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VIEWPOINT
Year : 2019  |  Volume : 12  |  Issue : 1  |  Page : 50-54  

DRUG REPOSITIONING: Revisiting the basic psychopharmacological mechanism of action for agomelatine and where it should be classified?


1 Department of Pharmacology and Therapeutics, University of Medical Sciences, Ondo City, Ondo State, Nigeria
2 Department of Internal Medicine, Irrua Specialist Teaching Hospital, Irrua, Edo State, Nigeria

Date of Submission22-Jun-2018
Date of Acceptance27-Sep-2018
Date of Web Publication18-Jan-2019

Correspondence Address:
Olumuyiwa John Fasipe
Department of Pharmacology and Therapeutics, Faculty of Basic Clinical Sciences, University of Medical Sciences, Ondo City, Ondo State
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mjdrdypu.mjdrdypu_98_18

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  Abstract 


Concerning Agomelatine, as of this present moment and deeply analyzing things from the psychopharmacological point of view, the utmost important question yet to be answered is “why should the drug Agomelatine be regarded as an antidepressant agent when it did not actually possess the necessary pharmacoactivities and mechanism of actions that adequately qualified it to be classified under the family of antidepressants as done in previously published reference literatures?” The mystery, approach, and rationale behind this act of classification phenomenon were actually and inevitably putting a square peg inside a round hole, which is scientifically deemed unfit and inappropriate. This act of classification phenomenon makes Agomelatine to be referred to as a paradoxical agent that contradicts itself. Agomelatine is a melatonergic MT1 and MT2 receptors agonist and a selective serotonergic 5-HT2B and 5-HT2C receptors antagonist (MASSA). The 5-HT2B receptors are poorly represented in the central nervous system (CNS) in contrast to the 5-HT2C receptors. Its prochronobiological activity resynchronizes circadian rhythms in experimental animal models of delayed sleep phase syndrome via its melatonergic MT1 and MT2 receptors agonistic effect. By antagonizing 5-HT2C receptors, Agomelatine disinhibits/increases norepinephrine and dopamine release specifically in the neocortical areas such as the prefrontal cortex but neither in the subcortical areas such as the striatum nor nucleus accumbens; therefore, it is sometimes referred to as a norepinephrine–dopamine disinhibitor (NDD). Furthermore, by antagonizing 5-HT2C receptors in the subcortical areas such as basal ganglia, mesolimbic cortex and hippocampus; Agomelatine produces anxiolytic effect clinically. Because Agomelatine lacks inhibitory pharmacoactivity at the monoaminergic reuptake transporter pumps (SERT, NET, and DAT), does not inhibit the enzyme monoamine oxidase, has neither weak antagonist nor partial agonist activity at the dopaminergic D2 receptor, and also lacks antagonistic activity at both the noradrenergic α2-receptor and N- methyl-D-aspartic acid (NMDA)-glutamatergic ionoceptor, it should not be regarded and accepted as an antidepressant but rather it should be classified as an anxiolytic sedative agent on account of its melatonergic MT1 and MT2 receptors agonist and selective serotonergic 5-HT2C receptor antagonistic (MASSA) properties.

Keywords: Agomelatine, antidepressant, anxiolytic-sedative, classification, drug repositioning, mechanism of action, paradoxical agent


How to cite this article:
Fasipe OJ, Ibiyemi-Fasipe OB, Akhideno PE, Fageyinbo MS. DRUG REPOSITIONING: Revisiting the basic psychopharmacological mechanism of action for agomelatine and where it should be classified?. Med J DY Patil Vidyapeeth 2019;12:50-4

How to cite this URL:
Fasipe OJ, Ibiyemi-Fasipe OB, Akhideno PE, Fageyinbo MS. DRUG REPOSITIONING: Revisiting the basic psychopharmacological mechanism of action for agomelatine and where it should be classified?. Med J DY Patil Vidyapeeth [serial online] 2019 [cited 2019 Apr 25];12:50-4. Available from: http://www.mjdrdypv.org/text.asp?2019/12/1/50/250450




