DELHI PSYCHIATRY JOURNAL Vol. 15 No.

OCTOBER 2012

Review Article

Melatonin agonists : a brief clinical review

Zainab Dawoodi1, Nilesh Shah2, Avinash De Sousa3
Department of Psychiatry, Masina Hospital, Mumbai
2
Department of Psychiatry, Lokmanya Tilak Muncipal Medical College & General Hospital, Mumbai
3
Consultant Psychiatrist & Psychotherapist, Mumbai
1

Introduction
The detection, assessment and treatment of
sleep/wake disorders are rapidly becoming a
standardized part of psychiatric evaluation. Present
day 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 mood
along 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 Pharmacological
agents include benzodiazepines, non-benzodiazepine benzodiazepine receptor agonists, antihistaminics, 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 1958.4 It is an indole-amine (n-acetyl methoxy268

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 cycle
that 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 biexponential pattern, with a first distribution half
life of two minutes, followed by a second of twenty
minutes.10 Circulating 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.10 In tissues of neural origin,
such as the retina and pineal gland, melatonin can
be de-acetylated to 5 methoxytryptamine.11 In the
brain 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 concentration during 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 acts
were characterized and cloned in humans.13 There

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

OCTOBER 2012

DELHI PSYCHIATRY JOURNAL Vol. 15 No.2

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 by
decr easing 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 in
hamsters as the human analogue of the cytoplasmic
enzyme quinolone reductase 2, which participates
in the protection against oxidative stress by
preventing electron transferring reaction 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.17 Behavioural, 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
Supr achiasmatic 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 tuberomamillary 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 promotes
sleep. 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. The
retinal 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 are
low.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 pharmacological responses mediated by each kind or
subtype of receptors. The second is its rapid
metabolic inactivation (short half life) which

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

269

DELHI PSYCHIATRY JOURNAL Vol. 15 No.2

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 MT1 and MT2 receptors 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 to
elicit 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 r ats 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 been
no reports of any significant effects on sleep in
males without sleep complaints.21 Agomelatine 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. 20 The 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 par oxetine and SNRIs such as
270

OCTOBER 2012

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 patients 20 , being
capable of phase shifting circadian rhythm in older
men. 21 Agomelatine also impr oves 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 affecting
daytime 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 MT1 and MT2 receptor
agonist.31-32 Ramelteon has very low affinity for the
MT 3 receptor. In comparision with Melatonin,
Ramelteon has 6 fold higher affinity for MT 1
receptor and 4 fold higher affinity for MT2 receptor,
but 94 fold lower affinity for MT 3 receptor. 31
Ramelteon has exhibited no measurable affinity for
gamma amino butyric acid receptor complex,
benzodiazepine, dopamine, nor adrenaline or
serotonin receptors.33 It 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

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

OCTOBER 2012

DELHI PSYCHIATRY JOURNAL Vol. 15 No.2

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.38 Compared 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 well
tolerated 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 MT 1 and MT 2
receptors in humans. In humans, Tasimelteon
impr oves 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. It
is 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 sleep
parameters 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.45,46 Blind individuals
who lack light per ception 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 demonstrated 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 described for Parkinsons disease,
Huntingtons chorea and other neurodegenerative
disorders. 50-53 Thus the field of Melatonin
therapeutics has great future prospects.
References
1. Rios ER, Venancio ET, Rocha NF, et al.
Melatonin : pharmacological aspects and
clinical trends. Int J Neurosci 2010; 120(9) :
583-590.
2. Reiter RJ, Tan DX, Fuentes-Broto L. Melatonin
: a multitasking molecule. Prog Brain Res 2010;
181 : 127-151.
3. Erman MK. Therapeutic options in the treatment of insomnia. J Clin Psychiatry 2005;
66(S9) : 18-23.
4. Lerner AB, Case JD, Heinzelman RW. Structure
of Melatonin. J Am Chem Soc 1959; 81 : 60846085.
5. Harderland R, Fuhrberg B. Ubiquitous melatonin : Presence and effects in unicells, plants
and animals. Trends Comp Biochem Physiol
1996; 2 : 25-45.
6. Reiter RJ. Pineal melatonin : cell biology of its
synthesis and of its physiological interactions.
Endocrine Rev 1991; 12 : 151-180.
7. Pandi SR, Srinivasan V, Maestroni GJM,

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

271

DELHI PSYCHIATRY JOURNAL Vol. 15 No.2

8.

9.

10.

11.

12.

13.

14.

15.

16.
17.

18.

19.

20.

