melatonin and sleep disorders associated with intellectual disability: a clinical review

Journal of Intellectual Disability Research doi: 10.1111/j.1365-2788.2006.00893.x

pp

–

©

The Authors. Journal Compilation ©

Blackwell Publishing Ltd

2

Blackwell Publishing LtdOxford, UKJIRJournal of Intellectual Disability Research

-

©

The Authors. Journal compilation ©


1213

Original Article

Melatonin and sleep disorders associated with intel-

lectual disabilityS. G. Sajith & D. Clarke

Correspondence: Dr David Clarke, Lea Castle Centre, Kidderminster DY

PP, UK (e-mail: [email protected]).

Melatonin and sleep disorders associated with intellectual disability: a clinical review

S. G. Sajith & D. Clarke

Lea Castle Centre, Kidderminster, UK

Abstract

Background

Melatonin is used to treat sleep disor-ders in both children and adults with intellectual disability (ID), although it has no product license for such use. The evidence for its efficacy, potential adverse effects and drug interactions are reviewed in the context of prescribing to people with ID.

Methods

A literature search was performed using multiple electronic databases. More literature was obtained from the reference lists of papers gathered through the searches.

Results

Most of the studies were uncontrolled and the few controlled trials available were of small size. Melatonin appears effective in reducing sleep onset latency and is probably effective in improving total sleep time in children and adolescents with ID. It appears to be ineffective in improving night-time awakenings. Melatonin is relatively safe for short-term use. Its safety for long-term use is not estab-lished. Potential drug interactions, possible effects on puberty and concerns regarding the use of melatonin in epilepsy, asthma and depressive disorders are discussed.

Conclusions

Melatonin appears to be an effective sleep-initiator for children and adolescents with ID

and probably has a similar effect for adults. There may be heterogeneity of response depending on the nature of the sleep problem and cause of the ID or associated disabilities. Further studies are necessary before firm conclusions can be drawn and guidelines for the use of melatonin for people with ID formulated.

Keywords

adverse reactions, drug interactions, efficacy, intellectual disability, melatonin, sleep disorder

Introduction

Children and adults with neurological, neuropsychi-atric and developmental disabilities are predisposed to chronic sleep–wake cycle disturbances (circadian rhythm sleep disorders). Conditions such as visual or hearing impairment, autism, central nervous system diseases and intellectual disability (ID) diminish the ability of these individuals to perceive and interpret cues for synchronizing their sleep with the environ-ment. Among children and adolescents, figures rang-ing from

.

% to

% have been reported and sleep problems are often persistent (Quine

). Com-mon problems are settling difficulties and night-time awakenings. The literature on sleep problems in adults with ID is limited and a prevalence of around

% has been reported (Gunning & Espie

).

Journal of Intellectual Disability Research

S. G. Sajith & D. Clarke •

Melatonin and sleep disorders associated with intellectual disability3

©



Sleep problems can be associated with deteriora-tion in daytime performance and an increase in chal-lenging behaviours during the day in both children (Wiggs & Stores

) and adults (Brylewski & Wiggs

) with ID. In children, sleep problems are asso-ciated with maternal stress and maternal irritability (Quine

).Medications such as antihistamines and benzodi-

azepines have been used to treat sleep problems in people with ID when sleep hygiene measures, envi-ronmental changes and behavioural programmes fail to achieve the desired outcome. Recently, melatonin has gained increasing acceptance as a treatment for sleep disorders associated with ID, especially for chil-dren and adolescents (Bramble & Feehan

). There are no established guidelines for its use. Use of melatonin for sleep problems associated with ID, evidence for its efficacy, information about potential adverse effects and interactions with other drugs are reviewed here in a format intended to be helpful to prescribers and others involved with the care of peo-ple who have ID.

Method

A literature search was performed using the elec-tronic databases MEDLINE (

to February

), EMBASE (

to February

), Allied & Complementary Medicine (

to February

) and PsycINFO (

to February

). The key-words used for the search were melatonin, sleep dis-orders, adverse reactions, toxicity, safety, interactions and the various terms used to refer to ID historically and in other countries (including mental retardation, mental handicap, intellectual disability, mental sub-normality and learning disability). No language restrictions were applied. Further references were obtained from articles identified during the search. No inclusion or exclusion criteria were applied and all the relevant articles, including single-case reports, were examined for the purpose of the review.