  Introduction Top


Concerning agomelatine, as of this present moment and deeply analyzing things from the psychopharmacological point of view, the utmost important question yet to be answered is “why should the drug Agomelatine be regarded as an antidepressant agent when it did not actually possess the necessary pharmacoactivities and mechanism of actions that qualified it to be classified under the family of antidepressants as done in previously published reference literatures?” The mystery, approach, and rationale behind this act of classification phenomenon were actually and inevitably putting a square peg inside a round hole, which is scientifically deemed unfit and inappropriate. This act of classification phenomenon makes Agomelatine to be referred to as a paradoxical agent that contradicts itself. Furthermore, drug like Cyproheptadine is potently a strong antagonist at the serotonergic 5-HT2A, 5-HT2B and 5-HT2C receptors, a strong antagonist/inverse agonist at the histaminergic H1 receptor and also exhibits a moderate unselective blockade/antagonism at the muscarinic acetylcholine [M] receptors. Nevertheless, Cyproheptadine is acceptable as an anxiolytic-sedative agent but is not worthy to be regarded and classified as an antidepressant agent based on these pharmacological properties. In addition, drug like Ramelteon or Tasimelteon is a melatonergic MT1 and MT2 receptors agonist used for the treatment of non-24-hour sleep–wake rhythm disorder (also called Non-24, N24 and N24HSWD). Yet, Ramelteon or Tasimelteon is acceptable as a sedative agent but is not worthy to be regarded and classified as an antidepressant agent based on these pharmacological properties. So, in a nutshell, why should Agomelatine (a melatonergic MT1 and MT2 receptors agonist and a selective serotonergic 5-HT2B and 5-HT2C receptors antagonist [MASSA]) be given a separate and different preferential treatment from Cyproheptadine, Ramelteon or Tasimelteon in the actual medical context? This implies that what is sauce for the goose is also sauce for the gander in the real sense!

Furthermore, to buttress our own point of view, the NMDA-glutamatergic receptor antagonist/inverse agonist/partial agonist such as ketamine, rapastinel and apimostinel produce their rapid and sustain antidepressant activity through a novel mechanism of action that involve the inhibition/blockade of the NMDA-glutamatergic ionoceptor which are unchallengeable and clinical obvious, in contrast to Agomelatine (MASSA) whose claimed antidepressant activity is quite ambiguous and highly questionable when used solely as a monotherapy for the treatment of depression disorders because of inadequate clinical efficacy and response in particular! The claimed but ambiguous and questionable antidepressant activity of Agomelatine in some documented previous reference literatures could be as a result of its sedative action via the melatonergic MT1 and MT2 receptors agonism with its anxiolytic action via the 5-HT2C receptor antagonism. This could easily be misinterpreted through a bias cloudy observation as a mild antidepressant effect clinically because some patients with depression disorders tend to present with complains/features of insomnia and anxiety which Agomelatine can help alleviate to some extent and they will feel better with these improvements.[1],[2],[3],[4]

Agomelatine was discovered and developed by the European pharmaceutical company Servier Laboratories Limited. Servier developed the drug and conducted its Phase III trials in the European Union. In March 2005, Servier submitted agomelatine to the European Medicines Agency (EMA) for licensing and marketing approval. On 27th July 2006, the Committee for Medical Products for Human Use of the EMA recommended a refusal of the marketing authorization. The major concern was that efficacy had not been sufficiently shown, while there were no special concerns about side effects. Again, in September 2007, Servier submitted a new marketing application to the EMA. In March 2006, Servier announced it had sold the rights to market agomelatine in the United States (US) to Novartis. It was undergoing several Phase III clinical trials in the United States, and until October 2011 Novartis listed the drug as scheduled for submission to the Food Drug Administration (FDA) no earlier than 2012. However, the development for the US market was discontinued and withdrawn in October 2011, when the results from the last of those trials became available. It received EMA approval for marketing in the European Union in February 2009 and Therapeutic goods administration (TGA) approval for marketing in Australia in August 2010.[1],[2],[3],[4]


