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.

Table 2 Metabolic 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
Borba et al[23], 2011	14 (8 M, 6 F); 6 (5 M, 1 F)	49 ± 7; 56 ± 9	8 mg/d Ramelton or placebo for 8 wk	SCZ (n = 11), SZA (n = 9)	Diagnosis of SCZ (as per DSM-IV criteria); aged between 18-65 yr; BMI > 27 kg/m2, insulin resistance or any component of metabolic syndrome or a BMI of > 30 kg/m2	Double-blind, placebo-controlled pilot trial	Waist circumference (cm), abdominal fat as measured by DEXA, glucose metabolism, C-reactive protin, lipids, psychopathology (PANSS; HDRS, HCQoL), sleep quality (SSS, FSI, MOSSS), adverse effects (SATEE)	Total cholesterol; cholesterol-to-HDL ratio; LDL particle number: Melatonin < Placebo	High
								Adverse effects: Melatonin vs control group: drowsiness (57% vs 33%), heart burn (21% vs 0%), cough (21% vs 0%), akathisia (21% vs 0%), increased urinary frequency (14% vs 0%), problems with memory or concentration (21% vs 0%)
								Arthralgia/myalgia and anxiety: Placebo > Melatonin
Modabbernia et al[24], 2014	18 (13 M, 5 F); 18 (12 M, 6 F)	32.7 ± 7.3; 32.8 ± 8.2	3 mg/d melatonin + Olanzapine or placebo + Olanzapine for 8 wk	SCZ (n = 36)	Diagnosis of SCZ (as per DSM-IV criteria); aged between 18-65 yr; in their first-episode eligible for starting olanzapine	Randomized, double- blind, placebo-controlled, and parallel-group study	Anthropometric measures, BP, FBS, fasting plasma insulin, Psychopathology (PANSS)	Weight, BMI and Waist circumference: Melatonin < Placebo	Some concerns
								PANSS total score: Melatonin < Placebo
Romo-Nava et al[25], 2014	20 (10 M, 10 F); 24 (12 M, 12F)	Overall: 29.5 ± 8.3	5 mg/d CR melatonin or placebo for 8 wk	SCZ (n = 24); BP (n = 20)	Diagnosis of SCZ or BP type I (as per DSM-IV criteria); aged between 18-45 yr, initiated treatment with SGAs < 3 mo	Double-blind, placebo-controlled study	Anthropometric measures, body composition, BP, Lipids, Glucose, PANSS, CGI-S. BPD only: HDRS, YMRS. Schizophrenia only: CDS	Weight gain, waist circumference, DBP, fat mass, triglycerides: Melatonin (BP only) < Placebo	Some concerns

BMI: Body mass index; BP: Bipolar disorder; BP: Blood pressure; CDS: Calgary depression scale; CGI-S: Clinical Global Impression-Severity of Illness; CR: Controlled-release; DEXA: Dual-energy x-ray absorptiometry; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, fourth edition; F: Female; FBS: Fasting blood sugar; FSI: Fatigue scale inventory; HCQoL: Heinrichs-Carpenter Quality of Life Scale; HDL: High-density lipoprotein; HDRS: Hamilton Depression Rating Scale; LDL: Low-density lipoprotein; M: Male; MOSSS: Medical outcomes study sleep scale; PANSS: Positive and Negative Syndrome Scale; SATEE: Systematic assessment for treatment emergent events; SCZ: Schizophrenia; SGA: Second generation antipsychotics; SSS: Stanford sleepiness scale; SZA: Schizoaffective disorder; YMRS: Young mania rating scale.

