Received: 11 February 2020 DOI: 10.1002/hup.2759 RESEARCH ARTICLE - - Revised: 12 May 2020 Accepted: 8 September 2020 The safety of agomelatine in standard medical practice in depressed patients: A 26‐week international multicentre cohort study Philip Gorwood1 | Jacques Benichou2 | Nicholas Moore3 | 4 5 6 Enric Álvarez Martínez | Joost Mertens | Eugenio Aguglia | Maria‐Luisa Figueira7 | Peter Falkai8 | Valérie Olivier9 | Marine Wattez9 | Françoise Picarel‐Blanchot9 | Christian de Bodinat9 1 GHU Paris Psychiatrie et Neurosciences (CMME, Hôpital Sainte‐Anne), Université de Abstract Paris & INSERM U1266, Paris, France Objective: The present observational cohort study documented the safety of ago- 2 Centre Hospitalier Universitaire de Rouen, melatine in current medical practice in out‐patients suffering from major depressive Unité de Biostatistiques, Rouen, France 3 Bordeaux PharmacoEpi CIC Bordeaux disorder. CIC1401 INSERM U1219 Hôpital Pellegrin, Method: The 6‐month evolution of agomelatine‐treated patients was assessed with Bordeaux, France a focus on safety (emergent adverse events, liver acceptability), severity of 4 Hospital de Sant Pau, Universitat Autònoma de Barcelona, Institut de Recerca Biomedica depression using the Clinical Global Impression Severity (CGI‐S) score, and func- Sant Pau, Barcelone, Spain tioning measured by the Sheehan Disability Scale (SDS). 5 De Velse GGZ, Velsen‐Zuid, The Netherlands Results: A total of 8453 depressed patients from 761 centres in 6 countries were 6 Clinica Psichiatrica, AOU Policlinico Vittorio‐ analysed (female: 67.7%; mean age: 49.1 � 14.8 years). Adverse events reported Emanuele, Catania, Italia 7 were in accordance with the known safety profile of agomelatine. Cutaneous events Faculty of Medicine, University of Lisbon, Lisbon, Portugal were reported in 1.7% of the patients and increased hepatic transaminases values 8 Department of Psychiatry, University of were reported in 0.9 % of the patients. The incidence of events related to suicide/ Munich, Munchen, Germany self‐injury was 1.0%. Two completed suicides, not related to the study drug, were 9 Institut de Recherches Internationales Servier (IRIS), Suresnes, France reported. CGI‐S total scores and SDS sub‐scores improved and numbers of days lost or underproductive decreased over the treatment period. Correspondence Conclusions: In standard medical practice, agomelatine treatment was associated Philip Gorwood, CMME, Hôpital Saint Anne, GHU Paris Psychiatrie et Neurosciences with a low incidence of side effects. No unexpected events were reported. A decrease Université Paris Descartes, 100 rue de la in the severity of the depressive episode and improved functioning were observed. santé, Paris, France. Email: p.gorwood@ghu-paris.fr Trial registration name: Observational cohort study to evaluate the safety of agomelatine in standard medical practice in depressed patients. A prospective, Funding information Servier observational (non‐interventional), international, multicentre cohort study. Trial registration number: ISRCTN53570733 KEYWORDS agomelatine, liver acceptability, observational, safety‐medical practice, skin events This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2020 The Authors. Human Psychopharmacology: Clinical and Experimental published by John Wiley & Sons Ltd. Hum Psychopharmacol Clin Exp. 2021;36:e2759. wileyonlinelibrary.com/journal/hup 1 of 11 https://doi.org/10.1002/hup.2759 2 of 11 - GORWOOD ET AL. 1 | INTRODUCTION 2 | METHODS Major depressive disorder (MDD) is the most common psychiatric 2.1 | Patients and study design disorder worldwide, with a lifetime prevalence of approximately 13% (Alonso et al., 2004; Bromet et al., 2011; Ferrari et al., 2013), asso- This was a prospective, observational, international, multi‐centre ciated with marked morbidity and premature mortality (Chesney, cohort study conducted in depressed patients followed‐up in current Goodwin, & Fazel, 2014). The antidepressant agomelatine (Val- medical practice for their current depressive episode. The study was doxan®) is a melatonergic MT1/MT2 receptor agonist with serotonin conducted in 761 centres in 6 countries. The physicians were 5‐HT2C