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Agomelat ne: The e dence fo ts placen the t eatment of dep ess on

Dan ela EseThomas C BaghaHans-J gen MlleDepa tment of Psych at yand Psychothe apy,Lud g-Max m l ans-Un e s ty,Mun ch, Ge many

Co espondence: Dan ela EseDepa tment of Psych at y andPsychothe apy, Lud g-Max m l an-Un e s ty of Mun ch, Nubaumst ae 7,D-80336, Mun ch, Ge manyEma l Dan ela.Ese @med.un -muenchen.de

Introduction: Depressive disorders are among the main causes o disability due to disease. Inspite o recent progress in the pharmacotherapy o depression, there is still a high nonresponserate o 30% to the rst antidepressant treatment. Furthermore, the latency o several weeksuntil su cient clinical improvement and the risk o side e ects remain unresolved problems.

There ore, there is still urther need or the development o new antidepressants. In the last yearsa variety o melatonin receptor agonists have been synthesized and evaluated or the treatment o sleep disorders. Animal studies suggested that agomelatine (S-20098), a synthetic melatonergicMT 1 and MT 2 receptor agonist with serotonin receptor antagonistic properties, may have addi-tional activating properties and may represent a new approach in the treatment o depression.Aims: Clinical trials that have demonstrated e cacy and sa ety o agomelatine or the treatmento depression are reviewed.Evidence review: In clinical trials, including phase III studies, superior e cacy compared to

placebo and good e cacy compared to standard antidepressants was shown or agomelatineor the acute treatment o major depression. In all studies published so ar agomelatine was

sa e and the overall tolerability pro le was superior to selective serotonin reuptake inhibitorsor selective serotonin and norepinephrine reuptake inhibitors.Place in therapy: Agomelatine may represent a novel perspective in the treatment o acutedepression. The improvement o sleep disturbances, the tolerability in terms o sexual sidee ects, and the lack o withdrawal symptoms a ter abrupt discontinuation o treatment mayrepresent important clinical bene ts compared to established antidepressants.Keywords: agomelatine, antidepressants, melatonin, major depression, evidence

Core evidence place in therapy summary for agomelatine in major depressionOutcome measure Evidence Implications

Patient-oriented evidencereduct on of dep ess esymptoms

Clea Agomelat ne mo e effect e than placebo and as effect eas pa oxet ne o enlafax ne

imp o ement of sleep Clea Ea l e and bette mp o ement on subject e gett ng to sleep

and on subject e qual ty of sleep compa ed to enlafax neDisease-oriented evidenceSymptom el ef n te ms of HAM-D educt on

Clea Agomelat ne mo e effect e than placebo and as effect eas pa oxet ne o enlafax ne

response to t eatment Clea Agomelat ne as effect e as pa oxet ne and enlafax nerem ss on afte t eatment Clea Agomelat ne as effect e as pa oxet ne and enlafax ne

Economic evidenceCost effect eness

Noe dence

So fa , no nfo mat on about costs of the d ug on Eu opeanma ket. Stud es equ ed to al date assumpt on thatbetter tolerability pro le will translate into improved costeffect eness

HAM-D, Ham lton at ng scale fo dep ess on.

Number of times this article has been viewed

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Scope, aims, and objectivesMelatonin secretion underlies strict circadian rhythms 1 and is regulated via the cAMP signal transduction cascade. 2 Several studies have reported bene cial e ects o melatonin

or the treatment o sleep disorders. However, the therapeu-tic use o melatonin, which is o ered as a supplement inthe US, is restricted by its low bioavailability. There ore,several melatonin agonists have been developed in recentyears and examined in clinical trials or the treatment o insomnia ( or a current review o melatonin receptor agonistdevelopment, see Turek and colleagues 3). To date, agomela-tine (S-20098; Valdoxan , Servier), a synthetic melatonergicMT 1 and MT 2 receptor agonist,

4 is the best characterized melatonin receptor agonist in terms o preclinical studies.In contrast to melatonin, agomelatine also possesses sero-tonin (5-HT 2C) receptor antagonistic properties

5 within thecentral nervous system (CNS). Several preclinical studiesindicated that agomelatine has activating 6 and antidepressante ects, which are comparable to the antidepressant e cacyo established antidepressants. There ore, agomelatine mayrepresent a new approach or the treatment o depression. Thee cacy and tolerability o agomelatine in the acute treatmento depressive disorders has been evaluated in several con-trolled clinical trials. In the ollowing article the evidence or agomelatines antidepressant e cacy will be reviewed and its

place in the acute treatment o depression will be discussed.

MethodsThe medical literature was reviewed or appropriate articlesrelating to agomelatine on PubMed (http://www.ncbi.nlm.nih. gov) using the search terms agomelatine OR S-20098.The search was updated on September 1, 2008. One hundred and sixteen articles were ound, o which 11 were written inlanguages other than English and were there ore excluded.Within those 105 publications, 12 reports rom clinicaltrials and 24 review articles have been identi ed. Out o thereports rom clinical trials, 10 are included and also cited inthis review (Table 1). Additionally, congress proceedings

ocussing on the e ects o agomelatine in the treatment o depression were also included where appropriate.

So ar no pharamacoeconomic studies o agomelatinehave been published. The results o the included clinical trialsare reviewed, ocussing on clinical e cacy, sa ety, and toler-ability o agomelatine in the treatment o major depression.

Disease overviewDepressive disorders are among the main causes o disabilitydue to disease and the World Health Organization (WHO)

estimates that they will be the second most important cause o disability by the year 2020. 7 Chronic depressive episodes arecommon and are associated with greater illness burden and socioeconomic disadvantage. 8 Throughout Europe, 23% o years o healthy li e are lost and approximately one-third o all burden o disease is caused by neuropsychiatric diseases. 9 The 1-year prevalence o depression in Europe is around 5%. 10 The li e time prevalence o depression varies widely

rom 3% in Japan to 16.9% in the US, with most countriesin the range between 8%12%. 11 Despite intensive biologi-cally oriented psychiatric research over the last decades, theetiology o depressive disorders is not yet ully understood,although a multi actorial genesis is supposed. Besides psy-chologic and social actors, biologic variables apparently

play a major role that lead to a disturbed CNS homeostasis.The so-called catecholamine- and serotonin-de iciencyhypothesis, 12 which postulates a de ciency o monoamines(norepinephrine and serotonin) within the synaptic cle t,

plays a major role in the understanding o the pathophysiol-ogy o depression.

Current therapy optionsThe treatment o depressive disorders consists o a complexmultimodal therapy that is determined by the current stateo the illness. The treatment o depression includes pharma-cotherapy, psychotherapy, and sociotherapy. Whereas phar-macotherapy is not always mandatory or less severe ormso depression, severe depression usually requires pharmaco-therapy or electroconvulsive therapy. In addition, a variety

Table 1 E dence base ncluded n the e eCategory Number of records

Full papers Abstracts

in t al sea ch 116

reco ds excluded 11

reco ds ncluded 105

Total eco ds ncluded 10 4

Le el 1 cl n cal e dence(systemat c e e , meta analys s) 0 0

Le el 2 cl n cal e dence (rCT) 5 1

Le el 3 cl n cal e dence

T als othe than rCT 2

Case epo ts

Othe outcome than dep ess on 3 3

Econom c e dence 0

For de nitions of levels of evidence, see Core Evidence ebs te (http://do ep ess.com/co e-e dence-jou nal).Abbreviation: rCT, andom zed cont olled t al.

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o other biologic interventions, such as sleep deprivation and bright light therapy, may be o use in certain patient sub-groups. The discovery o tricyclic antidepressants (TCAs) wasa milestone in the treatment o depression. However, in spiteo the undoubted e ectiveness o TCAs it soon became appar-ent that their anticholinergic and antihistaminergic side e ectsmay cause problems. As a consequence, new antidepressantswere developed with a more selective mode o action, whichmainly aimed at avoiding these side e ects. Currently, tri- and tetracyclic antidepressants with predominant serotonergic,noradrenergic, or mixed serotonergic/noradrenergic actionare available. In addition, selective and reversible inhibitorso the monoamine oxidase A, an irreversible monoamineoxidase B inhibitor, nonselective and irreversible inhibitors o the monoamine oxidase, selective serotonin reuptake inhibi-tors (SSRI), selective norepinephrine reuptake inhibitors, and antidepressants with a dual mode o action such as selectiveserotonin and norepinephrine reuptake inhibitors (SNRI), and noradrenergic and speci c serotonergic antidepressants actingvia blockade o al a 2 and 5-HT 2 receptors, are all available.

1317 The most recently investigated mechanism o action is theagonism at melatonergic MT 1 and MT 2 receptors and selec-tive antagonism at serotonergic 5-HT 2C receptors represented

by the antidepressant agomelatine, 5 which is currently under review by authorities in Europe.

Unmet needsAlthough newer antidepressants are better tolerated and cause

ewer side e ects, their speci c side-e ect pro le has to betaken into account during the treatment o depression. In addi-tion, the latency o several weeks until the onset o su cienttherapeutic e ects remains a serious and clinically relevant

problem. This principle holds true or each antidepressantand each class o antidepressant mechanisms. A urther general problem in pharmacotherapy o depression is the

possible nonresponse to the rst antidepressant treatment. 1820 Approximately 30% o depressed patients do not show su -

cient improvement a ter the rst course o an adequateantidepressant treatment and a urther 20% discontinue dueto tolerability problems. 21 Adequacy o treatment includes theuse o a treatment with proven e cacy during a time intervalo at least 46 weeks in a su cient therapeutic dose rangeincluding reliable patient adherence to therapy. 19,22,23 Hal o patients who do not respond adequately to a rst coursealso ail to respond to a second antidepressant treatmenttrial. I several antidepressant treatment trials have beenine cacious, even lower response rates a ter switching toanother drug may be observed. 24

Clinical evidence for agomelatinein the treatment of major depressionMelatonin secretion underlies strict circadian rhythms 1 and isregulated via the cAMP signal transduction cascade. 2 A varietyo animal studies and clinical trials in depressed patients sug-gest that agomelatine, a synthetic melatonergic MT 1 and MT 2 receptor agonist 4 with 5-HT

2Creceptor antagonistic properties 5

within the CNS, has activating and antidepressant e ects. 6

In several animal models o depression agomelatine has been shown to possess antidepressant e ects that were comparable to those o established antidepressants. In contrastto melatonin the bene cial e ects o agomelatine did notdepend on the time o administration, indicating that besidesthe chronobiotic, other properties may contribute to its anti-depressant-like activity. 25 Furthermore, agomelatine has beenshown to have chronobiotic activity similar to melatonin inanimal models o disturbed circadian rhythms. 26,27

Clinical ef cacy assessmentClinical trials ocus on symptomatic relie measured byspeci c scales, such as the Hamilton Depression Score(Hamilton Depression Rating Scale, HAM-D), 28 and de neresponse and remission in relation to these scores. Thetraditional de nition o response to antidepressant therapyincludes a 50% improvement in symptoms (usually 50%reduction o the baseline score). Remission is de ned as theabsence o depressive symptoms and a ull return to premor-

bid levels o unctioning. In most randomized controlled trials

an absolute rating scale threshold is de ned as remission(eg, HAM-D score 7). Goals o clinical management can

be divided into acute, intermediate, and long-term goals.The ultimate goal o acute treatment is to achieve remission,meaning not only being asymptomatic (in the sense o notmeeting the criteria or diagnosis o the disorder and havingno or only minimal residual symptoms) but also showingimprovement in psychosocial and occupational unctioning.The intermediate goal is urther stabilization and preventiono a relapse, elimination o subsyndromal symptoms, and restoration o the prior level o unctioning. The long-term

goal is ull recovery, 29 to prevent urther episodes, maintainunctioning, and ensure a satis actory quality o li e. 3032

Clinical ef cacy of agomelatinen phase ii and iii t als

Symptomat c el ef The clinical e cacy o agomelatine in the treatment o depressive disorders was rst investigated in a multinational,

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randomized, double-blind, placebo-controlled trial. 33 In thisstudy three di erent doses o agomelatine were compared with an active comparator. Seven hundred and eleven patientsaged between 18 and 65 years, who were su ering rommajor depressive disorder (n = 698) or bipolar II depres-sion (n = 13) according to the Diagnostic and StatisticalManual o Mental Disorders, Fourth Edition (DSM-IV), 34 with a minimum severity score o 22 in the 17 item HAM-D(HAM-D17) 35 were treated with agomelatine, paroxetine, or

placebo. A ter an obligatory 1-week placebo run-in period, patients were randomized to receive agomelatine 1, 5, or 25 mg once daily in the evening, paroxetine 20 mg/day inthe morning, or placebo during the 8-week study period.A ter exclusion o placebo responders during the run-in

period (de ned as HAM-D17 improvement 20%) themean HAM-D17 score at baseline was 27.4 and the meanMontgomery-Asberg Depression Rating Scale (MADRS) 36 score was 31.5, indicating a moderately to severely depressed study population. One-third o the patients had a depressiveepisode o severe intensity, de ned as HAM-D17 score 25.The treatment groups showed no signi cant di erences ineither demographic or clinical variables.

The intent-to-treat analysis using the last observationcarried orward method in patients who had received at leastone post-randomization treatment and had a baseline and atleast one postbaseline rating, showed a statistically signi cantsuperiority in the mean scores o all agomelatine-treated

patients taken together in comparison to the placebo-treated group. Subsequent distinct analyses o the three agomelatinetreatment groups, however, showed clear e ectivenessonly in the patient group that received 25 mg/day, whereasagomelatine 1 and 5 mg/day did not di er rom placebo.The time to rst response was signi cantly shorter in theagomelatine 25 mg/day group in comparison to placebo. Incontrast to paroxetine, which rst showed signi cant advan-tages a ter 4 weeks, agomelatine 25 mg/day was signi cantlysuperior to placebo already a ter 2 weeks o treatment.

The clinical e cacy o agomelatine in major depressionhas been con rmed in urther randomized, double-blind,

placebo-controlled studies. In the study published by Kennedyand Emsley, 37 212 outpatients were treated with agomelatine25 mg/day, with the possibility o increasing the dose to50 mg/day in case o insu cient improvement a ter 2 weekso treatment. 38 A ter a 6-week treatment period, agomelatinewas signi cantly more e ective in comparison with placebo.Patients treated with agomelatine had a signi icantlylower HAM-D score ( P = 0.0017) at endpoint (14.1 7.7)compared with patients receiving placebo (16.5 7.4).

Furthermore, there was a signi cant improvement o severityo disease measured with the Clinical Global ImpressionScale (CGI-S) score with agomelatine compared with placebo(3.2 1.3 versus 3.6 1.3; P = 0.0017). Thirty-six (34%)

patients in the agomelatine and 38 (37%) patients in the placebo group ailed to improve a ter 2 weeks o treatment.There ore, in the agomelatine group the dosage was increased to 50 mg/day, while placebo-treated patients continued toreceive placebo. Also in this subgroup o increased agomela-tine-treated patients, signi cant improvements in HAM-Dscore were observed at study endpoint. The HAM-D scoredecreased in the agomelatine-treated patients rom 26.1 2.6at baseline to 17.5 7.4 at week 6, compared with a decrease

rom 26.7 2.8 to 20.4 6.0 in the placebo group.In a urther double-blind, parallel-group, fexible-dosing

study, 39 an interactive voice response system was used as anovel blinding method. Two hundred and thirty-eight patientswith moderate-to-severe major depression were treated withagomelatine over 6 weeks. In case o insu cient improve-ment at week 2, dose adjustment rom agomelatine 25 to50 mg/day was possible. In terms o HAM-D nal scoresagomelatine was signi cantly more e cacious than placebowith an agomelatine-placebo di erence o 3.44 ( P = 0.001).Furthermore, in terms o severity o disease measured with CGI-S, agomelatine signi cantly improved CGI and decreased CGI-severity compared with placebo.

Further evidence or the e cacy o agomelatine camerom a double-blind, randomized study with the main goal

o investigating the e ects o agomelatine on sleep improve-ment. 40 In this fexible-dose study, 332 outpatients su ering

rom major depression were treated with agomelatine2550 mg/day or venla axine 75150 mg/day. A ter 6 weekso treatment the antidepressant e cacy o agomelatine interms o CGI global improvement was comparable to thato venla axine.

response and em ss onAnalysis o response and remission rates during agomelatinetreatment suggested that agomelatine exerts high e cacy inthe treatment o depressive disorders. In the rst random-ized, double-blind, placebo-controlled trial o agomelatine 33 response, de ned by an improvement o 50% in the HAM-Dscore, was achieved signi cantly more o ten in the agomela-tine 25 mg/day (61.5%) and agomelatine 1 mg/day (62.5%)group in comparison with placebo (46.3%) as shown by pair-wise comparison. In contrast, neither agomelatine 5 mg/day(51.4%) nor paroxetine (56.3%) was signi cantly superior to placebo. In this study remission de ned by a HAM-D17

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score at endpoint below 7 was achieved signi cantly moreo ten with agomelatine 25 mg/day (30.4%) and paroxetine(25.7%) than with placebo (15.4%).

Signi cant e cacy o agomelatine was also ound in arandomized, double-blind, multicenter study o agomelatineversus paroxetine published with the main goal o inves-tigating discontinuation symptoms in sustained remitted

patients. 41 During the rst part o the study 335 outpatientswith major depression (DSM-IV) with a mean MADRS scoreo 23 were treated a ter a drug- ree run-in period with either agomelatine 25 mg/day or paroxetine 20 mg/day once daily

or 12 weeks. One hundred and ninety-two patients achieved sustained remission, de ned as an MADRS score 12at weeks 8, 10, and 12. The rate o sustained remitters was52.7% in the agomelatine and 61.9% in the paroxetine group.At the time o the second randomization, at entry into thediscontinuation period, there were no statistically signi cantdi erences between the two groups.

Furthermore, in a recently published study by Kennedyet al, 42 investigating sexual dys unction in 276 depressed

patients during antidepressant therapy with agomelatine50 mg/day or the SNRI venla axine extended release150 mg/day over a period o 12 weeks, comparable highremission rates (de ned as an MADRS score 12) o 73%in the agomelatine and 66.9% in the venla axine group have

been observed.Although it has to be considered that unequal de nitions

o remission, di erent dosages, and di erent treatmentintervals might account or di erences in the observed remission rates, these study results indicate that agomelatineexerts antidepressant e cacy that leads not only to treatmentresponse but also to a rate o sustained remission similar tothat o established antidepressants.

Response rates were also signi icantly higher withagomelatine 2550 mg/day (54.3% and 49.1%) than with

placebo (35.5% and 34.2%) in two randomized, double-blind,fexible-dosing studies. 37,39

Speci c subgroups of depressed patientsThe antidepressant e cacy o agomelatine has also been

proven in the subgroup o severely depressed patients,de ned by the generally accepted criterion o a baselineHAM-D17 score 25.

In the study by Loo et al 33 an analysis o the subgroupo severely depressed patients (n = 586) revealed that

patients treated with agomelatine 25 mg/day (n = 120) butnot those receiving the lower doses di ered signi cantly

rom placebo-treated patients (n = 114) in terms o HAM-D

nal scores (13.14 8.4 versus 16.1 9.1). In contrast, theactive comparator paroxetine was not signi cantly superior to placebo in this study population (HAM-D nal score14.1 8.4).

Similarly, in the study published by Kennedy and Emsley, 37 76 severely depressed patients were treated withagomelatine and 75 severely depressed patients were treated with placebo. Treatment with agomelatine resulted in asigni cantly lower HAM-D score at endpoint compared with

placebo (14.4 7.9 versus 17.3 7.2; P = 0.024). Moreover,in the study population with severe depression, the di erencein mean HAM-D score at endpoint between agomelatine and

placebo exceeded the di erence in the ull study population(2.72 1.19 versus 2.30 1.02) indicating high e cacy o agomelatine in severely depressed patients.

In addition, rst results rom open-label studies indicated that agomelatine may not only be e ective in the treatmento major depression, but also in the treatment o bipolar and seasonal a ective disorder (SAD).

