Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa

Nature Reviews Drug Discovery
August 2010 Vol 9 No 8
1/30/2015 Prof M.A.Eldawy, by pharmacist: Yasser Alaa 1 of 24
Nature Reviews Drug Discovery August 2010 Vol 9 No 8 (Agomelatine, the first melatonergic antidepressant)
Prof M.A.Eldawy, by Pharmacist: Yasser Alaa 1/30/2015

Current management of major depression, a common and debilitating disorder
with a high social and personal cost, is far from satisfactory. All available
antidepressants act through monoaminergic mechanisms, so there is
considerable interest in novel non-monoaminergic approaches for potentially
improved treatment. One such strategy involves targeting melatonergic
receptors, as melatonin has a key role in synchronizing circadian rhythms, which
are known to be perturbed in depressed states. This article describes the
discovery and development of agomelatine, which possesses both melatonergic
agonist and complementary 5-hydroxytryptamine 2C (5-HT2C) antagonist
properties. Following comprehensive pharmacological evaluation and extensive
clinical trials, agomelatine (Valdoxan/Thymanax; Servier) was granted marketing
authorization in 2009 for the treatment of major depression in Europe, thereby
becoming the first approved antidepressant to incorporate a non-
monoaminergic mechanism of action.
Petersen, T; Dording, C; Neault, NB; Kornbluh, R; Alpert, JE; Nierenberg, AA; Rosenbaum, JF; Fava, M (January 2002). "A survey of prescribing practices in the
treatment of depression". Progress in Neuro-Psychopharmacology and Biological Psychiatry (Elsevier) 26 (1): 177–87. doi:10.1016/S0278-5846(01)00250-0.
PMID 11853110.

Definition:
also called major depression, is characterized by a combination of symptoms that
interfere with a person's ability to work, sleep, study, eat, and enjoy once–
pleasurable activities. Major depression is disabling and prevents a person from
functioning normally. An episode of major depression may occur only once in a
person's lifetime, but more often, it recurs throughout a person's life.
Mechanisms of Depression:
‘Monoaminergic Mechanism'
Stagnitti,M. (2005) Antidepressant Use in the US Civilian Non-Insitutionalised Population, 2002. Statistical Brief #77. Rockville,MD: Medical Expenditure Panel,
Agency for Healthcare Research and Quality.

A major hypothesis for the biology of depression was developed in the 1960s,
initially proposing that depletion of norepinephrine (NE), and later proposing
depletion of serotonin (5-HT) and dopamine (DA), underlie the illness. This
'monoamine hypothesis' was proposed because of the clinical observation that
depression often occurs in subjects taking reserpine, an antihypertensive
agent, which depletes monoamines from the synaptic vesicles. Also, consistent
with the hypothesis was that tricyclic antidepressants and MAO inhibitors were
found to increase synaptic monoamine concentrations. The hypothesis was
later modified to include alterations of monoamine receptor properties so that
it would encompass an explanation for the time (usually days to weeks)
required for an antidepressant to take clinical effect despite its immediate
action to elevate synaptic monoamine levels.
Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R (January 2008). "Selective publication of antidepressant trials and its influence on apparent
efficacy". N. Engl. J. Med. 358 (3): 252–60. doi:10.1056/NEJMsa065779. PMID 18199864
Kuhn, R (November 1958). "The Treatment of Depressive States with G 22355 (Imipramine Hydrochloride)". American Journal of Psychiatry (American Psychiatric
Association) 115 (5): 459–464. doi:10.1176/appi.ajp.115.5.459 (inactive 2009-10-24).
Stimmel, GL; Dopheide, JA; Stahl, SM (Jan-Feb 1997). "Mirtazapine: an antidepressant with noradrenergic and specific serotonergic effects".Pharmacotherapy
(American College of Clinical Pharmacy) 17 (1): 10–21. ISSN 0277-0008. PMID 9017762

Monoaminergicantidepressant drugs
Tatsumi M, Groshan K, Blakely RD, Richelson E. (1997). "Pharmacological profile of antidepressants and related compounds at human monoamine
transporters.". Eur J Pharmacol. 340 (2-3): 249–258. doi:10.1016/S0014-2999(97)01393-9. PMID 9537821