receptor antagonist activity (Guardiola‐Lemaitre et al., recruited firstly through hospitals, clinics or private practices, in the 2014). With this unique mechanism of action, agomelatine has speciality of psychiatry, then in the general practice. demonstrated a range of properties that suggest it could offer Inclusion criteria were: male or female patients, more than 18 advantages over current treatments for MDD (Kennedy & Rizvi, years of age, initiating agomelatine treatment for their current 2010). The antidepressant efficacy of agomelatine has been depressive episode, having signed an informed consent and accepting demonstrated at doses of 25–50 mg in the treatment of the full to give a personal reference contact. range of depressive symptoms in patients with moderate to severe Prescription of agomelatine resulted from a normal clinical MDD (de Bodinat et al., 2010) and agomelatine showed a similar evaluation according to the physician's clinical judgement, based on efficacy to other available treatments (Taylor, Sparshatt, Varma, & each patient's clinical profile and in line with the SmPC, including Olofinjana, 2014). contra‐indications, special warning and precautions for use. The Agomelatine is generally well tolerated and shows a different decision to enter a patient in the study, after his/her agreement, was profile of adverse events compared to selective serotonin reuptake done after the clinical decision to prescribe agomelatine. inhibitors (SSRIs) and serotonin‐norepinephrine reuptake inhibitor Patients were not enrolled if they participated in another study, (SNRIs), with a more favourable profile on gastrointestinal, psychi- if they had to stop a successful on‐going antidepressant treatment, if atric, cutaneous and vascular systems (Kennedy & Rizvi, 2010). they wished to continue another antidepressant treatment in addi- Agomelatine also preserves the integrity of sexual function (Montejo tion to agomelatine, or if they planned to move during the follow‐up et al., 2010, 2015) and is not associated with discontinuation syn- period of the study. No exclusion criteria were defined on potential drome after abrupt treatment cessation (Montgomery, Kennedy, comorbidities. Burrows, Lejoyeux, & Hindmarch, 2004). Nevertheless, cases of liver Patients were followed during 26 weeks of treatment with the transaminases increase (AST/ALT > 3 ULN in 1.25% on agomelatine usual clinical follow‐up provided by the involved clinicians. In case of 25 mg, 2.62% on 50 mg, 0.5% of patients on placebo—Summary of agomelatine discontinuation, an end‐of‐study visit was scheduled 2 product characteristics (SmPC) have been reported in agomelatine‐ weeks after agomelatine withdrawal to follow safety and withdrawal treated patients and in post marketing settings only, rare cases of symptoms. hepatic failure were observed; therefore, a liver monitoring scheme is For each patient, the dose and the duration of treatment were required and the drug is contraindicated in patients with impaired individually decided by the participating physician according to their liver function. usual medical practice, based on the approved SmPC and patients' At time of the product launch, in 2009, incidences of skin clinical profiles. The starting dose of agomelatine was 25 mg once emergent adverse events were similar in agomelatine and placebo daily. A dose increase from 25 to 50 mg/day could be decided by the groups (1.17 and 1.25 per 100 patient‐months respectively). Skin investigator. Patients who reported a dose of 25 mg/day throughout reactions were however considered as a potential risk to be further their follow‐up were considered in the ‘agomelatine 25 mg’ subgroup; monitored, based on the report of two serious cases (erythema patients with at least one intake of 50 mg were considered in the nodosum recovered under treatment; erythematous rash) on ‘agomelatine 25–50 mg’ subgroup. agomelatine treatment. In parallel, in depressed patients, the risk of suicide being high (American Psychiatric Association, 2003) this risk must be monitored. 