents (aged 5-20 years) with chronic insomnia. The language was restricted to English, Danish, Norwegian, and Swedish. Outcomes were non-serious adverse events and serious adverse events assessed 2-4 weeks after initiating treatment and pubertal development and bone health, with no restriction on definition or time of measurement. Observational studies were included for the assessment of long-term outcomes, and serious and non-serious adverse events were assessed via randomised studies. The certainty of the evidence was assessed using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). The protocol is registered with the Danish Health Authority. Findings: We identified 22 randomised studies with 1350 patients reporting on serious-and non-serious adverse events and four observational studies with a total of 105 patients reporting on pubertal development. Melatonin was not associated with serious adverse events, yet the number of patients experiencing non-serious adverse events was increased (Relative risk 1.56, 95% CI 1.01-2.43, 17 studies, I2 = 47%). Three studies reported little or no influence on pubertal development following 2-4 years of treatment, whereas one study registered a potential delay following longer treatment durations (>7 years). These findings need further evaluation due to several methodological limitations. Interpretation: Children who use melatonin are likely to experience non-serious adverse events, yet the actual extent to which melatonin leads to non-serious adverse events and the long-term consequences remain uncertain. This major gap of knowledge on safety calls for caution against complacent use of melatonin in children and adolescents with chronic insomnia and for more research to inform clinicians and guideline panels on this key issue. Funding: The Danish Health Authority. The Parker Institute, Bispebjerg and Frederiksberg Hospital, supported by the Oak Foundation.

Association between Global Assessment of Functioning scores and indicators of functioning, severity, and prognosis in first-time schizophrenia.

BACKGROUND: Assessment of psychosocial functioning in people with schizophrenia is important. The Global Assessment of Functioning (GAF-F) scale represents a widely applied, easy, and quick tool, but its validity and reliability have been debated. The aim was to investigate whether GAF-F scores are associated with other indicators of functioning, severity, and hospitalization. METHODS: A Danish population-based cohort study of adults (≥18 years) with a recorded GAF-F score at first-time schizophrenia diagnosis during 2004-2011 was performed. The internal validity of GAF-F was evaluated by assessing its association with other baseline measures of functioning and illness severity. Risk of schizophrenia hospitalization within 2 years was evaluated using Cox regression stratified by sex and adjusted for age, year of diagnosis, and inpatient/outpatient status at diagnosis. RESULTS: We identified 2,837 cases of schizophrenia with a GAF-F score at first-time diagnosis (73.0% inpatients; 62.6% males). GAF-F was associated with several baseline measures of functioning and illness severity, such as female sex, being in work, and a longer baseline hospitalization. Lower GAF-F scores were associated with higher hospitalization risk among males (reference GAF-F 61-100): GAF-F 51-60: hazard rate ratio (HRR) =1.24 (95% confidence interval [CI] =0.89-1.75); GAF-F 41-50: HRR =1.31 (95% CI =0.97-1.77); GAF-F 31-40: HRR =1.36 (95% CI =1.01-1.82); GAF-F 21-30: HRR =1.50 (95% CI =1.09-2.06); and GAF-F 1-20: HRR =2.30 (95% CI =1.36-3.90), fitting a dose-response relationship (P=0.031). This association was not found in females. CONCLUSION: GAF-F at first-time schizophrenia diagnosis showed good internal validity against other measures of functionality in a Danish hospital setting. Severe impairment (as measured by the GAF-F score) at first-time schizophrenia diagnosis was associated with a higher risk of 2-year hospitalization among males, which may indicate sex differences in the course of disease and treatment response.

Treatment of adult patients with schizophrenia and complex mental health needs - A national clinical guideline.

BACKGROUND AND AIM: The Danish Health and Medicines Authority assembled a group of experts to develop a national clinical guideline for patients with schizophrenia and complex mental health needs. Within this context, ten explicit review questions were formulated, covering several identified key issues. METHODS: Systematic literature searches were performed stepwise for each review question to identify relevant guidelines, systematic reviews/meta-analyses, and randomized controlled trials. The quality of the body of evidence for each review question was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Clinical recommendations were developed on the basis of the evidence, assessment of the risk-benefit ratio, and perceived patient preferences. RESULTS: Based on the identified evidence, a guideline development group (GDG) recommended that the following interventions should be offered routinely: antipsychotic maintenance therapy, family intervention and assertive community treatment. The following interventions should be considered: long-acting injectable antipsychotics, neurocognitive training, social cognitive training, cognitive behavioural therapy for persistent positive and/or negative symptoms, and the combination of cognitive behavioural therapy and motivational interviewing for cannabis and/or central stimulant abuse. SSRI or SNRI add-on treatment for persistent negative symptoms should be used only cautiously. Where no evidence was available, the GDG agreed on a good practice recommendation. CONCLUSIONS: The implementation of this guideline in daily clinical practice can facilitate good treatment outcomes within the population of patients with schizophrenia and complex mental health needs. The guideline does not cover all available interventions and should be used in conjunction with other relevant guidelines.

Association of antipsychotic polypharmacy with health service cost: a register-based cost analysis.

OBJECTIVE: To investigate the association of antipsychotic polypharmacy in schizophrenia with cost of primary and secondary health service use. METHOD: Comparative analysis of health service cost for patients prescribed antipsychotic polypharmacy versus antipsychotic monotherapy. Resource utilisation and costs were described using central Danish registers for a 2 year period (2007-2008). We included patients attached to one of two Danish psychiatric referral centres in 1 January 2008 and/or 1 January 2009. Their prescribed treatment with either antipsychotic polypharmacy or monotherapy at the two cross-sectional dates was recorded and used as proxy of polypharmacy exposure during the preceding year. A multivariate generalised linear model was fitted with total costs of primary and secondary health service use as dependent variable, and antipsychotic polypharmacy, diagnosis, age, gender, disease duration, psychiatric inpatient admissions, and treatment site as covariates. RESULTS: The sample consisted of 736 outpatients with a diagnosis in the schizophrenia spectrum. Antipsychotic polypharmacy was associated with significantly higher total health service costs compared with monotherapy (2007: 25% higher costs; 2008: 17% higher costs) when adjusting for potential confounders and risk factors. A subgroup analysis suggested that the excessive costs associated with antipsychotic polypharmacy were partly accounted for by the functional level of the patients. CONCLUSION: The results demonstrate that antipsychotic co-prescribing is associated with increased use of health care services, even though no causal relations can be inferred from an observational study.