Therapeutic use of melatonin in schizophrenia: A systematic review

Table 1 Sleep outcomes

Ref.	Sample size (sex) melatonin; control	Age (yr) melatonin; control	Dose, duration	Diagnosis	Inclusion criteria	Study design	Outcomes	Significant findings related to melatonin	Risk of bias
Shamir et al[18], 2000	14 (11 M, 3 F), 14 (11 M, 3 F)	Overall: 42.3 ± 13.1	2 mg CR melatonin or placebo/day for 3 wk	SZA (n = 2); Paranoid SCZ (n = 10); Disorganised SCZ (n = 2)	Diagnosis of chronic SCZ (as per DSM-IV criteria); poor sleep quality	Randomized, double-blind, crossover trial (1 wk washout)	Sleep latency (min), REM sleep (%), REM sleep latency (min), total sleep time (min), sleep efficiency (%), duration of wakefulness (min), stage 1 sleep (%), slow wave sleep (%)	REM Sleep latency (min): Melatonin: 1st night > 2nd night	High
								Sleep efficiency (%): Melatonin: 1st night < 2nd night
								Duration of wakefulness (min): Melatonin: 1st night > 2nd night
								Stage 1 sleep (%): Placebo: 1st night < 2nd night
Shamir et al[17], 2000	19 (12 M, 7 F); 19 (12 M, 7 F)	Overall: 42 ± 5	2 mg CR melatonin or placebo/day for 3 wk	SZA (n = 5); Paranoid SCZ (n = 9); Disorganised SCZ (n = 5)	Diagnosis of chronic SCZ (as per DSM-IV criteria); poor sleep quality	Randomized, double-blind, crossover trial (1 wk washout)	Urinary 6-SMT excretion, sleep efficiency (%), sleep latency (min), total sleep time (min), wake after sleep onset duration (min), fragmentation index (%), number of awakenings (N)	Sleep efficiency (%): Melatonin > Placebo	Some concerns
Suresh Kumar et al[19], 2007	20 (13 M, 7 F); 20 (14 M, 6 F)	38.4 ± 14.4; 36.0 ± 13.4	Patient determined dosage of melatonin or placebo for 15 d	Paranoid SCZ (n = 40)	Diagnosis of paranoid SCZ (as per DSM-IV criteria); illness duration < 1 yr; clinically stable; receiving same dose of haloperidol for the past month, insomnia present for past 2 wk	Double-blind, placebo-controlled study	Time taken to fall asleep (min), number of awakenings (n), duration of sleep (min), self-report sleep questionnaire	Number of awakenings (N): Melatonin < Placebo	High
								Duration of sleep (min): Melatonin > Placebo
								Self-report sleep questionnaire: Time to fall asleep, quality of sleep, depth of sleep, freshness on awakening, morning headache, morning mental dullness, mood, overall functioning were superior in Melatonin group vs Placebo
Mishra et al[20], 2020	PPS: 30 (15 M, 15 F); 30 (21 M, 9 F). PNS: 30 (21 M, 9 F); 30 (14 M, 16 F)	PPS: 38.6 ± 10.68; 34.0 ± 8.38. PNS: 34.97 ± 12.35; 37.87 ± 3.84	8 mg/d Ramelteon + monotherapy vs monotherapy alone for 4 wk	SCZ (n = 120). Patients were categorized into PPS (n = 60) and PNS (n = 60) groups based on PANSS scoring	Diagnosis of SCZ (as per DSM-5 criteria); aged between 18-65 yr; treatment naïve or had not taken treatment for 4 wk	Randomized, open-label, rater-blinded, parallel design clinical trial	Quality of sleep (PSQI), melatonin excretion (urinary melatonin 6aMTs), serum AANAT, symptom severity (PANSS)	Change in serum melatonin at 14:00 h: PPS and PNS: Melatonin > Control	High
								Change in serum melatonin 2 h after add on therapy: PPS and PNS: Melatonin > Control
								Change in urinary melatonin: PPS and PNS: Melatonin > Control
								Change in serum AANAT: PPS and PNS: Melatonin > Control
								PSQI: PPS and PNS: Melatonin > Control
								Change in PANSS total score: PPS and PNS: Total score improved Melatonin > Control; PPS: Decreased positive symptoms in Melatonin > Control; PNS: Decrease negative symptoms in Melatonin > Control
Baandrup et al[22], 2016	20 (11 M, 9 F); 28 (18 M, 10 F)	47.7 ± 8.2; 45.9 ± 10.3	2 mg/d PR melatonin or placebo for 24 wk	Paranoid SCZ (n = 38), Non-paranoid SCZ (n = 2), SZA (n = 2), BP (n = 6)	Diagnosis of SCZ, SZA or BP (as per ICD-10 criteria); treated with 1 antipsychotic and 1 BZD for 3 m	Randomized, double-blind clinical trial	Actigraphy (sleep and 24 h rhythm activity variables)	-	Some concerns
Baandrup et al[21], 2016	28 (14 M, 14 F); 27 (15 M, 12 F)	48.8 ± 7.1; 49.1 ± 12.2	2 mg/d PR melatonin or placebo for 24 wk	Paranoid SCZ (n = 42), non-paranoid SCZ (n = 2), SZA (n = 3), BP (n = 8)	Diagnosis of SCZ, SZA or BP (as per ICD-10 criteria); treated with 1 antipsychotic and 1 BZD for 3 mo	Randomized, double-blind clinical trial	PSQI, polysomnography (n = 23; total sleep time, sleep latency, REM latency, time awake after sleep onset, number of awakenings, sleep architecture)	PSQI sleep quality: Melatonin > Placebo	Some concerns

AANAT: Aryl-alkylamine-N-acetyl-transferase; BP: Bipolar disorder; BZD: Benzodiazepine; CR: Controlled-release; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, fourth edition; F: Female; ICD-10: International Classification of Diseases, Tenth Revision; M: Male; PANSS: Positive and Negative Syndrome Scale; PNS: Predominant negative symptom group; PPS: Predominant positive symptom group; PR: Prolonged-release; PSQI: Pittsburgh sleep quality index; REM: Rapid eye movement; SCZ: Schizophrenia; SZA: Schizoaffective disorder.