272

Cardinali DP. Melatonin : Natures most

versatile biological signal. FEBS J 2006; 273 :
2813-2838.
Harderland R, Pandi-Perumal SR, Cardinali DP.
Melatonin. Int J Biochem Cell Biol 2006; 38 :
313-316.
Tricoire H, Locatelli A, Chimeneau P, Malpaux
P. Melatonin enters the cerebrospinal fluid
through the pineal recesses. Endocrinology
2002; 143 : 84-90.
Claustrat B, Brun J, Chazot G. The basic
physiology and pathophysiology of Melatonin.
Sleep Med Rev 2005; 9 : 11-24.
Harderland R, Reiter RJ, Poeggler B. The
significance of the metabolism of the neurohormone melatonin : antioxidative protection
and formation of bioactive substances.
Neurosci Behav Rev 1993; 17 : 347-357.
Hirata F, Hayaishi O, Tokuyama T, Seno S. In
vitro and in vivo formation of two new
metabolites of melatonin. J Biol Chemistry
1974; 249 : 1311-1313.
Dawson D, Armstrong SM. Chronobiotics :
drugs that shift rhythms. Pharmacotherapy
1996; 69(1) : 15-36.
Reppert SM, Weaver DR, Ebisawa T. Cloning
and characterization of mammalian melatonin
receptor that mediates reproductive and circadian responses. Neuron 1994; 13 : 1177-1185.
Ekmekcioglu C. Melatonin receptors in humans
: biological role and clinical relevance. Biomed
Pharmacother 2006; 60 : 97-108.
Stahl SM. Essential psychopharmacology (3rd
ed), Cambridge University Press. 2008.
Rusak B. The mammalian circadian system :
models and physiology. J Biol Rhythms 1989;
4(2) : 121-134.
Inouye S, Kawamura H. Persistence of Circadian rhythmicity in a mammalian hypothalamic
island containing the supra-chiasmatic nucleus.
Proc.Natnl Acad Sci USA 1979; 76(11) : 59625966.
Hardeland R. Investigational melatonin
receptor agonists. Exp Opin Investig Drugs
2010; 19(6) : 747-764.
Guardiola Lemaitre BB. Agonists et antagonists de recepteurs melatoninergiques : effects
pharmacologiques et perspectives therapeutiques. Ann Pharm Fr 2005; 63 : 385-400.

OCTOBER 2012

21. Leproult R, Van Onderbergen A, Hermitte

Baleriaux M, Van Cauter E, Copinschi G. Phase
shifts of 24 hour rhythms of hormonal release
and body temperature following early evening
administration of the melatonin agonist
agomelatin in healthy older men. Clin
Endocrinol 2005; 63 : 298-304.
22. Deacon S, English J, Arendt J. Acute phase
shifting effects of Melatonin associated with
suppression of core body temperature in
humans. Neurosci Lett 1994; 178 : 32-34.
23. Descamps A, Rousser C, Millan MJ, Spedding
M, Delagrange P, Cespuglio R. Influence of
novel antidepressant and melatonin agonists /
serotonin 2C receptor antagonists , agomelatin
on r at sleep wake cycle ar chitecture.
Psychopharmacology 2009; 205(1) : 93-106.
24. Loo H, Hale A, DHaenen H. Determination of
dose of agomelatine, a melatonergic agonist and
selective 5HT2C antagonist, in the treatment of
major depressive disorder, a placebo controlled
dose range study. Int Clin Psychopharmacol
2002; 17 (5) : 239-247.
25. Kennedy SH, Emsley R. Placebo controlled
trial of agomelatine in treatment of major
depr essive disorder. Eur Neuropsychopharmacol 2006; 16(2) : 93-100.
26. Olie JP, Emsley R. Confirmed clinical efficacy
of agomelatin (25 -50 mg) in major depression:
two randomised double blind placebo
controlled studies. Eur Neuropsychopharmacol
2005; 15(suppl. 3) : S416-430.
27. Lemonie P, Guilleminault C, Alvarez E.
Improvement in subjective sleep in major
depr essive disorder with agomelatine :
randomised double blind comparision with
venlafaxine. J Clin Psychiatry 2007; 68(11) :
1723-1732.
28. San L, Arranz B. Agomelatine : a novel
mechanism of antidepressant action involving
melatonergic and serotonergic system. Eur
Psychiatry 2008; 23 : 396-402.
29. Montgomery SA. Major depressive disorders:
clinical efficacy and tolerability of agomelatine,
a new melatonergic agonist. Eur Psychopharmacol 2006; 16 : 5633-5638.
30. Montgomerry SA, Kennedy SH, Burrows GD,
et al. Absence of discontinuation symptoms with
agomelatine and occurrence of discontinuation