2.2 | Measurements As treatment proceeds, variations in depressive symptoms may be associated with fluctuations in suicide risk. This monitoring includes Physical examination and vital signs (heart rate, blood pressure, and evaluation of the presence of suicidal ideation and behaviours weight) were assessed according to the usual care practice at base- (American Psychiatric Association, 2010). line, follow‐up and end‐of‐study visits. Emergent adverse events The current cohort study was designed to evaluate, in conditions (EAEs), including skin events (SOC), were collected at each visit and of standard medical practice, the safety of a treatment with agome- were defined as events occurring after the first study drug intake and latine prescribed to depressed patients. A focus was made on hepatic up to 30 days after the last intake. disorders (hepatic events with or without clinical symptoms including The report of adverse event was spontaneous. Physicians had to increase of transaminases >3 ULN), skin events, and suicidality make sure that any adverse event/reaction or worsening of (suicidal ideations, behaviours, and acts). depression that occurred during the study was recorded. In GORWOOD ET AL. - 3 of 11 particular, exacerbation of symptoms related to depression, including Portugal (n ¼ 47) and Spain (n ¼ 154), from December 2009 to anxiety or other isolated symptoms possibly related to lack of effi- August 2014. cacy of the study treatment or to cessation of treatment were to be Psychiatrists recruited 60.1% of patients, while general practi- recorded. tioners recruited 39.9% of patients. Of the 8743 patients included, Liver function tests had to be performed as recommended in the 8453 patients with a signed inform consent and a date of agomela- agomelatine SmPC. Liver acceptability was assessed on both bio- tine first intake were included in the analysis. logical hepatic parameters with a focus on cases of aspartate Out of the patients excluded due to unavailable signed informed aminotransferase (AST) and/or alanine aminotransferase (ALT) >3 consent, 14 patients reported at least one adverse event and were ULN (upper limit of normal), and adverse events in accordance with thus included in the safety cohort, which therefore consisted of 8467 investigator's judgement, link or not to biological abnormalities. For patients. Main baseline characteristics of patients are presented in any AST and/or ALT > 3x ULN or evocating signs of hepatotoxicity, Table 1a. Patients had been depressed for more than 9 years in an adverse event had to be reported. A clinical review of narratives average and had a mean number of two major depressive episodes, of all patients presenting with potentially clinically significant including the current one. Based on the M.I.N.I. suicidality items, transaminases elevations (AST or ALT > 3 ULN) was made by 34.4% of patients had a suicidal risk, most (15.7%) at a low level, 7.8% a Liver Safety Committee composed of four hepatologists and a at a moderate level and 7.3% at a severe level of risk. Almost half of medical internist in order to assess causality of the reported the patients reported at least one concomitant disease at inclusion. abnormalities. The most frequently reported comorbidities were hypertension, Suicidality (suicide, suicide attempt, suicidal ideation and self‐ hypercholesterolemia, hypothyroidism, anxiety and diabetes mellitus injuries behaviour) was assessed through the analysis of adverse (Table 1b). events and using the Mini‐International Neuropsychiatric Interview The mean CGI‐S was 4.5 � 0.9 (median: 5, markedly ill) and (M.I.N.I.) items all along the study. Reviewing and adjudication pro- according to the SDS, on average, the patients felt moderately cedures were set up and, in cases of serious suicidal behaviour disrupted by disease symptoms and those linked to potential side (completed suicide or suicide attempt), were supervised by an effects for those on antidepressant treatments for the 3 functional external independent expert. domains. 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 3.2 | Patient disposition (CGI‐S), and the patients' functioning using the Sheehan Disability Scale (SDS; Sheehan, Harnett‐Sheehan, & Raj, 1996). No other psy- Most patients (76.1%) were treated with agomelatine 25 mg, chometric assessment tool was used as it was a non‐interventional whereas 23.9% of patients were treated with agomelatine 25–50 mg. study. 