J.neubiorev.2021.04.034 Ejemplo de Revisión

Neuroscience and Biobehavioral Reviews 127 (2021) 459–473
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Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev
Neurocognitive effects of melatonin treatment in healthy adults and

individuals with Alzheimer’s disease and insomnia: A systematic review
and meta-analysis of randomized controlled trials
Dewan Md. Sumsuzzman a, b, c, d, 1, Jeonghyun Choi a, b, c, d, 1, Yunho Jin b, c, d,
Yonggeun Hong a, b, c, d, e, *
a
Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, 50834, Republic of Korea
b
Biohealth Products Research Center (BPRC), Inje University, Gimhae, 50834, Republic of Korea
c
Ubiquitous Healthcare & Anti-aging Research Center (u-HARC), Inje University, Gimhae, 50834, Republic of Korea
d
Department of Physical Therapy, College of Healthcare Medical Science & Engineering, Gimhae, 50834, Republic of Korea
e
Department of Medicine, Division of Hematology/Oncology, Harvard Medical School-Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA
A R T I C L E I N F O A B S T R A C T
Keywords: Endogenous melatonin levels are inversely associated with age and cognitive deficits. Although melatonin can
Melatonin improve psychopathological behavior disturbances in clinical trials, whether melatonin may also enhance
Cognition cognitive function remains elusive. This study examined cognitive outcomes from randomized trials of melatonin
Alzheimer’s disease
treatment for Alzheimer’s disease (AD), insomnia, and healthy-subjects. Twenty-two studies met the inclusion
Insomnia
Healthy-subjects
criteria (AD = 9, insomnia = 2, healthy-subjects = 11). AD patients receiving >12 weeks of melatonin treatment
Systematic review improved mini-mental state examination (MMSE) score [MD: 1.82 (1.01; 2.63) p < 0.0001]. Importantly,
Meta-analysis melatonin significantly improved MMSE score in mild stage of AD [MD: 1.89 (0.96; 2.82) p < 0.0001]. In
healthy-subjects, although daytime melatonin treatment notably decreased in accuracy by correct responses
[SMD: -0.74 (-1.03; -0.45) p < 0.00001], the reaction-time score on different stimuli (p = 0.37) did not increased.
Additionally, by pooling of short-term, spatial, and visual memory scores, melatonin did not reduce memory
function (p = 0.08). Meta-analysis of MMSE score suggested that melatonin is effective in treatment for mild
stage of AD. Additionally, we propose that melatonin may be preferable to traditional hypnotics in management
of insomnia.
1. Introduction roughly 82 million people projected to have dementia by 2030 (World

Health Organization, 2019). Insomnia appears to be more prevalent in
The global aging of the population is rapidly becoming a daunting later life, and to be associated with increased risk of Alzheimer’s disease
healthcare challenge (Chang et al., 2019; He et al., 2016). Worldwide, (AD) (Osorio et al., 2011; Pallesen et al., 2014; Winsky-Sommerer et al.,
there were approximately 617 million people aged ≥ 65 years in 2016, 2019). There is accumulating evidence that insomnia significantly alters
which is expected to increase to nearly 1.6 billion by 2050 (He et al., attention and episodic memory (Fortier-Brochu and Morin, 2014;
2016). Therefore, understanding both the natural and pathological im Grau-Rivera et al., 2020; Haimov, 2006; Lowe et al., 2017). The mech
pacts of aging on cognitive changes will become increasingly important anism underlying the effect of insomnia in increasing the severity of AD
in the future (Bäckman et al., 2006; Harada et al., 2013; Helmchen and has been suggested to involve increased beta-amyloid production and
Reischies, 1998; Prinz et al., 1982; Raz and Rodrigue, 2006). Dementia decreased beta-amyloid clearance by poor sleep patterns (Cordone et al.,
is one of the most common syndromes in the elderly population, with 2019; Xie et al., 2013; Zhong et al., 2019). In addition, elderly subjects
almost 50 million people suffering from dementia worldwide, and with AD show significant sleep disturbance, including shortened sleep
* Corresponding author at: Department of Rehabilitation Science, Graduate School of Inje University, 197 Inje-ro, Gimhae, Gyeongsangnam-do, 50834, Republic of
Korea.
E-mail addresses: [email protected] (D.Md. Sumsuzzman), [email protected] (J. Choi), [email protected] (Y. Jin), [email protected]
(Y. Hong).
1
These authors contributed equally to this works.
https://doi.org/10.1016/j.neubiorev.2021.04.034
Received 4 July 2020; Received in revised form 1 April 2021; Accepted 30 April 2021
Available online 3 May 2021
0149-7634/© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
D.Md. Sumsuzzman et al. Neuroscience and Biobehavioral Reviews 127 (2021) 459–473
duration and fragmented sleep (Prinz et al., 1982; Spira et al., 2014; the results of the bibliographic database searches were screened, and a
Vitiello et al., 1990), as well as misalignment of circadian rhythm (Juby set of potentially eligible studies was identified.
et al., 1991; Uddin et al., 2020; Yesavage et al., 2004).
Melatonin is a naturally occurring hormone secreted by the pineal 2.2. Eligibility criteria
gland in the brain, and is thought to be beneficial in the management of
insomnia (Ferracioli-Oda et al., 2013; Luthringer et al., 2009; Wade Based Melatonin; cognition; Alzheimer’s disease; insomnia; healthy-
et al., 2011) and AD (Cardinali et al., 2002; Gehrman et al., 2009; subjects; systematic review; meta-analysis on the PICOS formula, the
Hossain et al., 2019; Luengo et al., 2019; Serfaty et al., 2002). The following selection criteria were used: Population: a) the included
mechanisms underlying these effects may be associated with balancing studies involved at least 50 % of participants with AD-type dementia
circadian rhythmicity (Hossain et al., 2019; Myers and Badia, 1995; diagnosed based on accepted criteria, such as Diagnostic and Statistical
Webb and Puig-Domingo, 1995), regulation of the immune system Manual of Mental Disorders-IV (DSM-IV), DSM-V, and National Institute
(Maestroni, 1993), and antioxidant properties (Hardeland et al., 1993; of Neurological and Communicative Disorders and Stroke-Alzheimer’s