‘Melatonergic Mechanism of Depression’
• Melatonin is a naturally occurring hormone secreted by the pineal gland, a pea-size
structure at the center of the brain. As our eyes register the fall of darkness and the onset
of night melatonin is produced. It signals to our body to prepare for sleep, our blood
pressure dips, there is a decrease in body temperature and we start to feel sleepy.
Melatonin is one of the central hormonal elements to regulating our circadian
rhythms.Melatonin is often referred to as the hibernation hormone.
• Melatonin & Depression
Melatonin is an important nighttime hormone associated with sleep and regeneration.
However, excessive levels or daytime melatonin can cause depressive disorders. Medical
research confirms the relationship between melatonin and mood disorders. The following
paragraphs explain how melatonin works and why it causes depression.
• Darkness & Melatonin
Melatonin is normally released by the pineal gland in the evening as sunlight is diminishing.
Melatonin causes us to feel tired and withdraw. This helps us to sleep, but if we have to be
awake when melatonin is in our system, we become lethargic, disoriented, irritable and
moody. This explains why shift work and jet lag can be so debilitating, and why depression
rates are highest in darker climates. Almost everyone with a mood disorder suffers worse in
the winter because of excess melatonin in his or her system.
• Daytime Melatonin
Just as with jet lag, other factors can cause our bodies to produce melatonin into the day.
Some causes such as trauma, stress, injury, age or lack of light will shift your body’s timing
or release of melatonin. This shift can create excessive levels during the day and not enough
melatonin at night.
1/30/2015 Prof M.A.Eldawy, by pharmacist: Yasser Alaa 6 Of 24
Pacchierotti, C. et al. Melatonin in Psychiatric Disorders: A Review on the Melatonin Involvement in Psychiatry. Frontiers in Neuroendocrinology. Volume 22,
Issue 1, January 2001, Pages 18-32.
Crasson, M. et al. Serum melatonin and urinary 6-sulfatoxymelatonin in major depression. Psychoneuroendocrinology. Volume 29, Issue 1, January 2004, Pages
1-12.

Redman, J. R., Guardiola-Lemaître, B., Brown, M., Delagrange, P. & Armstrong, S. M. Dose-dependent effects of, S20098, a melatonin agonist on direction
of re-entrainment of rat circadian rhythms. Psychopharmacology 118, 385–390 (1995).

The relationship between melatonin, the suprachiasmatic nucleus and circadian rhythms:
melatonergic actions of agomelatine in vivo. a | Light activates the glutamate (GLU)-
containing retinohypothalamic tract (RHT) that runs from the eye to the suprachiasmatic
nucleus (SCN). Through a polysynaptic projection, the SCN functionally inhibits the activity
of the superior cervical ganglia (SCG), which supply the pineal gland with an excitatory,
noradrenaline (NA)-containing input. This circuit allows light to suppress the production
and release of melatonin from the pineal gland and, correspondingly, melatonin secretion
is increased in the dark period. Melatonin reciprocally activates neurons in the SCN by
actions at melatonin 1 (MT1) and MT2 receptors. Serotonergic input from the raphe
nucleus modulates the SCN through actions at serotonin (also known as 5-
hydroxytryptamine; 5-HT) receptor 5-HT2C and other classes of 5-HT receptor. Daily
behaviours likewise influence output from the SCN, the neuronal master clock for
coordinating circadian rhythms. b | Melatonergic receptors recognized autoradiographically
in the SCN using [125I] iodomelatonin. c | Locomotor activity rhythms of rats drift
backwards when the onset of the dark period is delayed by several hours. Daily
administration of agomelatine (3.0 mg per kg, intraperitoneally) resynchronizes rhythms to
their usual circadian pattern (dark period commencing at 18:00 hours)

Agomelatine, thefirst melatonergic antidepressant
1.NAMEOF THE MEDICINALPRODUCT
Valdoxan 25 mg film-coated tablets
2.Composition:
Each film-coated tablet contains 25 mg of agomelatine.
3.PHARMACEUTICALFORM
Film-coated tablet [tablet].
Orange-yellow, oblong, film-coated tablet with blue imprint of company logo on one side.
4.Manufacturer:
Servier
5.ATCCode:
N06AX22
6.CASnumber
138112-76-2
www.emea.europa.eu/
http://en.wikipedia.org/wiki/Agomelatine

7.MARKETINGAUTHORISATIONHOLDER
Les Laboratoires Servier
22, rue Garnier
F-92200 Neuilly-sur-Seine
France
8.MARKETINGAUTHORISATIONNUMBER(S)
EU/1/08/499/001-008
9.DATEOF THE FIRSTAUTHORISATION/ RENEWALOF THE
AUTHORISATION
19/02/2009
www.emea.europa.eu/

