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A Benefit-Risk Assessment ofAgomelatine in the Treatmentof Major DepressionRobert H. Howland

University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, University of

Pittsburgh Medical Center, Pittsburgh, PA, USA

Contents

Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7091. Brief Overview of the Pharmacology of Agomelatine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7112. Short-Term Clinical Studies of Agomelatine for Major Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 712

2.1 European Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7122.2 US Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7152.3 Summary and Critique of Short-Term, Placebo-Controlled Studies of Agomelatine . . . . . . . . . . 7172.4 Multinational Clinical Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 717

3. Longer-Term Relapse Prevention Studies of Agomelatine for Major Depression . . . . . . . . . . . . . . . . . . 7184. Tolerability and Safety of Agomelatine in Placebo-Controlled Trials. . . . . . . . . . . . . . . . . . . . . . . . . . . . 719

4.1 Adverse Event Profile in Short-Term Trials. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7194.2 Adverse Event Profile in Long-Term Trials. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7194.3 Severe or Serious Adverse Event Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 720

5. Tolerability and Safety of Agomelatine in Other Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7205.1 Studies on Sexual Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7215.2 Studies on Sleep. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7215.3 Studies on Discontinuation Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7225.4 Studies in Various Other Psychiatric Indications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 722

6. Tolerability and Safety of Agomelatine in Overdose, Pregnancy and Paediatric Populations . . . . . . 7237. Hepatic Function and Agomelatine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7238. Renal Function and Agomelatine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7259. Bodyweight, Metabolic and Cardiovascular Safety of Agomelatine. . . . . . . . . . . . . . . . . . . . . . . . . . . 725

10. Safety of Agomelatine in Older Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72611. Drug Interactions and Agomelatine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72612. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72613. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 729

Abstract Agomelatine is an antidepressant drug that is a synthetic analogue of thehormone melatonin. It stimulates the activity of melatonin MT1 and MT2

receptors and inhibits the activity of serotonin 5HT2C receptor subtypes.The objective of this article is to critically review and evaluate the benefits

and risks of agomelatine for the treatment of major depression. The pub-lished literature through April 2011 for articles relating to agomelatine, to-gether with unpublished data on agomelatine available from the European

REVIEWARTICLEDrug Saf 2011; 34 (9): 709-731

0114-5916/11/0009-0709/$49.95/0

ª 2011 Adis Data Information BV. All rights reserved.

Medicines Agency, the US FDA, US ClinicalTrials.gov and the NovartisClinical Trial Results Database are reviewed.

The antidepressant efficacy of agomelatine has been systematically as-sessed in ten short-term, placebo-controlled studies and three longer-term,placebo-controlled, relapse prevention studies. Five short-term trials dem-onstrated clinically modest, but statistically significant, benefits over placebo,although two of these studies reported opposite effects for 25mg versus 50mgdoses. The other five short-term trials did not find agomelatine more effectivethan placebo, but in two of these studies the active control drug was moreeffective than placebo.

A meta-analysis of six European trials demonstrated a small, statisticallysignificant, marginally clinically relevant difference in efficacy favouringagomelatine over placebo. The only placebo-controlled study in elderly pa-tients did not demonstrate a significant benefit for agomelatine. Agomelatinewas shown to be more effective than placebo in one of three relapse preven-tion studies.

Agomelatine was generally well tolerated compared with placebo. Its ad-verse effect profile is different to that of other antidepressant drugs, but itsoverall tolerability in studies with other antidepressants as active controldrugs did not appear to be substantially better than the controls. Agomelatineis contraindicated in patients with impaired liver function and in patientstaking drugs that potently inhibit cytochrome P450 1A2 metabolic enzymes.Because elevated liver enzymes are common, and there is a rare risk of moreserious liver reactions, routine laboratory monitoring of liver function is rec-ommended periodically throughout treatment. Based on this comprehensivereview, agomelatine does not have clinically significant advantages comparedwith other antidepressant drugs, and it has certain limitations and dis-advantages. Because of the unique pharmacology of agomelatine and itsreported tolerability profile, it should only be considered as an alternativedrug for patients who do not respond to or cannot tolerate other antide-pressant drugs.

The lifetime prevalence of major depression invarious countries around the world ranges from1.5% to 19%.[1] Major depression is associatedwith significant social, educational, and voca-tional impairment, high utilization of social andhealthcare services, and increased medical mor-bidity and mortality. Other forms of depressioninclude dysthymia and minor depression, whichare characterized in part by their milder symptomseverity, and their prevalence ranges from 3% to10%.[2,3] Despite having ‘milder’ depressive symp-toms, patients with dysthymia or minor depres-sion have significant levels of impairment, arehigh utilizers of healthcare services, and have anincreased risk of developing major depression.[4,5]

The goal of antidepressant drug therapy fordepressive disorders should be to achieve full re-mission, as demonstrated by the absence of sig-nificant depressive symptoms along with a completerecovery of social and vocational function.[6]

With any first-choice antidepressant medication,about 50–70% of patients will have a significanttreatment response (usually defined as a 50% orgreater decrease in depressive symptoms).[6] Ofthese treatment responders, however, fewer thanhalf attain a full remission.[6] A significant pro-portion of patients with depression are thereforeleft with residual or persistent symptoms despiteapparently adequate antidepressant therapy. Thefailure to achieve remission with antidepressant

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ª 2011 Adis Data Information BV. All rights reserved. Drug Saf 2011; 34 (9)

therapy is associated with an increased risk ofrelapse or recurrence, higher levels of impairedsocial and vocational function, and a worse long-term prognosis. Symptomatic improvement ofdepression can facilitate the process of functionalrecovery, thereby reducing disability, and this canhelp prevent possible complications related to theillness such as substance abuse and suicide.[7]

Depression also worsens the health outcome andfunctioning of patients when occurring concomi-tantly with a variety of other medical disorders.[8]

Ineffectively or inadequately treating depressionmay therefore contribute to the substantial mor-bidity and mortality associated with many medi-cal conditions as well as with depression itself.

A broad spectrum of various classes of antide-pressant drugs, as well as other types of antide-pressant therapies (including multiple psychotropicaugmentation agents, several depression-focusedpsychotherapies, electroconvulsive therapy, vagusnerve stimulation, transcranial magnetic stimu-lation, exercise and other therapies), are availablefor treating depression, but their absolute effec-tiveness is limited.[6,9] Many patients do not re-spond to available drugs, or they have residualsymptoms despite adequate treatment. Some pa-tients respond to medication, but they developintolerable side effects and stop treatment. Forthese reasons, new drug therapies are alwaysneeded. Even though a new drug may not ne-cessarily be more effective on average comparedwith available drugs, it might be relatively moreefficacious or better tolerated for certain patients.

Agomelatine has been characterized as an anti-depressant compound with a novel mechanism ofaction, which has been extensively investigated inpreclinical studies.[10] It has also been investigated inclinical trials in Europe, South America and theUS for the treatment of major depression. It wasfirst recommended for approval by the EuropeanMedicines Agency (EMA) in November 2008.[11-13]

Agomelatine is not yet approved for marketing bythe US FDA.[14]

This article critically reviews the efficacy, tol-erability and safety of agomelatine for the treat-ment of major depression in adults. The efficacyof this agent in children and adolescents (youngerthan 18 years) with major depression has not

been investigated. The published literature onMEDLINE, PsychINFO and Google ScholarthroughApril 2011was searched for articles relatingto agomelatine, using the search terms ‘agomelatine’or ‘S-20098’. Additional literature potentially re-lated to agomelatine was searched for using theterms ‘melatonin’, ‘ramelteon’ or ‘TAK-375’. Un-published data on agomelatine was also sourcedfrom the EMA, FDA, US ClinicalTrials.gov andtheNovartis Clinical Trial ResultsDatabase.[11,14,15]

1. Brief Overview of the Pharmacologyof Agomelatine

Agomelatine is a synthetic analogue of the hor-mone melatonin, which is secreted by the pinealgland and normally serves to regulate variouscircadian (24-hour) rhythms, including sleep-wakecycles.[16] Agomelatine is a potent melatonin-receptor agonist drug that strongly binds to andstimulates the activity of melatonin MT1 andMT2 receptors, which are localized within thesuprachiasmatic nucleus of the hypothalamus.[17]

Stimulation of MT1 and MT2 receptors has anormalizing effect on disturbed circadian rhythmsand disrupted sleep-wake cycles. Agomelatine hasalso been characterized as a serotonin-receptorantagonist that binds to and inhibits the activityof serotonin 5HT2C receptor subtypes, but it doesnot bind to other serotonin receptor subtypes.[10]

Antagonism at the 5HT2C receptor is associatedwith antidepressant and anti-anxiety activity andalso increases slow-wave sleep (which is abnormallydiminished in depression).[18] Agomelatine does notdirectly affect the uptake of serotonin, noradrenaline(norepinephrine) or dopamine. By inhibiting 5HT2C

receptors, however, it secondarily increases nor-adrenaline and dopamine in the frontal cortex of thebrain.[19] This effect might contribute to its anti-depressant activity. Agomelatine does not bind toadrenergic, cholinergic or histamine receptors.

The pharmacology of agomelatine, with itscombined effects at MT1, MT2 and 5HT2C re-ceptors, is therefore unique and distinct comparedwith other antidepressant drugs. Sleep EEG studiesdemonstrate the benefits of agomelatine on sleep inpatients with depression (i.e. increases slow-wavesleep and sleep efficiency).[20] Increases in slow-wave

Benefit-Risk Assessment of Agomelatine in Major Depression 711


sleep (the deepest stage of sleep) typically corre-late with subjective daytime reports of having hada good night’s sleep and feeling well rested.[21]

Agomelatine has also been shown to influencecircadian rhythms in animals and humans.[22-24]

These effects are all consistent with what wouldbe expected based on MT1, MT2 and 5HT2C re-ceptor pharmacology. However, the degree towhich 5HT2C receptor antagonism explains orcontributes to the antidepressant or sleep effectsof agomelatine has been questioned.[25]

2. Short-Term Clinical Studies ofAgomelatine for Major Depression

The short-term effectiveness of agomelatinein the treatment of major depression has beeninvestigated through separate clinical researchprogrammes conducted in Europe and the US. Inaddition, one short-term multinational study hasbeen conducted at sites in Europe and SouthAmerica.[26]

2.1 European Clinical Trials

In Europe, the efficacy of agomelatine for majordepression has been investigated in three pub-lished[27-29] and three unpublished,[11] random-ized, double-blind, placebo-controlled pivotalstudies (see table I). Data from the unpublishedstudies are available from the EMA Committeefor Medicinal Products for Human Use (CHMP)Assessment Report for Valdoxan.[11] Paroxetineor fluoxetine was included in some of these trialsas an active control drug according to Europeanregulatory guidelines. For each of the pivotalstudies, the 17-item Hamilton Rating Scale forDepression (HAM-D) was the primary outcomemeasure.[34] The primary outcome efficacy vari-able was the HAM-D score for agomelatine ver-sus placebo at endpoint. Response and remissionrates based on the HAM-D were consideredsecondary outcome variables. Response was de-fined as a 50% decrease in the HAM-D scorefrom baseline to endpoint, and remission wasdefined as a HAM-D score of £6 at endpoint.

In an 8-week, dose-finding study involving711 patients (18–65 years of age), Loo and col-

leagues[27] compared three doses of agomelatine(1, 5 and 25mg/day), placebo and paroxetine20mg/day (as an active control drug). Agomela-tine 25mg (but not the two lower doses) andparoxetine were significantly more effective thanplacebo. The mean difference in HAM-D was 2.57for agomelatine (25mg) versus placebo (p= 0.034)and 2.25 for paroxetine versus placebo (p= 0.030).Response rates for agomelatine 1mg (62.5%[p = 0.021]) and 25mg (61.5% [p = 0.036]) weresignificantly better than for placebo (46.3%), butagomelatine 5mg (51.4%) and paroxetine (56.3%)were not significantly higher than placebo. Remis-sion rates for agomelatine 25mg (30.4% [p< 0.01])and paroxetine (25.7% [p< 0.05]) were significantlygreater than for placebo (15.4%), but the rates foragomelatine 1mg (21.3%) and 5mg (17.8%) werenot significantly better than placebo. The overallrate of treatment-emergent adverse events (TEAEs)was similar for agomelatine (51.1%) and placebo(54.7%), but slightly higher for paroxetine (66.0%).Most adverse events were experienced as mild tomoderate in severity. There was no significantdifference in dropout rates due to TEAEs be-tween agomelatine, placebo and paroxetine. Re-ported adverse events of headache, anxiety,abdominal pain, diarrhoea, nausea, somnolence,insomnia, rhinitis and dry mouth were no differ-ent between agomelatine and placebo, but nauseawas significantly more common with paroxetine(p = 0.001) compared with placebo and agomela-tine. There were no significant differences amongthe groups with respect to bodyweight changes,cardiovascular effects or laboratory studies.

In a 6-week study involving 212 patients(18–65 years of age), Kennedy and Emsley[28]

compared agomelatine 25–50mg/day and placebo.After an initial 2-week treatment with agomela-tine 25mg/day or placebo, the study medicationdosage of patients with poor response was in-creased under double-blind conditions to ago-melatine 50mg/day or matching placebo. Amongthe 106 patients taking agomelatine, 69 patientsstayed at 25mg/day and 36 patients increased to50mg/day. Agomelatine (both doses pooled) wassignificantly more effective than placebo. Themean difference in HAM-D was 2.30 for agome-latine versus placebo (p = 0.026). Response rates

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for agomelatine (49.1%) and placebo (34.3%) weresignificantly different (p = 0.03), but remissionrates for agomelatine (20.8%) and placebo (13.3%)were not significantly different (p = 0.152). Theoverall rate of TEAEs was similar for agomela-tine (30.2%) and placebo (36.2%). Most TEAEswere mild to moderate in severity. Dropout ratesdue to TEAEs were similar for placebo (4.8%) and

agomelatine (4.7%). Dizziness and rhinitis weremore common with agomelatine compared withplacebo, whereas headache, nausea, fatigue, drymouth and diarrhoea were more common withplacebo compared with agomelatine. There wereno differences between agomelatine and placebowith respect to bodyweight changes, cardiovasculareffects or laboratory studies.

Table I. Randomized controlled clinical efficacy studies of agomelatine for major depression

Study Location No. of

subjects

Duration

(wk)

Design Comparison (mg) Study outcome

Loo et al.[27] Europe 711 8 Efficacy and safety AGO 1

AGO 5

AGO 25

PBO

PAR 20

AGO 1mg =PBOAGO 5mg =PBOAGO 25mg >> PBO

PAR >> PBO

Kennedy and Emsley[28] Europe 212 6 Efficacy and safety AGO 25–50

PBO

AGO >> PBO

Olie and Kasper[29] Europe 238 6 Efficacy and safety AGO 25–50

PBO

AGO >> PBO

CL3-022[11] Europe 419 6 Efficacy and safety AGO 25

PBO

FLX 20

AGO =PBOFLX >> PBO


PBO

PAR 20

AGO =PBOPAR =PBO


AGO 50

PBO

FLX 20

AGO =PBOFLX =PBO

CL3-026[11] Europe 218 6 Efficacy and safety in

the elderly

AGO 25

PBO

AGO =PBO

Zajecka et al.[30] USA 511 8 Efficacy and safety AGO 25

AGO 50

PBO

AGO 25mg =PBOAGO 50mg >> PBO

Stahl et al.[31] USA 503 8 Efficacy and safety AGO 25

AGO 50

PBO

AGO 25mg >> PBO

AGO 50mg =PBO

CAGO178A2303[32] USA 503 8 Efficacy and safety AGO 25–50

PBO

PAR 20–40

AGO =PBOPAR >> PBO

Hale et al.[26] Multinational 515 8 Efficacy and safety AGO 25–50

FLX 20–40

AGO >> FLX

Goodwin et al.[33] Multinational 339 34 Relapse prevention AGO 25–50

PBO

AGO >> PBO

CL3-021[11] Europe 367 34 Relapse prevention AGO 25

PBO

AGO =PBO

CAGO178A2304[32] USA 633 52 Relapse prevention AGO 25–50

PBO

AGO =PBO

AGO = agomelatine; FLX = fluoxetine; PAR = paroxetine; PBO =placebo; >> indicates significantly better than;= indicates no significant

difference.



In a second 6-week study involving 238 pa-tients (18–65 years of age), Olie and Kasper[29]

compared agomelatine 25–50mg/day and place-bo. If patients did not respond adequately after2 weeks of agomelatine 25mg/day or placebo, thedosage was increased under double-blind condi-tions to 50mg/day or matching placebo. Amongthe 118 patients taking agomelatine, 82 stayedat a dosage of 25mg/day and 29 increased to50mg/day. Agomelatine (both doses pooled) wassignificantly more effective than placebo. Themean difference in HAM-D was 3.18 for agome-latine versus placebo (p = 0.002). Response ratesfor agomelatine (54.3%) and placebo (35.3%) weresignificantly different (p = 0.003), but remissionrates for agomelatine (17.2%) and placebo (11.8%)were not significantly different. The overall rateof TEAEs was similar for agomelatine (42.4%)and placebo (42.5%). Most TEAEs were of mildto moderate severity. Dropout rates due to TEAEswere slightly higher for placebo (5.8%) comparedwith agomelatine (3.4%). Fatigue, nausea, dizzi-ness, rhinitis and dry mouth were no differentbetween agomelatine and placebo, but headachewas significantly more common for placebo com-pared with agomelatine (p = 0.027). Sexual func-tioning, bodyweight changes, cardiovascular effectsand laboratory studies did not differ betweengroups.

In a 6-week unpublished study (CL3-022)[11]

involving 419 patients (18–60 years of age), in-vestigators compared agomelatine 25mg/day,placebo and the selective serotonin reuptake in-hibitor (SSRI) drug fluoxetine 20mg/day (as anactive control drug). Agomelatine was not sig-nificantly more effective than placebo (the meandifference in HAM-D was 1.4 for agomelatine vsplacebo). Response rates for agomelatine (53%)and placebo (47%) were not significantly differ-ent. Remission rates for agomelatine and placeboalso were not significantly different (actual rateswere not reported). By contrast, fluoxetine wassignificantly more effective than placebo (themean difference in HAM-D was 2.59 for fluox-etine vs placebo [p = 0.008]). Response and re-mission rates for fluoxetine were not reported.There was no significant difference in dropoutrates due to TEAEs during the 6-week trial be-

tween agomelatine, placebo and fluoxetine. Atthe end of 6 weeks, subjects responding to ago-melatine or fluoxetine were eligible for an 18-week,double-blind, placebo-controlled extension phase.Among these subjects, the depression score atthe end of the extension phase was lower in theagomelatine group than in the placebo group, butthe difference was not statistically significant.Nine subjects in the agomelatine group (14.3%),20 in the placebo group (33.3%) and 13 in thefluoxetine group (17.8%) relapsed during the ex-tension phase. The survival curve time to relapseanalysis showed a statistically significant dif-ference favouring the active drug (agomelatine[p = 0.017] or fluoxetine [p = 0.045]) comparedwith placebo.

In another 6-week unpublished study (CL3-023),[11] involving 418 patients (18–60 years of age),investigators compared agomelatine 25mg/day,placebo and paroxetine 20mg/day (as an activecontrol drug). Agomelatine was not significantlymore effective than placebo (the mean differencein HAM-D was 0.8 for agomelatine vs placebo).Response and remission rates for agomelatineand placebo were not significantly different (ac-tual rates were not reported). Paroxetine was notsignificantly more effective than placebo (themean difference in HAM-D was 1.6 for parox-etine vs placebo). Response and remission ratesfor paroxetine were not reported. During the6-week trial, there was no significant difference indropout rates due to TEAEs between agomela-tine, placebo and paroxetine. At the end of 6 weeks,subjects responding to agomelatine or paroxetinewere eligible for an 18-week, double-blind, placebo-controlled extension phase. There were no signif-icant differences in outcome between active drugsand placebo in the extension phase. Dropoutrates due to TEAEs during the extension phasewere similar for agomelatine (3.3%) and placebo(3.4%), but higher for paroxetine (8.6%).

In the last 6-week unpublished study (studyCL3-024)[11] involving 607 patients (18–65 yearsof age), investigators compared two doses ofagomelatine (25 and 50mg/day), placebo andfluoxetine 20mg/day (as an active control drug).Agomelatine 25mg was not significantly moreeffective than placebo (the mean difference in

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HAM-D was 1.4 for agomelatine vs placebo).Agomelatine 50mg was also not significantlymore effective than placebo (HAM-D data werenot reported). Similarly, fluoxetine was not sig-nificantly more effective than placebo (the meandifference in HAM-D was 0.53 for fluoxetine vsplacebo). Response and remission rates for ago-melatine and fluoxetine were not reported. At theend of 6 weeks, subjects responding to agomela-tine or fluoxetine were eligible for an 18-week,double-blind, placebo-controlled extension phase.In this phase, there were no significant differencesin outcome between active drugs and placebo.Throughout the acute and extension phases ofthe study, there was no significant difference indropout rates due to TEAEs between agomela-tine, placebo and fluoxetine.

In addition to the six pivotal studies, a 6-weekunpublished study (study CL3-026)[11] involving218 elderly patients (60 years of age and older) wasconducted comparing agomelatine 25mg/dayand placebo (see table I). For this study, theMontgomery Asberg Depression Rating Scale(MADRS)[35] was the primary outcome measureand the primary outcome efficacy variable wasthe MADRS score for agomelatine versus place-bo at endpoint. The response rate based on theMADRS was considered a secondary outcomevariable. Response was defined as a 50% decreasein the MADRS score from baseline to endpoint.Remission rates were not reported in this study.Agomelatine was not significantly more effectivethan placebo (the mean difference in MADRSwas 0.19 for agomelatine vs placebo). Responserates for agomelatine (46%) and placebo (52%)were not significantly different. At the end of6 weeks, subjects responding to acute treatmentwere eligible for an 18-week, double-blind, placebo-controlled extension phase. There were no sig-nificant differences in outcome between activedrugs and placebo during the extension phase. Inan unplanned post hoc subgroup analysis of datafrom this study, agomelatine was significantlymore effective than placebo among the subgroupof 86 patients with more severe levels of depres-sion.[11] In an unpublished post hoc pooled anal-ysis of data from the three published short-termpivotal studies,[27-29] which included subjects over

60 years of age, a significant antidepressant effectwas observed in the subgroup of 53 patients whowere 60–66 years of age.[11]

2.2 US Clinical Trials

Phase III clinical trials of agomelatine for majordepression (three placebo-controlled, short-termefficacy and safety trials and one placebo-controlled,longer-term relapse prevention trial)[30-32] havebeen conducted and completed in the US. All ofthese trials are listed on ClinicalTrials.gov.[36-39]

The findings from two of the short-term studieshave been published (reviewed in the paragraphsthat follow).[30,31] Results from the unpublishedshort-term and longer-term relapse preventionstudies are available on the Novartis Clinical TrialResults Database website.[32] A rapidly dissolvablesublingual tablet formulation of agomelatine isalso currently being evaluated in phase III effi-cacy and safety clinical trials (two short-term,placebo-controlled trials[40,41] and one open-label,longer-term trial[42]) for major depression in theUS, but these trials have not yet been completed.

The US trials were 8-week, randomized, double-blind, placebo-controlled, phase III studies (seetable I). In one unpublished study, paroxetinewas included as an active control drug. For eachof the studies, the 17-item HAM-D was the pri-mary outcome measure and the primary outcomeefficacy variable was the change in HAM-D scorefrom baseline to week 8 for agomelatine versusplacebo. Response and remission rates based onthe HAM-D were considered secondary outcomevariables. Response was defined as a 50% de-crease in the HAM-D score from baseline toendpoint. Remission was defined as a HAM-Dscore of £7 at endpoint.

In the first published US study[30] involving511 patients (18–70 years of age), investigatorscompared two doses of agomelatine (25mg/dayand 50mg/day) with placebo. Agomelatine 25mgwas not significantly more effective than placebo(the mean difference in HAM-D was 0.6 foragomelatine vs placebo [p = 0.505]). Agomelatine50mg was significantly more effective than pla-cebo (the mean difference in HAM-D was 2.5 foragomelatine vs placebo [p = 0.004]). Response



rates for agomelatine 25mg (42.3%) and placebo(37.7%) were not significantly different (p= 0.421),but were for agomelatine 50mg (49.7%) versusplacebo (p = 0.029). Remission rates for agome-latine 25mg (16.7% [p = 0.983]) and agomelatine50mg (22.4% [p = 0.202]) were not significantlydifferent compared with placebo (16.8%). Theoverall rate of TEAEs was similar for agomela-tine 25mg (75.9%), agomelatine 50mg (74.2%)and placebo (74.6%). Most adverse events wereexperienced as mild to moderate in severity.There was no significant difference in dropoutrates due to TEAEs for agomelatine 25mg (4.3%),agomelatine 50mg (6.1%) and placebo (6.5%).Psychiatric adverse events (e.g. worsening de-pression or suicidal ideation) was the primaryreason for placebo patients dropping out of thestudy, whereas a variety of psychiatric and med-ical adverse events were the reasons for dropoutsamong agomelatine-treated patients. For patientstaking agomelatine (both dose groups pooled)versus placebo, the most common adverse eventswere headache (16.3% vs 14.2%), nausea (12.0%vs 5.9%), diarrhoea (10.5% vs 7.1%), dizziness(8.6% vs 4.7%), dry mouth (7.1% vs 7.7%), som-nolence (7.1% vs 5.9%), sedation (6.8% vs 5.3%),fatigue (5.2% vs 4.1%), insomnia (5.2% vs 10.7%),constipation (3.4% vs 2.4%) and abnormaldreams (2.8% vs 0.6%). There were no significantdifferences among the three study groups withrespect to bodyweight changes or cardiovasculareffects. With the exception of liver function tests,there were no significant differences among thethree study groups on any laboratory tests. Sig-nificant liver enzyme elevations occurred moreoften in the agomelatine 50mg group (reviewedin more detail in section 7).

In the second published US study[31] involving503 patients (18–70 years of age), investigatorscompared two doses of agomelatine (25mg/dayand 50mg/day) with placebo. Agomelatine 25mgwas significantly more effective than placebo (themean difference in HAM-D was 2.2 for agome-latine vs placebo [p = 0.01]). Agomelatine 50mgwas not significantly more effective than placebo(the mean difference in HAM-D was 1.2 foragomelatine vs placebo [p = 0.144]). Responserates for agomelatine 25mg (46.8%) and placebo

(33.1%) were significantly different (p = 0.013),but agomelatine 50mg (41.6%) was not signif-icantly different to placebo (p = 0.116). Remissionrates for agomelatine 25mg (22.2% [p = 0.070])and agomelatine 50mg (17.4% [p = 0.457]) werenot significantly different compared with placebo(14.7%). The overall rate of TEAEs was similarfor agomelatine 25mg (69.9%), agomelatine50mg (70.7%) and placebo (65.5%). Most ad-verse events were experienced as mild to moder-ate in severity. There was no significant differencein dropout rates due to TEAEs for agomelatine25mg (4.3%), agomelatine 50mg (6.0%) andplacebo (4.8%). The reasons for dropping out didnot differ substantially among the three studygroups. For patients taking agomelatine (bothdose groups pooled) versus placebo, the mostcommon adverse events were headache (13.3% vs17.0%), somnolence (9.1% vs 4.2%), dizziness(7.3% vs 3.0%), diarrhoea (7.3% vs 6.7%), nausea(6.1% vs 4.8%), fatigue (5.8% vs 2.4%), sedation(5.2% vs 4.2%), dry mouth (4.8% vs 8.5%), in-somnia (3.3% vs 6.1%), anxiety (2.4% vs 3.0%),constipation (2.7% vs 1.8%) and abnormal dreams(2.1% vs 1.8%). There were no significant differ-ences among the three study groups with respectto bodyweight changes or cardiovascular effects.With the exception of liver function tests, therewere no significant differences among the threestudy groups on any laboratory tests. Significantliver enzyme elevations occurred only in theagomelatine 50mg group (reviewed in more de-tail in section 7).

In the unpublished US study (CAGO178A2303)[32] involving 503 patients (18–70 years ofage), investigators compared agomelatine (25–50mg/day) and paroxetine (20–40mg/day) withplacebo. Patients were started on agomelatine25mg/day, paroxetine 20mg/day or placebo. Thosepatients who did not show the minimum requiredresponse at the end of week 4 had their doses in-creased to 50mg/day, 40mg/day or matchingplacebo, respectively. Agomelatine 25–50mg wasnot significantly more effective than placebo (themean difference in HAM-D was 0.5 for agome-latine vs placebo [p= 0.539]). Paroxetine 20–40mgwas significantly more effective than placebo (themean difference in HAM-D was 3.4 for paroxetine

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vs placebo [p < 0.001]). Response rates accordingto HAM-D criteria were not reported, althoughclinical improvement based on the Clinical GlobalImpression-Improvement Scale[43] showed a sta-tistically significant benefit for paroxetine versusplacebo (p = 0.002), but no significant benefit foragomelatine versus placebo (p= 0.389). Remissionrates for agomelatine 25–50mg (5.6% [p = 0.018])and paroxetine 20–40mg (22.7% [p = 0.040]) wereeach significantly different from placebo (13.9%).The overall rate of TEAEs was similar for ago-melatine 25–50mg (71.9%), paroxetine 20–40mg(81.3%) and placebo (79.8%). There was nosignificant difference in dropout rates due toTEAEs for agomelatine 25–50mg (2.4%), par-oxetine 20–40mg (4.8%) and placebo (5.5%). Forpatients taking agomelatine versus paroxetineversus placebo, the most common adverse eventswere headache (13.2%, 18.7%, 18.4%, respectively),dry mouth (9.6%, 9.6%, 8.0%), somnolence (7.8%,9.0%, 9.2%), nausea (6.0%, 16.3%, 9.2%), fatigue(5.4%, 10.2%, 4.3%), sedation (5.4%, 4.2%, 3.1%),dizziness (4.8%, 6.0%, 3.7%) and stomach dis-comfort (4.2%, 1.8%, 0.0%). There were no sig-nificant differences among the three study groupswith respect to adverse effects on sexual functionor cardiovascular tests. With the exception ofliver function testing, there were no significantdifferences among the three study groups on anylaboratory tests. Significant liver enzyme eleva-tions occurred in three agomelatine-treatedpatients, one paroxetine-treated patient and noplacebo-treated patients (reviewed in more detailin section 7).

2.3 Summary and Critique of Short-Term,Placebo-Controlled Studies of Agomelatine

The antidepressant efficacy of agomelatine hasbeen systematically assessed in ten short-term,placebo-controlled studies conducted in Europeand the US. Five trials demonstrated only clini-cally modest, but statistically significant, benefitsfor agomelatine over placebo, although two ofthese studies found opposite effects for the twodoses of agomelatine. The opposite efficacy find-ings for agomelatine 25mg and 50mg from thetwo US studies is confusing and not readily in-

terpretable. Five trials demonstrated no differ-ence between agomelatine and placebo. Un-fortunately, not all studies have been published.Based on the unpublished data reviewed in thisarticle, it is clear that publication bias is present,such that favourable studies have generally beenpublished and unfavourable studies have gen-erally not been published. Of particular concern,fluoxetine and paroxetine (but not agomelatine)were each more effective than placebo in two ofthe unpublished trials. In two other unpublishedstudies, agomelatine, fluoxetine and paroxetinewere each found to be not more effective thanplacebo, perhaps due to low drug dosing or pos-sibly high placebo responder rates. Agomelatinewas generally well tolerated compared with pla-cebo in all studies, but the overall tolerability ofagomelatine did not appear to be substantiallybetter than the active drug controls.

2.4 Multinational Clinical Trial

In addition to the European and US studies,the short-term effectiveness of agomelatine versusfluoxetine for the treatment of major depressionhas been investigated in an 8-week, randomized,double-blind, multinational study conducted atsites in Europe and South America (see table I).[26]

The 17-item HAM-D was the primary outcomemeasure and the primary outcome efficacy variablewas the change in HAM-D score from baseline toweek 8 for agomelatine versus fluoxetine. Responseand remission rates based on the HAM-D wereconsidered secondary outcome variables. Responsewas defined as a 50% decrease in the HAM-D scorefrom baseline to endpoint. Remission was definedas a HAM-D score of £6 at endpoint.

In this study, 515 patients (18–65 years of age)received agomelatine 25–50mg/day or fluoxetine20–40mg/day. Patients initially took agomelatine25mg/day, but the dose could be increased to50mg/day after 2 weeks for an insufficient re-sponse. Similarly, patients initially took fluoxetine20mg/day, but the dose could be increased to40mg/day after 4 weeks for an insufficient re-sponse. Ultimately, 29.0% of agomelatine-treatedpatients took 50mg/day and 23.0% of fluoxetine-treated patients took 40mg/day. Agomelatine



was significantly more effective than fluoxetine(the mean difference in HAM-D was 1.49 foragomelatine vs fluoxetine [p = 0.024]). Responserates for agomelatine (71.7%) and fluoxetine (63.8%)were not significantly different (p= 0.060). Remis-sion rates for agomelatine (32.0%) and fluoxetine(28.4%) were also not significantly different(p = 0.381). The overall rate of TEAEs was sim-ilar for agomelatine (57.2%) and fluoxetine(56.3%). Most adverse events were experienced asmild to moderate in severity. There was no sig-nificant difference in dropout rates due to TEAEsfor agomelatine (4.0%) and fluoxetine (6.5%).The reasons for dropping out did not differ sub-stantially between the two study groups. For pa-tients taking agomelatine versus fluoxetine, themost common adverse events were headache(16.0% vs 11.4%), nausea (8.0% vs 11.4%), som-nolence (6.0% vs 3.4%), abdominal pain (4.4% vs2.7%), dry mouth (3.2% vs 3.0%), constipation(3.2% vs 1.1%), dizziness (2.8% vs 3.4%) anddiarrhoea (2.8% vs 2.7%). There were no signif-icant differences between the two study groupswith respect to bodyweight changes or cardio-vascular effects. With the exception of liver func-tion tests, there were no significant differencesbetween groups on any laboratory tests. Signif-icant liver enzyme elevations occurred in fiveagomelatine-treated patients and in one fluox-etine-treated patient (reviewed in more detail insection 7).

3. Longer-Term Relapse PreventionStudies of Agomelatine for MajorDepression

The effectiveness of agomelatine has beeninvestigated in one published[33] and two un-published[11,32] longer-term, randomized, double-blind, placebo-controlled, relapse preventionstudies in patients with recurrent major depres-sion (see table I). In two studies,[11,33] subjectswere eligible for the randomized phase if they hada response (50% reduction in HAM-D) or a re-mission (HAM-D <7) after open-label treatmentwith agomelatine in the acute phase. In these twostudies, relapse was defined as one of the follow-ing: a HAM-D score >15, withdrawal for lack of

efficacy, suicide or suicide attempt. In the thirdstudy,[32] subjects were eligible for the randomizedphase if they were in remission after open-labeltreatment in the acute phase with agomelatine. Inthis study, relapse was defined as one of the fol-lowing: a HAM-D score >15, withdrawal for lackof efficacy, suicide or suicide attempt, or hospi-talization due to depression.