  Pharmacological Properties of Agomelatine Top


Agomelatine is a melatonergic MT1 and MT2 receptors agonist and a selective serotonergic 5-HT2B and 5-HT2C receptors antagonist (MASSA). The 5-HT2B receptors are poorly represented in the central nervous system (CNS) in contrast to the 5-HT2C receptors. These 5-HT2B receptors are found predominantly in the periphery on platelets, and endothelial lining of the heart valves and blood vessels in the cardiovascular system. Binding studies indicate that it has no effect on monoaminergic reuptake transporter pumps and no affinity for noradrenergic, histaminergic, cholinergic, dopaminergic, benzodiazepine receptors nor other serotonergic receptor subtypes. Agomelatine prochronobiological activity resynchronizes circadian rhythms in experimental animal models of delayed sleep phase syndrome via its melatonergic MT1 and MT2 receptors agonistic effect. In humans, the MT1 receptors are expressed in the pars tuberalis and pars distalis of the anterior pituitary gland and suprachiasmatic nuclei of the hypothalamus where they mediate and control reproductive physiological function and melatonin's biological circadian rhythm activity, respectively. While the MT2 receptors are expressed in the retina and osteoblasts. These MT2 receptors' expression in the retina is indicative of melatonin's effect on the mammalian retina occurring through this receptor. Activation of melatonin MT2 receptors in the retina has been found to affect and delay several light-dependent functions, including phagocytosis and photopigment disc shedding. Also, the MT2 receptor regulates proliferation and differentiation of osteoblasts and further enhances their osteogenic function in depositing new bone matrices. Agonist activation of the pertussis toxin-sensitive inhibitory G-protein coupled (Gi/o) melatonergic MT1 and MT2 receptors leads to the inhibition of adenylyl cyclase and guanylyl cyclase activities respectively, with subsequent reduction of intracellular cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) second messengers, respectively. By antagonizing 5-HT2C receptors, Agomelatine disinhibits/increases norepinephrine and dopamine release specifically in the neocortical areas such as the prefrontal cortex but neither in the subcortical areas such as the striatum nor nucleus accumbens. Therefore, it is sometimes referred to as a norepinephrine–dopamine disinhibitor (NDD). It also worth mentioning here that dopaminergic and noradrenergic neurotransmission pathways in neocortical areas such as the prefrontal cortex, entorhinal cortex, cingulate cortex, superior temporal cortex, and orbital cortex are hypofunctionally impaired in depression disorders. Agomelatine has no influence on the extracellular levels of serotonin. It has been postulated to exhibit an antidepressant-like effect in experimental animal models of depression (learned helplessness test, despair test, and chronic mild stress) as well as in models with circadian rhythm desynchronisation disorder type 1 (CRDD-1) and in models related to stress, insomnia and anxiety. In fact, it has been demonstrated that genetically modified knockout experimental model mice lacking 5-HT2C receptors significantly exhibit/manifest reduced and limited anxiety symptoms. Hence, by antagonizing 5-HT2C receptor in the subcortical areas such as basal ganglia, mesolimbic cortex and hippocampus; Agomelatine produces anxiolytic effect clinically. In humans, agomelatine has positive phase shifting properties; it induces a phase advance of sleep, body temperature decline, and melatonin-like activity onset.[1],[2],[3],[4] From the psychopharmacological point of view, Agomelatine will be efficacious as an adjunct-augmenting pharmacotherapeutic agent for the treatment of patients having anxious depression disorders (that is, either major depression disorder [MDD] or bipolar depression or schizoaffective depression with anxiety disorder component). It will also be efficacious as a sole or combine pharmacotherapeutic agent for the treatment of patients having delayed sleep phase syndrome due to circadian rhythm desynchronisation disorder type 1 (CRDD-1) or Jetlag dysrhythmia, insomnia, anxiety disorders, selective serotonin reuptake inhibitor (SSRI)-induced sexual dysfunction and/or SSRI-induced nocturnal myclonus/akathisia. In circadian rhythm desynchronisation disorder type 1 (CRDD-1), there is deficiency of melatonin production as a result of lesional destruction of the pinealocytic neurons in the pineal gland. While circadian rhythm desynchronisation disorder type 2 (CRDD-2) occurs as a result of lesional destruction of the suprachiasmatic nuclei or loss of function mutation affecting the melatonergic MT1 receptors on the suprachiasmatic nuclei in the hypothalamus. It also worthy of note that the