Topic: Dissociative symptom disorder this is a

Received: 17 May 2016 Revised: 29 July 2016 Accepted: 13 September 2016

DO

I 10.1002/hup.2557

R E S E A R C H A R T I C L E

Effectiveness of agomelatine on anhedonia in depressed patients: an outpatient, open‐label, real‐world study

Pedro Damian Gargoloff1,2 | Ricardo Corral3 | Luis Herbst4 | Miguel Marquez5 |

Giovanni Martinotti6 | Pedro Rafael Gargoloff2

1 Hospital Alejandro Korn, Melchor Romero, La

Plata, Argentina

2 Clinica City Bell, La Plata, Argentina

3 Departamento de Docencia e Investigacion,

Hospital Jose T Borda, CABA, Argentina

4 Hospital Jose T. Borda, CABA, Argentina

5 ADINEU, CABA, Argentina

6 Department of Neuroscience, Imaging and

Clinical Science, Chieti, Italy

Correspondence

Pedro Damian Gargoloff, Hospital Alejandro

Korn, Melchor Romero, La Plata, Argentina.

Email: [email protected]

Hum Psychopharmacol Clin Exp 2016; 1–7

Abstract

Objective The aim of this real‐world study was to evaluate the effect of agomelatine on anhe-

donia as primary endpoint in outpatients under treatment of major depressive episodes.

Methods The study was an open‐label, multicenter, 8‐week phase IV trial. Two hundred fifty‐

seven (257) patients were recruited, and 143 patients were included in the analysis. Agomelatine

was administered orally as a 25‐mg tablet. The dose could be increased to 50 mg after 2 weeks of

treatment.

Results An improvement in the severity of anhedonia (Snaith‐Hamilton Pleasure Scale total

score) was observed from 8.5 points at baseline to 4.1 at week 8, statistically significant

(p < 0.05) from the first week. Significant decreases in scores on the severity of depression (Quick

Inventory of Depressive Symptomatology 16‐item Self‐Report [QIDS‐SR‐16]), anxiety (General-

ized Anxiety Disorder 7‐item scale), and in overall clinical status (CGI) were also found over

8 weeks, independently from the presence of a first or recurrence episode. Response (QIDS‐

SR‐16 score ≥ 50% of baseline) at week 8 was observed in 65.7% of the patients, while

49.6% of the patients achieved remission (QIDS‐SR‐16 score ≤ 5).

Conclusion Agomelatine was shown to be effective on anhedonia, depression, and anxiety in

subjects with major depression. The pragmatic design of the study reflects real‐world clinical

practice providing interesting insights into routine care management.

KEYWORDS

agomelatine, anhedonia, open‐label, real‐world

1 | INTRODUCTION

Depression is a major mood disorder with 12% prevalence over life-

time (Sadock & Sadock, 2009). The World Health Organization esti-

mated that depression makes a large contribution to the overall

burden of disease, being at third place worldwide and at first place in

middle‐ and high‐income countries. By the year 2030, depression is

estimated to be the first cause of disability‐adjusted life years among

the world's population.

While various pharmacological treatment options are available,

there are still unsatisfied needs, including the lack of consistent evi-

dence of improvement in anhedonia, identified as a loss of interest

and lack of reactivity to pleasurable stimuli in daily life, being one of

the two core symptoms of depression (Treadway & Zald, 2011). Anhe-

donia has been considered crucial for the diagnosis of depression

wileyonlinelibrary.com/jo

(Klein, 1984; Schrader, 1997), and is a transnosographic condition

reported in several psychiatric disorders (Hatzigiakoumis, Martinotti,

Di Giannantonio, & Janiri, 2011; Millan, Fone, Steckler, & Horan,

2014; De Berardis et al., 2015; Di Nicola et al., 2013, Pettorruso

et al., 2014a), including alcohol, and substance abuse (Martinotti,

Cloninger, & Janiri, 2008) and neurological disorders (Pettorruso

et al., 2014b). In major depression, anhedonia persistence is associated

with the prediction of unsatisfactory outcomes in the treatment of

depression, as patients do not achieve appropriate clinical remission,

with functional and quality‐of‐life impairment (McMakin et al., 2012;

Vrieze et al., 2013).

Agomelatine is an antidepressant with an novel mode of action. It is

antagonist at 5‐HT2C receptors, and antagonist at MT1 and MT2 recep-

tors (Audinot et al., 2003, Millan et al., 2003, De Berardis et al., 2013b).

These receptors act in synergy increasing dopamine and norepinephrine

Copyright © 2016 John Wiley & Sons, Ltd.urnal/hup 1

2 GARGOLOFF ET AL.

neurotransmission (Millan et al., 2003; Chenu, El Mansari, & Blier, 2013),

and there is a potentiation of dopamine and norepinephrine release in

the prefrontal cortex. Agomelatine has shown antidepressant efficacy in

several randomized placebo‐controlled studies and in studies versus

active controls (see Taylor, Sparshatt, Varma, & Olofinjana, 2014 and

Khoo et al., 2015 for a review and network meta‐analyses). Its effects

have been shown in different psychopathological conditions, well

beyond the diagnosis of major depression (Fornaro et al., 2013; De

Berardis et al., 2013a; Guglielmo, Martinotti, Di Giannantonio, & Janiri,

2013; De Berardis et al., 2012). Agomelatine has showed good

tolerability profile including low sexual dysfunction (Kennedy, Rizvi,

Fulton, & Rasmussen, 2008) and lack of discontinuation syndrome

(Montgomery, Kennedy, Burrows, Lejoyeux, & Hindmarch, 2004).

Agomelatine not only reduces negative affects such as depressed

mood or anxiety but also has particularly clinical actions on improving

positive affect, namely, targeting the improvement of anhedonia,

emotional blunting, and daytime sleepiness among others, which

differentiates agomelatine from serotonergic antidepressants (Stahl,

2014). To date, there are only two published studies that have

described the efficacy of agomelatine in the treatment of anhedonia

among depressive patients in which specific rating scales have been

used to assess these symptoms (Di Giannantonio et al., 2011;

Martinotti et al., 2012). In the first, an open‐label 8‐week study, the

primary endpoints were the effect on depressive and anxiety

symptoms while the effect on anhedonia was a secondary endpoint.

In the second, an open‐label 8‐week study, the effects of agomelatine

on anhedonia were compared with venlafaxine XR and anhedonia was

evaluated as primary endpoint and significant difference between

groups was observed in favor of agomelatine.

The aim of this study was to evaluate the effect of agomelatine on

anhedonia as primary endpoint in outpatients under treatment for

major depressive episode (MDE) under usual clinical practice condi-

tions, in a real‐world setting. Secondary endpoints were changes in

depression and anxiety in MDE patients.

2 | METHODS

This study was an open‐label, multicenter, 8‐week, phase IV trial of

agomelatine in outpatients with MDE.

All patients provided written informed consent prior to participa-

tion in the study, and the protocol was approved by a local ethic com-

mittee and conducted in accordance with the principles of good clinical

practice.

All planned procedures relating to this noninterventional/observa-

tional study were carried out only as part of the routine of diagnosis and

treatment of usual clinical practice. No intervention was undertaken

on or with the patient other than that related to usual clinical practice.

Forty‐six psychiatrists from the city of Buenos Aires, Argentina,

participated in this study.

Outpatients aged 25–65 years, diagnosed with MDE as defined by

the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edi-

tion, Text Revision, and treated with agomelatine were included in this

study. Diagnosis of major depressive disorder was confirmed by the

Mini International Neuropsychiatric Interview (Sheehan, Lecrubier, &

Sheehan, 1998). Only patients who provided written informed consent

were included, and each participant was assigned a number by which

he/she was identified to keep his or her privacy.

Study visit were scheduled for weeks 1, 4, and 8 after treatment

initiation. Only data collected in the respective windows intervals at

follow‐up visits (week 1 ± 3 days, week 4 ± 1 week, and week

8 ± 2 weeks) after treatment initiation were included.

Exclusion criteria were represented by hypersensitivity to

agomelatine or the excipients, hepatic failure (cirrhosis or active liver

disease), any kind of transaminase abnormalities, concomitant use of

potent CYP1A2 isoenzyme inhibitors (e.g., fluvoxamine, ciprofloxacin),

dementia, history of bipolar disorder, mania, or hypomania.

Agomelatine was administered orally as a 25‐mg tablet before

sleep. The dose could be increased at the discretion of the physician

to 50 mg after 2 weeks of treatment.

Anhedonia was evaluated by the Snaith–Hamilton Pleasure Scale

(SHAPS), the primary objective of this study (Snaith et al., 1995; Fresán

& Berlanga, 2013; Franken, Rassin, & Muris, 2007). It is a brief 14‐item

self‐report questionnaire designed to measure hedonic tone and its

absence, anhedonia.

Depression was assessed by The Quick Inventory of Depressive

Symptomatology 16‐item Self‐Report (QIDS‐SR‐16), a common self‐

reporting procedure used to establish inclusion criteria and to measure

changes to the medical treatment (Rush et al., 2003; Trivedi et al.,

2004). Response was defined as an improvement of ≥50% in QIDS‐

SR‐16 score from baseline, and remission was defined as a QIDS‐SR‐

16 score ≤ 5 at end point (Trivedi et al., 2006).