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 2.3 | Statistical analysis of depressive episodes, hospitalizations and suicidal risk; Table 1c). The mean treatment duration was 5.8 � 2.9 months; 60.1% of Quantitative variables were described by number of valid data, mean patients being treated with agomelatine for at least 6 months. value and standard deviation. For qualitative variables, absolute and Treatment duration was similar in patients treated with the 25 mg relative frequency distributions were presented. dose (5.7 � 2.9 months) and patients treated with the 25–50 mg dose Statistical analysis was performed on SAS® software, version 9.2. (6.3 � 2.7 months). The study was run in accordance with the principles stated in the A total of 2978 of patients (35.2%) were withdrawn from the Declaration of Helsinki, Finland, Good Pharmacoepidemiology Prac- study. The main reasons were remission or marked improvement tices (ISPE, 2008), Ethical Guidelines for Epidemiological, Studies (12.4% of patients), adverse event (8.6%), lack of efficacy (7.2%) and (Rose, 2009) and the applicable regulatory requirements. 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, 2829 (95%) stopped agomelatine, including 786 patients (27.8%) who 3 | RESULTS switched to another antidepressant treatment, as 5.0% of patients remained on agomelatine treatment. 3.1 | Baseline data During the study period, 67% of patients treated by agomelatine (65.3% in the 25 mg fixed group and 72.3% in the 25–50 mg group) The study involved 1205 physicians from 761 centres in France received at least one psychotropic concomitant treatment, anxio- (n ¼ 265), Germany (n ¼ 168), Italy (n ¼ 105), Netherlands (n ¼ 22), lytics (26.2% of patients) being the most common. 4 of 11 - GORWOOD ET AL. T A B L E 1A Baseline characteristics of patients Agomelatine cohort (N ¼ 8453) Age (mean � SD; years) 49.1 � 14.8 Male/female (%) 32.3/67.7 Body mass index (mean � SD) 25.5 � 4.9 Number depressive episodes (including current one; mean � SD) 2.0 � 1.9 Disease duration (mean � SD; years) 9.2 � 9.5 Current episode duration (mean � SD; months) 6.7 � 14.7 Concomitant diseases (%) 46.7 CGI severity of illness score (mean � SD) 4.5 � 0.9 SDS total score (mean � SD) 16.4 � 5.9 SDS work (mean � SD) 6.0 � 2.4 SDS social life (mean � SD) 6.2 � 2.1 SDS family life (mean � SD) 6.0 � 2.2 a Days unproductive (mean � SD) 4.1 � 2.6 Days lost (mean � SD) 2.8 � 2.8 Abbreviations: CGI, Clinical Global Impression; SD, standard deviation; SDS, Sheehan Disability Scale. a Patients felt so impaired by symptoms that their activity at school or at work was reduced. T A B L E 1B Concomitant diseases at selection (reported in at affected system organ classes were psychiatric disorders (8.7%), least 1.5% of MDD patients in the cohort) nervous system disorders (6.9%), infections and infestations (5.6%), Agomelatine and gastrointestinal disorders (5.2%). The most frequent EAEs were PT cohort (N ¼ 8453) headache, nausea, anxiety and insomnia (Table 2a). EAEs were All n (%) 3944 (46.7) considered as serious in 5.1% of patients and led to study treatment Hypertension n (%) 1197 (14.2) withdrawal in 7.7% of patients, mainly due to psychiatric and nervous system disorders (Table 2b). Hypercholesterolaemia n (%) 445 (5.3) During the study, 22 patients (0.3%) died, among them 16 were Hypothyroidism n (%) 284 (3.4) aged 65 or older. The most frequent causes were related to infections Anxiety n (%) 257 (3.0) and infestations (6 patients; 27.3%), general disorders malignant Diabetes mellitus n (%) 240 (2.8) neoplasms, and respiratory, thoracic and mediastinal disorders Osteoarthritis n (%) 227 (2.7) (5 patients each; 22.7%). A sudden death occurred 2 months after the first agomelatine intake in a paraplegic patient; a cardiac arrest Insomnia n (%) 173 (2.0) occurred in a patient with a severe motoneuron disease. Two patients Obesity n (%) 154 (1.8) completed suicide (vide supra). No death was considered related to Asthma n (%) 144 (1.7) the study treatment neither by the investigator