Results

Melatonin

Melatonin (N-acetyl-

-methoxy-tryptamine) is an endogenous hormone secreted by the pineal gland. It

is synthesized from tryptophan, which is converted first to serotonin (

-hydroxytryptamine), then to N-acetylserotonin, and finally to melatonin. Melatonin is also synthesized and secreted at various other sites in the body, including the retina and gastrointestinal tract. The synthesis of melatonin in the pineal gland is influenced by the cyclical change from daylight to darkness. It is mediated through a retinohypotha-lamic-pineal system involving the retinohypothalamic tract, suprachiasmatic nuclei (SCN) and the sympa-thetic nervous system with noradrenergic input to receptors in pinealocytes. During daylight hours, this system is quiescent and little melatonin is secreted. When it is dark, the system is activated, leading to synthesis and release of melatonin. The blood level of melatonin normally peaks at around

h, declines until early morning and then remains at a very low level during the day. Melatonin is removed from the body primarily through sulpho- and glucurono-conjugation, and the conjugates are then eliminated in the urine (Simonneaux & Ribelayga

). Mela-tonin secretion or serum level varies between individ-uals; it usually decreases with advancing age from a peak level at the age of

–

years to a very low level in old age (Waldhauser

et al

.

).There is substantial evidence that melatonin plays

an important role in the promotion of sleep. The onset of melatonin secretion coincides with the onset of sleep (Wehr

et al

.

) and a reduction in core body temperature (Cagnacci

et al

.

). Insomnia in the elderly has been linked to melatonin deficiency (Haimov

et al

.

). Impaired melatonin secretion has also been described in association with sleep problems in Rett syndrome (Miyamoto

et al

.

). Smith–Magenis syndrome is associated with an inver-sion of the circadian rhythm of melatonin (it is secreted during the day) and significant sleep diffi-culties (De Leersnyder

et al

.

). Dysfunctional melatonin production has been found in people with autism and may contribute to sleep difficulties observed in this population (Ritvo

et al

.

).The hypnotic effect of melatonin is thought to

occur through a variety of mechanisms. These include a direct phase-shifting effect on the SCN (Lewy

et al

.

), and a decrease in core body tem-perature, an effect that may induce sleepiness on its own (Cagnacci

et al

.

). It is also suggested that melatonin may affect the wakefulness-generating sys-tem of the central nervous system (Lavie

). Three


S. G. Sajith & D. Clarke •

Melatonin and sleep disorders associated with intellectual disability4

©



different types of G-protein coupled melatonin recep-tor have been identified. They are widely distributed in the brain and other body systems, but their exact role is not known (Dubocovich

et al

.

). Recent animal experiments indicate that melatonin’s hyp-notic properties may be mediated through its effect on GABA-A receptors or the GABA–benzodiazepine receptor complex (Wang

et al

.

).

Exogenous melatonin

Commercially synthesized melatonin is available as orally administered tablets, capsules and liquid. Stan-dard and sustained-release formulations are available. Melatonin is manufactured in strengths ranging from

.

mg to

mg. It can be bought through the Inter-net and over the counter in various countries (includ-ing the USA, where it is considered to be a nutritional supplement). In the UK, it is available as a prescription-only medication. Its manufacture is unregulated, and there has been some concern that commercially available formulations may contain impurities or vary markedly in bioavailability (Laforce

et al

.

).Melatonin taken orally in a dose of

.

mg is con-sidered to produce blood levels equivalent to peak physiological levels at night (Zhdanova

et al

.

). The bioavailability of melatonin is poor on oral administration because of prominent first pass metab-olism in liver and also varies widely between individ-uals (DeMuro

et al

.

). Pre-pubertal children appear to metabolize melatonin faster than adults (Cavallo & Ritschel

). The half-life of melatonin is around

min, and the standard oral preparation maintains a level above the physiological level up to

–

h. Slow-release preparations can give extended high plasma levels up to

h (Aldhous

et al

.