The Generalized Anxiety Disorder 7‐item scale (GAD‐7) is a self‐

reporting tool for the evaluation of anxiety disorders and to record

changes in anxiety severity (Spitzer, Kroenke, Williams, & Löwe,

2006; García‐Campayo et al., 2010).

The Clinical Global Impression of Severity (CGI‐S) and Improve-

ment (CGI‐I) were administered by the physician and constitute a gen-

eral measure of the patient's psychopathological state before and after

treatment implementation (Guy, 1976).

Each physician managed his patients according to their usual clini-

cal practice and recorded the visit follow‐up by using the electronic

medical report form provided. Safety evaluations were performed by

recording spontaneously reported adverse events and measurement

of aspartate transaminase and alanine transaminase levels according

to recommended intervals at baseline and at week 1, 4, and 8 of

treatment.

Data was expressed as mean ± SD. Primary and secondary analysis

were performed on the intention‐to‐treat population, which was

defined as all patients who took at least one dose of agomelatine. Data

were analyzed for normal distribution using the Kolmogorov–Smirnov

test and one‐way analysis of variance for repeated measure (Friedman

test) using the last‐observation‐carried‐forward was performed. Corre-

lation was analyzed with Spearman correlation. The difference was

considered significant if p < 0.05.

3 | RESULTS

Two hundred fifty‐seven (257) patients were recruited for the study,

and data of 143 patients were included in the analysis (81 were

TABLE 1 Baseline clinical characteristics of patients (n = 143)

Age (years, range) 47.8 ± 11.3 (25–65)

Female (%) 64

Recurrent MDE (%) 54.5

Melancholic MDE (%) 88.8

Average length of current MDE (month) 8.9 ± 23.3

Concomitant treatment at baseline with other antidepressant (%)

35.7

Concomitant treatment at baseline (other psychotropic drug) (%)

74.8

Note. MDE = major depressive episode.

GARGOLOFF ET AL. 3

excluded due to unconfirmed start date of treatment and 33 because

all visits were outside the recommended intervals; Figure 1).

Sixteen patients (11.2%) dropped out of treatment: eight patients

were lost to follow up and eight subjects because of adverse events,

three due to lack of efficacy, two due to insomnia, one due to somno-

lence, one due to muscular pain, and one due to compulsions. The dose

of agomelatine was increased from 25 to 50 mg in two patients (1.4%).

The main characteristics of the study population are shown in Table 1.

A significant reduction in the severity of anhedonia (SHAPS total

score) was observed (Figure 2), from 8.5 points at baseline to 4.1 at

week 8 (p < 0.001). This improvement was evident from the first week

(p < 0.01).

A significant decrease in scores on the severity of depression

(QIDS‐SR‐16) from 15.5 points at baseline to 6.9 at week

8 (p < 0.001) and anxiety (GAD‐7) from 14.0 points at baseline to 7.3

at week 8 (p < 0.001) was found (Figure 2).

The CGI‐I score improved from 2.9 in the first week to 2.0 at week

8. The CGI‐S score improved from 4.5 at baseline to 3.3 at week 8 with

a statistically significant difference found from the first week of

treatment.

In order to analyze the relation between percentages of changes in

SHAPS, QIDS‐SR‐16, and GAD‐7 scores at week 8 with agomelatine

treatment, Spearman correlation were carried out between these

parameters and a significant positive correlation was found in all cases

(SHAPS versus QIDS‐SR‐16:r = 0.5532, p < 0.0001; SHAPS versus

GAD‐7:r = 0.5383, p < 0.0001; QIDS‐SR‐16 versus GAD‐7:

r = 0.6513, p < 0.0001).

The proportion of patients achieving the given criteria for

response (QIDS‐SR‐16 score ≥ 50% of baseline) and remission

(QIDS‐SR‐16 score ≤ 5) is shown in Figure 3. Response at week

8 was observed in 65.7% of the patients while 49.6% of the patients

achieved remission.

Change in the QIDS‐SR‐16 was analysed excluding sleep items. A

significant improvement from the first week was also observed in this

analysis (p < 0.001), demonstrating that the decrease of the total score

was not driven by the decrease of the sleep items.

Data were analyzed in the subgroup of patients with recurrence

(n = 78) or first MDE episode (n = 65). Agomelatine showed a similar

and statistically significant (p < 0.05) improvement in SHAPS after

4 weeks of treatment. Improvements in QIDS‐SR‐16 and GAD‐7 were

FIGURE 1 Diagram of subject recruited and included

FIGURE 2 Mean change of SHAPS, QIDS‐SR‐16, and GAD‐7 scores. Results are expressed as mean ± SD, analysis of variance for repeated measure (LOCF), p < 0.05. * indicates significant differences with baseline

FIGURE 3 Response and remission rate

4 GARGOLOFF ET AL.

also similar between both groups and were statistically significant from

the second week of treatment (Table 2).

