The safety of agomelatine in standard medical practice in depressed patients: A 26‐week international multicentre cohort study

Abstract Objective The present observational cohort study documented the safety of agomelatine in current medical practice in out‐patients suffering from major depressive disorder. Method The 6‐month evolution of agomelatine‐treated patients was assessed with a focus on safety (emergent adverse events, liver acceptability), severity of depression using the Clinical Global Impression Severity (CGI‐S) score, and functioning measured by the Sheehan Disability Scale (SDS). Results A total of 8453 depressed patients from 761 centres in 6 countries were analysed (female: 67.7%; mean age: 49.1 ± 14.8 years). Adverse events reported were in accordance with the known safety profile of agomelatine. Cutaneous events were reported in 1.7% of the patients and increased hepatic transaminases values were reported in 0.9 % of the patients. The incidence of events related to suicide/self‐injury was 1.0%. Two completed suicides, not related to the study drug, were reported. CGI‐S total scores and SDS sub‐scores improved and numbers of days lost or underproductive decreased over the treatment period. Conclusions In standard medical practice, agomelatine treatment was associated with a low incidence of side effects. No unexpected events were reported. A decrease in the severity of the depressive episode and improved functioning were observed. Trial registration name Observational cohort study to evaluate the safety of agomelatine in standard medical practice in depressed patients. A prospective, observational (non‐interventional), international, multicentre cohort study. Trial registration number ISRCTN53570733


| INTRODUCTION
Major depressive disorder (MDD) is the most common psychiatric disorder worldwide, with a lifetime prevalence of approximately 13% (Alonso et al., 2004;Bromet et al., 2011;Ferrari et al., 2013), associated with marked morbidity and premature mortality (Chesney, Goodwin, & Fazel, 2014). The antidepressant agomelatine (Valdoxan ® ) is a melatonergic MT1/MT2 receptor agonist with serotonin 5-HT2C receptor antagonist activity (Guardiola-Lemaitre et al., 2014). With this unique mechanism of action, agomelatine has demonstrated a range of properties that suggest it could offer advantages over current treatments for MDD (Kennedy & Rizvi, 2010). The antidepressant efficacy of agomelatine has been demonstrated at doses of 25-50 mg in the treatment of the full range of depressive symptoms in patients with moderate to severe MDD (de Bodinat et al., 2010) and agomelatine showed a similar efficacy to other available treatments (Taylor, Sparshatt, Varma, & Olofinjana, 2014).
Agomelatine is generally well tolerated and shows a different profile of adverse events compared to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitor (SNRIs), with a more favourable profile on gastrointestinal, psychiatric, cutaneous and vascular systems (Kennedy & Rizvi, 2010).
Agomelatine also preserves the integrity of sexual function (Montejo et al., 2010(Montejo et al., , 2015 and is not associated with discontinuation syndrome after abrupt treatment cessation (Montgomery, Kennedy, Burrows, Lejoyeux, & Hindmarch, 2004). Nevertheless, cases of liver transaminases increase (AST/ALT > 3 ULN in 1.25% on agomelatine 25 mg, 2.62% on 50 mg, 0.5% of patients on placebo-Summary of product characteristics (SmPC) have been reported in agomelatinetreated patients and in post marketing settings only, rare cases of hepatic failure were observed; therefore, a liver monitoring scheme is required and the drug is contraindicated in patients with impaired liver function.
At time of the product launch, in 2009, incidences of skin emergent adverse events were similar in agomelatine and placebo groups (1.17 and 1.25 per 100 patient-months respectively). Skin reactions were however considered as a potential risk to be further monitored, based on the report of two serious cases (erythema nodosum recovered under treatment; erythematous rash) on agomelatine treatment.
In parallel, in depressed patients, the risk of suicide being high (American Psychiatric Association, 2003) this risk must be monitored.
As treatment proceeds, variations in depressive symptoms may be associated with fluctuations in suicide risk. This monitoring includes evaluation of the presence of suicidal ideation and behaviours (American Psychiatric Association, 2010).
The current cohort study was designed to evaluate, in conditions of standard medical practice, the safety of a treatment with agomelatine prescribed to depressed patients. A focus was made on hepatic disorders (hepatic events with or without clinical symptoms including increase of transaminases >3 ULN), skin events, and suicidality (suicidal ideations, behaviours, and acts).