suprachiasmatic nucleus function as the chronobiological clock of the human body and any disruption in its functional activity will inevitably affect the circadian (sleep-wake) rhythm cycle. Agomelatine alone may not be effective as a monotherapy for the treatment of unipolar depression or bipolar depression or schizoaffective depression because of its unique mechanism of action as a melatonergic MT1 and MT2 receptors agonist and a selective serotonergic 5-HT2C receptor antagonist (MASSA). Because Agomelatine lacks inhibitory pharmacoactivity at the monoaminergic reuptake transporter pumps (SERT, NET, and DAT), does not inhibit the enzyme monoamine oxidase, has neither weak antagonist nor partial agonist activity at the dopaminergic D2 receptor, and also lacks antagonistic activity at both the noradrenergic α2-receptor and N-methyl-D-aspartic acid (NMDA)-glutamatergic ionoceptor, it should not be regarded and accepted as an antidepressant but rather it should be classified as an anxiolytic sedative agent on account of its melatonergic MT1 and MT2 receptors agonist and selective serotonergic 5-HT2C receptor antagonistic (MASSA) properties. Moreover, Agomelatine remains a paradoxical agent that doesn't fit into any of the currently available classes of antidepressant agents and its pharmacological properties also deemed it unfit and inappropriate to be classified into another separate novel class of antidepressants contrary to the reports published in previous reference literatures.[5],[6],[7] The claimed but clinically ambiguous and highly questionable antidepressant activity of Agomelatine in some documented previous reference literatures could be as a result of its sedative action via the melatonergic MT1 and MT2 receptors agonism with its anxiolytic action via the 5-HT2C receptor antagonism. This could easily be misinterpreted through a bias cloudy observation as a mild antidepressant effect clinically because some patients with depression disorders tend to present with complains/features of insomnia and anxiety which Agomelatine can help alleviate to some extent and they will feel better with these improvements. [1-7] Furthermore, according to the results obtained from the systematic review and meta-analysis study conducted by Cipriani et al., (2018), [5] the questionable antidepressant activity and effect claimed to be exhibited by Agomelatine among a variety of antidepressants in the acute treatment of adults with unipolar major depressive disorder in their assessment of previously published and unpublished studies could also be attributed to the investigators bias as the pharmaceutical company that produces Agomelatine is quite desperate to market the drug as an antidepressant agent rather than marketing it as an anxiolytic-sedative agent. Also the study by Cipriani et al., (2018) [5] was funded by the National Institute for Health Research Oxford Health Biomedical Research Centre, and in conjunction with the Japan Society for the Promotion of Science. But this our own study do not receive funding from anyone, in which we are highly predisposed to say the truth even if we are going to be vividly criticized and disputed. In addition, the Cipriani et al., (2018) study [5] completely excluded the participants with bipolar depression, psychotic depression, or treatment-resistant depression; once again, if these researchers were quite very sure of the antidepressant activity of Agomelatine for these excluded disease conditions, these excluded patients with bipolar depression, psychotic depression, or treatment-resistant depression should have been included and considered since depression disorder was a significant component of their pathological conditions, as this deliberate action also justified their uncertainty concerning the efficacy of Agomelatine alone monotherapy for these depression disorders. One truthful fact that the pharmaceutical company producing Agomelatine is ignorance/unaware of today is that, if this drug is marketed primarily as an anxiolytic-sedative agent, this does not stop clinicians from using it as an adjunct-augmenting pharmacotherapeutic agent for the treatment of depression disorders. [6,7] From psychopharmacological stand point of view, it will be highly advisable for the pharmaceutical company producing Agomelatine to market it primarily as an anxiolytic-sedative agent; [6,7] so that the drug can quickly be approved by the FDA, to be widely accepted by the clinicians, and at the same time still being used secondarily (or off-label) as an adjunct-augmenting pharmacotherapeutic agent for the treatment of anxious depression disorders. [6,7] In addition, Agomelatine use was not associated with discontinuation or withdrawal symptoms after an abrupt/sudden cessation of treatment after 12 weeks duration of the pharmacotherapy.