Agomelatine 25 mg/day as an adjunctive therapy tolithium (n = 14) or valpromide (n = 7) signi cantly improved depressive symptoms in bipolar I patients a ter 6 weeks o treatment, 43 and agomelatine 25 mg/day yielded a signi -cant decrease in depressive symptoms measured with theStructured Interview Guide or the HAM-D SAD-version,CGI-S, and CGI-I in 37 patients su ering rom SAD. 44

Dep ess on-assoc ated sleep d stu bancesIn view o its pharmacologic pro le agomelatine is likely to

possess sleep-wake cycle regulating properties. In severalanimal models o disturbed circadian rhythms agomelatinehas been shown to have chronobiotic activity similar tomelatonin. These results are also o particular interest or the treatment o a ective disorders since a disorganizationo circadian rhythms is suggested to play an important rolein the pathophysiology o major depression. 45,46

The infuence o agomelatine 50 mg/day on circadianrhythms was investigated in a double-blind, placebo-controlled,crossover study in healthy, older, adult men. 47 At the end o the 15-day active treatment period, signi cant 2-hour phaseadvances in the 24-hour pro les o body temperature and cortisol levels were ound. Similar trends were seen in thyroid stimulating hormone secretion. Polysomnographic investiga-tions, however, showed no e ects o agomelatine on normalsleep patterns suggesting that agomelatine acilitates therealignment o overt circadian rhythms in older adults.

In addition, in patients with major depression treated withagomelatine 25 mg, polysomnography shows regulation o

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sleep-wake rhythms increasing the duration o slow wavesleep and normalizing its distribution through the night. 48 A ter 6 weeks o treatment sleep e ciency, time awake a ter sleep onset, and the total amount o slow wave sleep increased.In contrast agomelatine did not change rapid eye movement(REM) latency, amount o REM, or REM density. 49

In addition, in a dose- nding study, 33,50 somatic complaintsand symptoms related to sleep disturbances decreased substantially throughout the study, urther indicating thatagomelatine has bene icial e ects in the treatment o depression-related sleep disturbances.

In a double-blind, randomized study in 332 outpatientssu ering rom major depression, the e ects o agomelatine2550 mg/day and venla axine 75150 mg/day on subjec-tive sleep quality were compared. In contrast to venla axine,agomelatine showed an earlier and better improvement onsubjective getting to sleep and on subjective quality o sleepas well as a better improvement o daytime sleepiness. 40 These results indicate that agomelatine may contribute to anormalization o disrupted circadian rhythms in depressionvia phase-shi ting properties without direct sedation and there ore not disturbing the normal day-sleep rhythm.

Safety and tole ab l tyIn all clinical trials published to date, agomelatine has a better sa ety and tolerability pro le than established antidepres-sants, including the investigated SSRIs and SNRIs.

In a irst dose- inding pilot study in 28 patients nomodi ications o cardiovascular parameters or biologicabnormalities were seen a ter a 4-8 week treatment period with agomelatine 5 or 100 mg/day. 33,50 Slightly more adverseevents and severe treatment-related adverse events were seenin the 100 mg/day group.

In the above mentioned large, double-blind study bythe same authors, 33 56.5% o 711 patients reported at leastone adverse event that emerged or worsened during thestudy such as headache, abdominal pain, nausea, diarrhea,somnolence, or anxiety. No signi cant di erence betweenagomelatine and placebo was seen, whereas during parox-etine treatment signi cantly more gastrointestinal adverseevents, predominantly nausea, were seen than with placebo.Again no clinically relevant changes in vital signs, weight,or cardiovascular parameters, including electrocardiogramrecordings, were seen with agomelatine. In a urther pla-cebo-controlled trial, adverse events more common in theagomelatine group compared with placebo were dizziness(9.3% versus 4.8%), nasopharingitis (6.5% versus 3.8%),and infuenza (6.5% versus 2.9%). 37

Remarkably, although agomelatine amelioratessleep-related complaints, no sedation has been reported duringthe daytime. Impairment o sexual unction has been reported

or antidepressants and represents an important cause o noncompliance. 51 There ore, the e ects o agomelatine onsexual unction were studied in a speci c trial. 42,52 Usinga sexual unction questionnaire, sexual dys unction wascompared between agomelatine and venla axine extended release. 42 Treatment-emergent sexual dys unction wassigni cantly less prevalent in the agomelatine group. Desire,arousal, and orgasm scores and the total sexual dys unc-tion score was signi cantly greater in venla axine-treated

patients. In order to distinguish between medication-induced sexual side e ects and sexual symptoms associated withdepression an additional analysis o sexually active patientswho achieved remission (de ned by a decrease o at least50% in the MADRS score compared to baseline and a totalMADRS score 12 a ter 10 weeks o treatment) was carried out. In this analysis 7.3% o agomelatine-treated patientscompared with 15.7% o venla axine recipients reported a deterioration o sexual unction. While men more o tenreported a decline in drive and desire, women more o tenreported deterioration o orgasm.

Discontinuation symptoms were investigated in arandomized, placebo-controlled, double-blind study 41 in88 patients with major depression who were sustained responders a ter agomelatine 25 mg/day treatment lasting12 weeks (the control group received paroxetine 20 mg/day).Sixty-one patients continued agomelatine whereas 27 wereabruptly switched to placebo. A ter 1 week o treatmentinterruption no statistically signi cant di erence in thenumber o discontinuation symptoms between patientstreated with agomelatine and those receiving placebo wasobserved. In contrast to these ndings, 43 patients dis-continuing the SSRI paroxetine experienced signi cantlymore discontinuation symptoms, such as insomnia, muscleaches, dizziness, and nausea, than another 61 patients whocontinued treatment with the SSRI. A ter 2 weeks o treat-ment interruption the agomelatine group continued to showsimilar results to the placebo group and there were no sig-ni cant di erences between the paroxetine and the placebogroup. No signi cant di erences in the rates o relapse or

partial relapse were registered in either o the active treatmentgroups or in the placebo group during the observation period o 2 weeks, which was relatively short or the estimation o the relapse risk. Nevertheless, patients who discontinued rom

paroxetine experienced a signi cantly greater worsening inCGI and MADRS scores in comparison to patients continuing

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the medication, which might be attributed to the emergentwithdrawal symptoms in the paroxetine discontinuationgroup. Patients discontinuing agomelatine showed the samelow severity o depressive symptoms as patients continuingthe medication. During the discontinuation period no seriousadverse events were recorded.

This study showed agomelatine was not associated withdiscontinuation symptoms during the observation period o 2 weeks. Because the hal -li e o agomelatine is 2 hoursand the drug has no active metabolites, any discontinuationsymptoms would be expected during the rst week a ter discontinuation o the active drug. There ore, the 2-week observation period seems to be long enough to rule out anyemerging withdrawal or discontinuation symptoms. Theinclusion o only sustained remitters rules out the likeli-hood o registering reemergent depressive symptoms duringrelapses or partial relapses as discontinuation symptoms.There ore, agomelatine seems to be at lower risk or discon-tinuation symptoms a ter abrupt tapering, or example innoncompliant patients. This could be an important sa ety

bene t during antidepressant therapies.

Patient group/populationAgomelatine has been shown to be e ective in the treatmento major depression, especially in the subgroup o severelydepressed patients. In a pooled analysis o placebo-controlled studies, agomelatine 2550 mg was signi cantly more e ec-tive than placebo. 53 Agomelatine also ameliorates sleep-related complaints without sedation during the daytime suggestingthat it may be o special bene t in agitated patients.

No large-scale studies on the long-term e ects o agomelatine in the treatment o major depression have been

published so no de nite conclusion can be drawn at themoment in relation to long-term sa ety issues or e cacy inrelapse prevention. Because o this, in 2006 the Committee

or Medicinal Products or Human Use adopted a negativeopinion, recommending the re usal o a marketing authori-sation or the medicinal product Valdoxan/Thymanax (Servier) or the treatment o depression.

However, in a double-blind multicenter study indepressed patients the e cacy o agomelatine in relapse

prevention has been investigated. 54 A ter initial responseto agomelatine, 492 outpatients continued treatment withagomelatine or placebo. During the 6-month study period,46.6% o patients receiving placebo, but only 21.7% o

patients receiving agomelatine, relapsed. There ore, theseresults indicate that agomelatine might also be e ective inthe long-term treatment o depression.

Place in therapyAgomelatine is the rst melatonergic and 5-HT 2C receptor antagonistic antidepressant. In all clinical trials published todate, including large-scale phase III studies, agomelatine hasshown at least equal e cacy to active comparators such asSSRIs and SNRIs. Furthermore, agomelatine is also e ectivein the treatment o severe depression. In addition, agomela-tine is the rst antidepressant without antihistaminergic sidee ects that e ectively ameliorates sleep-related complaintswithout sedation during the daytime.

In all clinical studies the overall tolerability pro le o agomelatine was excellent and showed no impact on labora-tory parameters, vital signs, blood pressure, heart rate, and QTc time intervals. The rate o treatment-emergent adverseevents was not higher than with placebo. The sexual accept-ability o agomelatine represents an important clinical bene tas well as the lack o withdrawal symptoms a ter abruptdiscontinuation o treatment.

In summary, agomelatine represents a promising novelstrategy in the treatment o depression. For clinicians it isa novel perspective in the acute treatment o depressionthat will hope ully show good clinical e ectiveness paired with excellent tolerability also in the long-term treatment o depressed patients.

AcknowledgmentsDaniela Eser has no potential confict o interest. Thomas C.Baghai has accepted paid speaking engagements and acted as

a consultant or AstraZeneca, Janssen-Cilag, Organon, P zer,and Servier. Hans-Jrgen Mller has received grant/researchsupport, consulting ees, and honoraria rom AstraZeneca,Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Lundbeck, MSD, Novartis, Organon, Otsuka, P zer,Schwabe, Sepracor, Servier, and Wyeth.

References1. Lesieur D, Leclerc V, Chavatte P, Marcot C, Renard P, Guardiola-

Lemaitre B. Melatonin: a pertinent prototype or therapeuticintervention. Therapie . 1998;53:429437.

2. Foulkes NS, Borjigin J, Snyder SH, Sassone-Corsi P. Rhythmic tran-

scription: the molecular basis o circadian melatonin synthesis. Trends Neurosci . 1997;20:487492.3. Turek FW, Gillette MU. Melatonin, sleep, and circadian rhythms:

rationale or development o speci c melatonin agonists. Sleep Med .2004;5:523532.

4. Zlotos DP. Recent advances in melatonin receptor ligands. Arch Pharm(Weinheim) . 2005;338:229247.

5. Millan MJ, Gobert A, Lejeune F, et al. The novel melatonin agonistagomelatine (S20098) is an antagonist at 5-hydroxytryptamine2Creceptors, blockade o which enhances the activity o rontocorticaldopaminergic and adrenergic pathways. J Pharmacol Exp Ther . 2003;306:954964.

8/8/2019 ce-4-171

8/9




Dove press

6. Tuma S, Strubbe JJ, Mocaer E, Koolhaas JM. S20098 a ects theree-running rhythms o body temperature and ac tivity and decreases

light-induced phase delay o circadian rhythms o the rat. Chronobiol Int . 2002;18:781799.

7. WHO (World Health Organization). The Global Burden o DiseaseProject. 2002; Internet Communication.

8. Gilmer WS, Trivedi MH, Rush AJ, et al. Factors associated with chronicdepressive episodes: a preliminary report rom the STAR-D project.

Acta Psychiatr Scand . 2005;112:425433.9. Olesen J, Leonardi M. The burden o brain diseases in Europe. Eur J

Neurol . 2003;10:471477.10. Paykel ES, Brugha T, Fryers T. Size and burden o depressive disorders

in Europe. Eur Neuropsychopharmacol . 2005;15:411423.11. Andrade L, Caraveo-Anduaga JJ, Berglund P, et al. The epidemiology

o major depressive episodes: results rom the International Consortiumo Psychiatric Epidemiology (ICPE) Surveys. Int J Methods Psychiatr

Res . 2003;12:321.12. Burke MJ, Preskorn SH. Short term treatment o mood disorders with

standard antidepressants. In FE Bloom, DJ Kup er, editors. Psycho- pharmacology: the fourth generation of progress . (p. 10531065). NewYork: Raven Press; 1995. p. 10531065.

13. Stahl SM. Selecting an antidepressant by using mechanism o action to enhance e cacy and avoid side e ects. J Clin Psychiatry .1998;59:2329.

14. Kent JM. SNaRIs, NaSSAs, and NaRIs: new agents or the treatmento depression. Lancet . 2000;355:911918.

15. Blakely RD. Physiological genomics o antidepressant targets: keepingthe periphery in mind. J Neurosci . 2001;21:83198323.

16. Frazer, A. Serotonergic and noradrenergic reuptake inhibitors: pre-diction o clinical e ects rom in vitro potencies. J Clin Psychiatry .2001;62:1623.

17. Pacher P, Kohegyi E, Kecskemeti V, Furst S. Current trends in the devel-opment o new antidepressants. Curr Med Chem . 2001;8:89100.

18. Nierenberg AA, Amsterdam JD. Treatment-resistant depression:de init ion and treatment approaches. J Clin Psychiatry .1990;51 (Suppl):3947.

19. Sackeim HA. The de inition and meaning o treatment-resistantdepression. J Clin Psychiatry . 2001;62(Suppl 16):1017.

20. Charney DS, Grothe DR, Smith SL, et al. Overview o psychiatricdisorders and the role o newer antidepressants. J Clin Psychiatry .

2002;63:39.21. Sartorius N, Baghai TC, Baldwin DS, et al. Antidepressant medications

and other treatments o depressive disorders: a CINP Task Force report based on a review o evidence. Int J Neuropsychopharmacol . 2007;10:S1S207.

22. Fava GA. Can long-term treatment with antidepressant drugs worsenthe course o depression? J Clin Psychiatry . 2003;64:123133.

23. Kup er DJ, Charney DS. Di cult-to-treat depression. Biol Psychiatry .2003;53:633634.

24. Fava M, Rush AJ, Wisniewski SR, et al. A comparison o mirtazapineand nortriptyline ollowing two consecutive ailed medication treat-ments or depressed outpatients: a STAR*D report. Am J Psychiatry .2006;163:11611172.

25. Bourin M, Mocaer E, Porsolt R. Antidepressant-like activity o S 20098(agomelatine) in the orced swimming test in rodents: involvement o

melatonin and serotonin receptors. J Psychiatry Neurosci . 2004;29:126133.26. Armstrong SM, McNulty OM, Guardiola-Lemaitre B, Redman JR.

Success ul use o S20098 and melatonin in an animal model o delayed sleep-phase syndrome (DSPS). Pharmacol Biochem Behav .1993;46:4549.

27. Redman JR, Guardiola-Lemaitre B, Brown M, Delagrange P,Armstrong SM. Dose dependent e ects o S-20098, a melatoninagonist, on direction o re-entrainment o rat circadian activity rhythms.

Psychopharmacology (Berl) . 1995;118:385390.28. Hamilton M. Development o a rating scale or primary depressive

illness. Br J Soc Clin Psychol . 1967;6:278296.

29. Rush AJ, Kraemer HC, Sackeim HA, et al. Report by the ACNPTask Force on response and remission in major depressive disorder.

Neuropsychopharmacol . 2006;31:18411853.30. AHCPR (Agency or Health Care Policy and Research). Evidence

report on Treatment o depression: Newer Pharmacotherapies. 1999Washington DC. Available at http://www.ahrq.gov/clinic/epcsums/deprsumm.htm

31. APA (American Psychiatric Association). Practice guideline or thetreatment o patients with major depressive disorder (revision). Am J

Psychiatry . 2000a;157:145.32. Bauer M, Whybrow PC, Angst J, Versiani M, Mller H-J; WFSBP

Task Force on Treatment Guidelines or Unipolar Depressive Disorders.World Federation o Societies o Biological Psychiatry (WFSBP)guidelines or biological treatment o unipolar depressive disorder,

part 1: acute and continuation treatment o major depressive disorder.World J Biol Psychiatry . 2002;3:543.