Sumsuzzman et al., 2020). Misalignment of the circadian system and Disease and Related Disorders Association (NINCDS-ADRDA) (DSM-IV,
reduction of endogenous melatonin levels suggest that melatonin 1994; DSM-V, 2013; McKhann et al., 1984) of any level of severity
replacement therapy may be of considerable benefit for AD-type de measured by MMSE (Perneczky et al., 2006); b) included studies
mentia (Cardinali et al., 2014; Skene et al., 1990; Ohashi et al., 1999). involved participants with any type of typical insomnia features,
Although many studies have demonstrated that melatonin is effective in including persistent sleep difficulty, sufficient sleep opportunity, and
treating AD, the results were not consistent (Asayama et al., 2003; associated daytime dysfunction, diagnosed based on accepted criteria,
Dowling et al., 2008). Several meta-analyses have been performed such as DSM and self-reported sleep questionnaires (DSM-IV-TR, 2000;
regarding the use of melatonin to improve cognition in dementia (Jan Krystal et al., 2019); c) healthy adults.
sen et al., 2006; Wang et al., 2017; Xu et al., 2015), but these studies did Intervention and comparison: the included trials assessed the effects
not address how the duration of melatonin intervention differentially of orally administered melatonin monotherapy compared with placebo.
impacts cognition or which severity classes of AD show the greatest Outcome: cognition.
benefit of melatonin treatment. Study design: randomized controlled trials (RCTs), both parallel and
Benzodiazepines, a class of psychoactive drugs, are among the most crossover RCTs, with freely accessible full text, were considered for
widely prescribed medications for insomnia and circadian misalignment inclusion.
(Nowell et al., 1997; Scharf et al., 1990). Despite their crucial hypnotic We excluded the following: 1) other than AD-type dementia; 2)
effect, these medications also significantly decrease memory function apnea syndrome; 3) current/past history of serious medical illness; 4)
(Bixler et al., 1991; Chowdhury et al., 2016; Kamboj and Curran, 2006) circadian rhythm disturbances (jetlag-type, shiftwork type, altered sleep
and have other serious adverse effects (Glass et al., 2005; Guina and phase-type); and 5) case reports, case studies, reviews, bulletins, com
Merrill, 2018; Holbrook et al., 2000). Many studies have suggested that mentaries, and conference abstracts.
melatonin may be more suitable than benzodiazepines in the manage
ment of circadian misalignment and sleep disorders because melatonin 2.3. Study selection
improves sleep without significant performance impairment (Clay et al.,
2013; Ghaeli et al., 2018; Rogers et al., 2003, 1998). To date, there have Reporting of the reference management software may enhance
been no systematic reviews on the effects of melatonin on cognitive transparency, and reproducibility of systematic reviews. Therefore, we
function in adult participants with or without insomnia. used Mendeley as reference management software to organize and
This systematic review was performed to determine how the dura manage large volumes of references. Mendeley was also applied to
tion of melatonin intervention differentially impacts cognition in AD, remove duplicate articles. The remaining unique articles were then
which classes of AD according to severity show the greatest benefit of entered into the web-based systematic review app, Rayyan, specifically
melatonin treatment, to assess the clinical efficacy of melatonin inter designed to accelerate initial screening (Ouzzani et al., 2016). Two re
vention for cognitive function in insomnia, and to evaluate the clinical viewers then independently performed eligibility assessment. Dis
effectiveness of melatonin intervention for cognitive function in healthy agreements were resolved by discussion between the reviewers. During
subjects. primary screening, the records were screened based on the title and
abstract, and if a citation appeared eligible or ambiguous, its full text
2. Methods was considered. Any decision making after reading of the full text is
referred to as secondary screening. Finally, we contacted the authors to
The performance and reporting of this systematic review and meta- retrieve any missing data.
analysis (SR-MA) were performed in accordance with PRISMA guide
lines (Moher et al., 2009). This study also followed the recommenda 2.4. Data extraction
tions of Wager et al. (Wager and Wiffen, 2011) for the ethical
publication of SR-MA. Two investigators individually extracted the following information:
author name and year of publication, location, study design, sample size,
2.1. Search strategy population characteristics, interventions, and measured outcomes. With
regard to continuous data, the mean and standard deviation (SD) of
First, database searches were conducted in February 2020 using change score from baseline and the total number of participants for each
comprehensive search strings in PubMed, Embase, CINAHL, and intervention group at each time point were extracted. Where changes in
Cochrane library. Search strings were formulated from the following means and SDs from baseline to follow-up were not reported, the mean,
term sets: 1) sleep, insomnia, AD-type dementia, 2) melatonin, and 3) SD, and number of participants for each intervention group at each
study type. Citation retrieval was limited to human studies, English endpoint were extracted if available.
language, and age (18+). Second, the journals Sleep, Sleep Medicine, and
Journal of Pineal Research were searched for additional pertinent studies. 2.5. Risk of bias analysis
Third, we also screened the references of selected reports to identify
further studies. The literature search was completed on February 19, For risk of bias (RoB) analysis, the Cochrane RoB tools (Higgins and
2020. The search strings used for each database are shown in Appendix- Altman, 2008) were used to estimate performance, attrition, detection,
A. Finally, citation chasing was performed using Google Scholar after selection, and reporting biases. The RoB evaluation items included
460
generating random sequence, allocation concealment, blinding of pa 3. Results