10. Chemical Structure:
11. Formula:
C15H17NO2
12. Systematic (IUPAC)name:
N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide
13. Melatonin vs. Agomelatine:
Melatonin (top) vs. agomelatine (bottom);
The chemical structure of agomelatine is very similar to that of melatonin. Where
melatonin has an NH group, agomelatine has an HC=CH group. Thus melatonin contains
an indole part, whereas agomelatine has a naphthalene bioisostere instead.
11 of 24
1/30/2015 Prof M.A.Eldawy, by pharmacist: Yasser Alaa
B. Tinant, J.-P. Declercq, J. H. Poupaert, S. Yous, D. Lesieur (1994). "N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide, a potent melatonin analog". Acta Cryst. C 50:
907-910. doi:10.1107/S0108270193012922

14. Therapeutic indications
Treatment of major depressive episodes in adults.
15. Posologyand method ofadministration
The recommended dose is 25 mg once daily taken orally at bedtime.
After two weeks of treatment, if there is no improvement of symptoms, the dose
may be increased to 50 mg once daily, i.e. two 25 mg tablets, taken together at
bedtime.
Liver function tests should be performed in all patients : at initiation of treatment,
and then periodically after around six weeks (end of acute phase), twelve weeks
and twenty four weeks (end of maintenance phase).
Patients with depression should be treated for a sufficient period of at least 6
months to ensure that they are free of symptoms.
Valdoxan tablets may be taken with or without food.
12 of 24
1/30/2015 Prof M.A.Eldawy, by pharmacist: Yasser Alaa
www.emea.europa.eu/

16. MechanismofAction:
Agomelatine is a melatonergic agonist (MT1 and MT2 receptors) and 5-HT2C antagonist.
Binding studies indicate that agomelatine has no effect on monoamine uptake and no
affinity for α, β adrenergic, histaminergic, cholinergic, dopaminergic and benzodiazepine
receptors.
Agomelatine resynchronises circadian rhythms in animal models of circadian rhythm
disruption.
Agomelatine increases noradrenaline and dopamine release specifically in the frontal
cortex and has no influence on the extracellular levels of serotonin.
13 of 241/30/2015 Prof M.A.Eldawy, by pharmacist: Yasser Alaa
"Summary of Product Characteristics" (PDF). European Medicine Agency. 2003. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000915/WC500046227.pdf. Retrieved 2010-09-22.

14 of 241/30/2015 Prof M.A.Eldawy, by pharmacist: Yasser Alaa
Gerdin, M. J. et al. Short-term exposure to melatonin differentially affects the functional sensitivity and trafficking of the hMT1 and hMT2 receptors. J.
Pharmacol. Exp. Ther. 304, 931–939 (2003).

15 of 24Prof M.A.Eldawy, by pharmacist: Yasser Alaa
Aloyo, V. J., Berg, K. A., Spampinato, U., Clarke, W. P. & Harvey, J. A. Current status of inverse agonism at serotonin2A (5-HT2A) and 5-HT2C receptors.
Pharmacol. Ther. 121, 160–173 (2009)
1/30/2015

16 of 24Prof M.A.Eldawy, by pharmacist: Yasser Alaa
Barden, N. et al. Antidepressant action of agomelatine (S20098) in a transgenic mouse model. Prog. Neuropsychopharmacol. Biol. Psychiatry 29, 908–916
(2005).
1/30/2015

17. Absorption and bioavailability:
Agomelatine is rapidly and well (≥ 80%) absorbed after oral administration. Absolute
bioavailability is low (< 5% at the therapeutic oral dose) and the interindividual
variability is substantial. The bioavailability is increased in women compared to men.
The bioavailability is increased by intake of oral contraceptives and reduced by smoking.
The peak plasma concentration is reached within 1 to 2 hours.
In the therapeutic dose-range, agomelatine systemic exposure increases proportionally
with dose. At higher doses, a saturation of the first-pass effect occurs.
Food intake (standard meal or high fat meal) does not modify the bioavailability or the
absorption rate.
The variability is increased with high fat food.
18. Distribution:
Steady state volume of distribution is about 35 l and plasma protein binding is 95%
irrespective of the concentration and is not modified with age and in patients with renal
impairment but the free fraction is doubled in patients with hepatic impairment.
17 of 24Prof M.A.Eldawy, by pharmacist: Yasser Alaa1/30/2015
www.emea.europa.eu/

