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Critical Appraisal and Update on the Clinical Utility of Agomelatine, a Melatonergic Agonist, for the Treatment of Major Depressive Disease in Adults

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Critical Appraisal and Update on the Clinical Utility of Agomelatine, a Melatonergic Agonist, for the Treatment of Major Depressive Disease in Adults Neuropsychiatric Disease and Treatment Dovepress open access to scientific and medical research Open Access Full Text Article EX P ERT op I N I on Critical appraisal and update on the clinical utility of agomelatine, a melatonergic agonist, for the treatment of major depressive disease in adults Robert H Howland Abstract: This article describes the pharmacology of the novel atypical antidepressant drug agomelatine, critically reviews and evaluates its clinical use for the treatment of major depres- University of Pittsburgh School of Medicine, Western Psychiatric sion, and suggests areas for further research. Agomelatine is a synthetic analog of the hormone Institute and Clinic, University of melatonin. It stimulates the activity of melatonin MT1 and MT2 receptors and inhibits the activity Pittsburgh Medical Center, Pittsburgh PA, USA of serotonin 5HT-2C receptor subtypes. Three acute trials demonstrated clinically modest, but statistically significant benefits over placebo. Three acute trials did not find agomelatine more effective than placebo. A meta-analysis of these six trials demonstrated a small, statistically significant, marginally clinically relevant difference between agomelatine and placebo. The only placebo-controlled study in elderly patients did not demonstrate a significant benefit for agomelatine. It was more effective than placebo in only one of two relapse prevention studies. Agomelatine was generally well tolerated compared to placebo. Its side-effect profile is different than and compares favorably to other antidepressant drugs. The overall tolerability of agomela- tine in head-to-head comparisons was not substantially better than active drug comparators. Agomelatine is contraindicated in patients with impaired liver function and in patients taking drugs that potently inhibit CYP-1A2 metabolic enzymes. Because elevated liver enzymes are common, and there is a rare risk of more serious liver reactions, routine laboratory monitoring of liver function is recommended periodically throughout treatment. Agomelatine does not have clinically significant advantages compared to other antidepressant drugs, and it has cer- tain limitations and disadvantages. Because of its unique pharmacology and relatively benign tolerability profile, however, it may be a useful alternative for patients who do not respond to or cannot tolerate other antidepressant drugs. Keywords: agomelatine, melatonin, serotonin, antidepressant, major depression Introduction The goal of antidepressant drug therapy for major depression should be to achieve full remission, as demonstrated by the absence of significant depressive symptoms along with a complete recovery of social and vocational function.1 With any first- Correspondence: Robert H Howland choice antidepressant medication, about 50% to 70% of patients will have a signifi- Associate Professor of Psychiatry, University of Pittsburgh School of cant treatment response (usually defined as a 50% or greater decrease in depressive Medicine, Western Psychiatric Institute symptoms). Of these treatment responders, however, only about one-half to one-third and Clinic, University of Pittsburgh Medical Center, 3811 O’Hara Street, attain a full remission. A significant proportion of depressed patients are therefore Pittsburgh PA 15213, USA left with residual or persistent symptoms despite apparently adequate antidepressant Tel +1 412-246-5749 therapy. The failure to achieve remission with antidepressant therapy is associated Fax +1 412-246-5750 Email [email protected] with an increased risk of relapse or recurrence, higher levels of impaired social submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2009:5 563–576 563 Dovepress © 2009 Howland, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. Howland Dovepress and vocational function, and a worse long-term prognosis. agomelatine was searched using the terms “melatonin,” Chronic or recurrent depression is associated with persis- “ramelteon,” or “TAK-375.” tent social and vocational disability, an increased risk of suicide, greater medical morbidity and mortality, and higher Pharmacology and pharmacodynamic health care utilization and costs.2–4 Patients with depressive profile of agomelatine symptoms less severe than major depression also suffer from After a drug is administered, it is eventually distributed significant impairment.5,6 to its site of action where it interacts with its particular Symptomatic improvement of depression can facilitate targets. Pharmacodynamics refers