tients and outcome assessors, incomplete outcome data, and selective
reporting. Two reviewers conducted the RoB assessment independently 3.1. Search results
of each other and then crosschecked their findings.
The electronic database search yielded 2642 articles, 881 of which
2.6. Data synthesis and statistical analysis were duplicates. After reviewing the titles and abstracts, 44 studies were
included for full text evaluation. A total of 22 trials were selected in this
Statistical analysis was performed using RevMan version 5.3 systematic review after application of eligibility criteria (Fig. 1).
(Cochrane Collaboration). We enumerated the mean differences (MDs)
where studies exercised the same scale for each outcome (Deeks et al., 3.2. Characteristics of studies
2011a), and the standardized mean differences (SMDs) where trials used
different scales (Deeks et al., 2011b). In parallel group studies, the mean Twenty-two RCTs met the inclusion criteria and investigated the
change scores were retrieved from baseline to follow-up for melatonin impact of melatonin on cognition in AD, insomnia, and healthy subjects.
and placebo treatment groups. Furthermore, in the case of multi-arm Of these, nine trials in AD patients (Asayama et al., 2003; Gao et al.,
intervention trials, we divided the shared group into two groups of 2009; Gehrman et al., 2009; Morales-Delgado et al., 2018; Rie
smaller sample size and included two comparisons (Higgins et al., mersma-van der Lek et al., 2008; Serfaty et al., 2002; Singer et al., 2003;
2011a), which reduced bias and overcame unit analysis error. If Wade et al., 2014; Xu et al., 2020), two in insomnia patients (Jean-Louis
reporting was vague, such as missing SD (change from baseline), as this et al., 1998; Luthringer et al., 2009), and 11 in healthy subjects
information was often not available from trial reports and has to be (Atkinson et al., 2005; Dollins et al., 1993, 1994; Gorfine et al., 2007;
imputed (Higgins et al., 2011b), the corresponding authors of the studies Gorfine and Zisapel, 2007; Lieberman et al., 1984; Otmani et al., 2008;
were emailed to request the missing information. If the authors did not Paul et al., 2003; Rogers et al., 2003, 1998; Suhner et al., 1998) were
respond, we calculated the missing values from other similar trials identified by citation searching. Eight of nine AD trials had a parallel
included in the same meta-analysis. In this case, we first computed the design (Asayama et al., 2003; Gao et al., 2009; Gehrman et al., 2009;
correlation using the following formula: Morales-Delgado et al., 2018; Riemersma-van der Lek et al., 2008;
Singer et al., 2003; Wade et al., 2014; Xu et al., 2020) and the remaining
Corr = SD2baseline + SD2follow-up− SD2change/2 × SDbaseline × SDfollow-up.
trial was a crossover study (Serfaty et al., 2002). Two of the nine AD
SDs of the changes from baseline were then calculated using the trials were excluded from the meta-analyses of cognitive outcomes as
formula: (Higgins et al., 2011c). the SDs of the change scores were not available for each measurement
time point reported in the studies (Gehrman et al., 2009; Serfaty et al.,
SDchange = √SD2baseline + SD2follow-up− (2 × Corr × SD baseline × SD follow- 2002). However, cognitive outcome data obtained with the MMSE were
up) pooled from seven studies (Asayama et al., 2003; Gao et al., 2009;
Morales-Delgado et al., 2018; Riemersma-van der Lek et al., 2008;
To avoid bias, we conducted sensitivity analyses by assuming cor
Singer et al., 2003; Wade et al., 2014; Xu et al., 2020), and data obtained
relation coefficients of 0.5 (low positive correlation) and 0.0 (negligible
with ADAS-Cog were pooled from three studies (Asayama et al., 2003;
correlation) (Mukaka, 2012). In the AD population, we performed our
Singer et al., 2003; Wade et al., 2014). Data from two studies (Gao et al.,
pre-planned subgroup analysis to determine how the duration of mela
2009; Riemersma-van der Lek et al., 2008) represented both short-term
tonin intervention differentially impacte from other similar trials inc
(< 12 weeks) and long-term (> 12 weeks) follow-up time points. Of
d cognition, and in which AD severity types melatonin treatment was
these, one study (Riemersma-van der Lek et al., 2008) included two of
most beneficial. In subgroup analysis, if the data of subgroups were in
four treatment and control arms studied with regard to the effects of
dependent, we used a fixed-effect inverse-variance weighted average
bright light and melatonin on the cognitive and non-cognitive symptoms
method; otherwise, a random-effects model was used (Deeks et al.,
of AD. The data pertaining to the groups that received bright light and
2011c).
bright light plus melatonin were not included in the analysis. Another
If there were no carry-over or period effects, the most appropriate
study also included more than one intervention group, i.e., one receiving
analysis of continuous data for a crossover study is the paired t-test
melatonin at a dose of 2.5 mg and another with a dose of 10 mg (Singer
(Higgins et al., 2011d). However, not all studies clearly reported paired
et al., 2003). These two groups were included in the meta-analysis, and
analyses. Therefore, for each study and each comparison, we calculated
the placebo group was split by sample size. Based on the severity of AD,
the SMD, the pooled SD, and the SE of the SMD (Higgins et al., 2011e).
three trials (Gao et al., 2009; Wade et al., 2014; Xu et al., 2020) were
When the correlation coefficient could not be obtained from raw data, a
classified as mild AD and four trials (Asayama et al., 2003; Moral
conservative value of 0.5 was assumed (Follmann et al., 1992). In our
es-Delgado et al., 2018; Riemersma-van der Lek et al., 2008; Singer
meta-analysis, we did not amalgamate change scores and final values in
et al., 2003) as moderate AD. For insomnia patients, one of two was
any analysis of SMDs. To avoid bias, we also did not unify the data from
crossover trial (Jean-Louis et al., 1998) and the another (Luthringer
parallel group and crossover trials. In addition, if the data could only be
et al., 2009) had a parallel design. Due to the review criteria and het
attained from figures, the data were extracted with GetData v 2.26
erogeneous outcomes, these studies were not included in the
software (Graph Digitizer). We pooled the available data using the
meta-analysis. On the other hand, all of the studies in healthy subjects
generic inverse variance approach, and applied a random-effects model
had a crossover design. Four of the eleven trials included were excluded
(Deeks et al., 2011d). In the absence of clinical or statistical heteroge
from the meta-analyses of cognitive outcomes as the SDs of the baseline
neity, we also applied a fixed-effect model for pooling. To assess sta
or change scores were not available for each measurement time point
tistical heterogeneity, we performed the chi2 test and calculated the I2
reported in the studies (Gorfine et al., 2007; Gorfine and Zisapel, 2007;
value (Deeks et al., 2011d). An estimate ≥ 50 % was taken to indicate
Otmani et al., 2008; Paul et al., 2003). However, cognitive outcome
moderate heterogeneity, and scores ranging from 75%–100% were
data, obtained from the reaction time, were pooled from seven studies
taken to indicate substantial heterogeneity (Higgins et al., 2003). To
(Atkinson et al., 2005; Dollins et al., 1993, 1994; Lieberman et al., 1984;
explore the possible factors for statistical heterogeneity, we performed
Rogers et al., 2003, 1998; Suhner et al., 1998), those regarding accuracy
post hoc subgroup analysis based on several melatonin doses and time of
subdomain with the number of correct responses were pooled from three
day of melatonin administration. In all analyses, p < 0.05 was taken to
studies (Dollins et al., 1993, 1994; Suhner et al., 1998), and those
indicate statistical significance.
regarding memory were pooled from three studies (Atkinson et al.,
2005; Rogers et al., 2003; Suhner et al., 1998). Melatonin doses ranged
461
Fig. 1. Flow diagram of the systematic review and literature search results of the meta-analysis.
from 5 to 80 mg; four trials used 5 mg (Atkinson et al., 2005; Rogers 3.3. Participant characteristics
et al., 2003, 1998; Suhner et al., 1998), two trials used 10 mg (Dollins
et al., 1993, 1994), and one trial used > 10 mg (Lieberman et al., 1984). The AD trials included in the analysis evaluated a total of 569 par
With regard to the time of day of melatonin administration in in ticipants with a mean age of 78.95 years. Overall, 43.76 % of partici
vestigations of the effect on memory, melatonin was administered at pants were male and 56.24 % were female. Several inventories were
noon (11:45, 12:00) in two trials (Atkinson et al., 2005; Rogers et al., applied for diagnosis of AD patients (Table 2). The effects of melatonin
2003), and afternoon (16:30) in one trial (Suhner et al., 1998). A wide on cognition were assessed in a total of 50 subjects with insomnia, with a
variety of outcome measures were used within these selected trials. We mean age of 64.77 years. Overall, 56.00 % of the participants with
divided these different outcome measures into three cognitive domains insomnia were male and 44.00 % were female. In healthy subjects, the
(Table 1). The detailed characteristics of the selected trials are shown in effects of melatonin on cognition were assessed in a total of 182 par
Table 2. ticipants with a mean age of 29.14 years. Overall, 71.48 % of the healthy
participants were male and 28.52 % were female.
462
Table 1 3.5. Effects of melatonin intervention on AD

Cognitive domains and related tests.
Cognitive Domain Test Long-term (> 12 weeks) melatonin treatment was more effective
than short-term (< 12 weeks) melatonin treatment as determined using
Mini mental state examination
Global cognitive function
Alzheimer’s disease assessment scale-cog the MMSE scale. Taken together, four studies (Gao et al., 2009; Rie
Delayed recall mersma-van der Lek et al., 2008; Wade et al., 2014; Xu et al., 2020) (220
Digit span participants) that used MMSE to measure cognitive function showed
Rivermead memory test that long-term melatonin treatment significantly improved global
Picture recognition task
Memory
California verbal learning test
cognitive function (MD = 1.82; 95 % CI: [1.01, 2.63]; p < 0.0001,
Spatial memory task I2 = 40 %) (Fig. 4). However, short-term melatonin treatment in five
GEMAT test studies (Asayama et al., 2003; Gao et al., 2009; Morales-Delgado et al.,
Recognition Reaction Time 2018; Riemersma-van der Lek et al., 2008; Singer et al., 2003) (319
Choice reaction time
participants) did not improve global cognitive function (MD = 0.30; 95
Wilkinson auditory vigilance task
Vigilance test % CI: [− 0.30, 0.90]; p = 0.33, I2 = 0%) (Fig. 4).
Digit vigilance task Based on the severity of AD, melatonin treatment significantly
Power of attention improved MMSE score in mild level AD (MMSE ≥ 20), while moderate
Serial reaction time AD (MMSE = 10–20) remained unchanged. Pooling the results of three
Serial subtraction task
Attention Multitask score
studies (Gao et al., 2009; Wade et al., 2014; Xu et al., 2020) (171 par
Choice visual reaction time ticipants) using MMSE to measure cognitive function in participants
Logical reasoning task with mild AD showed that melatonin treatment significantly improved
Beck-TENSOR global cognitive function (MD = 1.89; 95 % CI: [0.96, 2.82]; p < 0.0001,
Signal-detection
I2 = 55 %) (Fig. 5). In four studies in participants with moderate AD
Simple auditory reaction time
Digit symbol substitution test (Asayama et al., 2003; Morales-Delgado et al., 2018; Riemersma-van der
Motor reaction time Lek et al., 2008; Singer et al., 2003) (288 participants), melatonin
Verbal function Logical reasoning treatment did not improve global cognitive function (MD = − 0.01; 95 %
CI: [− 0.80, 0.79]; p = 0.98, I2 = 0%) (Fig. 5).
We calculated the correlation coefficients from the study by Wade
3.4. Risk of bias
et al. (Wade et al., 2014) to ascertain missing SDs. As sensitivity analysis,
we applied correlation coefficients of 0.5 and 0.0. Using a correlation
We separately appraised the RoB for parallel and crossover design
coefficient of 0.5 (> 12 weeks, p < 0.00001; mild AD, p < 0.0001)
trials; the abridged RoB assessment graph is shown in Fig. 2, and the
(Table 3, Supplementary Fig. 1&2), as well as 0.0 (> 12 weeks, p =
individual RoB scores of each study are shown in Fig. 3. Four parallel
0.0001; mild AD, p = 0.0001) (Table 3, Supplementary Fig. 3&4), the
design studies (Gao et al., 2009; Gehrman et al., 2009; Luthringer et al.,
pooled difference between treatment and placebo remained statistically
2009; Xu et al., 2020) inadequately reported methods for generating
significant.
random sequences, and two trial (Gao et al., 2009; Xu et al., 2020)
In terms of ADAS-Cog, both < 12 weeks and moderate AD subgroups
provided insufficient details about the allocation concealment, and were
had the same number and identical studies, likewise both > 12 weeks
considered unclear risks of selection bias (Fig. 2A, Fig. 3A). Based on
and mild AD subgroups. The meta-analysis results from all subgroup
adequate information pertaining to the blinding of participants and
trials using ADAS-Cog to measure cognitive impairment showed that
outcome assessment, we rated almost all trials as low risk of perfor
melatonin did not improve global cognition with treatment for < 12
mance as well as detection bias, with the exception of one study (Gao
weeks/moderate AD (MD = − 1.86; 95 % CI: [− 4.14, 0.43]; p = 0.11,
et al., 2009) with unclear RoB. We considered the risk of attrition bias to
I2 = 53 %) (Fig. 6) or > 12 weeks/mild AD (MD = 0.26; 95 % CI: [− 2.76,
be unclear in one study (Gehrman et al., 2009), and one study (Gehrman
3.28]; p = 0.87) (Fig. 6).
et al., 2009) apprised as unclear risk of selective reporting bias owing to
lack of information about completion of study by all the participants. We
3.6. Effects of melatonin on healthy subjects
considered one study (Gehrman et al., 2009) to have unclear risk of
other bias due to lack of information about study funding or potential
3.6.1. Effects of melatonin on attention domain
conflicts of interest of the investigators/authors; two studies (Luthringer
Fig. 7 summarizes the results related to the attention domain. We
et al., 2009; Wade et al., 2014) were at high RoB as the authors reported
divided the attention domain into two subdomains, i.e., 1) reaction time
having received financial support from a pharmaceutical company and
(higher score indicates poor outcome) and 2) accuracy (lower score
the sponsor/funder had directly engaged with the design, collection,
indicates poor outcome). Seven crossover trials (Atkinson et al., 2005;
management, analysis, and interpretation of the data; and one study was
Dollins et al., 1993, 1994; Lieberman et al., 1984; Rogers et al., 2003,
