Objectives: To assess the evidence for adverse events (AEs) associated with short-term and longer-term melatonin treatment for sleep disorders. Background: Melatonin is widely available either on prescription for the treatment of sleep disorders or as an overthe-counter dietary supplement. Melatonin has also recently been licensed in the UK for the short-term treatment of jet-lag. Little is known about the potential for AEs, in particular AEs resulting from long-term use. Particular concern has been raised over the possible risks of exposure in certain populations including pre-adolescent children and patients with epilepsy or asthma. Methods: A literature search of the PubMed/Medline database and Google Scholar was conducted to identify randomised, placebo-controlled trials (RCTs) of exogenous melatonin administered for primary or secondary sleep disorders. Studies were included if they reported on both the types and frequencies of AEs. Studies of pre-term infants, studies of less than one week in duration or involving single doses of melatonin and studies in languages other than English were excluded. Findings from open-label studies that raised particular concerns relating to AE reports in patients were also examined. Studies were assessed for quality of reporting against the Consolidated Standards of Reporting Trials (CONSORT) checklist and for risk of bias against the Cochrane Collaboration risk of bias criteria. Results: Thirty-seven RCTs met criteria for inclusion. Daily melatonin doses were from 0.15 to 12 mg/day. Subjects were monitored for up to 29 weeks, but most studies were of much shorter duration (four weeks or less). The most frequently reported AEs were daytime sleepiness (1.66%), headache (0.74%), other sleep-related AEs (0.74%), dizziness (0.74%) and hypothermia (0.62%).. Very few AEs that were considered to be serious or of clinical significance were reported. These included agitation, fatigue, mood swings, nightmares, skin irritation and palpitations. The large majority of AEs either resolved spontaneously within a few days with no adjustment in melatonin, or immediately upon withdrawal of treatment. Melatonin was generally regarded as safe and well-tolerated. Many studies predated publication of the CONSORT checklist and consequently did not conform closely to the guidelines. Similarly, only eight studies were judged 'good' overall with respect to the Cochrane risk of bias criteria. Of the remaining papers 16 were considered 'fair' and 13 'poor' but publication of almost half of the papers preceded that of the earliest version of the guidelines. Conclusion: Few, generally mild to moderate, AEs were associated with exogenous melatonin. No AEs that were life threatening or of major clinical significance were identified. The scarcity of evidence from long-term RCTs, however, limits the conclusions regarding the safety of continuous melatonin therapy over extended periods. There are insufficient robust data to allow a meaningful appraisal of concerns that melatonin may result in more clinicallys...

Background The safety and effectiveness of intramuscular olanzapine or haloperidol compared to midazolam as the initial pharmacological treatment for acute agitation in emergency departments (EDs) has not been evaluated. Methods A pragmatic, randomised, double-blind, active-controlled trial was conducted from December 2014 to September 2019, in six Hong Kong EDs. Patients (aged 18–75 years) with undifferentiated acute agitation requiring parenteral sedation were randomised to 5 mg intramuscular midazolam ( n = 56), olanzapine ( n = 54), or haloperidol ( n = 57). Primary outcomes were time to adequate sedation and proportion of patients who achieved adequate sedation at each follow-up interval. Sedation levels were measured on a 6-level validated scale (ClinicalTrials.gov Identifier: NCT02380118). Findings Of 206 patients randomised, 167 (mean age, 42 years; 98 [58·7%] male) were analysed. Median time to sedation for IM midazolam, olanzapine, and haloperidol was 8·5 (IQR 8·0), 11·5 (IQR 30·0), and 23·0 (IQR 21·0) min, respectively. At 60 min, similar proportions of patients were adequately sedated (98%, 87%, and 97%). There were statistically significant differences for time to sedation with midazolam compared to olanzapine ( p = 0·03) and haloperidol ( p = 0·002). Adverse event rates were similar across the three arms. Dystonia ( n = 1) and cardiac arrest ( n = 1) were reported in the haloperidol group. Interpretation Midazolam resulted in faster sedation in patients with undifferentiated agitation in the emergency setting compared to olanzapine and haloperidol. Midazolam and olanzapine are preferred over haloperidol's slower time to sedation and potential for cardiovascular and extrapyramidal side effects. Funding Research Grants Council, Hong Kong.

Observational studies have been recognised to be essential for investigating the safety profile of medications. Numerous observational studies have been conducted on the platform of large population databases, which provide adequate sample size and follow-up length to detect infrequent and/or delayed clinical outcomes. Cohort and case–control are well-accepted traditional methodologies for hypothesis testing, while within-individual study designs are developing and evolving, addressing previous known methodological limitations to reduce confounding and bias. Respective examples of observational studies of different study designs using medical databases are shown. Methodology characteristics, study assumptions, strengths and weaknesses of each method are discussed in this review.

(250 words)Purpose Antipsychotic prescribing patterns remain unclear in Asia. The aims of our study were to investigate prescribing trends of antipsychotic medication in the general population, children, and older patients by drug generation (first or second), the prescribing trend in pregnant women, the probable indication for antipsychotic prescription, and the prescribing trend by dosage form. Over the study period, the prevalence of antipsychotic prescribing increased from 1.06% to 1.54% in the general population, from 0.10% to 0.23% in children (3-17 years old), and from 2.61% to 3.26% in older patients (≥65 years old). The prevalence of second-generation antipsychotics increased but the prevalence of first-generation antipsychotics did not. Prevalence of antipsychotic prescribing in pre-pregnancy, pregnancy, and postpartum timeframes varied from 0.18% to 0.38%. The percentage of incident prescriptions with a diagnosis of psychosis decreased from 54.1% to 47.5%. MethodsConclusions Antipsychotics have been increasingly prescribed in the general population, children, and older patients. There is an increase in second-generation antipsychotic prescribing.Over half of incident users had a recent diagnosis of a non-psychotic mental disorder in 2014, suggesting that off-label prescribing of antipsychotics might be common.

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