Table 3 Tardive dyskinesia

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[26], 2000	19 (8 M, 11 F); 19 (8 M, 11 F)	Overall: 74.0 ± 9.5	2 mg/d CR melatonin or placebo for 4 wk	SCZ (n = 19)	Diagnosis of SCZ of > 20 yr (as per DSM-IV criteria), TD > 5 yr, antipsychotic treatment > 10 yr	Double-blind, placebo-controlled, crossover trial (2 wk washout)	AIMS	-	Some concerns
Shamir et al[27], 2001	22 (11 F, 11 M); 22 (11 F, 11 M)	Overall: 64.2 ± 14.3	10 mg/d CR melatonin or placebo for 6 wk	SCZ (n = 22)	Diagnosis of SCZ and anti-psychotic-induced TD (as per DSM-IV criteria)	Double-blind, placebo-controlled, crossover trial (4 wk washout)	AIMS	AIMS: Melatonin < Placebo	Some concerns
Castro et al[28], 2011	7; 6 (sex NR)	Overall: 59.9 ± 2.7	20 mg/d melatonin or placebo for 12 wk	SCZ (n = 11); BP (n = 2)	Diagnosis of neuroleptic-induced TD (as per DSM-IV criteria)	Randomized, double blind, placebo-controlled pilot study	AIMS; BPRS	-	High

AIMS: Abnormal Involuntary Movement Scale; BP: Bipolar disorder; BPRS: Brief psychiatric rating scale; CR: Controlled-release; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, fourth edition; F: Female; M: Male; NR: Not reported; SCZ: Schizophrenia; TD: Tardive dyskinesia.

Table 4 Cognitive function

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
Shirayama et al[29], 2014	10 (NR); -	42.5 ± 7.3	8 mg/d melatonin for 6 mo	SCZ (n = 10)	Diagnosis of SCZ (as per DSM-IV criteria); symptoms stable for 3 mo	Open-label study	TMT (A and B), WCST, VFT, Stroop Test, DSPDT, IGT, RAVLT	RAVLT (total, delayed recall and recognition): Improved at 6-mo compared to baseline	High
Baandrup et al[30], 2017	40 (21 M, 19 F); 40 (24 M, 16 F)	47.4 ± 8.6; 49.0 ± 12.1	2 mg/d CR melatonin or placebo for 24 wk	Paranoid SCZ (n = 62), non-paranoid SCZ (n = 6), SZA (n = 3), BP (n = 9)	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	BACS (domains: verbal memory, working memory, motor speed, verbal fluency, letter fluency, attention and processing speed, executive function), WHO-Five WBI, SWN, PSP, UKU, PANSS	-	Low

BACS: Brief assessment of cognition in schizophrenia; BP: Bipolar disorder; BZD: Benzodiazepine; CR: Controlled-release; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, fourth edition; DSPDT: Digit span distraction test; F: Female; ICD-10: International Classification of Diseases, Tenth Revision; IGT: Iowa gambling task; M: Male; NR: Not reported; PANSS: Positive and negative syndrome scale; PSP: Personal and social performance scale; RAVLT: Rey auditory verbal learning test; SCZ: Schizophrenia; SWN: Subjective wellbeing under neuroleptic treatment scale; SZA: Schizoaffective disorder; TMT: Trail-making test; part A and part B; UKU: Udvalget for Kliniske Undersoegelser side effect rating scale; VFT: Verbal fluency test; WCST: Wisconsin card sorting test; WHO-Five WBI: WHO-five wellbeing index.

Table 5 Benzodiazepine discontinuation

Ref.	Sample size (sex) melatonin; control	Age (yr) melatonin; control	Dose, duration	Diagnosis	Inclusion criteria	Study design	Outcomes	Significant findings	Risk of bias
Baandrup et al[12], 2016	42 (23 M, 19 F); 44 (25 M, 19 F)	47.9 ± 8.7; 49.4 ± 12.3	2 mg/d PR melatonin or placebo for 24 wk	Paranoid SCZ (n = 67), Non-paranoid SCZ (n = 6), SZA (n = 3), BP (n = 10)	Diagnosis of SCZ, SZA or BP (as per ICD-10 criteria); treated with 1 antipsychotic drug and 1 BZD drug for 3 mo; able to understand Danish	Randomized, double-blind clinical trial	Mean daily dosage of BZD, pattern of BZD dosage, BZD cessation proportion, BWSQ-2	-	Some concerns

BP: Bipolar disorder; BWSQ-2: Benzodiazepine Withdrawal Symptom Questionnaire; BZD: Benzodiazepine; ICD-10: International Classification of Diseases, Tenth Revision; PR: Prolonged release; SCZ: Schizophrenia; SZA: Schizoaffective disorder.