In a multinational trial reported by Goodwinand colleagues,[33] 492 patients (19–65 years ofage) were initially treated openly with agomela-tine 25–50mg/day for up to 10 weeks. After 2 weeksof agomelatine 25mg/day, the dosage for poorresponders was increased to 50mg/day. The 339patients who were responders or remitters werethen randomized to receive double-blind treat-ment with agomelatine (at their current dose) orplacebo for up to 24 weeks until they suffered arelapse. At the time of randomization, 22% ofsubjects were taking 50mg/day and the remainingpatients were taking 25mg/day. Among all patients,70% taking agomelatine completed the 24-weekstudy compared with only 52% taking placebo.Overall, agomelatine patients had a significantlylower cumulative relapse rate (21.7%) comparedwith placebo patients (46.6%) [p = 0.0001]. In apost hoc data analysis, the cumulative relapse ratefor agomelatine-treated patients (22.7%) was sig-nificantly lower than the rate for placebo-treatedpatients (50.4%) among the subgroup of patientswith more severe levels of depression (p = 0.0001).The overall rate of TEAEs was similar for ago-melatine (51.5%) and placebo (52.3%). The mostcommon TEAEs were headache (agomelatine7.9%, placebo 6.3%), rhinitis (agomelatine 6.7%,placebo 9.8%) and back pain (agomelatine 5.5%,placebo 3.4%). Agomelatine was not associatedwith significant effects on sexual functioning,bodyweight, cardiovascular effects or laboratorystudies.

In an unpublished trial (study CL3-021),[11]

551 patients (19–67 years of age) initially receivedagomelatine 25mg/day open-label for up to 8weeks.The 367 patients who were responders or re-mitters were then randomized to receive double-blind treatment with agomelatine or placebo forup to 34 weeks until they suffered a relapse. Over-all, agomelatine-treated patients had a similar

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cumulative relapse rate (25.9%) compared withplacebo-treated patients (23.5%). In a post hocdata analysis, the cumulative relapse rate foragomelatine-treated patients (21.3%) was sig-nificantly lower than the rate for placebo-treatedpatients (31.3%) among the subgroup of patientswith more severe levels of depression (p = 0.046).

One unpublished phase III, placebo-controlled,longer-term, relapse prevention trial has been con-ducted and completed in the US (CAGO178A2304).[32] In this study, 633 patients (18–70 years ofage) were initially treated openly with agomela-tine 25–50mg/day for 4–12 weeks. After 4 weeksof agomelatine 25mg/day the dosage for poorresponders was increased to 50mg/day. After thisinitial phase, 406 patients in remission were thenentered into a 12-week stabilization phase wherethey continued to take the same dose. After thestabilization phase, the 281 patients who werestill in remission were then randomized to receivedouble-blind treatment with agomelatine (at theircurrent dose) or placebo for up to 52 weeks untilthey suffered a relapse. At the time of randomi-zation, 154 subjects were taking 50mg/day and127 were taking 25mg/day. Among all patients,44.3% taking agomelatine completed the 52-weekstudy compared with only 51.8% taking placebo.There was no significant difference in the time torelapse for agomelatine versus placebo (p= 0.6668).Agomelatine patients had a relapse rate (23.0%)that was not significantly different from placebopatients (26.2% [p = 0.5319]). The proportion ofpatients who were in remission at week 52 was notsignificantly different for agomelatine (51.4%) ver-sus placebo (56.4% [p = 0.4050]).

A rapidly dissolvable sublingual tablet for-mulation of agomelatine is also currently beingevaluated in a phase III, open-label, long-termsafety and tolerability trial for major depressionin the US, but it has not yet been completed.[42]

4. Tolerability and Safety of Agomelatinein Placebo-Controlled Trials

4.1 Adverse Event Profile in Short-Term Trials

The tolerability and safety of agomelatine hasbeen assessed extensively in the six short-term

pivotal studies conducted as part of the Europeanresearch programme.[11,27-29] Safety data from thesestudies were pooled and analysed (analysis avail-able from the EMA CHMP report) and included1120 patients taking agomelatine 25–50mg/day,998 patients taking placebo, 284 patients takingfluoxetine 20mg/day and 283 patients takingparoxetine 20mg/day.[11] The overall rate of TEAEswas similar for agomelatine (52.8%), placebo(51.7%) and fluoxetine (49.3%), but slightly higherfor paroxetine (67.5%). The most commonly re-ported adverse events for agomelatine (in de-scending order of their incidence) were headache,nausea, dizziness, dry mouth, diarrhoea, somno-lence, fatigue, upper abdominal pain and anxiety.Each of these adverse events was reported in<15% of patients. The incidence of adverse eventswas slightly higher for the 50mg dose comparedwith the 25mg dose. Most agomelatine adverseevents were mild to moderate in severity. Theonly adverse events with a significantly higher in-cidence for agomelatine compared with placebowere dizziness, paresthesias and blurred vision.For the two SSRI drugs pooled together, the mostcommonly reported adverse events (in descendingorder of their incidence) were nausea, headache,dry mouth, diarrhoea, somnolence, fatigue, in-somnia, dizziness and anxiety. Each of these wasreported in <16% of patients. The largest differ-ence between agomelatine and the SSRI drugs inthe incidence of any adverse event was for nausea,which favoured agomelatine.

Although findings from all of the clinicalstudies conducted in the US have not been com-prehensively reported, the tolerability and safetydata of agomelatine described in the two pub-lished reports by Zajecka et al.[30] and Stahlet al.,[31] the unpublished study (CAGO178A2303)[32] and the findings from the multinationalstudy by Hale et al.,[26] do not appear to differsubstantially from the European experience.

4.2 Adverse Event Profile in Long-Term Trials

In addition to the three relapse preventionstudies (described in section 3 above),[11,32,33]

many of the short-term pivotal studies conductedin Europe had optional extension phases. Based



on data collected from the relapse prevention andextension phase studies altogether, longer-termtolerability and safety of agomelatine has beenassessed for up to 52 weeks.[11]

In an analysis of pooled data from thesestudies in patients taking agomelatine for up to34 weeks, there were 511 patients taking agome-latine 25–50mg/day, 406 patients taking placebo,222 patients taking fluoxetine 20mg/day and 105patients taking paroxetine 20mg/day.[11] Theoverall rate of TEAEs was similar for agomela-tine (38.8%) and placebo (38.4%), but slightlylower for fluoxetine (32.0%) and slightly higherfor paroxetine (44.8%). The rate of TEAEs washigher for agomelatine 50mg/day (48.3%) thanfor 25mg/day (35.8%). The most commonly re-ported adverse events for agomelatine (in de-scending order of their incidence) were headache,back pain and insomnia, each of which was re-ported in <10% of patients. The only adverse eventthat was significantly higher for agomelatinecompared with placebo was insomnia (p-valuenot reported). For the two SSRI drugs pooledtogether, the most commonly reported adverseevents (in descending order of their incidence)were headache, diarrhoea, insomnia and anxiety.Each of these was reported in <9% of patients.There were no major differences in long-term tol-erability between the SSRI drugs and agomelatine.

A limited number of patients (n = 400) in theEuropean studies took agomelatine for 1 year.[11]

There were few TEAEs during this extended time(each occurring in fewer than 3% of patients), andnone were different from what was seen in theshort- and long-term studies. No comparisonswere available with placebo or SSRI drugs.

The short-term, phase III clinical trials con-ducted in the US all had open-label extensionphases lasting up to 52 weeks, but tolerability andsafety data are not available from these studies.In the unpublished 52-week relapse preventionstudy conducted in the US (CAGO178A2304),[32]

the overall rate of TEAEs was similar for ago-melatine 25mg (75.0%), agomelatine 50mg(68.0%) and placebo (72.1%). Dropout rates dueto TEAEs were 4.3% for agomelatine 25–50mgversus 2.1% for placebo. The most commonTEAEs for agomelatine 25–50mg versus placebo

were headache (11.5%, 17.1 %, respectively), rhi-nitis (10.8%, 9.3%), diarrhoea (7.9%, 5.0%), in-somnia (5.8%, 5.7%), anxiety (5.0%, 5.0%), nau-sea (4.3%, 1.4%), vomiting (4.3%, 0.7%) and backpain (3.6%, 7.9%). Effects on sexual functioningor bodyweight were not reported. Overall, 29 pa-tients taking agomelatine during the open-labelphase developed newly occurring liver functiontest elevations, and during the double-blindphase three patients taking placebo developednewly occurring liver function test elevations.

4.3 Severe or Serious Adverse Event Profile

Among all patients enrolled in the Europeanclinical studies (pooled analysis reported inEMA CHMP report),[11] there was no significantdifference in the overall rate of serious adverseevents for agomelatine 25mg/day (125 of 3052patients [4.1%]) and 50mg/day (26 of 588 patients[4.4%]) compared with placebo (34 of 826 pa-tients [4.1%]). The most common serious adverseevents were suicide attempts (agomelatine 0.6%vs placebo 0.4%), depression (agomelatine 0.5%vs placebo 0.8%) and falls (agomelatine 0.3% vsplacebo 0.3%). In this analysis, deaths (all butone due to suicide) were reported in 4 of 3956patients taking agomelatine (0.1%), 1 of 826 pa-tients taking placebo (0.1%) and 3 of 449 patientstaking paroxetine (0.7%). In the published studiesby Zajecka et al.,[30] Stahl et al.,[31] and Haleet al.,[26] there were no reported suicide attemptsor patient deaths. In clinical trials in patients withconditions (unspecified) other than depression,the percentage of deaths among patients takingagomelatine (16 of 782 patients [2.0%]) washigher than for patients taking placebo (1 of 327patients [0.3%]).[11] Fifteen of the 16 deaths inagomelatine-treated patients occurred in a studyof 356 elderly patients who had Alzheimer’s de-mentia (a mortality rate of 4.2%).

5. Tolerability and Safety of Agomelatinein Other Clinical Trials

In addition to the randomized, placebo-controlled studies of agomelatine for major de-pression, data on the use of the drug are available

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from other clinical trials. These studies were notdesigned primarily to definitively test the efficacy ofagomelatine for major depression, but they do pro-vide additional data on its tolerability and safety.

In an early, 4-week, phase II, safety and effi-cacy pilot study, 28 hospitalized patients withmajor depression (18–65 years of age) were ran-domized to receive double-blind treatment atone of two doses of agomelatine (5mg/day vs100mg/day).[11,44] There was no placebo-controland the MADRS was the primary outcomemeasure. MADRS scores decreased significantlyin both groups and there was no significant differ-ence between groups. One subject in each groupdropped out because of adverse events and twodropped out in each group because of lack ofefficacy. Acceptability of both doses was reported tobe good, but there were slightly more TEAEs andsevere TEAEs in the 100mg group. There were noobserved adverse cardiovascular effects or abnor-mal laboratory studies in either group.

5.1 Studies on Sexual Function

In a 12-week, randomized, double-blind studyinvolving 276 male and female patients with majordepression (18–60 years of age), Kennedy andcolleagues[45] compared agomelatine (50mg/day)and the serotonin-noradrenaline (norepinephrine)reuptake inhibitor (SNRI) antidepressant venla-faxine (titrated from 75mg/day to 150mg/dayafter 2 weeks). The primary objective of this studywas to compare the effects of these two drugs onsexual function using data taken from the SexEffects Scale. On the primary outcome measureof sexual function, there was a numerical ad-vantage favouring agomelatine over venlafaxine,but these results were not statistically significant.Only several of the secondary outcome measuresof sexual function showed statistically significantdifferences in favour of agomelatine. The overallrate of TEAEs for agomelatine (20.4%) was lowerthan for venlafaxine (38.1%). The most commonlyreported adverse events were nausea (agomela-tine 11.7% vs venlafaxine 17.3%) and headache(agomelatine 10.2% vs venlafaxine 7.9%). Drop-out rates due to TEAEs were 2.2% for agomela-tine and 8.6% for venlafaxine. There was no

difference in antidepressant efficacy between thetwo drugs.