).Exogenous melatonin is considered to have similar

effects to naturally occurring melatonin. It rapidly induces sedation (Zhdanova

et al

.

; Cajochen

et al

.

) and has a hypothermic effect (Cagnaacci

et al

.

). Melatonin reduces sleep onset latency and latency to stage

sleep while having little effect on REM sleep (Zhdanova

et al

.

). It has been successfully used to induce sleep prior to electroen-cephalogram recording (Wassmer

et al

.

). Mela-tonin has been found to have hypnotic properties whether given during the day or in the evening (Zhdanova

et al

.

; Cajochen

et al

.

).

Efficacy

Most of the studies on melatonin to treat sleep prob-lems associated with ID are open trials or case series of children and adolescents. A few published ran-domized controlled trials (RCTs) have studied rela-tively small numbers of people. There were no studies on use of melatonin exclusively for adults with ID.

The findings of the available RCTs are summa-rized in Table

. Other studies are listed in Table

.There is substantial evidence from the available

studies of a positive effect of melatonin on sleep latency (time to get to sleep) in people with ID. This is especially relevant in people who have difficulty getting to sleep (settling difficulties), with delayed sleep phase syndrome and free-running circadian rhythms (the latter mostly in people with severe visual impairments). Melatonin also improves total sleep time, but there is some inconsistency of evidence between studies. It has been found that the more severe the sleep problem at baseline, the greater the improvement likely to be achieved with melatonin. Night-time awakenings show little improvement with melatonin treatment. Studies that used standard preparations of melatonin reported no or minimal effect on the number of awakenings during the night. As noted by Jan

et al

. (

), this could be explained by the relatively short half-life of melatonin. The use of a slow-release formulation or a higher dose of a standard formulation may prove effective in such cases.

Studies of melatonin for sleep problems in children and adults with normal intelligence have reported similar results, improvement in sleep onset latency being the most consistent finding (Kayumov

et al

.

; Smits

et al

. ).

Adverse effects of melatonin

Most studies of melatonin involving people with ID have reported no adverse effects (Jan et al. ; O’Callaghan et al. ; Dodge & Wilson ). In a double-blind placebo-controlled study of poten-tial toxicity of melatonin, Seabra et al. () found no effect on blood count, renal function, liver function, thyroid function, uric acid, cortisol, lipid profile or blood glucose as a result of giving mg melatonin daily for weeks to healthy volunteers.


S. G. Sajith & D. Clarke • Melatonin and sleep disorders associated with intellectual disability5

© The Authors. Journal Compilation © Blackwell Publishing Ltd

Tabl

e 1

Dou

ble-

blin

d pl

aceb

o-co

ntro

lled

stud

ies

of m

elat

onin

for

chi

ldre

n an

d ad

oles

cent

s w

ith

inte

llect

ual

disa

bilit

ies

(ID

)

Stu

dyS

ubje

cts

Do

se o

f m

elat

oni

n*M

ajo

r o

utco

me

Co

mm

ents

Cam

field

et a

l. (1

996)

6 ch

ildre

n (3

–13

year

s) w

ith

mod

erat

e ID

0.5–

1 m

g gi

ven

at 1

800

hN

o m

ajor

ben

efits

in t

otal

sle

ep t

ime

or

num

ber

of a

wak

enin

gsR

elat

ivel

y sm

all d

ose

of m

elat

onin

; pr

obab

ly g

iven

too

ear

ly in

the

eve

ning

.

Jan

et a

l. (1

994)

15 c

hild

ren

(6 m

onth

s-14

yea

rs)

with

mul

tiple

dis

abili

ties

2.5–

5 m

g gi

ven

in t

he

even

ing

Impr

oved

sle

ep in

80%

of

subj

ects

; moo

d an

d di

spos

ition

als

o im

prov

ed9

child

ren

had

visu

al im

pair

men

t.