at low risk of other bias due to insufficient information about study
1998; Suhner et al., 1998) (118 patients) investigated the effects of
funding or potential conflicts of interest of the investigators/authors.
melatonin on reaction time using different assessment tools. The
All except one of the crossover studies had inappropriate de
following outcome measures were identified from these studies and
scriptions of the methods used for generating random sequences, allo
pooled: 1) Choice reaction time (CRT), 2) Choice visual reaction time
cating concealment, or blinding of participants and assessors; the one
(CVRT), 3) Vigilance tasks, and 4) Beck tensor analysis. The results
exception was a study that reported low risk of bias (Serfaty et al., 2002)
obtained by pooling of seven studies (Atkinson et al., 2005; Dollins et al.,
(Fig. 2B, Fig. 3B). Although the majority of studies had a low risk of
1993, 1994; Lieberman et al., 1984; Rogers et al., 2003, 1998; Suhner
attrition bias, three trials (Dollins et al., 1994; Lieberman et al., 1984;
et al., 1998) showed that melatonin did not increase the reaction time
Suhner et al., 1998) reported high risk of attrition bias due to handling of
scores (SMD = 0.29; 95 % CI: [− 0.34, 0.92]; p = 0.37, I2 = 89 %)
incomplete outcome data, and one study (Serfaty et al., 2002) had low
(Fig. 7A). We imputed a correlation coefficient of 0.5 for all crossover
risk of attrition bias. Most of the trials had a low risk of reporting bias,
trials. Our conclusions did not change when the melatonin and placebo
while the risk of reporting bias was unclear for five studies (Atkinson
results were substituted as sensitivity analysis with correlation co
et al., 2005; Dollins et al., 1994, 1993; Jean-Louis et al., 1998; Lieber
efficients of 0.8 (SMD = 0.30; 95 % CI: [− 0.33, 0.93]; p = 0.35, I2 = 96
man et al., 1984) due to insufficient information.
%) (Table 3, Supplementary Fig. 5) and 0.0 (SMD = 0.27; 95 % CI:
[− 0.36, 0.91]; p = 0.40, I2 = 78 %) (Table 3, Supplementary Fig. 8).
463
Table 2
Characteristics of the studies.
Author, Year (Location) Study Participants Diagnosis criteria Intervention (Time) Control Cognitive outcomes
design
AD
Serfaty et al., 2002 (UK) Cross- Total: n = 25 (16 male, DSM-IV MT-6 mg/day for 2 wk PLA MMSE
over 9 female); 84.2 ± 7.6 y (Before bed)
Total: n = 20 (3 male,
17 female); 79.2 ± 6.4
y
Asayama et al., 2003 Parallel- MT-3 mg/day for 4 wk
1. MT group: n = 11 NINCDS-ADRDA, DSM-IV PLA MMSE, ADAScog
(Japan) group (Before bed)
(78.9 ± 7.3 y)
2. PLA group: n = 9
(79.4 ± 5.3 y)
Total: n = 157 (69
male, 88 female); 1. MT-2.5 mg/day for 8 wks
77.4 ± 8.9 y
Parallel- 1. MT group (2.5 mg):
Singer et al., 2003 (USA) NINCDS-ADRDA PLA MMSE, ADAScog
group n = 54
2. MT-10 mg/day for 8 wks
2. MT group (10 mg): n
(Before bed)
= 51
2. PLA group: n = 52
78 female); 85.5 ± 5 y
Riemersma-van der Lek
Parallel- 1. MT group: n = 46 MT-2.5 mg/day for 6 wks-
et al., 2008 NINCDS-ADRDA, DSM-IV PLA MMSE
group (86 ± 5 y) 3.5 y (Before bed)
(Netherlands)
(85 ± 5 y)
Total: n = 36 (All
Parallel- male); 77.0 ± 2.9 y MT-2.9 mg/day for 24 wks
Gao et al., 2009 (China) NINCDS-ADRDA PLA MMSE
group 1. MT group: n = 15 (Before bed)
female 28); 82.9 ± 7.0 MT-10 mg (8.5 mg
Gehrman et al., 2009 Parallel-
y NINCDS-ADRDA IR + 1.5 mg SR)/day for 10 PLA MMSE
(USA) group
1. MT group: n = 24 days (Before bed)
Wade et al., 2014 (U.S.A Parallel- 39 female); 75.3 y MT-2 mg/day for 24 wks
MMSE score ≥ 15 PLA MMSE, ADAScog
and U.K) group 1. MT group: n = 39 (Before bed)
24 female); 82.65 y
Morales Delgado et al., Parallel- 1. MT group: n = 21 MT-5 mg/day for 8 wks
DSM-V, CDR = 1− 2 PLA MMSE
2018 (Mexico) group (82.2 ± 5.8 y) (Before bed)
(83.1 ± 7.4 y)
37 female); 66.40 y
Parallel- 1. MT group: n = 40 MT-0.15 mg/day for 24 wks
Xu et al., 2020 (China) DSM-IV PLA MMSE
group (66.3 ± 8.8 y) (Before bed)
(66.5 ± 8.3 y)
Insomnia
Self-reported sleep-wake disturbances:
Jean-Louis et al., 1998 Cross- Total: n = 10 (4 male, 6 MT-6 mg/day for 10 days
(1) difficulty initiating sleep, and (2) PLA Delayed recall
(U.S.A) over female); 68.8 ± 15.8 y (Before bed)
frequent nocturnal awakenings
16 female)
Luthringer et al., 2009 Parallel- 1. MT group: n = 20 MT-2 mg/day for 3 wk
DSM-IV criteria for primary insomnia PLA MRT, RRT
(Israel) group (59.6 ± 2.9 y) (Before bed)
(61.9 ± 4.8 y)
Healthy-subject
Atkinson et al., 2005 (U. Cross- Total: n = 12 (all
Healthy-subject MT-5 mg single dose (11:45) PLA Digit span, CRT
K) over male); 25.2 ± 5.0 y
Dollins et al., 1993 (U.S. Cross- Total: n = 20 (all MT-10, 20, 40, 80 mg single
Healthy-subject PLA WAV, CRT
A) over male); 25 y dose (11:45)
Dollins et al., 1994 (U.S. Cross- Total: n = 20 (all MT- 0.1, 0.3, 1.0, 10 mg
Healthy-subject PLA WAV, CRT
A) over male); 23.05 y single dose (11:45)
Gorfine et al., 2007 Cross- Total: n = 13 (7 male, 6 MT-2 mg single dose
Healthy-subject PLA fMRI
(Israel) over female); 25.7 ± 3 y (12:30− 14:00)
Gorfine and Zisapel, 2007 Cross- Total: n = 12 (7 male, 5
Healthy-subject MT-2 mg single dose (16:00) PLA fMRI
(Israel) over female); 26 ± 3.7 y
Healthy-subject MT-2 mg for 2 days (20:00) PLA DVT, POA, PRT, RMT
(continued on next page)
464
Table 2 (continued )
Author, Year (Location) Study Participants Diagnosis criteria Intervention (Time) Control Cognitive outcomes
design
Otmani et al., 2008 Cross- Total: n = 16 (12 male,