The objective of another study was to comparethe effects of agomelatine and paroxetine onsexual function in healthy non-depressed malesubjects.[46] In this 8-week, double-blind study,92 subjects (18–30 years of age) were randomizedto one of two doses of agomelatine (25 or50mg/day), placebo or paroxetine (20mg/day).On the primary and secondary outcomemeasuresof sexual function (using data taken from thePsychotropic-Related Sexual Dysfunction Ques-tionnaire), agomelatine (at both doses) and pla-cebo were not significantly different. These threegroups were significantly less impaired than theparoxetine-treated group.

5.2 Studies on Sleep

In a 6-week, randomized, double-blind studyinvolving 332 male and female patients with majordepression (18–65 years of age), Lemoine andcolleagues[47] compared agomelatine (25–50mg/day)and venlafaxine (75–150mg/day). The primaryobjective of this study was to compare the effectof these two drugs on sleep using the Leeds SleepEvaluation Questionnaire (LSEQ). On the primaryoutcome measure of sleep, and on most of thesecondary outcome measures, there was a clinicallymodest, but statistically significant advantage fa-vouring agomelatine over venlafaxine. The overallrate of TEAEs was slightly lower for agomelatine(52%) compared with venlafaxine (57%). The mostcommonly reported adverse events (agomelatinevs venlafaxine) were nausea (6.0% vs 22.6%), head-ache (9.6% vs 11.9%), dizziness (1.8% vs 9.5%),vomiting (1.2% vs 4.8%), diarrhoea (4.8% vs 1.8%)and somnolence (3.6% vs 4.8%). Rates of dis-continuation due to TEAEs were 4.2% for ago-melatine and 13.2% for venlafaxine. There was nodifference in antidepressant efficacy between thetwo drugs.

A 6-week, randomized, double-blind studyinvolving 313 male and female patients with majordepression (18–60 years of age) compared agome-latine (25–50mg/day) and the SSRI drug sertraline(50–100mg/day).[48] The primary study objectivewas to compare the effects of agomelatine and



sertraline on changes of the relative amplitude ofthe individual rest-activity cycles, collected fromcontinuous records using wrist actigraphy andsleep logs, from baseline to week 6. Secondaryobjectives of this study were to compare the effectof these two drugs on objective measures of sleep(sleep efficiency and sleep latency) using actigraphy-derived recordings, and on subjective measures ofsleep (getting to sleep and sleep quality) using theLSEQ. The 17-item HAM-D was used as a sec-ondary outcome efficacy measure (assessing thechange in HAM-D score from baseline to week 6for agomelatine vs sertraline). Response and re-mission rates based on the HAM-D were alsoconsidered secondary outcome variables. Responsewas defined as a 50% decrease from baseline inthe HAM-D score at endpoint. Remission wasdefined as a HAM-D score of £6 at endpoint. Inthis study, patients initially took agomelatine25mg/day, but the dose could be increased to50mg/day after 2 weeks for an insufficient re-sponse. Similarly, patients initially took sertra-line 50mg/day, but the dose could be increased to100mg/day after 2 weeks for an insufficient re-sponse. Ultimately, 25.3% of agomelatine-treatedpatients took 50mg/day and 24.5% of sertraline-treated patients took 100mg/day. On the primaryoutcome measure (changes in amplitude of therest-activity cycle), agomelatine was significantlybetter than sertraline by week 1, but there was nodifference between drugs from week 2 to week 6.On the secondary measure of actigraphy-derivedsleep efficiency and sleep latency, agomelatinewas significantly superior to sertraline through-out the 6 weeks. On the secondary measures ofgetting to sleep and quality of sleep, derived fromthe LSEQ, agomelatine was superior to sertralineat week 2, but the drugs were similar at weeks 4and 6. On the secondary outcome measures (de-pression), agomelatine was significantly moreeffective than sertraline (the mean difference inHAM-D was 1.68 for agomelatine vs sertraline).Response rates for agomelatine (70.0%) and ser-traline (61.5%) were not significantly different.Remission rates for agomelatine (32.7%) andsertraline (28.8%) were also not significantly dif-ferent. The overall rate of TEAEs was similar foragomelatine (48.0%) and sertraline (49.1%). Most

adverse events were experienced as mild to mod-erate in severity. Dropout rates due to TEAEs foragomelatine (3.2%) were lower than for sertraline(8.8%). For patients taking agomelatine versussertraline, the most common adverse events wereheadache (8.6% vs 10.1%), fatigue (5.9% vs 1.3%),dry mouth (5.3% vs 5.0%), diarrhoea (3.9% vs5.7%) and sweating (0.0% vs 5.0%). There wereno significant differences between the two studygroups with respect to bodyweight changes orcardiovascular effects. With the exception of liverfunction testing, there were no significant differ-ences between groups on any laboratory tests.Significant liver enzyme elevations occurred inone agomelatine-treated patient and in none ofthe sertraline-treated patients (reviewed in moredetail in section 7).

5.3 Studies on Discontinuation Symptoms

The effects of abruptly discontinuing agome-latine and paroxetine have been compared in arandomized, double-blind, placebo-controlledstudy.[49] After 12 weeks of double-blind treat-ment with agomelatine 25mg/day or paroxetine20mg/day, 192 patients with major depressionwho were in sustained remission were random-ized to continue taking their current drug or toswitch to placebo for 2 weeks. Discontinuationsymptoms (rated on the Discontinuation Emer-gent Signs and Symptoms checklist) were signif-icantly higher in the paroxetine-discontinuationgroup during the first week of placebo, but notduring the second week. Discontinuation symp-toms were not observed in the agomelatine-discontinuation group during the first or secondweek of taking placebo.

5.4 Studies in Various Other PsychiatricIndications

Calabrese et al.[50] conducted an open-labelstudy of agomelatine 25mg/day for 21 male andfemale patients (19–76 years of age) with bipolardisorder (type I, currently depressed). Subjectswere also taking mood-stabilizer medication(either lithium or valpromide). They were treatedfor 6 weeks, and were then able to continue open-label treatment during a 46-week extension phase

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(total of 1 year of treatment). On the primaryoutcome measure of efficacy (50% improvementon the 17-item HAM-D), 17 of 21 subjects (81%)were considered treatment responders after6 weeks. Eight of 21 subjects (38.1%) achievedremission (a HAM-D score of £6) after 6 weeks.Of the 19 subjects who continued agomelatinebeyond 6 weeks, 16 (84%) were considered treat-ment responders at some point during the exten-sion phase. Eleven subjects took agomelatine forthe entire year. The overall rate of TEAEs was71.%. Specific side effects were not reported.There were no dropouts related to TEAEs duringthe 6-week acute phase. Three patients dis-continued treatment due to TEAEs during theextension phase. Three cases of mania or hypo-mania and two cases of agitation were reported asserious adverse events among the 21 subjects.There were no reported adverse effects on body-weight, cardiovascular function or laboratorystudies.

Pjrek et al.[51] described the results of an open-label study of agomelatine 25mg/day for patientswith depression and seasonal affective disorder.The 37 male and female subjects (20–60 years ofage) were treated for 14 weeks. The primary out-come measure was the seasonal affective disorder(SAD) version of the HAM-D (SAD-HAM-D).[52]

After 14 weeks, 75.7% of subjects were consideredtreatment responders (50% improvement on theSAD-HAM-D) and 70.3% were in remission(SAD-HAM-D score of £7). Reported side effectswere minimal. One patient experienced daytimefatigue and 12 patients reported mild sleepiness.There were no dropouts due to TEAEs.

In a 12-week, randomized, double-blind, pla-cebo-controlled study involving 121 male andfemale patients with generalized anxiety disorder(18–65 years of age), Stein and colleagues[53]

compared agomelatine (25–50mg/day) and pla-cebo. If patients did not respond adequately after2 weeks of agomelatine 25mg/day or placebo, thedosage was increased under double-blind condi-tions to 50mg/day or matching placebo. Agomela-tine was significantly more effective than placeboon the primary outcome measure of anxiety (totalscore on the Hamilton Anxiety Rating Scale.[54]

The overall rate of TEAEs was similar for ago-

melatine 25mg (36.1%), 50mg (38.5%) and pla-cebo (34.5%). The most common TEAEs thatwere reported more frequently in the agomelatinegroup than in the placebo group were dizziness(7.9% vs 3.4%) and nausea (4.8% vs 1.7%). MostTEAEs were of mild to moderate severity.Dropout rates due to TEAEs were slightly lowerfor placebo (none) compared with agomelatine(1.6%). Cardiovascular effects and laboratorystudies did not differ between groups.

6. Tolerability and Safety of Agomelatinein Overdose, Pregnancy and PaediatricPopulations

There is limited clinical experience with agome-latine overdose in humans.[11] Reported overdoseswith agomelatine (up to 525mg) have not resultedin significant or serious sequelae. It should also benoted that in the earliest clinical studies, healthysubjects took agomelatine doses as high as 1200mgand the maximum tolerated dose was 800mg. Inanimals, the LD50 dose (i.e. the dose that kills 50%of the experimental animals) is at least 100-foldgreater than the comparable human dose. Hence,agomelatine has a relatively favourable safety pro-file with regards to acute toxic effects

There are no specific data on the safety ofagomelatine during pregnancy or with breast-feeding. Two phase I studies (one in men, one inwomen) did not demonstrate any adverse effectof agomelatine on various gonadotrophic hor-mones, spermogram or menstrual cycle.[11] Re-production toxicity studies in animals did notreveal any adverse effect of agomelatine on ferti-lity or on embryonic or fetal development.

A small, open-label sleep study in nine pae-diatric patients (6–17 years of age) with Smith-Magenis syndrome reported that agomelatinewas well tolerated.[55] The tolerability and safetyof agomelatine has not otherwise been studied inchildren and adolescents.

7. Hepatic Function and Agomelatine

Agomelatine is almost entirely metabolizedthrough the liver and undergoes extensive first-passhepatic metabolism. One specific study investigated



the influence of liver insufficiency in patients withhepatic cirrhosis on plasma levels of agomela-tine.[11] In patients with mild hepatic impairment,the increase in agomelatine exposure was morethan 50-fold higher compared with healthy sub-jects, and for patients with moderate hepatic im-pairment the exposure was more than 100-foldhigher compared with healthy subjects. In addi-tion, because of decreases in plasma proteins, theunbound free fraction of agomelatine was in-creased in subjects with hepatic insufficiency. Thefree fraction was approximately twice as greatin patients with moderate hepatic impairment.Liver insufficiency therefore results in a significantincrease in the exposure to agomelatine. Because thesafety of such large concentrations of agomelatineis unknown, it should not be used in patients withhepatic insufficiency, such as cirrhosis or otheractive liver disease.

The major cytochrome P450 (CYP) enzymeinvolved in the metabolism of agomelatine isCYP1A2 (accounting for about 90% of its me-tabolism), with minor metabolic contributions byCYP2C9 and CYP2C19.[10] Agomelatine has atleast four main metabolites. The pharmacologi-cal activity of the metabolites at the 5HT2C, MT1

and MT2 receptors is not clearly established.None of the metabolites have any known toxiceffects. Agomelatine does not appear to inhibit orinduce the activity of any CYP enzymes in hu-mans, but enzyme induction has been demon-strated in animal studies.[11]

In humans, the oral bioavailability of agome-latine at doses of 25 and 50mg is very low. Thebioavailability may increase at higher doses,perhaps due to saturation of first-pass hepaticmetabolism or non-linear pharmacokinetics. Theoral bioavailability of agomelatine is estimated tobe relatively higher in women compared withmen, and to be relatively higher in elderly versusyounger individuals, perhaps due to sex and ageeffects on hepatic blood flow and metabolic en-zyme activity.[11] However, because of significantintra- and inter-individual pharmacokineticvariability, dose changes based on age or sex arenot considered to be routinely necessary.

In an analysis of data pooled from Europeanclinical trials (available in the EMA CHMP re-

port), significant elevations of liver enzymes (i.e.increases >3 · the upper limit of normal [ULN])occurred in 1.39% of patients taking agomelatine50mg/day, 1.04% taking 25mg/day and 0.72%taking placebo.[11] For this analysis, the total num-ber of subjects taking agomelatine 25/50mg/daywas 4068; the number of subjects taking placebowas not clearly indicated. These liver reactionsoccurred at various times throughout the 6-monthobservation period of these studies. They weredetected in patients only through laboratorymonitoring, because they did not have obviousclinical signs or symptoms indicating liver injury.Some reactions recovered during continued treat-ment and some recovered after treatment dis-continuation. Serious liver reactions, includinghepatitis and enzyme elevations >10 · the ULN,were reported less frequently. One patient devel-oped hepatitis that did not recover at follow-up(2.5 years after discontinuation of agomelatine).These reactions in humans are not inconsistentwith the findings from animal studies. Repeateddose toxicity studies in rats and monkeys have in-dicated that the liver is the target organ of toxicity.Agomelatine causes hepatic enzyme induction inthese animals, and they consequently showed en-larged livers or hepatocellular hypertrophy.[11]

In the short-term US study by Zajecka et al.,[30]

significant liver enzyme elevations (i.e. increases>3 · the ULN) occurred in seven subjects (4.5%)taking agomelatine 50mg, but in none of theagomelatine 25mg or placebo subjects. The liverenzyme elevations were noted between weeks 6and 8. One subject stopped the drug and theirliver function tests normalized. Six patients con-tinued to take agomelatine (including five duringan extension phase) and their liver function testsall normalized. The investigators noted at base-line that the prevalence of pre-existing hepato-biliary disorders was 3.1% in the agomelatine50mg group, 0.6% in the 25mg group and 0.6%in the placebo, but they did not report whetherpre-existing hepatobiliary disease was associatedwith the later development of significant liverenzyme elevations.

In the short-term US study by Stahl et al.,[31]

significant liver enzyme elevations (i.e. increases>3 · the ULN) occurred in five subjects (3.0%)

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taking agomelatine 50mg, in one subject (0.6%)taking 25mg and in one subject taking placebo(1.3%). The liver enzyme elevations were notedbetween weeks 6 and 8. Two agomelatine 50mgsubjects stopped the drug and their liver func-tion tests normalized. Four patients continuedto take agomelatine during an extension phaseand their liver function tests normalized. Onesubject with liver enzyme elevations was lost tofollow-up.

In the unpublished short-term US study (CA-GO178A2 303),[32] significant liver enzyme ele-vations (i.e. increases >3 · the ULN) occurred intwo subjects (1.3%) taking agomelatine 25mg, inone subject (0.6%) taking 50mg and in one sub-ject (0.6%) taking paroxetine 20mg. One patienttaking agomelatine stopped the drug and theirliver function tests normalized, while two patientscontinued to take agomelatine and their liverfunction tests normalized. One subject with liverenzyme elevations taking paroxetine was switch-ed to agomelatine during an open-label extensionphase and liver function tests normalized.

In the unpublished longer-term US relapse pre-vention study,[32] 29 of 633 patients (4.6%) takingagomelatine during the open-label phase developednewly occurring liver function test elevations. Theoutcome of these cases was not described.

In the multinational study by Hale et al.,[26]

significant liver enzyme elevations (i.e. increases>3· the ULN) occurred in five agomelatine-treatedpatients and in one fluoxetine-treated patient. Allthese subjects continued to take their medicationand apparently (according to the study authors)their liver function tests normalized, but no ad-ditional information about these subjects wasreported.

In the study by Kasper et al.,[48] significant liverenzyme elevations occurred in one agomelatine-treated patient and in none of the sertraline-treatedpatients. The patient who developed elevated liverenzymes was described as an ‘alcoholic’, but nofurther details were given in the report.

8. Renal Function and Agomelatine

Agomelatine and its metabolites are mainlyexcreted through the kidneys. The elimination

half-life of agomelatine is very short (about2–3 hours). The effects of renal function on ago-melatine pharmacokinetics were investigated in astudy of healthy subjects and subjects with severeimpairment of renal function.[11] In the subjectswith severe renal impairment, exposure to ago-melatine increased more than 25% comparedwith healthy subjects.[11]

Agomelatine does not significantly affect renalfunction. In patients with normal hepatic function,impaired renal function would be expected toresult in greater exposure to agomelatine meta-bolites rather than to the parent drug. Availablesafety data from the clinical trials in patients withmajor depression did not demonstrate any sig-nificant tolerability or safety issues with the use ofagomelatine compared with placebo among pa-tients with mildly to moderately impaired renalfunction;[11] however, experience in patients withmore severe renal impairment is unknown. Al-though agomelatine can be used in patients withrenal impairment, such patients should be mon-itored more closely.

9. Bodyweight, Metabolic andCardiovascular Safety of Agomelatine

Agomelatine has not been associated withsignificant bodyweight gain or adverse metaboliceffects. In the European studies, only 4 of 400 pa-tients taking agomelatine for 1 year gained body-weight.[11] Data presented in section 4 from theEuropean and US studies have also not demon-strated that agomelatine is associated with ad-verse cardiac effects (e.g. ECG or blood pressurechanges). A single published case report described a58-year-old depressed woman who developed acorrected QT interval prolongation during treat-ment with agomelatine, which fully reversedwhen the drug was stopped.[56] A proposed studycomparing the effect of agomelatine and fluox-etine on heart rate variability in patients withmajor depression has been withdrawn before en-rolment.[57] The reason for withdrawing the studyis not known. With the exception of potentialadverse liver effects, animal and human studieshave not identified any other significant toxi-cities, even with excessively high doses.



10. Safety of Agomelatine inOlder Patients

Among patients older than 65 years, safetydata are available from the European studies on109 patients taking agomelatine and 76 takingplacebo.[11] Rates of TEAEs were similar foragomelatine (63.3%) and placebo (59.2%). Dis-continuation rates due to TEAEs were 12.8% foragomelatine and 9.2% for placebo. Serious adverseevents occurred in 4.6% of patients taking ago-melatine and 5.2% taking placebo. The two pub-lished US studies included subjects up to age70 years, but findings from these studies on thesafety and tolerability of agomelatine among thoseolder than 65 years have not been specificallyreported.[30,31]

11. Drug Interactions and Agomelatine

Similar to most other psychotropic drugs,agomelatine is highly protein bound (its plasmaprotein binding is >95%).[58] Taking multipledrugs that bind to the same plasma protein cansometimes cause displacement of the protein-bound fraction of a drug, resulting in higher con-centrations of the free fraction. Based on in vitrostudies, agomelatine does not modify free concen-trations of drugs highly bound to plasma proteins,nor do other drugs affect its protein binding;[11] how-ever, this has not been studied in vivo in humans.

Agomelatine does not appear to inhibit or in-duce the activity of any CYP enzymes in humans,suggesting a low likelihood that it will affect thehepatic metabolism of other drugs, but enzymeinduction has been demonstrated in animalstudies.[11] Although the oral bioavailability ofagomelatine at doses of 25 and 50mg is very low,it is relatively higher in non-smokers versus smokersand in women taking oestrogen-containing drugscompared with women who do not. These findingsare explained by the metabolic enzyme-inducingeffects of smoking and the enzyme-inhibiting ef-fects of oestrogens. Agomelatine does not affectthe pharmacokinetics of the bronchodilator drugtheophylline, which is a substrate for CYP1A2.The SSRI drug fluvoxamine is a potent inhibitorof CYP1A2 and a moderate inhibitor of CYP2C9,

and it can significantly increase serum concen-trations of agomelatine. By contrast, the SSRIparoxetine is a moderate inhibitor of CYP1A2 anddoes not significantly increase the concentrationof agomelatine. The antifungal drug fluconazoleis a potent inhibitor of CYP2C9, but it has notbeen shown to significantly influence the phar-macokinetics of agomelatine. Specific drug-druginteraction studies involving lithium, lorazepam,alcohol and valproic acid have not demonstratedany significant effects of these drugs on thepharmacokinetics of agomelatine.[11]

12. Discussion

The antidepressant efficacy of agomelatine hasbeen systematically assessed in ten short-term,placebo-controlled acute studies and three longer-term, placebo-controlled, relapse prevention stud-ies. Five short-term trials demonstrated clinicallymodest but statistically significant benefits overplacebo, although two of these studies foundopposite effects for the agomelatine 25 and 50mgdoses. Five short-term trials did not find agomel-atine to be more effective than placebo. Fluoxetine20mg/day was more effective than placebo in oneof these negative trials. Paroxetine 20–40mg/dayalso was more effective than placebo in anothernegative trial. Low-dose fluoxetine and low-doseparoxetine were not more effective than placeboin the other two negative trials. The lack of effi-cacy of the active control drugs in these two trialswere believed mainly to be due to an insufficientdose and possibly to unusually high placebo re-sponder rates.[11]

The only controlled study conducted in elderlypatients did not demonstrate a significant benefitfor agomelatine compared with placebo. Ago-melatine was more effective than placebo in onlyone of the three relapse prevention studies. Un-like many other antidepressant drugs, agomela-tine has not been systematically studied beyondcontinuation-phase treatment. A meta-analysisof the six short-term trials submitted to the EMAdemonstrated a small, statistically significanttreatment effect of about 1.5 on the HAM-D infavour of agomelatine over placebo.[11] The re-sults from these studies suggest that agomelatine

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25mg/day is probably less effective than otherantidepressant drugs. In their summary in approv-ing agomelatine, the EMA concluded that somepositive treatment effect of agomelatine in majordepression was demonstrated, but that the mag-nitude of effect was considered to be of marginalclinical relevance.[11] The two published US studiesalso demonstrated small positive treatment ef-fects for agomelatine, but the positive outcomeswere opposite for 25mg/day versus 50mg/day inthe two studies. Neither dose was consistentlyeffective in both studies. That there might be anunusual nonlinear or differential dose-responsepharmacological effect of agomelatine on CNSprocesses is consistent with a recent study con-ducted in non-depressed subjects.[59] In this 7-daystudy, agomelatine 25mg/day (but not 50mg/day)significantly facilitated positive versus negativeaffective memory recall and reduced the percep-tion of sadness. Hence, more work is needed tobetter understand the dose-response character-istics of agomelatine in a wider range of popula-tions of patients with depression.

In these clinical trials, agomelatine was gen-erally well tolerated compared with placebo. Themost common side effects associated with ago-melatine are headache, nausea, dizziness, drymouth, diarrhoea, somnolence, fatigue, upperabdominal pain and anxiety. The relatively be-nign side effect profile of agomelatine (especiallythe lack of clinically significant bodyweight gain,the low risk of sexual dysfunction, the low in-cidence of gastrointestinal symptoms and theabsence of discontinuation symptoms) is differ-ent from and compares favourably with SSRIand SNRI drugs. However, the overall tolerabilityof agomelatine was not substantially better thanactive drug controls, as evidenced by the ap-proximately similar rates of TEAEs and similardropout rates due to TEAEs.

