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Email: [email protected] 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(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 Received: 17 May 2016 Revised: 29 July 2016 Accepted: 13 September 2016 DOI 10.1002/hup.2557 Hum Psychopharmacol Clin Exp2016; 1–7 Copyright © 2016 John Wiley & Sons, Ltd.wileyonlinelibrary.com/journal/hup1 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 ifp< 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 2GARGOLOFF ET AL . 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 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.

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.* indicatessignificant differences with baseline GARGOLOFF ET AL .3 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 abnormalitiesreported 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 FIGURE 3 Response and remission rate TABLE 2 Assessment in MDE patients with first MDE and with recurrent MDE First MDE Recurrent MDE Baseline Week 1 Week 4 Week 8 Baseline Week 1 Week 4 Week 8 SHAPS9.9 ± 3.9 8.2 ± 4.4 6.0 ± 5.0* 4.1 ± 4.9* 7.4 ± 4.5 6.2 ± 4.5 6.2 ± 3.8* 4.1 ± 4.3* QIDS‐SR‐1615.0 ± 5.1 11.9 ± 6.4* 8.8 ± 7.1* 6.1 ± 6.2* 16.0 ± 4.2 11.0 ± 5.8* 8.0 ± 5.9* 6.9 ± 5.5* GAD‐713.0 ± 4.8 10.8 ± 4.8* 8.0 ± 5.2* 6.2 ± 4.9* 14.7 ± 4.1 11.3 ± 4.6* 8.6 ± 5.1* 8.3 ± 5.3* CGI‐S4.5 ± 0.7 4.2 ± 0.9 3.8 ± 1.1* 3.5 ± 1.4* 4.4 ± 0.7 3.9 ± 0.9* 3.3 ± 1.1* 3.0 ± 1.2* CGI‐I—2.8 ± 0.8 2.5 ± 1.0 2.0 ± 1.0—2.9 ± 0.9 2.3 ± 1.0 2.0 ± 1.4 Note.CGI‐I = Clinical Global Impression of Improvement; CGI‐S = Clinical Global Impression of Severity; GAD‐7 = Generalized Anxiety Disorder 7‐item scale; MDE = major depressive episode; QIDS‐SR‐16 = Quick Inventory of Depressive Symptomatology 16‐item Self‐Report; SHAPS = Snaith–Hamilton Pleasure Scale.

Results are expressed as mean ± SD, analysis of variance for repeated measure (LOCF),p< 0.05.

*Significant differences with baseline. 4GARGOLOFF ET AL . areas, namely, prefrontal cortex without influence in extracellular sero- tonin levels (Millan et al 2003). Enhancement of dopaminergic and nor- adrenergic neurotransmission has been related to the improvement of interest and pleasure (Nutt et al., 2006), while SSRIs increasing the extracellular serotonin levels may dampen the activity of NA and DA neurons (Blier & Briley, 2011). In this study, most of the coadministra- tions occurred with SSRIs and they may dampen the effect of agomelatine when administered concomitantly to depressed patients.

This peculiar effect of agomelatine on anhedonia may be determined by an interaction with neurotrophic factors, a hypothesis recently pro- posed in other studies (Martinotti, Orsolini, et al., 2016a).

These results are consistent with a significant number of other tri- als, but with the relevant parameter of the real‐life setting. Daily clini- cal practice requires a complex interplay between experience and judgment and must draw on data not only from classical randomized controlled trials but also from pragmatically designed studies that bet- ter reflect real‐life clinical practice, as the case of this study run by 46 psychiatrists from the city of Buenos Aires. Studies designed to reflect a more naturalistic, real‐life management approach can provide inter- esting insights into the differences between randomized clinical trials management and routine care management, and the potential implica- tions of ecology of care on treatment outcomes.

An interesting finding is the significant clinical improvements detected in anhedonia, depression, and anxiety symptoms observed both in first episode as in patients with a story of multiple episodes.

This data show and confirm how agomelatine effect is independent from the presence of subjects in a drug‐naive condition, and may represent a good possibility also in patients with a long psychiatric history.

In our study, when the items of the QIDS‐SR‐16 were analyzed separately, an improvement from the first week was still observed despite of excluding the sleep, suggesting that the score of the QIDS was not driven by the score of the sleep items. In fact, naturalistic studies have revealed that the relief of sleep complains with agomelatine had a very low predictive value for treatment response (Gorwood et al., 2013).