McA

rthu

r &

Bud

den

(199

8)9

fem

ales

(4–1

7 ye

ars)

with

Ret

t sy

ndro

me

2.5–

7.5

mg

give

n 1

h be

fore

the

usu

al

bedt

ime

Impr

ovem

ent

in s

leep

ons

et la

tenc

y† ; No

chan

ge in

num

ber

of a

wak

enin

gsIm

prov

emen

t gr

eate

r in

chi

ldre

n w

ith

wor

se b

asel

ine

slee

p qu

ality

; tot

al s

leep

im

prov

ed in

3 p

atie

nts.

O’C

alla

ghan

et a

l. (1

999)

7 pa

tient

s (2

–28

year

s) w

ith

tube

rous

scl

eros

is5

mg

give

n 20

min

bef

ore

the

usua

l bed

time

Sign

ifica

nt im

prov

emen

t in

tot

al s

leep

tim

e;

no e

ffect

on

num

ber

of a

wak

enin

gsSl

eep

onse

t lat

ency

† als

o im

prov

ed in

a fe

w

patie

nts

Dod

ge &

Wils

on

(200

1)20

chi

ldre

n (1

–15

year

s) w

ith

mod

erat

e ID

5 m

g gi

ven

at 2

000

hIm

prov

emen

t in

sle

ep o

nset

late

ncy† ;

no

chan

ge in

num

ber

of a

wak

enin

gsPa

rent

al v

iew

of

slee

p pr

oble

ms

bett

er

whi

le o

n m

elat

onin

; tot

al s

leep

tim

e im

prov

ed in

a fe

w p

atie

nts;

44%

dro

pout

ra

te.

Cop

pola

et a

l. (2

004)

25 s

ubje

cts

(3.6

–26

year

s) w

ith

ID3

mg

give

n at

usu

al

bedt

ime

Sign

ifica

nt im

prov

emen

t in

sle

ep o

nset

la

tenc

y†

* A

ll th

e ab

ove

stud

ies

used

sta

ndar

d fo

rmul

atio

n of

mel

aton

in f

or a

per

iod

rang

ing

from

t

o w

eeks

.† T

ime

to g

et t

o sl

eep.




Tabl

e 2

Ope

n/ob

serv

atio

nal

stud

ies

of m

elat

onin

for

chi

ldre

n an

d ad

oles

cent

s w

ith

inte

llect

ual

disa

bilit

ies

Stu

dyS

ubje

cts

Do

se o

f m

elat

oni

n*M

ajo

r o

utco

me

Co

mm

ents

Palm

et a

l. (1

997)

8 pa

tient

s (3

–23

year

s)0.

5–4

mg

give

n 30

–60

min

be

fore

bed

time

Impr

oved

sle

ep–w

ake

patt

erns

in a

ll pa

tient

sA

ll ha

d vi

sual

impa

irm

ent

and

mar

kedl

y di

stur

bed

circ

adia

n rh

ythm

s pr

ior

to

trea

tmen

t

Zhd

anov

a et

al.

(199

9)13

chi

ldre

n (2

–10

year

s) w

ith

Ang

elm

an s

yndr

ome

0.3

mg

give

n 30

–60

min

bef

ore

bedt

ime

Impr

ovem

ent

in s

leep

dur

atio

n an

d re

duct

ion

in m

otor

act

ivity

dur

ing

slee

p

Jan

(200

0)10

chi

ldre

n (1

–11

year

s)3

mg

give

n 1–

2 h

befo

re

desi

red

bedt

ime

Impr

ovem

ents

in t

he n

umbe

r of

aw

aken

ings

, nu

mbe

r of

nig

hts

with

de

laye

d sl

eep

onse

t and

ear

ly m

orni

ng

arou

sals

7 ch

ildre

n ha

d vi

sual

impa

irm

ent

Ros

s et

al.