It has a mean terminal half-life of about 2 h 20 min (140 min). After oral administration, Agomelatine is rapidly (0.5–4 h) and well absorbed (80%), and the time at which the maximum blood concentration was achieved was between 45 min and 90 min after a single oral dose of 25–50 mg. However, its bioavailability is indeed low at the therapeutic oral dose due to the high first-pass metabolism, which may be of concern, especially in elderly patients over 75 years or in subjects with hepatic compromise.[2],[3] It has a moderate volume of distribution of approximately 35 L and a plasma protein binding of 95%, and the peak plasma concentration is achieved within 1–2 h after oral administration. At the therapeutic levels, Agomelatine blood concentration increases proportionally with dose; at higher doses, a saturation of the first-pass effect may occur. About 80% of the drug is eliminated through urinary excretion of the metabolites, whereas a small amount of the metabolites undergoes fecal excretion. The major enzymes involved in the biotransformation of Agomelatine are CYP1A2 (90%) and to a lesser extent CYP2C9/CYP2C19.[2],[3],[4]


  Conclusion Top


Agomelatine remains a paradoxical agent that doesn't fit into any of the currently available classes of antidepressant agents and its pharmacological properties also deemed it unfit and inappropriate to be classified into another separate novel class of antidepressants contrary to the reports published in previous reference literatures. Because Agomelatine lacks inhibitory pharmacoactivity at the monoaminergic reuptake transporter pumps (SERT, NET and DAT), does not inhibit the enzyme monoamine oxidase, has neither weak antagonist nor partial agonist activity at the dopaminergic D2 receptor, and also lacks antagonistic activity at both the noradrenergic α2-receptor and NMDA-glutamatergic ionoceptor, it should not be regarded and accepted as an antidepressant but rather it should be classified as an anxiolytic sedative agent on account of its melatonergic MT1 and MT2 receptors agonist and selective serotonergic 5-HT2C receptor antagonistic (MASSA) properties.

What this drug reposition article adds to the body of knowledge:



  • Agomelatine remains a paradoxical agent that doesn't fit into any of the currently available classes of antidepressant agents and its pharmacological properties also deemed it unfit and inappropriate to be classified into another separate novel class of antidepressants contrary to the reports published in previous reference literatures.
  • Because Agomelatine lacks inhibitory pharmacoactivity at the monoaminergic reuptake transporter pumps (SERT, NET, and DAT), does not inhibit the enzyme monoamine oxidase, has neither weak antagonist nor partial agonist activity at the dopaminergic D2 receptor, and also lacks antagonistic activity at both the noradrenergic α2-receptor and NMDA-glutamatergic ionoceptor, it should not be regarded and accepted as an antidepressant but rather it should be classified as an anxiolytic sedative agent on account of its melatonergic MT1 and MT2 receptors agonist and selective serotonergic 5-HT2C receptor antagonistic (MASSA) properties.
  • From the psychopharmacological point of view, Agomelatine will be efficacious as an adjunct-augmenting pharmacotherapeutic agent for the treatment of patients having anxious depression disorders (that is, either major depression disorder [MDD] or bipolar depression or schizoaffective depression with anxiety disorder component). It will also be efficacious as a sole or combine pharmacotherapeutic agent for the treatment of patients having delayed sleep phase syndrome due to circadian rhythm desynchronisation disorder type 1 (CRDD-1) or Jetlag dysrhythmia, insomnia, anxiety disorders, selective serotonin reuptake inhibitor (SSRI)-induced sexual dysfunction and/or SSRI-induced nocturnal myclonus/akathisia.
  • Agomelatine alone may not be effective as a monotherapy for the treatment of unipolar depression or bipolar depression or schizoaffective depression because of its unique mechanism of action as a melatonergic MT1 and MT2 receptors agonist and a selective serotonergic 5-HT2C receptor antagonist (MASSA).
  • In addition, by antagonizing 5-HT2C receptors, Agomelatine disinhibits/increases norepinephrine and dopamine release specifically in the neocortical areas such as the prefrontal cortex but neither in the subcortical areas such as the striatum nor nucleus accumbens, therefore it is sometimes referred to as a norepinephrine–dopamine disinhibitor (NDD). Lastly, by antagonizing 5-HT2C receptors in the subcortical areas such as basal ganglia, mesolimbic cortex and hippocampus; Agomelatine produces anxiolytic effect clinically.


Financial support and sponsorship

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Conflicts of interest

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  References Top

1.
Kasper S, Hajak G, Wulff K, Hoogendijk WJ, Montejo AL, Smeraldi E, et al. Efficacy of the novel antidepressant agomelatine on the circadian rest-activity cycle and depressive and anxiety symptoms in patients with major depressive disorder: A randomized, double-blind comparison with sertraline. J Clin Psychiatry 2010;71:109-20.  Back to cited text no. 1
    
2.
Heun R, Coral RM, Ahokas A, Nicolini H, Teixeira JM, Dehelean P. “1643 – Efficacy of agomelatine in more anxious elderly depressed patients. A randomized, double-blind study vs. Placebo”. Eur Psychiatry 2013;28 Suppl 1:1.  Back to cited text no. 2
    
3.
Stein DJ, Picarel-Blanchot F, Kennedy SH. Efficacy of the novel antidepressant agomelatine for anxiety symptoms in major depression. Hum Psychopharmacol 2013;28:151-9.  Back to cited text no. 3
    
4.
Koesters M, Guaiana G, Cipriani A, Becker T, Barbui C. "Agomelatine efficacy and acceptability revisited: systematic review and meta-analysis of published and unpublished randomised trials". Br J Psychiatry 2013;203:179-87. doi:10.1192/bjp.bp.112.120196. PMID 23999482.   Back to cited text no. 4
    
5.
Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y. et al. (2018). Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet 2018;391:1357-66. doi: 10.1016/S0140- 6736(17)32802-7.   Back to cited text no. 5
    
6.
Fasipe OJ, Osho PO, Osho ES, Akhideno PE, Ibiyemi-Fasipe OB. (2018). Agomelatine repositioning as a novel anxiolytic-sedative agent for the treatment of circadian rhythm desynchronisation disorder type 1, insomnia and anxiety disorders in clinical practice. The Society Francophone of Chronobiology (SFC) Book of Abstracts and Conference Proceedings, 2018;76. Research Presentation at the 46th Conference of the Society Francophone of Chronobiology (SFC), which took place at the Hassan II Institute of Agronomy and Veterinary Medicine, Rabat City, Morocco from 22nd to 25th October, 2018.   Back to cited text no. 6
    
7.
Fasipe OJ. (2018). Neuropharmacological classification of antidepressant agents based on their mechanisms of action. Arch Med Health Sci 2018;6:81 94. https://www.amhsjournal.org. DOI: 10.4103/amhs.amhs_7_18.  Back to cited text no. 7
    




 

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