| Patients and study design
This was a prospective, observational, international, multi-centre cohort study conducted in depressed patients followed-up in current medical practice for their current depressive episode. The study was conducted in 761 centres in 6 countries. The physicians were recruited firstly through hospitals, clinics or private practices, in the speciality of psychiatry, then in the general practice.
Inclusion criteria were: male or female patients, more than 18 years of age, initiating agomelatine treatment for their current depressive episode, having signed an informed consent and accepting to give a personal reference contact.
Prescription of agomelatine resulted from a normal clinical evaluation according to the physician's clinical judgement, based on each patient's clinical profile and in line with the SmPC, including contra-indications, special warning and precautions for use. The decision to enter a patient in the study, after his/her agreement, was done after the clinical decision to prescribe agomelatine.
Patients were not enrolled if they participated in another study, if they had to stop a successful on-going antidepressant treatment, if they wished to continue another antidepressant treatment in addition to agomelatine, or if they planned to move during the follow-up period of the study. No exclusion criteria were defined on potential comorbidities.
Patients were followed during 26 weeks of treatment with the usual clinical follow-up provided by the involved clinicians. In case of agomelatine discontinuation, an end-of-study visit was scheduled 2 weeks after agomelatine withdrawal to follow safety and withdrawal symptoms.
For each patient, the dose and the duration of treatment were individually decided by the participating physician according to their usual medical practice, based on the approved SmPC and patients' clinical profiles. The starting dose of agomelatine was 25 mg once daily. A dose increase from 25 to 50 mg/day could be decided by the investigator. Patients who reported a dose of 25 mg/day throughout their follow-up were considered in the 'agomelatine 25 mg' subgroup; patients with at least one intake of 50 mg were considered in the 'agomelatine 25-50 mg' subgroup.

| Measurements
Physical examination and vital signs (heart rate, blood pressure, and weight) were assessed according to the usual care practice at baseline, follow-up and end-of-study visits. Emergent adverse events (EAEs), including skin events (SOC), were collected at each visit and were defined as events occurring after the first study drug intake and up to 30 days after the last intake.
The report of adverse event was spontaneous. Physicians had to make sure that any adverse event/reaction or worsening of depression that occurred during the study was recorded. In particular, exacerbation of symptoms related to depression, including anxiety or other isolated symptoms possibly related to lack of efficacy of the study treatment or to cessation of treatment were to be recorded.
Liver function tests had to be performed as recommended in the agomelatine SmPC. Liver acceptability was assessed on both biological hepatic parameters with a focus on cases of aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3 At each visit (baseline, follow-up and end-of-study visits), the investigator assessed the severity of depression using the Clinical Global Impression (CGI; Guy, 1976, pp. 217-222) severity of illness (CGI-S), and the patients' functioning using the Sheehan Disability Scale (SDS; Sheehan, Harnett-Sheehan, & Raj, 1996). No other psychometric assessment tool was used as it was a non-interventional study.

| Statistical analysis
Quantitative variables were described by number of valid data, mean value and standard deviation. For qualitative variables, absolute and relative frequency distributions were presented.
Statistical analysis was performed on SAS ® software, version 9.2.
The study was run in accordance with the principles stated in the Declaration of Helsinki, Finland, Good Pharmacoepidemiology Practices (ISPE, 2008), Ethical Guidelines for Epidemiological, Studies (Rose, 2009) and the applicable regulatory requirements.