(200

2)46

chi

ldre

n (1

–13

year

s) w

ith

deve

lopm

enta

l or

neur

olog

ical

di

sord

ers

2.5–

10 m

g gi

ven

at b

edtim

eIm

prov

emen

ts in

tota

l sle

ep ti

me,

leng

th

of in

terr

uptio

ns in

sle

ep a

nd t

ime

at

onse

t of

sle

ep

No

sign

ifica

nt e

ffect

on

the

num

ber

of s

leep

inte

rrup

tions

Paav

onen

et a

l. (2

003)

15 c

hild

ren

(6–1

7 ye

ars)

with

A

sper

ger

synd

rom

e3

mg

give

n at

bed

time

Impr

ovem

ent

in s

leep

ons

et la

tenc

y†N

o ch

ange

in s

leep

dur

atio

n

* A

ll th

e ab

ove

stud

ies

used

sta

ndar

d fo

rmul

atio

n of

mel

aton

in.

† Tim

e to

get

to

slee

p.




Side effects have been reported, although rarely, when melatonin is used on its own or in combination with other drugs. These side effects include nausea, headache (Smits et al. ), and confusion and morning sleepiness when coadministered with zolpi-dem (Suhner et al. ). Single-case reports of adverse events include optic neuropathy following concomitant use of melatonin with sertraline and a high protein diet (Lehman & Johnson ), emer-gence of a psychotic episode (Force et al. ), autoimmune hepatitis (Hong & Riegler ) and symptoms similar to Crohn’s disease (Calvo et al. ). Buscemi et al. (), in their meta-analysis on melatonin, reported headaches, dizziness, nausea and drowsiness as the most commonly reported adverse effects, occurrence of which were at rates similar to placebo.

Melatonin and puberty

Several studies in humans have found a progressive reduction in serum melatonin levels with increasing age, beginning in early childhood; some suggest a significant reduction around puberty, indicating a probable inhibitory role of melatonin on puberty (Waldhauser et al. ; Molina-Carballo et al. ). Supporting this view, Waldhauser et al. () found lower serum levels of melatonin in children with pre-cocious puberty compared with unaffected children of similar age. In another study, endogenous noctur-nal serum melatonin levels were found to be increased in males with hypogonadotropic hypogo-nadism and delayed puberty compared with age-matched pubertal controls (Luboshitzky et al. ). However, several other studies tend to suggest that decline of serum melatonin level is simply a reflection of a general trend of age-related decrease in melato-nin concentrations starting from early childhood to old age and has no relationship to puberty or preco-cious puberty (Ehrenkranz et al. ; Attanasio et al. ; Cavallo ). Another possibility is that the reported reduction in melatonin levels is a secondary effect of the hormonal changes happening during puberty.

Effects on sexual and endocrine functions

In adults, there is speculation that melatonin, on long-term administration, may adversely affect sperm

concentration and motility (Luboshitzky et al. ). It has been found that single high doses ( mg) of melatonin can elevate serum prolactin and growth hormone levels (Waldhauser et al. ). Melatonin can increase growth hormone release in smaller doses and produce dose-dependent changes in circulating concentrations of oxytocin and vasopressin, the .-mg dose being stimulatory, while mg was inhibitory (Forsling et al. ). Voordouw et al. () found that months of melatonin treatment in women sig-nificantly decreased mean luteinizing hormone levels and inhibited the secretion of progestrogen and oestradiol, an effect similar to oral contraceptives. It has also been suggested that melatonin may have a direct role in regulating ovarian function (Woo et al. ). With regard to use of melatonin during lacta-tion in pregnancy, no studies were available in humans. One animal study reported no teratogenic effects of melatonin in the offspring (Jahnke et al. ).

Melatonin and epilepsy

One small uncontrolled study by Sheldon () reported worsening or triggering of seizures in four out of six children with multiple neurological deficits. All improved after stopping melatonin. Smits et al. () also reported the emergence of seizures in one of children after treatment with melatonin for months. However, many other published trials on sleep disorders in ID indicate that melatonin is safe in patients with epilepsy and may have a beneficial effect on seizure control (Jan et al. ; Molina-Carballo et al. ; Peled et al. ). Several mech-anisms have been proposed for melatonin’s beneficial effect on seizures, including its influence on the GABA–benzodiazepine receptor complex (Wang et al. ) and its antioxidant and antiexcitotoxic roles (Acuna-Castroviejo et al. ).