(Israel) over 4 female); 59.4 ± 3.2 y
Paul et al., 2003 (Canada) Cross- Total: n = 23 (9 male Healthy-subject MT-6 mg single dose (09:45) PLA SRT, LRT, SST,
over and 14 female); multitask score
29.9 ± 10.3 y
Rogers et al., 1998 Cross- Total: n = 16 (10 male Healthy-subject MT-5 mg single dose (12:30) PLA CVRT
(Australia) over and 6 female), 22.4 y
Rogers et al., 2003 Cross- Total: n = 16 (6 male Healthy-subject MT-5 mg single dose (12:00) PLA Spatial memory,
(Australia) over and 10 female), 21.4 y vigilance test, logical
reasoning
Suhner et al., 1998 Cross- Total: n = 20 (12 male Healthy-subject MT-5 mg single dose (16:30) PLA GEMAT test, signal-
(Switzerland) over and 8 female); 31 y detection, Beck-
TENSOR
Lieberman et al., 1984 (U. Cross- Total n = 14 (all male); Healthy-subject MT-80 mg 3 times 2 h period PLA CRT
S.A) over 31.5 y (12:00− 14:00)
Age data are mean ± standard deviation.

AD, Alzheimer’s disease; n, Number; y, Years; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders-IV; MT, Melatonin; wk, Week; PLA, Placebo; MMSE, Mini-
Mental State Examination; NINCDS-ADRDA, National institute of neurological and communicative disorders and stroke and the Alzheimer’s disease and related
disorders association; ADAS-cog, Alzheimer’s disease assessment scale-cog; MRT, Motor reaction time; RRT, Recognition reaction time; CRT, Choice reaction time;
CLVT, California verbal learning test; WAV, Wilkinson auditory vigilance task; fMRI, functional magnetic resonance imaging; DVT, Digit vigilance task; POA, Power of
attention; PRT, Picture recognition task; RMT, Rivermead memory test; SRT, Serial reaction time; LRT, Logical reasoning task; SST, Serial subtraction task; CVRT,
Choice visual reaction time.
Fig. 2. Risk of bias graph. (A) Parallel studies, (B) Crossover studies.
On the other hand, three crossover trials (Dollins et al., 1993, 1994; trials. Our conclusions did not change when the melatonin and placebo
Suhner et al., 1998) (60 patients), investigated the effects of melatonin results were substituted as sensitivity analysis with correlation co
on accuracy using different assessment tools. The following outcome efficients of 0.8 (SMD = − 0.77; 95 % CI: [− 1.10, − 0.44]; p < 0.00001,
measures were identified from these studies and pooled: 1) Wilkinson I2 = 69 %) (Table 3, Supplementary Fig. 6), and 0.0 (SMD = − 0.74; 95
auditory vigilance (WAV) task and 2) signal detection. The results from % CI: [− 1.15, − 0.33]; p = 0.0004, I2 = 0%) (Table 3, Supplementary
pooling of these three studies (Dollins et al., 1993, 1994; Suhner et al., Fig. 9). However, the heterogeneity increased with a correlation coef
1998) showed that melatonin significantly decreased accuracy ficient of 0.8 and heterogeneity decreased with a correlation coefficient
(SMD = − 0.74; 95 % CI: [− 1.03, − 0.45]; p < 0.00001, I2 = 19 %) of 0.0.
(Fig. 7B). We imputed a correlation coefficient of 0.5 for all crossover
465
Fig. 3. Risk of bias summary. (A) Parallel studies, (B) Crossover studies.
Fig. 4. Forest plot comparing the changes in the MMSE scale score between melatonin and placebo groups with short-term (< 12 weeks) and long-term (> 12 weeks)
treatment in AD. MMSE, mini-mental state examination; AD, Alzheimer’s disease; CI, confidence interval; SD, standard deviation; IV, independent variable.
466
Fig. 5. Forest plot comparing the changes in the MMSE scale score between melatonin and placebo groups according to different severity of AD. MMSE, mini-mental
state examination; AD, Alzheimer’s disease; CI, confidence interval; SD, standard deviation; IV, independent variable.
Table 3
Summary of sensitivity analysis.
Correlation coefficient 0.80 Correlation coefficient 0.00
Outcome measures
2
Trials (n) Effect size (95 %CI) p-value I Trials (n) Effect size (95 %CI) p-value I2
Reaction time 7 SMD 0.30 [-0.33, 0.93] 0.35 96 % 7 SMD 0.27 [-0.36, 0.91] 0.40 78 %
Accuracy 3 SMD -0.77 [-1.10, -0.44] <0.00001 69 % 3 SMD -0.74 [-1.15, -0.33] 0.0004 0%
Memory 3 SMD -0.82 [-1.72, 0.08] 0.07 94 % 3 SMD -0.76 [-1.67, 0.14] 0.10 71 %
MMSE (<12 weeks) 5 MD 0.18 [-0.53, 0.88]* 0.62 0% 5 MD 0.07 [-0.71, 0.86] 0.85 0%
MMSE (>12 weeks) 4 MD 1.88 [1.13, 2.63]* <0.00001 0% 4 MD 1.84 [0.89, 2.79] 0.0001 0%
MMSE (moderate level AD) 4 MD -0.05 [-0.89, 0.80]* 0.91 0% 4 MD -0.06 [-0.93, 0.80] 0.88 0%
MMSE (mild level AD) 3 MD 1.91 [1.06, 2.75]* <0.0001 17% 3 MD 1.87 [0.91, 2.84] 0.0001 0%
SMD = standardized mean difference; CI = confidence interval, MMSE = mini mental state examination, AD = Alzheimer’s disease; MD = mean difference.
*
Correlation coefficient 0.50.
Fig. 6. Forest plot comparing the changes in the ADAS-Cog scale score between melatonin and placebo groups based on the duration of treatment and severity of AD.
ADAS-Cog, Alzheimer’s Disease Assessment Scale cognitive subscale; AD, Alzheimer’s disease; CI, confidence interval; SD, standard deviation; IV, indepen
dent variable.
3.6.2. Effects of melatonin on memory domain different assessment tools. The following outcome measures were
Fig. 8 summarizes the results of the memory domain. Three crossover identified from these studies and pooled: 1) short-term memory by digit
trials (Atkinson et al., 2005; Rogers et al., 2003; Suhner et al., 1998) (48 span test, 2) spatial memory test, and 3) visual memory by GEMAT test.
patients) investigated the effects of melatonin on memory using The results of pooling of these three studies (Atkinson et al., 2005;
467
Fig. 7. Forest plot comparing the changes in attention between melatonin and placebo groups in healthy subjects. (A) Reaction time. (B) Accuracy. CI, confidence
interval; SD, standard deviation; IV, independent variable.
Fig. 8. Forest plot comparing the changes in memory function between melatonin and placebo groups in healthy subjects. CI, confidence interval; SD, standard
deviation; IV, independent variable.
Rogers et al., 2003; Suhner et al., 1998) showed that melatonin did not placebo results were substituted as sensitivity analysis with correlation
reduce memory domain (SMD = − 0.79; 95 % CI: [− 1.70, 0.11]; p = coefficients of 0.8 (SMD = − 0.82; 95 % CI: [− 1.72, 0.08]; p = 0.07,
0.08, I2 = 85 %) (Fig. 8). We imputed a correlation coefficient 0.5 for all I2 = 94 %) (Table 3, Supplementary Fig. 7), and 0.0 (SMD = − 0.76; 95
crossover trials. Our conclusions did not change when the melatonin and % CI: [− 1.67, 0.14]; p = 0.10, I2 = 71 %) (Table 3, Supplementary
Fig. 9. Forest plot comparing the changes in reaction time among several doses of melatonin and placebo groups in healthy subjects. CI, confidence interval; SD,
standard deviation; IV, independent variable.
468
Fig. 10). in insomnia patients based on these studies. One of the two studies re
ported that chronic nighttime melatonin treatment improved memory
3.6.3. Subgroup analysis without any detrimental effects (Jean-Louis et al., 1998). This study
We performed subgroup analysis to examine heterogeneity. Ac suggested that prolonged melatonin treatment might yield better results
cording to the reaction time, we found I2 = 89 %, which indicated with regard to cognition and non-cognition behavior because melatonin
considerable heterogeneity, and therefore performed post hoc subgroup can improve sleep quality, which further might be involved in cognition
analysis based on different melatonin doses. Four trials (Atkinson et al., and non-cognition behavior improvement. The remaining one study
2005; Rogers et al., 2003, 1998; Suhner et al., 1998) assessed the showed that daytime cognitive performance was not impaired by
effectiveness of a melatonin dose of 5 mg compared with placebo ac melatonin and consistently improved cognition compared with placebo.
cording to reaction time. The meta-analysis demonstrated that mela
tonin did not increase the reaction time scores (SMD = − 0.36; 95 % CI: 4. Discussion
[− 0.79, 0.07]; p = 0.10, I2 = 64 %) (Fig. 9). The heterogeneity among
the trials was low (I2 = 64 %, p = 0.10) (Fig. 9). Two trials (Dollins et al., This systematic review summarized the available evidence regarding