| Baseline data
The study involved 1205 physicians from 761 centres in France Psychiatrists recruited 60.1% of patients, while general practitioners recruited 39.9% of patients. Of the 8743 patients included, 8453 patients with a signed inform consent and a date of agomelatine first intake were included in the analysis.
Out of the patients excluded due to unavailable signed informed consent, 14 patients reported at least one adverse event and were thus included in the safety cohort, which therefore consisted of 8467 patients. Main baseline characteristics of patients are presented in Table 1a. Patients had been depressed for more than 9 years in average and had a mean number of two major depressive episodes, including the current one. Based on the M.I.N.I. suicidality items, 34.4% of patients had a suicidal risk, most (15.7%) at a low level, 7.8% at a moderate level and 7.3% at a severe level of risk. Almost half of the patients reported at least one concomitant disease at inclusion.
The most frequently reported comorbidities were hypertension, hypercholesterolemia, hypothyroidism, anxiety and diabetes mellitus (Table 1b).
The mean CGI-S was 4.5 � 0.9 (median: 5, markedly ill) and according to the SDS, on average, the patients felt moderately disrupted by disease symptoms and those linked to potential side effects for those on antidepressant treatments for the 3 functional domains.
Patients treated with the 25-50 mg dose had more severe depressive disorders and a higher disability at baseline than patients treated with the 25 mg fixed dose (e.g., in terms of disease duration, number of depressive episodes, hospitalizations and suicidal risk; Table 1c).
The mean treatment duration was 5.8 � 2.9 months; 60.1% of patients being treated with agomelatine for at least 6 months.
Treatment duration was similar in patients treated with the 25 mg dose (5.7 � 2.9 months) and patients treated with the 25-50 mg dose (6.3 � 2.7 months).
A total of 2978 of patients (35.2%) were withdrawn from the study. The main reasons were remission or marked improvement (12.4% of patients), adverse event (8.6%), lack of efficacy (7.2%) and non-medical reason (3.9%); 67 patients (0.8%) did not come back for the end-of-study visit. Out of the patients withdrawn from the study,

| Adverse events
The percentages of patients who reported at least one emergent adverse event (EAE) on treatment was 27.8%. The most frequently affected system organ classes were psychiatric disorders (8.7%), nervous system disorders (6.9%), infections and infestations (5.6%), and gastrointestinal disorders (5.2%). The most frequent EAEs were headache, nausea, anxiety and insomnia (Table 2a). EAEs were considered as serious in 5.1% of patients and led to study treatment withdrawal in 7.7% of patients, mainly due to psychiatric and nervous system disorders (Table 2b).
During the study, 22 patients (0.3%) died, among them 16 were aged 65 or older. The most frequent causes were related to infections and infestations (6 patients; 27.3%), general disorders malignant neoplasms, and respiratory, thoracic and mediastinal disorders (5 patients each; 22.7%). A sudden death occurred 2 months after the first agomelatine intake in a paraplegic patient; a cardiac arrest occurred in a patient with a severe motoneuron disease. Two patients completed suicide (vide supra). No death was considered related to the study treatment neither by the investigator nor by the sponsor.

| Hepatic disorders
Hepatic EAEs, whatever the presence, nature or level of biological abnormalities, were reported for a total of 196 out of 8467 patients (2.3%).
The incidence was 2.0% with the 25 mg fixed dose and 3.3% with the 25-50 mg dose. The most frequent EAE was 'ALT increased' (1.3% of patients). 'GGT increased' and 'AST increased' were also reported (0.7% each).
Of note, among the 196 patients with emergent adverse events related to hepatic disorders, 139 (71%) did not present with transaminases increases >3x ULN.   These transaminases increase occurred mainly within the first 3 months of treatment for 36 out of 57 patients. Among the ten patients who had transaminases value >10 ULN (7 patients on agomelatine 25 mg, 3 on agomelatine 25-50 mg), 5 cases occurred in a context of biliary colic associated with concomitant increase in total bilirubin above 2 ULN (2 patients), alcohol intoxication (2 patients), or intake of concomitant hepatotoxic treatment (1 patient). After reviewing of the 10 cases by the Liver Safety Committee, to assess the causality of the abnormalities, 3 cases were considered as probably related to agomelatine, 3 possibly related to agomelatine, 1 unlikely related to agomelatine, and 3 not related to agomelatine.