Liver function appears to be of particularconcern with the use of agomelatine. Significantelevations of liver enzymes were common in theEuropean studies and were also noted in the USand multinational clinical trials. In the Europeantrials, these hepatic changes were sometimes veryserious and included rare cases of hepatitis, butserious liver injury was not described in the more

recently published studies by Zajecka et al.,[30]

Stahl et al.[31] and Hale et al.[26] Some of the datareviewed previously suggest that liver enzymeelevations might be dose-related and might bemore likely with agomelatine compared withother antidepressant drugs. Because these hepaticreactions were not predictable based on clinicalsymptoms or the duration of treatment, mon-itoring of liver enzyme levels of all patients hasbeen recommended (by the EMA)[11] before startingtreatment, after 6, 12 and 24 weeks of treatment,and then thereafter when clinically indicatedbased on the judgement of the treating physician.‘Real-world’ patients in general practice are likelyto be quite different from patients enrolled inclinical trials.[60] As a result, the relative safety ofagomelatine is unknown when used in patientswho might have undetected liver impairment orliver disease, or in patients who are at risk fordeveloping liver disease. This would include, forexample, depressed patients at risk for developingviral hepatitis, and patients who use alcohol,paracetamol (acetaminophen) or other prescrip-tion and non-prescription drugs that affect theliver. Also, pharmacokinetic studies indicate thateven mild hepatic insufficiency results in veryelevated concentrations of agomelatine. For thisreason, agomelatine is contraindicated in patientswith any degree of liver impairment, such as cir-rhosis or other active liver disease.[11] All of theseissues regarding the liver are of obvious concernfor the routine use of agomelatine. Liver precautionsand the need for laboratorymonitoring are a distinctdisadvantage for the use of agomelatine comparedwith virtually all other antidepressant drugs.

Agomelatine is metabolized primarily byCYP1A2 enzyme in the liver, with lesser meta-bolic contributions from CYP2C9/2C19. Basedon this, the use of agomelatine is contraindicatedin patients taking drugs strongly inhibiting thisenzyme (e.g. fluvoxamine). Moderate inhibitorsof CYP1A2, such as oestrogen-containing oralcontraceptives and paroxetine, increase agome-latine concentrations to a lesser degree. Patientstaking any drugs having moderate inhibitoryeffects on CYP1A2 or drugs having inhibitoryeffects on CYP2C9/2C19 should simply be mon-itored for increased adverse effects. It is possible



that patients taking one or more drugs that havemoderate metabolic enzyme inhibiting effectswould benefit from taking and staying on loweragomelatine doses (i.e. 25mg/day or lower). Bycontrast, patients who smoke, and those takingdrugs that induce CYP1A2 enzyme activity (e.g.the proton pump inhibitor drug omeprazole),may be more likely to require doses of 50mg/dayor possibly even higher doses (although this hasnot been evaluated clinically).

In patients with normal hepatic function, im-paired renal function may result in higher con-centrations of agomelatine metabolites ratherthan the parent drug. Patientswith renal impairmentdo not require any special laboratory monitor-ing with the use of agomelatine, but they shouldstill be monitored for increased adverse effects.

Because the oral bioavailability of agomela-tine is very low at recommended doses, its phar-macokinetics, efficacy, tolerability and safety inpatients taking doses higher than 50mg/day de-serves further study. In clinical practice, it islikely that some prescribers will use agomelatinein the 50–100mg/day dose range.

The efficacy, tolerability and safety of agomela-tine for depression should be further investigatedin ‘real-world’ patient populations, paediatric andgeriatric patients, maintenance therapy studies ex-tending for more than 6 months, bipolar disorderand seasonal affective disorder. Information isalso needed about the effects of agomelatine dur-ing pregnancy and breastfeeding.[61,62]

The relative effectiveness of agomelatine shouldbe further evaluated in comparison with SSRIdrugs, SNRI drugs and other antidepressantdrugs using their full dose range, rather thanminimally effective doses.[9,63] Because of ago-melatine’s unique pharmacology and putativelyfavourable clinical profile (e.g. putative claimsthat it has a low risk of adverse effects on sexualfunction and the gastrointestinal system, low riskof bodyweight gain and a positive effect on sleep),comparing it with the antidepressant drugsbupropion, nefazodone and mirtazapine in par-ticular would be of interest. Bupropion is a non-serotonergic drug that has relatively benigneffects on sexual function, the gastrointestinalsystem and bodyweight. Nefazodone is a 5HT2A

receptor antagonist, with favourable effects onsleep, anxiety, sexual function, the gastrointestinalsystem and bodyweight. Mirtazapine has a com-plicated pharmacology that includes 5HT2A, 5HT2C,and 5HT3 receptor antagonism, and it has fa-vourable effects on anxiety, sleep, gastrointestinalfunction and sexual function, but is prone to se-dation and bodyweight gain. Trazodone also has5HT2A and 5HT2C receptor antagonist effects;however, it is most commonly used in low dosesas a hypnotic and is rarely used as an antide-pressant because of sedation and the risk in menof developing priapism when used at higherantidepressant therapeutic doses.

SSRI and SNRI drugs have been extensivelyinvestigated, approved and marketed for the treat-ment of different anxiety disorders. Except for asingle published study in generalized anxiety dis-order, the effectiveness of agomelatine for thetreatment of various anxiety disorders is notknown.[53] A 16-week, placebo-controlled, phase IIclinical trial with agomelatine for obsessive-compulsive disorder is currently being conducted,but findings have not yet been reported.[64] A re-cent randomized, placebo-controlled, 8-weekstudy (published only in abstract form) found nobenefit for agomelatine over placebo in obsessive-compulsive disorder.[65] The authors also re-ported that clinically notable aminotransferaseelevations were observed transiently in the ago-melatine 50mg dose group.

For patients not responding adequately to aninitial antidepressant medication, or for patientswho cannot tolerate the medication, the twomaintreatment approaches are switching or augmen-tation.[9] The unique pharmacology of agomelatinesuggests a potential role not only as an appro-priate switch agent for medication intolerance ornon-response, but also as an augmentation agentthat could be used in combination with otherantidepressant drugs. Combining antidepressantdrugs for treatment non-responders is commonlydone in clinical practice. Combining agomelatineand other antidepressant drugs, especially SSRIand SNRI drugs, could be tried to achieve asynergistic antidepressant effect. Similarly, the5HT2C receptor antagonist effects of agomelatinemight justify its use in combination with SSRI or

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SNRI drugs as a way to counter serotonin-relatedadverse effects, such as sexual dysfunction, gas-trointestinal complaints or insomnia. Controlledstudies investigating the use of agomelatine as aswitch agent or in combination with other anti-depressant drugs for these clinical purposes arewarranted.

13. Conclusions

Given the wide variety of potentially effectiveantidepressant therapies, the initial selection ofan antidepressant medication should be governedby an overall assessment of such factors as costand availability, patient preference, past treat-ment history, family treatment history, clinicalsymptoms, expected side effect profile and safety,and the need for medical/laboratory monitor-ing.[66] Comparative data on the relative efficacy,tolerability, safety and acceptability of antide-pressant drugs would be helpful but are oftenlacking.[67,68] As a relatively newer product, less isknown about many of these issues with agome-latine vis-a-vis other antidepressant drugs. Thechoice of drug treatment for an individual patientshould be based as much as possible on the bestunbiased clinical and scientific information available.Agomelatine does not have clinically significantadvantages compared with other antidepressantdrugs, and it has certain limitations and dis-advantages. Controlled studies have demon-strated that agomelatine has a small, statisticallysignificant, but marginally clinically relevant, anti-depressant effect compared with placebo. Basedon the entire published and unpublished data re-viewed in this article, it is clear that publicationbias is present, such that more favourable ago-melatine studies have been published. For example,fluoxetine and paroxetine (but not agomelatine)were each shown to be more effective than pla-cebo in two of the unpublished trials. The adverseeffect profile of agomelatine is different fromother antidepressant drugs, but the overall toler-ability of agomelatine was not substantially betterthan active drugs included as controls. Agomel-atine is contraindicated in patients with impairedliver function and in patients taking drugs thatpotently inhibit CYP1A2 metabolic enzymes.

Because elevated liver enzymes are common, andthere is a rare risk of more serious liver reactions,routine laboratory monitoring of liver function isrecommended periodically throughout treat-ment. Because of the unique pharmacology ofagomelatine and its reported tolerability profile,it should be considered only as an alternativedrug for patients who do not respond to or can-not tolerate other antidepressant drugs.

Acknowledgements

No sources of funding were used to prepare this manuscript.Dr Howland has received past grant support from Novartis.

References1. Hirschfeld RMA, Weissman MM. Risk factors for major

depression and bipolar disorder. In: Davis KL, Charney D,Coyle JT, et al., editors. Neuropsychopharmacology: thefifth generation of progress. Philadelphia (PA): LippincottWilliams & Wilkins, 2002: 1017-25

2. Browne G, Steiner M, Roberts J, et al. Prevalence of dys-thymic disorder in primary care. J Affect Disord 1999; 54:303-8

3. Kessler RC, Zhao S, Blazer DG, et al. Prevalence, correlates,and course of minor depression and major depression in theNational Comorbidity Survey. J Affect Disord 1997; 45: 19-30

4. Howland RH. Health status, health care utilization, andmedical comorbidity in dysthymia. Int J Psychiatry Med1993; 23 (3): 211-38

5. Howland RH, Schettler PJ, Rapaport MH, et al. Clinicalfeatures and functioning of patients with minor depression.Psychother Psychosom 2008; 77: 384-9

6. Rush AJ, Kraemer HC, Sackeim HA, et al. Report by theACNP task force on response and remission in major de-pression. Neuropsychopharmacol 2006; 31: 1841-53

7. Koplan C, Charuvastra A, Compton MT, et al. Preventionpsychiatry. Psychiatr Ann 2007; 37: 319-28

8. Baune BT, Adrian I, Jacobi F. Medical disorders affecthealth outcome and general functioning depending on co-morbid major depression in the general population. J Psy-chosomatic Res 2007; 62: 109-18

9. Howland RH. Therapeutic armamentarium for treating de-pression. Postgrad Med 2010; 122 (4): 66-93

10. de Bodinat C, Guardiola-Lemaitre B, Mocaer E, et al.Agomelatine, the first melatonergic antidepressant: dis-covery, characterization, and development. Nat Rev DrugDiscov 2010; 9 (8): 628-42

11. European Medicines Agency. CMHP assessment report forvaldoxan. 20 November 2008 [online]. Available fromURL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000915/WC500046226.pdf [Accessed 2011 Jul 13]

12. European Medicines Agency, Committee for MedicinalProducts for Human Use. Summary of positive opinionfor valdoxan. 20 November 2008. Doc. Ref. EMEA/CHMP/575411/2008 [online]. Available from URL: http://



www.emea.europa.eu/pdfs/human/opinion/Valdoxan_57541108en.pdf [Accessed 2011 Jul 13]

13. European Medicines Agency. Valdoxan product informa-tion: summary of product characteristics [online]. Avail-able from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000915/WC500046227.pdf [Accessed 2011 Jul 13]

14. United States Food andDrugAdministration [online]. Availablefrom URL: http://www.fda.gov/ [Accessed 2011 Jul 13]

15. ClinicalTrials.gov, a service of the US National Institutes ofHealth [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jul 13]

16. Zlotos DP. Recent advances in melatonin receptor ligands.Arch Pharm Chem Life Sci 2005; 338: 229-47

17. Rajaratnam SMW, Cohen DA, Rogers NL. Melatonin andmelatonin analogues. Sleep Med Clin 2009; 4: 179-93

18. Landolt HP, Wehrle R. Antagonism of serotonergic5-HT2A/2C receptors: mutual improvement of sleep, cog-nition, and mood? Eur J Neurosci 2009; 29: 1795-809

19. Millan MJ, Gobert A, Lejeune F, et al. The novel melatoninagonist agomelatine is an antagonist at 5-hydoxy-tryptamine-2C receptors, blockade of which enhances theactivity of frontocortical dopaminergic and adrenergicpathways. J Pharmacol Exp Ther 2003; 306 (3): 954-64

20. Quera-Salva MA, Vanier B, Laredo J, et al. Major depres-sive disorder, sleep EEG and agomelatine: an open-labelstudy. Int J Neuropsychopharmacol 2007; 10: 691-6

21. Kupfer DJ. Depression and associated sleep disturbances:patient benefits with agomelatine. Eur Neuropsycho-pharmacol 2006; 16 Suppl. 5: S639-43

22. Leproult R, Van Onderbergen A, L’Hermite-Baleriaux M,et al. Phase-shifts of 24-h rhythms of hormonal release andbody termperature following early evening administrationof the melatonin agonist agomelatine in healthy older men.Clin Endocrinol 2005; 63: 298-304

23. Descamps A, Rousset C, Millan M, et al. Influence of thenovel antidepressant and melatonin agonist/serotonin2Creceptor antagonist, agomelatine, on the rat sleep-wakecycle architecture. Psychopharmaology 2009; 2005: 93-106

24. Racagni G, Riva MA, Popoli M. The interaction betweenthe internal clock and antidepressant efficacy. Int ClinPsychopharmacol 2007; 22 Suppl. 2: S9-14

25. Sharpley AL, Rawlings NB, Brain S, et al. Does agomelatineblock 5-HT2c receptors in humans? Psychopharmacology2011; 213 (2-3): 653-5

26. Hale A, Corral RM, Mencacci C, et al. Superior antide-pressant efficacy results of agomelatine versus fluoxetine insevere MDD patients: a randomized double-blind study.Int Clin Psychopharmacol 2010; 25: 305-14

27. Loo H, Hale A, D’Haenen H. Determination of the doseof agomelatine, a melatoninergic agonist and selective5-HT2C antagonist, in the treatment of major depressivedisorder: a placebo-controlled dose range study. Int ClinPsychopharmacol 2002; 17 (5): 239-47

28. Kennedy SH, Emsley R. Placebo-controlled trial of agome-latine in the treatment of major depressive disorder. EurNeuropsychopharmacol 2006; 16 (2): 93-100

29. Olie JP, Kasper S. Efficacy of agomelatine, a MT1/MT2receptor agonist with 5-HT2C antagonistic properties, in

major depressive disorder. Int J Neuropsychopharmacol2007; 10: 661-73

30. Zajecka J, Schatzberg A, Stahl S, et al. Efficacy and safety ofagomelatine in the treatment of major depressive disorder.J Clin Psychopharmacol 2010; 30: 135-44

31. Stahl SM, Fava M, Trivedi MH, et al. Agomelatine in thetreatment of major depressive disorder: an 8-week multi-center randomized placebo-controlled trial. J Clin Psychi-atry 2010; 71 (5): 616-26

32. Novartis. Clinical trial results database [online]. Availablefrom URL: http://www.novctrd.com/ctrdWebApp/clinicaltrialrepository/public/login.jsp [Accessed 2011 Jul 13]

33. Goodwin GM, Emsley R, Rembry S, et al. Agomelatineprevents relapse in patients with major depressive disorderwithout evidence of a discontinuation syndrome: a 24-weekrandomized double-blind placebo-controlled trial. J ClinPsychiatry 2009; 70 (8): 1128-37

34. Hamilton M. A rating scale for depression. J Neurol Neu-rosurg Psychiatry 1960; 23: 56-62

35. Montgomery SA, Asberg M. A new depression scale de-signed to be sensitive to change. Br J Psychiatry 1979; 134:382-9

36. Novartis. A placebo- and paroxetine-controlled study of theefficacy, safety and tolerability of agomelatine (25 or50mg) in the treatment of major depressive disorder(MDD) [ClinicalTrials.gov identifier NCT00463242]. USNational Institutes of Health, ClinicalTrials.gov [online].Available from URL: http://www.clinicaltrials.gov [Ac-cessed 2011 Jul 13]

37. Novartis. Efficacy, safety and tolerability of agomelatine inthe treatment of major depressive disorder [ClinicalTri-als.gov identifier NCT00411242]. US National Institutes ofHealth, ClinicalTrials.gov [online]. Available from URL:http://www.clinicaltrials.gov [Accessed 2011 Jul 13]

38. Novartis. Efficacy, safety and tolerability of agomelatine inthe treatment of major depressive disorder [ClinicalTri-als.gov identifier NCT00411099]. US National Institutes ofHealth, ClinicalTrials.gov [online]. Available from URL:http://www.clinicaltrials.gov [Accessed 2011 Jul 13]

39. Novartis. Efficacy, safety and tolerability of agomelatine inthe prevention of relapse of major depressive disorder[ClinicalTrials.gov identifier NCT00467402]. US NationalInstitutes of Health, ClinicalTrials.gov [online]. Availablefrom URL: http://www.clinicaltrials.gov [Accessed 2011Jul 13]

40. Novartis. Efficacy, safety and tolerability of agomelatinesublingual tablets in the treatment of major depressivedisorder [ClinicalTrials.gov identifier NCT01110889]. USNational Institutes of Health, ClinicalTrials.gov [online].Available from URL: http://www.clinicaltrials.gov [Ac-cessed 2011 Jul 13]

41. Novartis. Efficacy, safety and tolerability of agomelatinesublingual tablets in the treatment of major depressive dis-order (MDD) [ClinicalTrials.gov identifier NCT01110902].US National Institutes of Health, ClinicalTrials.gov [on-line]. Available from URL: http://www.clinicaltrials.gov[Accessed 2011 Jul 13]

42. Novartis. Open-label long term (52 weeks) safety and toler-ability of agomelatine sublingual tablets in major depressivedisorder (MDD) [ClinicalTrials.gov identifier NCT01156415].US National Institutes of Health, ClinicalTrials.gov [online].

730 Howland


Available from URL: http://www.clinicaltrials.gov [Accessed2011 Jul 13]

43. Guy W. Clinical Global Impression (CGI) ECDEU As-sessment Manual for Psychopharmacology. US Depart-ment of Health Education and Welfare publication(ADM); 1976: 76-338

44. Loo H, Dalery J, Macher JP. Pilot study comparing in blindthe therapeutic effect of two doses of agomelatine, mela-toninergic agonist and selective 5HT2C receptors antag-onist, in the treatment of major depressive disorders [inFrench]. Encephale 2002; 28 (4): 356-62

45. Kennedy SH, Rizvi S, Fulton K, et al. A double-blindcomparison of sexual functioning, antidepressant efficacy,and tolerability between agomelatine and venlafaxine XR.J Clin Psychopharmacol 2008; 28: 329-33

46. Montejo AL, Prieto N, Terleira A, et al. Better sexual ac-ceptability of agomelatine (25 and 50mg) compared withparoxetine (20mg) in healthy male volunteers: an 8-weekplacebo-controlled study using the PRSEXDQ-SALSEXscale. J Psychopharmacol 2010; 24 (1): 111-20

47. Lemoine P, Guilleminault C, Alvarez E. Improvement insubjective sleep in major depressive disorder with a novelantidepressant agomelatine: randomized double-blind com-parison with venlafaxine. J Clin Psychiatry 2007; 68: 1723-32

48. Kasper S, Hajak G, Wulff K, et al. Efficacy of the novel anti-depressant agomelatine on the circadian rest-activity cycle anddepressive and anxiety symptoms in patients with major de-pressive disorder: a randomized double-blind comparisonwithsertraline. J Clin Psychiatry 2010; 71 (2): 109-20

49. Montgomery SA, Kennedy SH, Burrows GD, et al. Absenceof discontinuation symptoms with agomelatine and oc-currence of discontinuation symptoms with paroxetine: arandomized, double-blind, placebo-controlled discontinua-tion study. Int Clin Psychopharmacol 2004; 19 (5): 271-80

50. Calabrese JR, Guelfi JD, Perdrizet-Chevallier C. Agomela-tine adjunctive therapy for acute bipolar depression: pre-liminary open data. Bipolar Disord 2007; 9 (6): 628-35

51. Pjrek E, Winkler D, Konstantinidis A, et al. Agomelatine inthe treatment of seasonal affective disorder. Psycho-pharmacology 2007; 190: 575-9

52. Williams JBW, Link MJ, Rosenthal NE, et al. Structuredinterview guide for the Hamilton Depression Rating Scale-Seasonal Affective Disorder. 2002 rev. New York (NY):New York State Psychiatric Institute, 2002

53. Stein DJ, Ahokas AA, de Bodinat C. Efficacy of agomela-tine in generalized anxiety disorder: a randomized double-blind placebo-controlled study. J Clin Psychopharmacol2008; 28: 561-6

54. Hamilton M. A rating scale for anxiety. J Neurol NeurosurgPsychiatr 1959; 23: 56-62

55. Fabiano A, de Leersnyder H. Agomelatine efficacy onmajorsleep disturbances in Smith-Magenis syndrome: an ex-ploratory open study in children [abstract]. Eur Neuro-psychopharmacol 2007; 17 Suppl. 4: S567

56. Kozian R, Syrbe G. QTc-Zeit-Verlangerung unter Therapiemit Agomelatin. Psychiat Prax 2010; 37: 405-7

57. National Taiwan University Hospital. The effect of agome-latine or fluoxentine on heart rate variability in patientswith major depressive disorder [ClinicalTrials.gov identi-fier NCT00451490]. US National Institutes of Health,ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jul 13]

58. Dolder CR, Nelson M, Snider M. Agomelatine treatment ofmajor depressive disorder. Ann Pharmacother 2008; 42:1822-31

59. Harmer CJ, de Bodinat C, Dawson GR, et al. Agomelatinefacilitates positive versus negative affective processing inhealthy volunteer models. J Psychopharmacol. Epub 2010Jul 21

60. Wisniewski SR, Rush AJ, Nierenberg AA, et al. Can phaseIII trial results of antidepressant medications be general-ized to clinical practice? A STAR*D report. Am J Psychi-atry 2009; 166: 599-607

61. Howland RH. Evaluating the safety of medications duringpregnancy and lactation. J Psychosoc Nurs Ment HealthServ 2009; 47 (3): 19-22

62. Howland RH. Prescribing psychotropic medications duringpregnancy and lactation: principles and guidelines. J Psy-chosoc Nurs Ment Health Serv 2009; 47 (5): 19-23

63. Trivedi MH, Rush AJ, Gaynes BN, et al. Maximizing theadequacy of medication treatment in controlled trials andclinical practice: STAR*D measurement-based care. Neu-ropsychopharmacology 2007; 32: 2479-89

64. Servier. Efficacy of agomelatine in patients with obsessive-compulsive disorder [ClinicalTrials.gov identifierNCT01108393]. US National Institutes of Health, Clin-icalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jul 13]

65. Marques Cabezas P, Cabus Pinol G, Coullaut-ValeraGarcıa J, et al. Agomelatine in the treatment of obsessive-compulsive-disorder: potential for clinical effectiveness. A4-week multicenter randomized placebo-controlled trial[abstract]. Eur Psychiatry 2011; 26 Suppl. 1: 974

66. Howland RH. Medication adherence. Psychiatr Ann 2008;38 (5): 323-6

67. Howland RH. Limitations of evidence in the practice ofevidence-based medicine. Psychiatr Ann 2008; 38 (5): 334-6

68. Wisniewski SR, FavaM, Trivedi MH, et al. Acceptability ofsecond-step treatments to depressed outpatients: aSTAR*D report. Am J Psychiatry 2007; 164: 753-60

Correspondence: Robert H. Howland, MD, Associate Pro-fessor of Psychiatry, University of Pittsburgh School ofMedicine, Western Psychiatric Institute and Clinic,University of Pittsburgh Medical Center, 3811 O’HaraStreet, Pittsburgh, PA 15213, USA.E-mail: [email protected]



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