nor by the sponsor. Type 2 diabetes mellitus n (%) 137 (1.6) Alcoholism n (%) 123 (1.5) 4.2 | Hepatic disorders Osteoporosis n (%) 129 (1.5) Note: n, number of patients with the described concomitant disease. Hepatic EAEs, whatever the presence, nature or level of biological Percentage ¼ (n/N) � 100. abnormalities, were reported for a total of 196 out of 8467 patients Abbreviation: MDD, major depressive disorder. (2.3%). The incidence was 2.0% with the 25 mg fixed dose and 3.3% with 4 | SAFETY RESULTS the 25–50 mg dose. The most frequent EAE was ‘ALT increased’ (1.3% of patients). ‘GGT increased’ and ‘AST increased’ were also 4.1 | Adverse events reported (0.7% each). Of note, among the 196 patients with emergent adverse events The percentages of patients who reported at least one emergent related to hepatic disorders, 139 (71%) did not present with trans- adverse event (EAE) on treatment was 27.8%. The most frequently aminases increases >3x ULN. GORWOOD ET AL. - 5 of 11 T A B L E 1C Baseline characteristics of MDD patients in the cohort by dose of agomelatine Agomelatine 25 mg Agomelatine 25–50 mg fixed (N ¼ 6431) (N ¼ 2022) Duration of the disease (mean � SD; years) 8.9 � 9.4 10.1 � 9.7 Number of depressive episodes (including present one; mean � SD) 1.9 � 1.8 2.3 � 2.2 Patients previously hospitalized for MDE (%) 7.5 12.8 Patients with previous treatment for depression (within 12 months; %) 28.4 37.3 Suicidal risk (%) 16.1 23.6 Patients with previous suicide attempts (%) 7.3 13.2 Suicidality scale (MINI; %) 29.2 40.7 Days unproductive (mean � SD) 4.0 � 2.6 4.6 � 2.5 Days lost (mean � SD) 2.7 � 2.7 3.1 � 2.8 Abbreviations: MDD, major depressive disorder; MINI, Mini‐International Neuropsychiatric Interview; SD, standard deviation. T A B L E 2A EAEs reported in at least All 0.5% of patients overall and by dose agomelatine (Agomelatine safety cohort) doses 25 mg fixed 25–50 mg (N ¼ 8467) (N ¼ 6439) (N ¼ 2028) Preferred term n % n % n % ALL 2351 27.8 1703 26.4 648 32.0 Depression 229 2.7 127 2.0 102 5.0 Headache 213 2.5 151 2.3 62 3.1 Nausea 175 2.1 146 2.3 29 1.4 Anxiety 155 1.8 112 1.7 43 2.1 Insomnia 140 1.7 100 1.6 40 2.0 Alanine aminotransferase increased 107 1.3 68 1.1 39 1.9 Dizziness 102 1.2 80 1.2 22 1.1 Restlessnes 65 0.8 44 0.7 21 1.0 Fatigue 65 0.8 38 0.6 27 1.3 Gamma‐glutamyltransferase increased 62 0.7 42 0.7 20 1.0 Aspartate aminotransferase increased 61 0.7 37 0.6 24 1.2 Suicidal ideation 56 0.7 31 0.5 25 1.2 Note: n, Number of patients with at least one EAE in a given level. Percentage (n/N)*100. Abbreviation: EAE, emergent adverse events. T A B L E 2B Type of emergent adverse events in the agomelatine safety cohort, per dose of agomelatine, and in the subset of patients aged ≥65 years Agomelatine safety cohort Agomelatine 25 mg Agomelatine 25–50 mg Patients ≥65 years Type of adverse events* (N ¼ 8467) (N ¼ 6439) (N ¼ 2028) (N ¼ 1256) Serious EAE n (%) 433 (5.1) 278 (4.3) 155 (7.6) 86 (6.8) Severe EAE n (%) 293 (3.5) 194 (3.0) 99 (4.9) 55 (4.4) EAE related to treatment 761 (9.0) 559 (8.7) 202 (10.0) 111 (8.8) n (%) Withdrawal due to EAE 651 (7.7) 550 (8.5) 101 (5.0) 121 (9.6) n (%) Note: n, Number of patients with at least one EAE of the described type. Percentage (n/N)*100. Abbreviation: EAE, emergent adverse events. 6 of 11 - GORWOOD ET AL. Emergent hepatic disorders led to study drug withdrawal in 72 18 days with the 25 mg dose, completed suicide 21 days after having patients (36.7% of patients with events, i.e., 0.9% of the Agomelatine decided to stop treatment. One 39‐year‐old patient with impulsive Safety Cohort). In about half of the patients with emergent hepatic personality treated with the 50 mg dose completed suicide after disorders (99/196, 50.5%, i.e., 1.2% of the Agomelatine Safety 3 months of treatment. The patient had a high risk of suicide Cohort) these EAEs were considered as treatment related by the according to MINI suicidality scale at baseline. All cases of completed investigators. All hepatic EAEs considered as study treatment‐related suicides and suicide attempts (24 cases) were reviewed by an expert: by the investigators were listed in the Reference Safety Information events were judged