When considering the results obtained in monotherapy with

agomelatine or with concomitant use of other antidepressants

(Table 3), a statistically significant (p < 0.05) SHAPS improvement

was observed from the first week in patients treated with agomelatine

only (n = 92), while in those with concomitant use of other antidepres-

sant (n = 51) the significant improvement was observed from week 4

(p < 0.05). An improvement in QIDS‐SR‐16, GAD‐7, and CGI was also

observed in both groups from the first week of treatment.

The improvements in scores of all the scales evaluated (SHAPS,

QIDS‐SR‐16, GAD‐7, CGI‐S, CGI‐I) were observed both in patients

with moderate anxiety (GAD‐7 ≥ 10, n = 116) and in patients with

severe anxiety (GAD‐7 ≥ 15, n = 69) (data not shown).

Taking into account the whole population (n = 257), 27 adverse

drug reactions (ADR) were reported (10.5%). Seventeen corresponded

to nonserious ADR: headache (n = 4), insomnia (n = 3), nausea (n = 2),

somnolence (n = 2), epigastralgia (n = 2); two of them were upgraded

to serious ADR by the sponsor: dizziness and hypersomnia. Six adverse

events (AE) were informed, and two of them corresponded to an event

included in the risk management plan (transitory increase of liver

enzymes‐ < 1.5 ULN). However, both of them were not considered

as connected to use of agomelatine.

Three cases of lack of efficacy were reported. One pregnancy was

reported (with normal, spontaneous delivery, and no abnormalities

TABLE 2 Assessment in MDE patients with first MDE and with recurrent

First MDE

Baseline Week 1 Week 4 Wee

SHAPS 9.9 ± 3.9 8.2 ± 4.4 6.0 ± 5.0* 4.1 ±

QIDS‐SR‐16 15.0 ± 5.1 11.9 ± 6.4* 8.8 ± 7.1* 6.1 ±

GAD‐7 13.0 ± 4.8 10.8 ± 4.8* 8.0 ± 5.2* 6.2 ±

CGI‐S 4.5 ± 0.7 4.2 ± 0.9 3.8 ± 1.1* 3.5 ±

CGI‐I — 2.8 ± 0.8 2.5 ± 1.0 2.0 ±

Note. CGI‐I = Clinical Global Impression of Improvement; CGI‐S = Clinical Global MDE = major depressive episode; QIDS‐SR‐16 = Quick Inventory of Depressive Scale.

Results are expressed as mean ± SD, analysis of variance for repeated measure

*Significant differences with baseline.

reported in the child). Two cases of elevation of liver enzimes (GGT)

were reported but both of them were not considered as AE connected

to use of agomelatine.

Among the 27 ADR, agomelatine was definitively discontinued in

six cases, the dose was reduced in four subjects, reintroduced in one

patient (in which the drug was interrupted by patient's decision), and

maintained with no change in 16 cases. There were no clinically signif-

icant changes in body weight, blood pressure, or heart rate.

4 | DISCUSSION

To our knowledge, this is the first study in Argentina evaluating anhe-

donia in depression and the effect of an antidepressant treatment as

the primary endpoint. The main finding of this real‐world, observa-

tional, multicenter 8‐week study was that agomelatine produced, as

early as the first week following the treatment initiation, a significant

improvement in anhedonia in a population of depressed patients. This

positive effect on anhedonia is consistent with previous reports (Di

Giannantonio et al., 2011; Martinotti et al., 2012) despite the higher

baseline SHAPS score in our study, which reflects a more severe

anhedonic population.

Agomelatine improved depressive symptoms measured by the

QIDS‐16 SR and anxiety symptoms as seen with the GAD‐7, in both

cases statistically significant since the first week. The beneficial effects

in depression and anxiety symptoms are also in line with previous stud-

ies (Stein, Picarel‐Blanchot, & Kennedy, 2013, Taylor et al., 2014; De

Berardis et al., 2013b; Di Giannantonio and Martinotti, 2012), and pos-

itive significant correlations between SHAPS, QIDS‐SR‐16, and GAD‐7

were found in the total population. However, when the patients in

monotherapy were evaluated, SHAPS improved faster than depression

or anxiety scales in comparison to patients with concomitant treat-

ments. Drug–drug interaction appears unlikely to have happened

because there are no pharmacodynamic interactions known between

agomelatine and other antidepressive agents, and there were no anti-

depressants inhibitors of CYP 1A2 in the market in Argentina at the

time the study was performed. A possible explanation lies in the phar-

macology of the antidepressants used in the study: We hypothesize

that the effect of agomelatine in anhedonia is due to its mode of

action, by releasing noradrenaline and dopamine in specifically limbic

M

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