33. Loo H, Hale A, Dhaenen H. Determination o the dose o agomela-tine, a melatoninergic agonist and selective 5-HT(2C) antagonist, inthe treatment o major depressive disorder: a placebo-controlled doserange study. Int Clin Psychopharmacol . 2002;17:239247.

34. APA (American Psychiatric Association). Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition . Washington DC:American Psychiatric Association; 2000b.

35. Hamilton M. The Hamilton rating scale or depression. In:Sartorius N, Ban TA, editors. Assessment of Depression . Berlin;Springer: 1986. p. 143152.

36. Montgomery SA, Asberg M. A new depression scale designed to besensitive to change. BrJ Psychiatry . 1979;134:382389.

37. Kennedy SH, Emsley R. Placebo-controlled trial o agomelatine in thetreatment o major depressive disorder. Eur Neuropsychopharmacol .2006;16:93100.

38. Olie JP, Emsley R. Con rmed clinical e cacy o agomelatine (2550 mg)in major depression: two randomized, double-blind, placebo-controlled studies. Eur Neuropsychopharmacol . 2005;15Abstract S416.

39. Olie JP, Kasper S. E cacy o agomelatine, a MT1/MT2 receptor agonistwith 5-HT 2C antagonistic properties, in major depressive disorder. Int

J Neuropsychopharmacol . 2007;10:661673.40. Lemoine R Guilleminault C, Alvarez E. Improvement in subjec-

tive sleep in major depressive disorder with a novel antidepressant,agomelatine: randomized, double-blind comparison with venla axine.

J Clin Psychiatry . 2007;68:17231732.41. Montgomery SA, Kennedy SH, Burrows GD, Lejoyeux M,

Hindmarch I. Absence o discontinuation symptoms with agomela-tine and occurrence o discontinuation symptoms with paroxetine:a randomized, double-blind, placebo-controlled discontinuation study.

Int Clin Psychopharmacol . 2004;19:271280.42. Kennedy SH, Rizvi S, Fulton K, Rasmussen J. A double-blind

comparison o sexual unctioning, antidepressant e cacy, and tolerabil-ity between agomelatine and venla axine XR. J Clin Psychopharmacol .2008;28:329333.

43. Calabrese JR, Guel i JD, Perdrizet-Chevallier C; AgomelatineBipolar Study Group. Agomelatine adjunctive therapy or acute

bipolar depression: preliminary open data. Bipolar Disord . 2007;6:628635.

44. Pjrek E, Winkler D, Konstantinidis A, Willeit M, Praschak-Rieder N,

Kasper S. Agomelatine in the treatment o seasonal a ective disorder. Psychopharmacology (Berl) . 2006;190:575579.45. Wehr TA, Wirz-Justice A. Circadian rhythm mechanisms in a ec-

tive illness and in antidepressant drug action. Pharmacopsychiatria .1982;15:3139.

46. Wirz-Justice A. Biological rhythm disturbances in mood disorders. Int Clin Psychopharmacol . 2006;21(Suppl 1):S11S15.

47. Leproult R, Van OA, Lhermite-Baleriaux M, Van CE, Copinschi G.Phase-shi ts o 24-h rhythms o hormonal release and body tempera-ture ollowing early evening administration o the melatonin agonistagomelatine in healthy older men. Clin Endocrinol (Oxf) . 2005;63:298304.

8/8/2019 ce-4-171

9/9

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48. Quera-Salva MA, Vanier B, Chapotot F, et al. E ect o agomelatineon the sleep EEG in patients with major depressive disorder. Eur

Neuropsychopharmacol . 2005;15(Suppl 3):435.49. Quera-Salva MA, Vanier B, Laredo J, et al. Major depressive disorder,

sleep EEG and agomelatine: an open-label study. Int J Neuropsycho- pharmacol . 2007;10:691696.

50. Loo H, Dalery J, Macher JP, Payen A. Pilot study comparing in blind the therapeutic e ect o two doses o agomelatine, melatonin- agonistand selective 5HT2c receptors antagonist, in the treatment o major depressive disorders. Encephale . 2003;29:165171.

51. Rosen RC, Lane RM, Menza M. E ects o SSRIs on sexual unction:a critical review. J Clin Psychopharmacol . 1999;19:6785.

52. Kennedy SH. Sexual unction in remitted depressed patients ollowingagomelatine and venla axine XR treatment. Eur Neuropsycho-

pharmacol . 2005;15: Abstract S440.53. Montgomery SA, Kasper S. Severe depression and antidepressants:

ocus on a pooled analysis o placebo-controlled studies on agomelatine. Int Clin Psychopharmacol . 2007;22:283291.

54. Goodwin G, Rouillon F, Emsley R. Long-term e cacy o agomelatine,a novel antidepressant, in the prevention o relapse in out-patients withmajor depressive disorder. Eur Neuropsychopharm . 2007;17(Suppl 4):Abstract S361.
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