Melatonin and asthma

Sutherland et al. () found that melatonin was pro-inflammatory and associated with an increased production of inflammatory cytokines such as inter-leukins and and tumour necrosis alpha in both healthy volunteers and people with asthma (especially those with nocturnal asthma). Sutherland et al. () found elevated levels of endogenous melato-




nin in people with nocturnal asthma and that the melatonin serum concentration was inversely corre-lated with measures of respiratory function. However, Campos et al. (), in a randomized double-blind placebo-controlled study, found that melatonin improved sleep in people with asthma, with no evi-dence of worsening of respiratory symptoms.

Melatonin and depressive disorders

It has been suggested that melatonin may exacerbate dysphoria in depressed patients (Carman et al. ). More recent studies have found that melatonin either improves or has no effect on depressive symptoms (Dolberg et al. ; Lewy et al. ). It is interest-ing to note that agomelatine (S), a novel anti-depressant (in development at present), is an agonist at melatonin receptors, in addition to its effect on serotonin receptors (Millan et al. ).

Effects on other systems

Melatonin, even at a low dose of mg, can cause a significant reduction of both systolic and diastolic blood pressure, the pulsatality index in the internal carotid artery and catecholamine levels in blood. This effect is more pronounced in people with higher base-line blood pressure and is probably due to the inhib-itory effect of melatonin on the sympathetic nervous system (Arangino et al. ). Melatonin is also known to reduce intraocular pressure (Samples et al. ). It has been found that melatonin can inhibit platelet aggregation (Cardinali et al. ). Melato-nin has also been found to cause impairment of glu-cose tolerance (Cagnacci et al. ).

Drug interactions

Beta-blockers, alcohol and non-steroidal anti-inflam-matory drugs such as aspirin and ibuprofen have been found to reduce endogenous melatonin secre-tion (Brismar et al. ; Murphy et al. ; Ekman et al. ), but their effect on exogenous melatonin is not known. Alprazolam (a benzodiazepine) given at night also suppresses nocturnal melatonin secre-tion (McIntyre et al. ), and no interactions with exogenously administered melatonin have been reported. It is possible that sedative effects, and pos-sibly adverse effects, will be exaggerated in combina-

tion with exogenous melatonin. A combination of zolpidem and melatonin resulted in an increase in adverse effects in one study of jet lag (Suhner et al. ). Coadministration with fluvoxamine (and probably paroxetine) could increase the serum level of melatonin by interfering with its metabolism in the liver (Hartter et al. , ; von Bahr et al. ). Fluoxetine, citalopram, imipramine and desipramine were not found to have any significant effect on mela-tonin metabolism. Chlorpromazine has been shown to increase serum concentration of melatonin (Smith et al. ). Animal studies indicate that concomitant administration of melatonin with methamphetamine can exacerbate the serotonergic deficits induced by the latter (Gibb et al. ), which raises the possi-bility of similar effects occurring in humans. Concur-rent use of melatonin with nifedipine has been found to reduce the antihypertensive effect of the latter and could result in loss of control of hypertension (Lus-ardi et al. ). However, it is also possible that melatonin may potentiate the effects of antihyperten-sive drugs. Similarly, effects on intraocular pressure may become clinically important in patients taking medications for glaucoma. The inhibitory effect on platelet aggregation could potentially add to the effects of other anticoagulant agents such as aspirin and especially warfarin (Herxheimer ). The immunomodulatory and pro-inflammatory effects of melatonin could, theoretically, counteract the effects of anti-inflammatory agents, including corticoster-oids (Sutherland et al. ).

Discussion

Our review indicates that melatonin is particularly effective in improving time to get to sleep (sleep onset latency). This is especially relevant in individuals suf-fering from circadian rhythm sleep disorders (delayed sleep phase syndrome and those with free-running circadian rhythms) and settling difficulties at bed-time. Melatonin may also improve total sleep time. Melatonin in standard formulation has little effect on the number of night-time awakenings.