1993, 1994) assessed the effectiveness of a melatonin dose of 10 mg the effects of melatonin on cognitive function in AD, insomnia, and
compared with placebo according to reaction time. The meta-analysis healthy subjects. Our meta-analysis suggested that patients with AD
demonstrated that melatonin significantly increases the reaction time could eventually show benefits with regard to increased MMSE scores (p
scores (SMD = 1.12; 95 % CI: [0.73, 1.52]; p < 0.00001, I2 = 0%) < 0.0001) after 12 weeks of melatonin therapy, while the ADAS-Cog
(Fig. 9). There was no statistical heterogeneity among the trials (I2 = 0%, scale remained unchanged. Furthermore, melatonin treatment may be
p < 0.00001) (Fig. 7). Only one trial (Lieberman et al., 1984) assessed more effective in mild than moderate AD (p < 0.0001). However,
the effectiveness of a melatonin dose > 10 mg compared with placebo inconsistent effects of melatonin have appeared on the ADAS-Cog scale.
according to reaction time. The meta-analysis demonstrated that mela One possible explanation for this discrepancy is that the ADAS-Cog scale
tonin significantly increases the reaction time scores (SMD = 1.40; 95 % is not subtle enough to record and monitor variance in the mildest stages
CI: [0.66, 2.14]; p < 0.00001) (Fig. 9). of AD (Hobart et al., 2013; Kueper et al., 2018). Further work is required
For the memory domain, I2 = 85 % indicated considerable hetero to modify the ADAS-Cog scale or develop a new test. Previous
geneity. Therefore, we performed post hoc subgroup analysis based on meta-analyses had many limitations. First, they only investigated the
time of day of melatonin administration. Two trials (Atkinson et al., overall effects of melatonin intervention, and all of the studies reported
2005; Rogers et al., 2003) assessed the effectiveness of melatonin that cognitive function did not change significantly with melatonin
administered at noon according to the memory domain. The therapy (Jansen et al., 2006; Wang et al., 2017; Xu et al., 2015). These
meta-analysis demonstrated that melatonin significantly decreased three meta-analyses did not clarify how the duration of melatonin
memory (short-term and spatial memory) (SMD = − 1.24; 95 % CI: intervention differentially impacted cognition, and which types of AD
[− 1.74, − 0.74]; p < 0.00001, I2 = 0%) (Fig. 10). There was no statistical with regard to severity showed the greatest benefit after melatonin
heterogeneity among the trials (I2 = 0%, p < 0.00001). Only one trial treatment (Jansen et al., 2006; Wang et al., 2017; Xu et al., 2015). Next,
(Suhner et al., 1998) assessed the effectiveness of melatonin adminis it is generally accepted that analysis based on changes from the baseline
tered in the afternoon according to the memory domain. The are more reliable than studies based on the final values (Deeks et al.,
meta-analysis demonstrated that melatonin did not decrease memory 2011e). We calculated the change score in our meta-analysis, while
(visual memory) (SMD = − 0.02; 95 % CI: [− 0.45, 0.41]; p = 0.93) Wang et al. (Wang et al., 2017) used final values. Although Xu et al. (Xu
(Fig. 10). et al., 2015) calculated the change score in their meta-analysis, they did
not split the placebo group with smaller sample size from one study
(Singer et al., 2003), which increased unit-of-analysis error (Higgins
3.7. Effects of melatonin on subjects with insomnia et al., 2011a). To address this issue, we divided the placebo group into
smaller sample sizes for independent comparison, which was therefore
Although there have been few studies of cognitive outcomes in free of unit analysis error. Overall, our study not only solved the above
insomnia patients, our literature search identified two studies (Jean- limitations, but also added more citations than previous meta-analyses.
Louis et al., 1998; Luthringer et al., 2009) that assessed several cognitive Therefore, this study was more valuable than previous similar studies.
outcomes after melatonin treatment in subjects with insomnia. Although There is accumulating evidence that melatonin restores the sleep/
we could not combine the data due to the differences in study design and wake cycle, enhances sleep quality and daytime activity, and sustains
outcomes measured, we descriptively analyzed the effects of melatonin
Fig. 10. Forest plot comparing the changes in memory function between ingestion of melatonin at noon and afternoon and placebo groups in healthy subjects. CI,
confidence interval; SD, standard deviation; IV, independent variable.
469
the physiological sleep structure in insomnia patients (Lemoine and day had no such negative effect on reaction time (Atkinson et al., 2005;
Zisapel, 2012; Wade et al., 2007, 2011). This may explain why mela Suhner et al., 1998).
tonin showed a greater beneficial effect on cognition in mild to moderate Our review had several intrinsic limitations, the most pronounced of
AD patients with insomnia as a comorbidity (Wade et al., 2014). which is that we were only able to find and combine small amounts of
Importantly, the management of sleep complaints with long-established data, e.g., we only combined data on the global cognitive scale, and were
hypnotics may not be advantageous and even detrimental in healthy not able to include other cognitive outcomes, including attention, short-
middle-aged and elderly subjects due to the loss of cognitive function term memory, and long-term memory in AD patients. In addition, we
associated with these drugs (Chavant et al., 2011; Leufkens et al., 2009; were unable to perform a meta-analysis of results in insomnia patients
Otmani et al., 2008). In addition, long-term ingestion of benzodiazepine due to the heterogeneity of study design and outcome measures. Most of
has been linked to an increased risk of dementia (Ettcheto et al., 2020; the included crossover studies did not provide sufficient details
Gray et al., 2016; He et al., 2019; Wu et al., 2009). Our systematic re regarding selection, performance, and detection domain, which is a
view showed that chronic nighttime melatonin treatment improved major drawback of these crossover studies and led to unclear risk of bias.
cognition without any detrimental effects, and daytime cognitive per Despite the promising fields of application, various aspects require
formance was not impaired by melatonin and consistently improve further research. The AD trials included in the analysis were primarily
cognition with melatonin treatment when compared with placebo. As focused on the impacts of melatonin on the global cognitive score
melatonin improves sleep without any significant risk of memory or (MMSE, ASAS-Cog). Nonetheless, it would be intriguing to examine its
cognitive decline, the improvement of sleep can also contribute to effects on other cognitive domains, such as episodic memory. Further
improvement of cognition by melatonin in AD and/or insomnia patients, more, we could not determine the differential impacts of melatonin
as suggested in the present systematic review and meta-analysis. A ingestion according to sex in AD patients, so further sex-specific trials
recent review of published results on the use of melatonin in mild are required. We were unable to perform meta-analysis of the results in
cognitive impairment yielded 12 reports (2 open-label retrospective insomnia patients due to heterogeneity of studies, and therefore addi
study, 1 cohort study, 9 randomized controlled trials) that supported tional parallel studies with larger sample sizes in different cognitive
melatonin administration improves cognitive performance and sleep domains are required. Additionally, we were unable to analyze how
quality (Cardinali, 2019). melatonin individually impacts short-term, spatial, visual, and working
In healthy subjects, the present meta-analysis showed that daytime memory due to the unavailability of the abundance of studies, and