19.Biotransformation:
Following oral administration, agomelatine is rapidly metabolised mainly via
hepatic CYP1A2; CYP2C9 and CYP2C19 isoenzymes are also involved but with a low
contribution. The major metabolites, hydroxylated and demethylated agomelatine,
are not active and are rapidly conjugated and eliminated in the urine.
20.Elimination:
Elimination is rapid, the mean plasma half-life is between 1 and 2 hours and the
clearance is high (about 1,100 ml/min) and essentially metabolic.
Excretion is mainly (80%) urinary and in the form of metabolites, whereas
unchanged compound recovery in urine is negligible. Kinetics are not modified after
repeated administration.
INRenalimpairment
No relevant modification of pharmacokinetic parameters in patients with severe
renal impairment has been observed (n=8, single dose of 25 mg), but caution
should be exercised in patients with severe or moderate renal impairment as only
limited clinical data are available in these patients
www.emea.europa.eu/

21.POSSIBLESIDEEFFECTS:
Like all medicines, Valdoxan can cause side effects, although not everybody gets
them.
Most side effects are mild or moderate. They usually occur within the first two
weeks of the treatment and are usually temporary.
- Common side effects: dizziness, sleepiness (somnolence), difficulty in sleeping
(insomnia), migraine, headache, feeling sick (nausea), diarrhoea, constipation,
upper abdominal pain, excessive sweating (hyperhidrosis), back pain, tiredness,
anxiety, increased levels of liver enzymes in your blood.
- Uncommon side effects: pins and needles in the fingers and toes
(paraesthesia), blurred vision and eczema.
- Rare side effects: serious skin eruption (erythematous rash), hepatitis.
- Other possible side effects: suicidal thoughts or behaviour, agitation
(frequency not known).
Papakostas, G. I. Tolerability of modern antidepressants. J. Clin. Psychiatry 69, 8–13 (2008).
Mathew, S. J., Manji, H. K. & Charney, D. S. Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology 33, 2080–2092 (2008).
Lemoine, P., Guilleminault, C. & Alvarez, E. Improvement in subjective sleep in major depressive disorder with a novel antidepressant, agomelatine:
randomized, double blind comparison with venlafaxine. J. Clin. Psychiatry 68, 1723–1732 (2007).

22.Interactionwith other medicinalproductsandother forms of interaction:
Potential interactions affecting agomelatine:
Agomelatine is metabolised mainly by cytochrome P450 1A2 (CYP1A2) (90%) and
by CYP2C9/19 (10%). Medicinal products that interact with these isoenzymes may
decrease or increase the bioavailability of agomelatine.
Fluvoxamine, a potent CYP1A2 and moderate CYP2C9 inhibitor markedly inhibits
the metabolism of agomelatine resulting in a 60-fold (range 12-412) increase of
agomelatine exposure.
Consequently, co-administration of Valdoxan with potent CYP1A2 inhibitors (e.g.
fluvoxamine, ciprofloxacin) is contraindicated.
Combination of agomelatine with oestrogens (moderate CYP1A2 inhibitors)
results in a several fold increased exposure of agomelatine. While there was no
specific safety signal in the 800 patients treated in combination with oestrogens,
caution should be exercised when prescribing agomelatine with other moderate
CYP1A2 inhibitors (e.g. propranolol, grepafloxacine, enoxacine) until more
experience has been gained
www.emea.europa.eu/

23.Fertility, pregnancyandlactation
Fertility
Reproduction studies in the rat and the rabbit showed no effect of agomelatine on
fertility.
Pregnancy
Reproduction studies in the rat and the rabbit showed no effect of agomelatine on
embryofoetal development and pre- and post natal development.
For agomelatine, no clinical data on exposed pregnancies are available. Animal
studies do not indicate direct or indirect harmful effects with respect to pregnancy,
embryonal/foetal development, parturition or postnatal development
Caution should be exercised when prescribing to pregnant women.
Breast-feeding
It is not known whether agomelatine is excreted into human milk. Agomelatine or
its metabolites are excreted in the milk of lactating rats. Potential effects of
agomelatine on the breast-feeding infant have not been established. If treatment
with Valdoxan is considered necessary, breastfeeding should be discontinued.
"Summary of Product Characteristics"(PDF). European Medicine Agency. 2003. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000915/WC500046227.pdf. Retrieved 2010-09-22.