Two recent reviews on the efficacy of melatonin in sleep problems in children and adolescents with ID (Armour & Paton ; Phillips & Appleton ) have reached similar conclusions to ours, with the improvement in sleep latency being the most consis-tent finding. A meta-analysis (Brzezinski et al. )




Tabl

e 3

Mel

aton

in a

nd o

ther

com

mon

ly u

sed

med

icat

ions

for

sle

ep p

robl

ems

in p

eopl

e w

ith

inte

llect

ual

disa

bilit

ies

Med

icat

ion

Mo

de o

f ac

tio

nS

leep

pro

blem

tha

tre

spo

nds

best

Co

mm

on

side

eff

ects

Tole

ranc

e, d

epen

denc

e o

r

wit

hdra

wal

phe

nom

ena

Mel

aton

inPh

ase-

shift

on

SCN

; ?re

duct

ion

in c

ore

body

tem

pera

ture

; ??

GA

BA

-A r

ecep

tors

Cir

cadi

an r

hyth

m d

isor

ders

es

peci

ally

del

ayed

sle

ep p

hase

sy

ndro

me

and

free

-run

ning

rh

ythm

s; se

ttlin

g di

fficu

lties

Non

e or

min

or in

the

sho

rt t

erm

. Lo

ng-t

erm

saf

ety

not

esta

blis

hed

Non

e re

port

ed

Benz

odia

zepi

nes

GA

BA

-A r

ecep

tors

Non

e sp

ecifi

edD

row

sine

ss a

nd li

ghth

eade

dnes

s ne

xt d

ay,

amne

sia,

conf

usio

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of melatonin for insomnia in people with normal intelligence indicated that, although the effect was small, melatonin significantly reduced sleep onset latency and increased sleep efficiency and total sleep duration. However, a recent meta-analysis by Bus-cemi et al. () concluded that melatonin has little effect on sleep onset latency and sleep efficiency (sig-nificant improvement in the melatonin group, though probably not clinically relevant). This analysis suf-fered from significant heterogeneity and combined studies of melatonin in people with and without ID, which may be inappropriate.

Doses of melatonin used in the studies of people with ID range from . mg to mg. Most of the trials with positive results used a dose of . mg and above. Children may require higher doses than adults because of their faster metabolism of melatonin. There is little guidance from the literature about how long to continue treatment. Most studies report ben-eficial effects within the first few days. In one study of children with normal intelligence, of children were off melatonin, apparently free of sleep problems, at -month follow-up (Smits et al. ).

Melatonin appears to be remarkably free of serious adverse effects in the short term even at high doses. It is unclear whether melatonin has any influence on the initiation of puberty. Reports that melatonin may have a contraceptive action and can affect ovarian functions are of clinical importance when used in women of reproductive age. Negative effects on sperm count and quality in men on long-term treat-ment also raise concerns. It is advisable to limit the use of melatonin to the shortest possible duration, especially for children and adolescents.

Although several studies indicate that melatonin is safe (and may be beneficial) in epilepsy, considering the variability in melatonin’s effects between individ-uals, prescribers should be alert to any worsening of seizure control. Caution is advised when prescribing melatonin to people with asthma in view of its poten-tial pro-inflammatory properties. Clinicians should also be alert to any worsening of mood symptoms when treating patients with depression. Patients with high blood pressure who are receiving multiple med-ications or of fragile cardiovascular status should be monitored when taking melatonin. Caution is advised when melatonin is used for people who have diabetes mellitus. It is not advisable to use melatonin during pregnancy and lactation.

Melatonin has advantages over many other medi-cations used in the treatment of sleep problems in ID (see Table ). Unlike antihistamines and benzodiaz-epines, it is remarkably free of side effects in the short term, and there are no reports of rebound insomnia, tolerance, physical dependence or withdrawal phe-nomena. Because melatonin is considered ‘naturally occurring’, it may be more appealing to patients as well as their carers. However, formulations of mela-tonin are not standardized and the possible presence of impurities is of some concern. The information on potential adverse effects and effects on bodily systems or functioning, especially in the long term, are also inadequate.

Finally, this review has its own limitations, includ-ing its non-systematic nature. Further research directed at people with ID is required before more robust conclusions about melatonin’s efficacy and safety are made.

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Accepted 5 June

melatonin and sleep disorders associated with intellectual disability: a clinical review

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