not related to the agomelatine treatment in except one hepatic steatosis and 3 liver disorders (1 liver intolerance, 17 patients and doubtfully related in 7 patients. According to the and 2 minor increases in liver values of which one was presumably expert's judgement, all these cases are particularly eloquent of the preexisting fatty liver). scientific literature on the topic of treatment emergence or wors- Biological abnormalities were evaluated in patients with at least ening of suicidal behaviour. Whatever the delay of occurrence of the one post‐baseline value of ALT or AST, that is, 6687 patients (79.0% suicidal act after the initiation of the treatment, all the patients were of the cohort) of whom 57 (0.9%) had at least one AST and/or ALT > carrying many risk factors, particularly a past history of suicide 3 ULN (Table 3). Among those 57 patients, 54.4% had values between attempt, a significant suicide risk at baseline and were difficult to 3 ULN and 5 ULN, 28.1% had values between 5 ULN and 10 ULN, and treat (comorbidities, lack of response to previous treatments, family 17.5% had values >10 ULN. Agomelatine was discontinued in 48 conflicts). This explains why it cannot be assumed that any of the patients, temporarily interrupted in 3 patients (according to SmPC), described cases may be directly attributable to the antidepressant and the dose was reduced in 2 patients, the study drug being main- investigated. Patients aged <30 years were not at increased suicidal tained in 4 patients of whom 3 recovered on treatment. At the last risk (incidence rate: 0.7%). available laboratory test, 37 out of 57 patients (64.9%) with trans- aminases values >3 ULN recovered, 8 patients (14.0%) were recov- ering between 1 and 2 ULN, 4 patients (7.0%) were recovering 4.4 | Skin reaction between 2 ULN and 3 ULN, and 6 patients (10.5%) did not recover. These transaminases increase occurred mainly within the first A total of 144 patients (1.7%) reported at least one EAE in the skin 3 months of treatment for 36 out of 57 patients. Among the ten and subcutaneous tissue disorders (MEDRA, System Organ Class), patients who had transaminases value >10 ULN (7 patients on ago- without dose related effect (1.8% and 1.4% in 25 mg and 25/50 mg melatine 25 mg, 3 on agomelatine 25–50 mg), 5 cases occurred in a respectively). The most frequent (>10 patients) were hyperhidrosis context of biliary colic associated with concomitant increase in total (28 patients, 19.4%), eczema (15 patients, 10.4%), alopecia, pruritus bilirubin above 2 ULN (2 patients), alcohol intoxication (2 patients), or and pruritic rash (11 patients for each, 7.6% each), except alopecia intake of concomitant hepatotoxic treatment (1 patient). After these events are already listed for agomelatine. These events led to reviewing of the 10 cases by the Liver Safety Committee, to assess study treatment withdrawal in 39 out of the 144 patients (27.1%; the causality of the abnormalities, 3 cases were considered as 0.5% of the whole cohort) and were considered as study treatment probably related to agomelatine, 3 possibly related to agomelatine, related in 60 patients (41.6%; 0.7% of the cohort). For most patients 1 unlikely related to agomelatine, and 3 not related to agomelatine. (81%,3%), the first event occurred within the first 3 months of All cases recovered. treatment. All but 5 out of 164 EAEs resolved (1 with sequelae: a No hepatic failure with fatal outcome, or resulting in liver dermatitis) or were recovering at the cut‐off date; the 5 events transplantation, was reported. not resolved were 2 eczemas, 1 acne, 1 pruritus generalised and 1 hidradenitis (Table 5). Serious skin reactions were reported in 10 patients, presenting 4.3 | Suicidality 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 A total of 85 patients (1.0%) reported at least one emergent event were recovered or recovering at the end of the study. related to suicide/self‐injury. Suicidal ideation and suicide attempt were the most commonly reported (56 patients, 0.7% and 23 pa- tients, 0.3%, respectively) and were more frequent with the 25–50 4.5 | Patients aged 65 years or older mg dose; they were notified as serious in 