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

OCTOBER 2012

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

DELHI PSYCHIATRY JOURNAL Vol. 15 No.2

symptoms with paroxetine : a randomised

double blind placebo control discontinuation
study. Int Clin Psychopharmacol 2004; 19 : 271280.
Uchikawa O, Fukatsu K,Tokunoh R. Synthesis
of a novel series of tricyclic indan derivatives
as Melatonin receptor agonists. J Med Chem
2002; 45 : 4222-4239.
Kato K, Hirai K, Nishiyama K. Neurochemical
properties of ramelteon : a selective MT1/MT2
receptor agonist. Neuropharmacology 2005; 48
: 301-310.
Miyamoto M, Kata K, Hirai K, Uchikawa O,
Ohkawa S. TAK 375 and its active metabolite:
lack of binding to non ML receptor binding
sites. Sleep 2003; 26(S) : 49-51.
Richardson GS, Zee PC, Wang Weigand S, et
al. Circadian phase shifting effects of repeated
Ramelteon administration in healthy adults. J
Clin Sleep Med 2008; 4(5) : 456-461.
Roth T, Stubbs C, Wash JK. Ramelteon : a
selective MT1/MT2 receptor agonist reduces
latency to persistent sleep in a model of
transient insomnia related to novel sleep
environment. Sleep 2005; 28(3) : 303-307.
Zammit G, Schwartz H, Roth T, et al. The effects
of Ramelteon in a first night model of transient
insomnia. Sleep Med 2009; 10 : 55-59.
Borja NL, Daniel KL. Ramelteon for the
treatment of insomnia. Clin Ther 2006; 28 :
1540-1555.
Erman M, Seiden D, Zammit G, et al. An
efficacy , safety and dose response study of
Ramelteon in patients with chronic primary
insomnia. Sleep Med 2006; 7 : 17-34.
Griffiths R, Suess P, Johnson M. Ramelteon and
Triazolam in humans : behavioural effects and
abuse potential. Sleep 2005; 28 : 44-60.
Neubauer DN. A review of ramelteon in the
treatment of sleep disorders. Neuropsychiatr
Dis Treat 2008; 4(1) : 69-79.
Ferguson SA, Shanta MW, Dawson D.
Melatonin agonists and insomnia. Exp Rev
Neurother 2010; 10(2) : 305-318.
Rajaratnam SMW, Polymeropolous MH, Fisher
DM. Melatonin agonist Tasimelton for transient
insomnia after sleep time shift : two

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

randomised controlled multicentre trials.

Lancet 2009; 373(9662) : 482-491.
Herxheimer A, Petrie KJ. Melatonin for
treatment and prevention of jet lag (Cochrane
review). Cochrane Database System review, 2,
CD001520 (2002).
Buscemi N, Vandermeer B, Hoooton N. The
efficacy and safety of exogenous melatonin for
primary sleep disorders : a metaanalysis. J Gen
Int Med 2005; 20(12) : 1151-1158.
Lockley SW, Skene DJ, James K, et al.
Melatonin administration can entrain the free
running Circadian system of blind subjects. J.
Endocrinol 2000; 164(1), 1-6.
Sack RL, Brandes RW, Kendall AR, Lewy AJ.
Entrainment of free running circadian rhythms
by blind people. N.Engl J Med 2000; 343(15) :
1070-1077.
Wurtman RJ, Zhdanova IV. Improvement of
sleep quality by melatonin. Lancet 1995;
346(8988) : 1491-1493.
Maestroni GJ, Conti A, Pierpaoli W. Role of
pineal gland in immunity. J Neuroimmunol
1986; 13 : 19-30.
Regodon S, Martin-Palamino P, FernandesMontesinos R,et al. The role of melatonin as a
vaccine agent. Vaccine 2005; 23 : 5321-5327.
Srinivasan V, Pandi Perumal SR, Maestroni GJ,
et al. Role of melatonin in neurodegenerative
disease. Neurotox Res 2005; 7 : 293-318.
Schernhammer E,Chen H, Ritz B. Circulating
melatonin levels : possible link between
Parkinsons disease and cancer risk. Cancer
2006; 17 : 577-582.
Christofides J, Bridel M, Egerton M. Blood 5hydroxy tryptamine, 5-hydroxy indole acetic
acid and melatonin levels in patients with either
Huntingtons disease or chronic brain injury. J
Neurochem 2006; 97 : 1078-1088.
Rocchita G, Migheli R, Esposito G.
Endogenous melatonin protects L-DOPA from
autooxidation in the striatal extracellular
compartment of freely moving rat : potential
implication for long L-DOPA therapy in
Parkinsons disease. J Pineal Res 2006; 23 : 112119.

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

273