All cases recovered.
No hepatic failure with fatal outcome, or resulting in liver transplantation, was reported.  0.5% of the whole cohort) and were considered as study treatment related in 60 patients (41.6%; 0.7% of the cohort). For most patients (81%,3%), the first event occurred within the first 3 months of treatment. All but 5 out of 164 EAEs resolved (1 with sequelae: a dermatitis) or were recovering at the cut-off date; the 5 events not resolved were 2 eczemas, 1 acne, 1 pruritus generalised and 1 hidradenitis (Table 5).

| Skin reaction
Serious skin reactions were reported in 10 patients, presenting with 12 SAEs of which 2 were considered as severe (one case of cold sweats and one decubitus ulcer). All the serious skin adverse events were recovered or recovering at the end of the study.
Among patients aged 65 years or older, 36 (2.9%) reported at least one emergent hepatic disorder. The incidence of emergent abnormal AST and/or ALT value (1%) was similar as in the whole cohort (Table 3).
Patients aged ≥65 years were not at increased suicidal risk (incidence rate: 0.7%).
Patients aged 65 years or older reported similar incidence rate of skin reactions (2.1%) with one serious, a decubitus ulcer. The first event occurred within the first 3 months of treatment (for 76.9% of patients), 3 out of 30 skin events were not recovered, 2 eczema and 1 pruritus generalised.

| Functional improvement and CGI severity of illness score
The mean CGI-Severity illness scores decreased between baseline (median: 5, markedly ill) and the last post-baseline assessment (mean change of À 1.9 � 1.5).
For the three SDS sub scores, patients reported less symptomrelated impairments over the treatment period in terms of work/daily activities (mean change from baseline to last visit: À 3.3 � 2.9), in social life (À 3.4 � 2.8), and in family life (À 3.3 � 2.8). Numbers of days lost and underproductive days were also diminished (mean change from baseline to last visit: À 1.7 � 2.8 and À 2.6 � 2.8, respectively; Table 6). Abbreviation: EAE, emergent adverse events.     with no emergence of severe symptomatic cases. As consequence,  (Nischal, Tripathi, Nischal, & Trivedi, 2012). For all antidepressants, this risk can be anticipated and managed clinically and there is a need for early follow-up and encouraging support and supervision of patients, especially in the early phase of treatment. A first limitation of this prospective study was that physicians who accepted the study, compared to those who never answered or refused, were probably more prone to work in accordance with recommendations of treatment for depression or product SmPC.

T A B L E 5 EAEs related to Skin and subcutaneous tissue disorders-Safety cohort and patients aged
Second, it cannot be ruled out that the duration of exposure has been inflated by the recruitment of patients who were more compliant or more concerned by the disease, and as such might more easily adhere to the study medication. Finally, as a result of the non-interventional design, investigations were limited, thus no detailed information was collected regarding the evolution of the different symptoms associated with depression.
The results of this international, observational, prospective, noninterventional study confirm under daily practice conditions the safety profile of agomelatine given at the therapeutic recommended doses. While patients' functioning and symptomatic distress were improved by the treatment, collected safety data did not reveal any new risk compared to those described in the SmPC and allowed a more accurate assessment of potential risks in usual practice. These findings obtained in a large representative population of out-patients suffering from MDD confirm the favourable tolerability profile of agomelatine.

CONFLICT OF INTERESTS
Philip Gorwood received during the last 5 years fees for presentations at congresses or participation in scientific boards from Alcediag-Alcen, Angelini, GSK, Janssen, Lundbeck, Otsuka, SAGE and GORWOOD ET AL.
-9 of 11 Servier; Jacques Benichou received during the last 10 years fees for