International Expert Opinions and Recommendations on the Use of Melatonin in the Treatment of Insomnia and Circadian Sleep Disturbances in Adult Neuropsychiatric Disorders

Abstract

Introduction: Insomnia and circadian rhythm disorders, such as the delayed sleep phase syndrome, are frequent in psychiatric disorders and their evaluation and management in early stages should be a priority. The aim of this paper was to express recommendations on the use of exogenous melatonin, which exhibits both chronobiotic and sleep-promoting actions, for the treatment of these sleep disturbances in psychiatric disorders.Methods: To this aim, we conducted a systematic review according to PRISMA on the use of melatonin for the treatment of insomnia and circadian sleep disorders in neuropsychiatry. We expressed recommendations for the use of melatonin in psychiatric clinical practice for each disorder using the RAND/UCLA appropriateness method.Results: We selected 41 studies, which included mood disorders, schizophrenia, substance use disorders, attention deficit hyperactivity disorders, autism spectrum disorders, neurocognitive disorders, and delirium; no studies were found for both anxiety and eating disorders.Conclusion: The administration of prolonged release melatonin at 2–10 mg, 1–2 h before bedtime, might be used in the treatment of insomnia symptoms or comorbid insomnia in mood disorders, schizophrenia, in adults with autism spectrum disorders, neurocognitive disorders and during sedative-hypnotics discontinuation. Immediate release melatonin at <1 mg might be useful in the treatment of circadian sleep disturbances of neuropsychiatric disorders.

Melatonin: From Neurobiology to Treatment

“…In 2007 the European Medicines Agency EMA authorized the use of melatonin 2 mg Prolonged Release (PR) (Circadin ® ) as medication but melatonin is also used as a dietary supplement. Prolonged release melatonin formulation PRM (2 mg), has been approved for the treatment of chronic insomnia characterized by poor quality of sleep in people aged ≥ 55 and it is available on the market with medical prescription [69][70][71]. The maximum concentration allowed for melatonin-based food supplements is instead 1 mg with lack of evidence about efficacy and safety of the different commercial products on insomnia [72].…”

“…Usually, in young/middle-aged human patients, pharmacokinetic studies show that immediate release formulations reached the peak at approximately between 20 min and 2 h, displays a short blood half-life and a fast turnover. The prolonged-release formulation of melatonin (PR-melatonin or Circadin ® , Neurim Pharmaceuticals, Tel-Aviv, Israel) results in peak plasma levels 2.6 h after ingestion, which are maintained for at least 3.5 h. This formulation has a promoter effect on sleep and is present as a drug on the pharmacological market and recommended for the treatment of insomnia in subjects >55 years old [69][70][71]. PRM 2 mg showed to mimics the physiological release of melatonin by releasing melatonin gradually and acting on melatonin receptors.…”

“…Few reports regard disadvantages accompanying melatonin administration. The most common disadvantages described were headache, dizziness, and less frequently nausea and drowsiness with no significant difference between melatonin administration and placebo in some studies [71]. Limitations about the use of exogenous melatonin are essentially related to pregnancy because its use is not well studied during this period of women life.…”

“…Limitations about the use of exogenous melatonin are essentially related to pregnancy because its use is not well studied during this period of women life. Although there are concerns because it crosses the placenta and may have an impact on the development of circadian rhythms and reproductive function in the offspring, it may also have some potential fetal protective effects [71,76].…”

“…Accumulating evidence suggest the role PRM 2 in the treatment of insomnia comorbid with different neuropsychiatric conditions including, schizophrenia, substance abuse disorders, benzodiazepines discontinuation, neurocognitive disorders and delirium, while a dosage ranging from 2 to 8 mg may be necessary for treating insomnia in mood disorders [71].…”