Adverse Events Associated with Melatonin for the Treatment of Primary or Secondary Sleep Disorders: A Systematic Review

Background: Melatonin is widely available either on prescription for the treatment of sleep disorders or as an over-the-counter dietary supplement. Melatonin has also recently been licensed in the UK for the short-term treatment of jetlag. Little is known about the potential for adverse events (AEs), in particular AEs resulting from long-term use. Concern has been raised over the possible risks of exposure in certain populations including pre-adolescent children and patients with epilepsy or asthma. / Objectives: The aim of this systematic review was to assess the evidence for AEs associated with short-term and longer-term melatonin treatment for sleep disorders. / 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 < 1 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 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: 37 RCTs met criteria for inclusion. Daily melatonin doses ranged from 0.15 mg to 12 mg. Subjects were monitored for up to 29 weeks, but most studies were of much shorter duration (4 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 considered to be serious or of clinical significance were reported. These included agitation, fatigue, mood swings, nightmares, skin irritation and palpitations. Most 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 clinically significant adverse effects in potentially at-risk populations. Future studies should be designed to comply with appropriate quality standards for RCTs, which most past studies have not

Antipsychotics and Risk of Neuroleptic Malignant Syndrome: A Population-Based Cohort and Case-Crossover Study

BACKGROUND: Neuroleptic malignant syndrome (NMS) is a rare and acute adverse drug reaction associated with antipsychotic therapy. However, few data on the risk and epidemiology of NMS are available. OBJECTIVES: The aim of this study was to ascertain the incidence risk and all-cause mortality of NMS associated with antipsychotic use, and to assess the association of recent antipsychotic exposure and NMS. METHODS: We did a population-based study using data from the Hong Kong Hospital Authority’s Clinical Data Analysis and Reporting System database. Cases had a first diagnosis of NMS between 1 January 2004 and 30 November 2017. A case-crossover analysis was used to compare antipsychotic exposure 30 days before the diagnosis of NMS (index date) and a reference period 91–120 days before the index date. To adjust for potential time trends in antipsychotic exposure, we sampled from cases to match current cases and future cases, and further adjusted for select medications and acute medical conditions. RESULTS: 297,647 patients were prescribed antipsychotics, and the incidence risk of NMS was 0.11%. Of the 336 cases included in the case-crossover analysis, 20 (6%) died within 30 days after the index date; only one case had NMS recorded as the primary cause of death. When compared with the reference period, cases were more frequently prescribed multiple antipsychotics (15.8% vs 26.8%; standardized mean difference [SMD] 0.27) and short-acting injectable antipsychotics (3.6% vs 13.7%; SMD 0.37) during the 30 days prior to the diagnosis of NMS. Odds ratios for antipsychotic exposure in the case-crossover, case-crossover adjusted for time trend, and case-crossover adjusted for time trend and potential confounders analysis were 8.00 (95% confidence interval 3.42–18.69), 5.88 (2.46–14.04), and 4.77 (1.95–11.66). CONCLUSIONS: Our results suggest that recent use of antipsychotics is associated with NMS. Although a case-only design inherently controls for confounding by time-invariant factors, residual confounding by acute medical conditions with similar presentations to NMS cannot be fully excluded

Prescribing trends and indications of antipsychotic medication in Hong Kong from 2004 to 2014: General and vulnerable patient groups

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. METHODS: This descriptive study identified and included all patients prescribed with antipsychotic in Hong Kong from 2004 to 2014 using the Clinical Data Analysis and Report System. This study calculated and reported the prevalence of antipsychotic prescribing in patient groups of interest, the percentage with diagnoses of mental disorders were derived, and the prevalence of antipsychotic by dosage forms. RESULTS: The study included 10 109 206 prescriptions of any antipsychotics to 256 903 patients. 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 prepregnancy, 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%. CONCLUSIONS: 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 nonpsychotic mental disorder in 2014, suggesting that off-label prescribing of antipsychotics might be common. Copyright © 2017 John Wiley & Sons, Ltd

Intramuscular midazolam, olanzapine, or haloperidol for the management of acute agitation: A multi-centre, double-blind, randomised clinical trial

© 2021 The Authors 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

Tolerability and safety profile of cariprazine in treating psychotic disorders, bipolar disorder and major depressive disorder: a systematic review with meta-analysis of randomized controlled trials

Background Cariprazine is a novel antipsychotic agent recently approved for treating schizophrenia and bipolar mania in the USA. The sample sizes of published randomized controlled trials (RCTs) of the drug are small; previous meta-analyses included few RCTs and did not specifically investigate the tolerability/safety profile of cariprazine. Objective Our objective was to conduct a meta-analysis of published RCTs to systematically review the tolerability and safety of cariprazine versus placebo. Methods We searched the clinical trial registers (the metaRegister of controlled trials, ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform) and electronic databases (PubMed, Embase, PsycINFO and Cochrane library) up to June 2016 to identify phase II/III RCTs of cariprazine in patients with schizophrenia, bipolar disorder or major depressive disorder. We conducted a meta-analysis to investigate outcomes, including risks of discontinuation due to adverse events (AEs), extrapyramidal side effects (EPS) or related events, metabolic syndrome and cardiovascular-related events. Results We included nine RCTs, with a total of 4324 subjects. The risk of discontinuation due to AEs for cariprazine was similar to that for placebo (risk ratio [RR] 1.13, 95 % confidence interval [CI] 0.77–1.66). Cariprazine was associated with higher risks of EPS-related events than was placebo, including risk of akathisia (RR 3.92, 95 % CI 2.83–5.43), tremor (RR 2.41, 95 % CI 1.53–3.79) and restlessness (RR 2.17, 95 % CI 1.38–3.40). The cariprazine treatment group was more likely to have clinically significant weight gain (RR 1.68, 95 % CI 1.12–2.52). No statistically significant differences in results were found in other metabolic parameters or cardiovascular-related events. Conclusion There was a statistically significant higher risk of EPS-related AEs and a slight increase in mean body weight with cariprazine. There were no statistically significant effects on prolactin level or cardiovascular parameters. EPSs were the main short-term adverse reactions reported in the limited number of patients studied. Further clinical and post-marketing pharmacovigilance studies are needed to investigate the long-term safety of cariprazine