to the pharmacological the process of functional recovery, thereby reducing dis- mechanism of action of a drug at its particular targets, ability, and this can help prevent possible complications which includes its therapeutic effects as well as any adverse related to the illness such as substance abuse and suicide.7 effects. Psychotropic drug targets typically are various Complications related to depression also extend to its effect enzymes, transporters, and receptors that regulate the syn- on various medical conditions. Depression worsens the thesis, transmission, and degradation of different chemical health outcome and functioning of patients with a variety neurotransmitters in the central nervous system. How a drug of medical disorders.8 For example, heart disease, diabe- will affect patient function overall depends on the net effect tes, and osteoporosis are significantly worse in depressed of its intended therapeutic use together with any unintended compared to nondepressed patients.9–12 Having depression effect on other organ systems throughout the body.23 also contributes to poor treatment adherence for other medi- Agomelatine has been extensively investigated in pre- cal conditions, and treating depression can improve medical clinical studies.24 It also has been investigated in clinical adherence.13–16 Depression not only affects existing medical trials in Europe for the treatment of depression and was disorders, but can be associated with an increased risk of the first recommended for approval by the European Medicines later development of some medical conditions. Compared to Agency in November 2008.25–27 Clinical trials of agomelatine nondepressed people, depressed patients are more likely to for depression (3 short-term efficacy and safety trials and later develop heart disease, diabetes, and osteoporosis.10,17–19 1 longer-term relapse prevention trial) have been conducted Depression also can adversely affect pregnancy outcome in the United States, but the findings from these studies have (eg, prematurity and low birthweight).20,21 Ineffectively or not been released and it is not yet approved by the US Food inadequately treating depression may therefore contrib- and Drug Administration.28 Agomelatine is a synthetic analog ute to the substantial morbidity and mortality associated of the hormone melatonin.29 with many medical conditions as well as with depression Melatonin is secreted by the pineal gland and normally itself. serves to regulate various circadian (24-hour) rhythms, Many types of antidepressant drugs are available, but including sleep–wake cycles. Disturbances in circadian their absolute effectiveness is limited.22 Many patients rhythms have been implicated in the development of mood do not respond to available drugs, or they have residual disorders as well as disrupted sleep patterns.30 Phase-shift symptoms despite adequate treatment. Some patients hypotheses suggest that depression results from internal cir- respond to medication, but they develop intolerable side cadian rhythms that are phase delayed (or phase advanced in effects and stop treatment. For these reasons, new drug some patients) relative to external clock time (as exemplified therapies are always needed. Even though a new drug may by the light–dark cycle) and to sleep–wake cycles, resulting not necessarily be more effective on average compared to in a pathological desynchronization of ordinarily closely available drugs, it might be relatively more efficacious or linked biological rhythms. The central internal (endogenous) better tolerated for certain patients. In this paper, I will circadian rhythm pacemaker (regulating such 24-hour bio- describe the pharmacology of the novel atypical antide- logical cycles as endocrine function and body temperature) pressant drug agomelatine, critically review and evaluate is located in the suprachiasmatic nucleus (SCN) of the its clinical use for the treatment of major depression, and hypothalamus.31 Light influences SCN function via a neural outline suggested areas for further research investigating pathway from the retina to the SCN. A pathway from the this unique drug. The literature was reviewed for articles SCN to the pineal gland regulates the synthesis and release relating to agomelatine on MEDLINE, PsychINFO, and of the melatonin. It is notable that melatonin is synthesized Google Scholar using the search terms “agomelatine” from the neurotransmitter serotonin.32 Melatonin secretion or “S-20098.” Additional literature potentially related to is regulated internally by the normal autonomous activity of 564 submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2009:5 Dovepress Dovepress Critical appraisal of agomelatine the SCN as well as externally by light exposure on the retina. Stress-response systems are abnormally activated in Melatonin is effective for circadian
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