melatonin administration did not impair memory function (p = 0.08, therefore more RCT with larger sample sizes in different memory do
I2 = 85 %) or reaction time (p = 0.37, I2 = 89 %), although melatonin mains are urgently warranted. Both immediate and sustained-release
significantly decreased accuracy subdomain with the number of correct formulations of melatonin were used in our included trials. A study re
responses (p < 0.00001, I2 = 19 %). We performed subgroup analyses ported that these preparations exert similar therapeutic benefits related
due to the high degree of heterogeneity between memory and reaction to melatonin’s action as an antioxidant (Rybka et al., 2016). However,
time outcomes. Based on the time of day of melatonin administration in the question of whether different melatonin formulations have similar
the memory domain, the subgroup analysis demonstrated that treatment efficacy in improving cognition deserves further research in well-design
with melatonin at noon significantly reduced memory function (p < multicenter clinical trials. Finally, we recommend improving the
0.00001, I2 = 0%), while administration in the afternoon did not (p = reporting system for crossover studies to reduce the risk of bias.
0.93). Although these two timepoints assess different types of memory,
this finding is important as several studies reported that melatonin had 5. Conclusion
beneficial effects when administered in the afternoon compared with
other times of the day (Claustrat et al., 1992; Crowley and Eastman, The available evidence suggests that melatonin treatment for > 12
2013; Eastman and Burgess, 2009; Nickelsen et al., 1989). In addition, weeks may be effective for improvement of cognitive functioning in AD.
the results of this study indicated that memory function was decreased In particular, patients with mild AD may show greater beneficial effects
following ingestion of melatonin at noon, but was unchanged by mela of melatonin intervention than those with moderate AD. This will be
tonin administered in the afternoon, which also supported the results of valuable for caregivers to decrease the burden of AD. Although daytime
a previous study (Suhner et al., 1998). Furthermore, subgroup analysis melatonin administration produced a significant reduction of accuracy,
demonstrated that a melatonin dose of 5 mg administered during the day the other cognitive subdomains, such as reaction time and memory,
did not negatively correlate with reaction time score (p = 0.10, I2 = 64 remained unchanged by melatonin treatment. Therefore, we propose
%); however, doses of 10 mg (p < 0.00001, I2 = 0%) and ≥ 10 mg (p = that melatonin may be preferable to traditional hypnotics, such as
0.0002) adversely correlate with reaction time score. These findings benzodiazepines, in the management of circadian disruption and
interpret that a low dose of melatonin did not negatively induce neu insomnia. Finally, before melatonin intervention can be recommended
robehavioral performance; however, a higher dose of melatonin shows for the improvement of cognition, as adjuvant AD therapy or as an
the opposite effect. In human trials, acute melatonin treatment may alternative of traditional hypnotics, further high-quality studies with
increase subjective feelings of fatigue and cause a reduction in perfor larger sample sizes and longer duration are needed.
mance. The previous literatures demonstrated that a large acute dose of
melatonin ingested at noon increases reaction time and induces Funding
drowsiness and sometimes sleep (Lieberman et al., 1982; Nickelsen
et al., 1989). Furthermore, many studies reported that ingestion of ≥ This work was supported in part by grants from the National
10 mg of melatonin at midday was associated not only with a significant Research Foundation(2017R1D1A1B0302956514, 2020R1A2C201215
reduction in oral temperature, feelings of vigor, and decrease 511 to Y.H.), Korea. J.C. is supported by a post-doctoral fellowship from
working-memory, but also increases feeling of sleepiness, fatigue, National Research Foundation (NRF-2019R1A6A3A01091422 to J.C.),
confusion, and reaction time (Dollins et al., 1993; Lieberman et al., Korea. This work was also supported by the 2016-2018 Creative
1982; Nickelsen et al., 1989). Interestingly, administration of 5 mg of Research Program of Inje University, Korea.
melatonin at the same time of day had no negative association with
reaction time score (Atkinson et al., 2005; Lok et al., 2019; Suhner et al., Author contributions
1998). Our meta-analysis agreed with the consensus of previous studies
that ingestion of melatonin at a dose ≥ 10 mg at midday increased re Conceptualization, Y.H.; methodology, D.M.S. and J.C.; software, D.
action time (Dollins et al., 1993; Lieberman et al., 1982; Nickelsen et al., M.S., J.C. and Y.J.; validation, Y.H.; formal analysis, D.M.S., J.C. and Y.
1989), while a dose of 5 mg of melatonin ingested at the same time of J.; investigation, D.M.S., J.C. and Y.J.; resources, D.M.S., J.C. and Y.J.;
470
data curation, D.M.S., J.C. and Y.J.; writing-original draft preparation, Crowley, S.J., Eastman, C.I., 2013. Melatonin in the afternoons of a gradually advancing
sleep schedule enhances the circadian rhythm phase advance. Psychopharmacology
Y.H. and D.M.S.; writing-review and editing, Y.H. and D.M.S.; visuali
(Berl.) 225, 825–837. https://doi.org/10.1007/s00213-012-2869-8.
zation, D.M.S., J.C. and Y.J.; supervision, Y.H.; project administration, Deeks, J.J., Higgins, J.P.T., Altman, D.G., 2011a. https://handbook-5-1.cochrane.
Y.H.; funding acquisition, Y.H. All authors have read and agreed to the org/chapter_9/9_2_3_1_the_mean_difference_or_difference_in_means.htm (accessed
published version of the manuscript. 13 May 2020).
Deeks, J.J., Higgins, J.P.T., Altman, D.G., 2011b. https://handbook-5-1.cochrane.
org/chapter_9/9_2_3_2_the_standardized_mean_difference.htm (accessed 13 May
2020).
Declaration of Competing Interest Deeks, J.J., Higgins, J.P.T., Altman, D.G., 2011c. https://handbook-5-1.cochrane.org/ch
apter_9/9_6_3_1_is_the_effect_different_in_different_subgroups.htm (accessed 13 May
2020).
The authors report no declarations of interest. Deeks, J.J., Higgins, J.P.T., Altman, D.G., 2011d.https://handbook-5-1.cochrane.org/cha
pter_9/9_analysing_data_and_undertaking_meta_analyses.htm (accessed 13 May
2020).
Acknowledgments Deeks, J.J., Higgins, J.P.T., Altman, D.G., 2011e. https://handbook-5-1.cochrane.org/
chapter_9/9_4_5_2_meta_analysis_of_change_scores.htm (accessed 13 May 2020).
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Neuroscience and Biobehavioral Reviews 127 (2021) 459–473

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

Neurocognitive effects of melatonin treatment in healthy adults and

1. Introduction roughly 82 million people projected to have dementia by 2030 (World

generating random sequence, allocation concealment, blinding of pa 3. Results

Table 1 3.5. Effects of melatonin intervention on AD

Otmani et al., 2008 Cross- Total: n = 16 (12 male,

Age data are mean ± standard deviation.

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J.neubiorev.2021.04.034 Ejemplo de Revisión

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J.neubiorev.2021.04.034 Ejemplo de Revisión

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J.neubiorev.2021.04.034 Ejemplo de Revisión

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Neuroscience and Biobehavioral Reviews 127 (2021) 459–473

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

Neurocognitive effects of melatonin treatment in healthy adults and

1. Introduction roughly 82 million people projected to have dementia by 2030 (World

generating random sequence, allocation concealment, blinding of pa­ 3. Results

Table 1 3.5. Effects of melatonin intervention on AD

Otmani et al., 2008 Cross- Total: n = 16 (12 male,

Age data are mean ± standard deviation.

You might also like

generating random sequence, allocation concealment, blinding of pa 3. Results