Linnik, I. V. et al. The novel antidepressant, agomelatine, blocks cerebral 5-HT2C receptors in vivo: a phMRI challenge study in rats. Eur.
Neuropsychopharmacol. 19, S259 (2009).
Agomelatine represents an innovative approach to treating depression as it is the first
regulatory approved agent to incorporate a non-monoaminergic mechanism.
Its antidepressant activity across a broad range of experimental procedures in animal
models and its distinctive therapeutic profile in humans probably reflect a synergistic
interplay of its melatonergic (agonist) and 5-HT2C (antagonist) properties.
Extensive clinical trials have established both the short-term and long-term efficacy of
agomelatine in major depression in mildly and severely ill patients, with an improvement of
sleep quality, preservation of sexual function, absence of weight gain and good tolerability.
Moreover, discontinuation is not associated with withdrawal symptoms. This overall profile
compares favourably to currently available antidepressants and should encourage
adherence throughout the extensive treatment period, 6 months or more, recommended
for durable improvement of a major depressive episode. Further studies and clinical
use will clarify the full potential of agomelatine as an antidepressant. There is also rich
potential, as highlighted above, for exploration of the broader use of agomelatine in the
treatment of other central nervous system disorders.

References
23 of 24
Petersen, T; Dording, C; Neault, NB; Kornbluh, R; Alpert, JE; Nierenberg, AA; Rosenbaum, JF; Fava, M (January 2002). "A survey of prescribing practices in the
treatment of depression". Progress in Neuro-Psychopharmacology and Biological Psychiatry (Elsevier) 26 (1): 177–87. doi:10.1016/S0278-5846(01)00250-0.
PMID 11853110.
Stagnitti,M. (2005) Antidepressant Use in the US Civilian Non-Insitutionalised Population, 2002. Statistical Brief #77. Rockville,MD: Medical Expenditure Panel,
Agency for Healthcare Research and Quality.
Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R (January 2008). "Selective publication of antidepressant trials and its influence on apparent
efficacy". N. Engl. J. Med. 358 (3): 252–60. doi:10.1056/NEJMsa065779. PMID 18199864
Kuhn, R (November 1958). "The Treatment of Depressive States with G 22355 (Imipramine Hydrochloride)". American Journal of Psychiatry (American Psychiatric
Association) 115 (5): 459–464. doi:10.1176/appi.ajp.115.5.459 (inactive 2009-10-24).
Stimmel, GL; Dopheide, JA; Stahl, SM (Jan-Feb 1997). "Mirtazapine: an antidepressant with noradrenergic and specific serotonergic effects". Pharmacotherapy
(American College of Clinical Pharmacy) 17 (1): 10–21. ISSN 0277-0008. PMID 9017762
Tatsumi M, Groshan K, Blakely RD, Richelson E. (1997). "Pharmacological profile of antidepressants and related compounds at human monoamine
transporters.". Eur J Pharmacol. 340 (2-3): 249–258. doi:10.1016/S0014-2999(97)01393-9. PMID 9537821
Pacchierotti, C. et al. Melatonin in Psychiatric Disorders: A Review on the Melatonin Involvement in Psychiatry. Frontiers in Neuroendocrinology. Volume 22,
Issue 1, January 2001, Pages 18-32.
Crasson, M. et al. Serum melatonin and urinary 6-sulfatoxymelatonin in major depression. Psychoneuroendocrinology. Volume 29, Issue 1, January 2004, Pages
1-12.
www.emea.europa.eu/
Gerdin, M. J. et al. Short-term exposure to melatonin differentially affects the functional sensitivity and trafficking of the hMT1 and hMT2 receptors. J.
Pharmacol. Exp. Ther. 304, 931–939 (2003).
Aloyo, V. J., Berg, K. A., Spampinato, U., Clarke, W. P. & Harvey, J. A. Current status of inverse agonism at serotonin2A (5-HT2A) and 5-HT2C receptors.
Pharmacol. Ther. 121, 160–173 (2009)
Barden, N. et al. Antidepressant action of agomelatine (S20098) in a transgenic mouse model. Prog. Neuropsychopharmacol. Biol. Psychiatry 29, 908–916
(2005).
Papakostas, G. I. Tolerability of modern antidepressants. J. Clin. Psychiatry 69, 8–13 (2008).
Mathew, S. J., Manji, H. K. & Charney, D. S. Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology 33, 2080–2092 (2008).
Lemoine, P., Guilleminault, C. & Alvarez, E. Improvement in subjective sleep in major depressive disorder with a novel antidepressant, agomelatine:
randomized, double blind comparison with venlafaxine. J. Clin. Psychiatry 68, 1723–1732 (2007).
Prof M.A.Eldawy, by pharmacist: Yasser Alaa1/30/2015

Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa

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Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa