melatonin agonists a brief clinical review

7/25/2019 Melatonin Agonists a Brief Clinical Review

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DELHI PSYCHIATRY JOURNAL Vol. 15 No.2 OCTOBER 2012

Delhi Psychiatry Journal 2012; 15:(2) Delhi Psychiatric Society268

Review Article

Melatonin agonists : a brief clinical reviewZainab Dawood i1, Nilesh Shah2, Avinash De Sousa3

1Department of Psychiatry, Masina Hospital, Mumbai2Department of Psychiatry, Lokmanya Tilak Muncipal Medical College & General Hospital, Mumbai

3Consultant Psychiatrist & Psychotherapist, Mumbai

Introduction

The detection, assessment and treatment of

sleep/wake disorders are rapidly becoming a

standardized part of psychiatric evaluation. Presentday clinicians consider sleep as a psychiatric vital

sign requiring routine evaluation and symptomatic

treatment whenever a sleep problem is encountered.

Insomnia is a common condition characterized by

difficulty falling asleep, increased night time

wakefulness or inadequate sleep duration. Insomnia

can result in daytime consequences, including

tiredness, difficulty concentrating, and irritability

as well as increased health care utilization and

reduced work productivity, lower quality of life or

of social relationships and decrements in moodalong with memory or cognitive functioning.1,2

Another group of sleep disorders apart from

insomnias that has drawn attention is the circadian

rhythm sleep disorders which include disturbances

of the normal sleep wake rhythm. Its subtypes

include jetlag, delayed sleep phase syndrome,

advanced sleep phase syndrome, irregular sleep

wake rhythm and shift work sleep disorders.

Management of sleep disorders includes sleep

hygiene education, cognitive behavioural therapy

and pharmacological therapy.

2

Pharmacologicalagents include benzodiazepines, non-benzodiaze-

pine benzodiazepine receptor agonists, antihista-

minics, antidepressants, melatonin and melatonin

agonists, certain herbal products and certain

nutritional supplements.3 The current article reviews

the role of melatonin and its agonists in management

of sleep disorders and especially circadian rhythm

disorders.

Melatonin

Melatonin was first identified by Aaron Lerner

in 1958.4It is an indole-amine (n-acetyl methoxy-

tryptamine) widely distributed in nature and occurs

in plants, algae, bacteria and humans. In humans it

functions as a neuro-hormone released from the

pineal gland in association with the light-dark cyclethat regulates sleep.5,6 Although melatonin is

synthesized in numerous organs like the pineal

gland, retina, lymphocytes, gastrointestinal tract,

etc., circulating melatonin in mammals is mainly

pineal in origin.7,8 Once synthesized, melatonin,

because of its high lipid solubility, diffuses out into

the capillary blood and cerebrospinal fluid. In blood

it is 70 % protein bound. Melatonin reaches the

CSF through the pineal recesses and its

concentration in the third ventricle is twenty times

higher than in blood.

9

The half-life of melatonin shows a bi-

exponential pattern, with a first distribution half

life of two minutes, followed by a second of twenty

minutes.10Circulating melatonin is metabolised in

liver by hydroxylation, dependent on cytochrome

p450 monooxygenases and then conjugated with

sulphate (6-sulphatoxy melatonin) and to a lesser

extent with glucoronide.10In tissues of neural origin,

such as the retina and pineal gland, melatonin can

be de-acetylated to 5 methoxytryptamine.11 In the

br ain however melatonin is metabolised to

derivatives of Kynuramine.12 The most striking

feature of melatonin is its rhythmicity. The pineal

production of melatonin shows a circadian rhythm

with low circulating levels during the day and high

plasma concent ra tion dur ing the night.7 This

rhythmicity is controlled by the endogenous clock,

the suprachiasmatic nucleus of the hypothalamus

which in turn is regulated by the light dark

cycle.7,8

Melatonin Receptors

In 1994, the receptors where melatonin actswere characterized and cloned in humans.13 There


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OCTOBER 2012 DELHI PSYCHIATRY JOURNAL Vol. 15 No.2

Delhi Psychiatry Journal 2012; 15:(2) Delhi Psychiatric Society 269

are three types of melatonin receptors. Type 1 and

2 are both involved in sleep physiology. Both the

MT1 and MT2 type of receptors belong to the

family of G-protein coupled membrane receptors

linked to the inhibition of adenylyl-cyclase and

subsequent decrease of cyclic AMP.14 The two

receptors are described in almost all structures of

CNS, although the highest density is found in the

hypothalamic suprachiasmatic nucleus (SCN) and

the pars tuberalis of the pituitary. This distribution

explains the action of melatonin as a chronobiotic

as well as its modulatory effects on the

neuroendocrine reproductive axis.15

MT1 mediated inhibition of neurons in the

suprachiasmatic nucleus helps to promote sleep bydecreasing the wake promoting action of

suprachiasmatic nucleus. MT2 mediates signals in

suprachiasmatic nucleus which helps in phase

shifting effects.16 MT1 and MT2receptors are also

present in gastrointestinal tract, lungs, thymus,

smooth muscles of blood vessels, adipocytes,

lymphocytes and neutrophils. The peripheral

receptors could explain some of the melatonin

effects on cardiovascular, gastrointestinal and

immune systems.16 The third type of melatonin

membrane receptor MT3 has been described inhamsters as the human analogue of the cytoplasmic

enzyme quinolone reductase 2, which participates

in the protection against oxidative stress by

pr event ing electron transferring react ion of

quinones.16

Neurobiology of Circadian Rhythms

The daily rhythm of life for most organisms

reflects an interaction between an internally

generated rhythm and the external environmental

cycle of day and night.17Behavioural, physiological

and biochemical processes such as core body

temperature and production of hormones (like

melatonin) contribute to maintenance of Circadian

rhythm. Most importantly the bodys central clock

that controls the Circadian rhythm is located in the

Suprachiasmatic nucleus (SCN) of the

hypothalamus.18 There are two main groups of

pathways that promote wakefulness. The first passes

from the upper brain stem nuclei (locus ceruleus

and median raphe nucleus) and ventral

periaqueductal area receiving inputs from tubero-

mamillary nucleus of the hypothalamus and basal

forebrain neurons and then on to the whole cortex.

The tuberomamillary nucleus projections to the

cortex cause release of histamine and promote sleep.

At the same time histaminergic projections from

the tuberomamillary nucleus cause inhibition of the

venterolateral preoptic nucleus (which is sleep

promorter area).17 The second pathway is the cortico

striatal thalamic cortical loop. This loop regulates

arousal by controlling the thalamic filter

(GABAergic transmission) from the striatum

creates the sensory filter in the thalamus, thus

regulating arousal by filtering out sensory input for

normal sleep and allowing sensory input to cortex

for normal wakefulness.16

There is a different pathway that promotessleep. The ventrolateral preoptic nucleus (VLPO)

is the primary seat of the sleep onset process .It

sends inputs to the arousal pathways through the

neurotransmitter GABA to damp the arousal

process and allow sleep. It receives an indirect input

from the suprachiasmatic nucleus. The Circadian

process is strongly related to light. Light activates

a group of retinal cells that contain the pigment

melanopsin. These cells then project to a group of

neurons in the lateral geniculate body which in turn

project on to the suprachiasmatic nucleus. Theretinal ganglion cells mentioned here are distinct

from rods and cones which explain the maintenance

of a 24hour rhythm in blind people.17

The production of melatonin is turned on in

the darkness by the nor adrenaline neurons of the

sympathetic nervous system in the upper spinal cord

that pass into the pineal gland via the superior

sympathetic ganglia. This release of melatonin acts

through a beta adrenoreceptor. During daytime the

SCN suppresses the nor adrenaline input to the

pineal gland and hence the melatonin levels arelow.18

Melatonin Agonists

The relatively simple structure of Melatonin,

the known relationships between the structure and

function, offer many possibilities for development

of synthetic analogues.19 Also the use of natural

molecule as a drug presents some limitations. The

first is the difficulty to obtain selective pharma-

cological responses mediated by each kind or

subtype of receptors. The second is its rapid

metabolic inactivation (short half life) which


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signifies a low oral bioavailability as well as a great

inter-individual variation.20

Agonists are defined as agents that bind to and

change the activity of a receptor. A number of

agonists have been developed on the basis of their

action on melatonin receptors, three of which are

described in this article i.e. Agomelatine,

Tasimelteon and Ramelteon.

Agomelatine

It binds to both MT1and MT

2receptors as well

as has antagonistic properties at 5-HT2B

and 5HT2C

serotonergic receptors. The evidence for

agomelatine as a chronobiotic drug is quite

compelling especially in relation to the ability toelicit phase advances.21 In a research study,

Agomelatine was found to cause a 70 min phase

advance in human subjects versus 89 min with plain

melatonin alone.22 In another study it was noted that

100 mg Agomelatine administered to human

subjects causes a phase advance of 2 hours over

15 days.21

A study in rats demonstrated the sleep

promoting effects of Agomelatine in form of an

increase in rapid eye movement and slow wave

sleep.

23

However in humans studies there have beenno reports of any significant effects on sleep in

males without sleep complaints.21Agomelatine is

reported to improve sleep quality in subjects with

major depression and depressive symptoms.24-27 It

has been cited in studies that Agomelatine does not

have the same negative tolerance and hangover

effects as some other antidepressants.

Through the antagonism at 5 HT2C

receptors,

Agomelatine is associated with mood regulation.28

It may be considered as a novel treatment for

depression and lack of side effects indicate a

significant potential in this regard. Agomelatine is

regarded by some authors as the first melatonergic

antidepressant.20The antidepressant efficacy of

agomelatine has been demonstrated in comparison

with placebo at various levels severity of

depression. Indeed, it seems the treatment effect of

agomelatine tends to increase with the severity of

depression.29 The results also indicate an early

response of depressive symptoms and good

response rates. Agomelatine has also been shown

to have comparable efficacy profile to the SSRIs

such as paroxetine and SNRIs such as

venlafaxine.30 Furthermore, agomelatine prevents

treatment related sexual dysfunction and has

positive effects on relief of sleep disturbances in

depression.31 It is the only antidepressant to have

specific action on circadian rhythms, which are

often imbalanced in depressed patients20, being

capable of phase shifting circadian rhythm in older

men.21 Agomelatine also improves daytime

alertness.

In addition, a placebo controlled double blind

study comparing agomelatine with paroxetine

showed after one week of treatment discontinuation,

no signs of discontinuation symptoms were seen in

Agomelatine group compared to significant

discontinuation symptoms in the paroxetine group.30

The antidepressant efficacy of Agomelatine is seen

at a standard dose of 25mg once daily in the

evening.24 Agomelatine, irrespective of dose, has

been shown to have a remarkable tolerability and

safety profile.29 The most common side effects

reported are headache, nausea and fatigue. They

usually resolve within two weeks. The clinical

advantage of Agomelatine derives from its

mechanism of action which gives this molecule

antidepressant properties together with the ability

to regulate sleep wake rhythm without affectingdaytime vigilance.

Ramelteon

It is a melatonin receptor agonist approved by

the US FDA in July 2005 for treatment of insomnia

characterised by difficulty with sleep onset. It is a

tricyclic indan derivative that is a potent and

selective human Melatonin MT1and MT

2receptor

agonist.31-32Ramelteon has very low affinity for the

MT3 receptor. In comparision with Melatonin,

Ramelteon has 6 fold higher affinity for MT1receptor and 4 fold higher affinity for MT

2receptor,

but 94 fold lower affinity for MT3 receptor.31

Ramelteon has exhibited no measurable affinity for

gamma amino butyric acid receptor complex,

benzodiazepine, dopamine, nor adrenaline or

serotonin receptors.33It shows very low affinity for

5HT 2B receptor.

Evidence from animal and human models

suggest that Ramelteon provides a strong phase shift

signal to the circadian timing system. Studies

conducted in human volunteers indicate a decreased

sleep onset latency and increased total sleep


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duration.34-36 The recommended dose for the

treatment of insomnia is 8mg orally administered

within 30 minutes of bedtime. 37 Headache,

dizziness, fatigue, somnolence and nausea. There

are no reports of withdrawal effects or rebound

insomnia.38Compared to Triazolam, Ramelteon was

found not to have any significant effects on

cognitive performance, behaviour or abuse

potential.39 Since CYP1A2 is the major isoenzyme

responsible for the hepatic metabolism of

Ramelteon, the inhibitors of this enzyme, such as

amiodarone, fluvoxamine and ciprofloxacin

increase the side effects of this drug. Ramelteon is

not to be used in patients with severe hepatic

impairment. Ramelteon is shown to be welltolerated in clinical studies with little residual

sedation and has not been associated with physical

dependence and abuse liability.40

Tasimelteon

It has high affinity for both MT1 and MT

2

receptors in humans. In humans, Tasimelteon

improves sleep initiation and maintenance

following a 5 hour advance of light dark and sleep

wake cycle.42 It improves initiation and maintenance

of sleep in human subjects compared to placebo. Itis under development for treatment of sleep and

mood disorders.41

Melatonin

The action of melatonin on its receptors in SCN

is thought to be the mechanism by which the

hormone alleviates circadian misalignment

associated with circadian rhythm sleep disorders

(CRSD). A Cochrane review concluded that

melatonin is an effective treatment for jet lag based

on changes recorded using a jet lag global visual

analogue scale and measurement of sleepparameters such as sleep onset latency and total

sleep time.43

A meta-analysis review shows that melatonin

agonists are effective for the treatment of Delayed

sleep phase disorders.44 Daily administration of

melatonin to blind individuals with non 24 hour

sleep wake disorder entrains endogenous circadian

rhythms and improves sleep.45,46Blind individuals

who lack light perception often experience

symptoms similar to those reported by shift workers,

international travellers and others suffering from

CRSDs .Strong evidence to date suggests that

melatonin is an effective and appropriate treatment

for these individuals. There have not been published

studies, to the best of our knowledge, that report

efficacy of melatonin agonists in treatment of

chronic sleep wake disturbances associated with

CRSDs. The literature reporting treatment of

insomnia with melatonin remains inconclusive.

However, melatonin and its agonists have been

reported to improve sleep parameters such as

latency to sleep and sleep efficacy, in chronic

insomnia and age related insomnia.47

The Future of Melatonin Agonists

The role of melatonin as an immune-enhancer48

has opened up interest in its use in treatment of

HIV infection. Melatonin implants have demon-

strated that they enhance the T-Helper immune

response.49

The antioxidant effects of Melatonin protect

neurons against the amyloid beta induced effects

in Alzheimers disease. Similar positive effects have

been describ ed for Par kinsons disease,

Huntingtons chorea and other neurodegenerative

disorders.50-53 Thus the field of Melatonin

therapeutics has great future prospects.References

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melatonin agonists a brief clinical review

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