The results of agomelatine on anhedonia from this study in com- parison to those from large clinical trials in major depressive disorder should be interpreted with caution, where anhedonia was considered only as one of the many depressive symptoms and precisely it wasnot included as primary or secondary study endpoint. From the mode of action of agomelatine, it could be expected that its effect on anhe- donia is specific and not due to the remission in depression because improvement in anhedonia appears earlier than the efficacy on depres- sion scales in patients treated with monotherapy with agomelatine.

These results confirm those obtained in a previous pilot randomized study versus venlafaxine, where both products had similar efficacy in the decrease of the Hamilton Depression rating scale (HAMD) and Hamilton Anxiety rating scale (HAMA) scores over the 8 weeks of treatment while agomelatine showed a significant greater efficacy than venlafaxine from the first week of treatment in anhedonia measured by the SHAPS scale (Martinotti et al., 2012).

In contrast, and in line to the mode of action of SSRI, a study with sertraline administered to depressed patients showed that depression and anxiety responded earlier to the antidepressant than the improve- ment of anhedonia (Boyer, Tassin, Falissart, & Troy, 2000).

The absence of a placebo group, the open design, and the exclusive use of self‐report scales are limitations of the study. However, a high number of patients (n= 143) were enrolled and considered for the anal- ysis, with consistent results compared with previous studies (n=30in each) (Di Giannantonio et al., 2011; Martinotti et al., 2012). Although there was a significant number of patients that could not be included in the analysis for unconfirmed start date of treatment (n= 81), we observed that this group had similar response compared to included patients in all parameters considered in the study. On the other hand, observational real‐world studies include more heterogeneous populations with a variety of medical conditions and interventions, as is the case of this study, which could reflect more closely the daily clinical practice.

In conclusion, this real‐world study confirms the effectiveness of agomelatine in the improvement of anhedonia in a cohort of depressed patients in Argentina and supports the data that demonstrated the effi- cacy of agomelatine in depression and in anxiety within depression. The efficacy of available antidepressants in anhedonia has been poorly eval- uated in the past, even though anhedonia is considered, together with depressed mood, as one of the two symptoms of depression essentials for the diagnosis of the disease (DSM IV, 5). Some psychotropic drugs, also outside the class of antidepressants, have some good potentiality for this core dimension (Jaehne, Corrigan, Toben, Jawahar, & Baune, 2015; Martinotti, Pettorruso, et al., 2016b; Lally et al., 2015), but data are still insufficient to draw any conclusion. Even if the results of TABLE 3 Assessment in MDE patients with or without concomitant use of other antidepressants. Without concomitant use of other ATD With concomitant use of other ATD Baseline Week 1 Week 4 Week 8 Baseline Week 1 Week 4 Week 8 SHAPS8.5 ± 4.5 6.7 ± 4.5* 4.6 ± 4.5* 3.7 ± 4.5* 8.6 ± 4.4 7.8 ± 4.6 5.6 ± 4.5* 4.8 ± 4.7* QIDS‐SR‐1614.8 ± 4.5 10.3 ± 5.7* 7.4 ± 5.8* 5.6 ± 5.1* 16.8 ± 4.7 13.4 ± 6.3* 10.1 ± 7.2* 8.2 ± 6.7* GAD‐713.6 ± 4.8 10.7 ± 4.7* 8.3 ± 5.1* 7.1 ± 5.2* 14.6 ± 3.9 11.8 ± 4.6* 8.4 ± 5.3* 7.7 ± 5.5* CGI‐S4.4 ± 0.7 4.0 ± 0.8* 3.6 ± 1.0* 3.3 ± 1.3* 4.5 ± 0.7 4.1 ± 1.0 3.6 ± 1.3* 3.2 ± 1.3* CGI‐I—2.8 ± 0.7 2.4 ± 0.9 1.9 ± 1.1—2.9 ± 1.0 2.4 ± 1.2 2.1 ± 1.4 Note.ATD = antidepressant; CGI‐I = Clinical Global Impression of Improvement; CGI‐S = Clinical Global Impression of Severity; GAD‐7 = Generalized Anx- iety Disorder 7‐item scale; MDE = major depressive episode; QIDS‐SR‐16 = Quick Inventory of Depressive Symptomatology 16‐item Self‐Report; SHAPS = Snaith–Hamilton Pleasure Scale.

Results are expressed as mean ± SD, analysis of variance for repeated measure (LOCF),p< 0.05.

*Significant differences with baseline. GARGOLOFF ET AL .5 agomelatine in this important symptom deserve to be confirmed in larger real‐life studies, they offer a very important property to this novel anti- depressant that can have an impact in the management of depressed patients especially while considering quality of life and remission.

CONFLICT OF INTEREST The authors have declared no conflict of interest.

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