80% of patients and led to treatment withdrawal in 46% of patients. The event occurred firstly The percentages of patients who reported at least one EAE was within the first month of treatment for 26 out of 85 patients (30.6%) 28.7%; serious EAEs were reported in 6.8% of patients (agomelatine and in the second month for 17 patients (20.0%). All but one patient 25 mg: 5.9%; agomelatine 25–50 mg: 10.9%). with suicidal ideation had relevant medical history and/or triggering Among patients aged 65 years or older, 36 (2.9%) reported at factors (Table 4). least one emergent hepatic disorder. The incidence of emergent Two patients completed suicide. One 30‐year‐old patient, with abnormal AST and/or ALT value (1%) was similar as in the whole bipolar disorder history and 6 previous suicide attempts, treated for cohort (Table 3). GORWOOD ET AL. - 7 of 11 T A B L E 3 Emergent abnormal AST and/or ALT value (>3 ULN) in the safety cohort, per dose of agomelatine, and in the subset of patients aged ≥65 years Abnormal values Safety Cohort Agomelatine 25 mg Agomelatine 25–50 mg Patients ≥65 years Classes (N ¼ 6687) (N ¼ 4923) (N ¼ 1764) (N ¼ 1033) All n (%) 57 (0.9) 39 (0.8) 18 (1.0) 10 (1.0) ]3–5 ULN] n (%) 31 (0.5) 23 (0.5) 8 (0.5) 5 (0.5) ]5–10 ULN] n (%) 16 (0.2) 9 (0.2) 7 (0.4) 4 (0.4) >10 ULN n (%) 10 (0.1) 7 (0.1) 3 (0.2) 1 (0.1) Notes: N, number of patients with at least one post‐baseline ALT and/or AST value on treatment period. n, Number of patients with at least one event. Percentage (n/N)*100. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal. TABLE 4 Estimated incidence of suicidal ideation, suicide attempt and completed suicide during the treatment period All agomelatine doses 25 mg fixed 25–50 mg Patients ≥ 65 years Patients < 30 years EAE (N ¼ 8467) (N ¼ 6439) (N ¼ 2028) (N ¼ 1256) (N ¼ 855) Suicidal ideation 56 (0.66) 31 (0.48) 25 (1.23) 6 (0.5) 4 (0.5) n (%) Suicide attempt 23 (0.27) 11 (0.17) 12 (0.59) 3 (0.2) 2 (0.2) n (%) Completed suicide 2 (0.02) 1 (0.02) 1 (0.05) ‐ ‐ n (%) Note: n, Number of patients with at least one EAE. ‐, no case. Percentage (n/N)*100. Abbreviation: EAE, emergent adverse events. TABLE 5 EAEs related to Skin and subcutaneous tissue disorders—Safety cohort and patients aged ≥ 65 years EAE leading to drug EAE related EAE Severe EAE Serious EAE withdrawal to study drug n % n % n % n % n % Safety cohort (N ¼ 8467) 144 1.7 7 0.1 10 0.1 39 0.5 60 0.7 Patients ≥ 65 years (N ¼ 1256) 26 2.1 3 0.2 1 0.1 8 0.6 7 0.6 Note: n, Number of patients with at least one EAE. Percentage (n/N)*100. Abbreviation: EAE, emergent adverse events. Patients aged ≥65 years were not at increased suicidal risk For the three SDS sub scores, patients reported less symptom‐ (incidence rate: 0.7%). related impairments over the treatment period in terms of work/daily Patients aged 65 years or older reported similar incidence rate of activities (mean change from baseline to last visit: 3.3 � 2.9), in skin reactions (2.1%) with one serious, a decubitus ulcer. The first social life ( 3.4 � 2.8), and in family life ( 3.3 � 2.8). Numbers of event occurred within the first 3 months of treatment (for 76.9% of days lost and underproductive days were also diminished (mean patients), 3 out of 30 skin events were not recovered, 2 eczema and change from baseline to last visit: 1.7 � 2.8 and 2.6 � 2.8, 1 pruritus generalised. respectively; Table 6). 5 | EFFECTIVENESS 6 | DISCUSSION 5.1 | Functional improvement and CGI severity of Non‐interventional studies give the opportunity to obtain further illness score information on a medecine's safety in a real‐life situation without selecting population as in clinical trials. The present observational The mean CGI‐Severity illness scores decreased between baseline study aimed at evaluating the safety of agomelatine treatment in (median: 5, markedly ill) and the last post‐baseline assessment (mean current medical practice conditions and results confirm the known change of 1.9 � 1.5). tolerability profile of this drug (de Bodinat et al., 2010; Servier 8 of 11 - GORWOOD ET AL. T A B L E 6 SDS mean change from Change between baseline and baseline during agomelatine treatment. last visit on treatment period ALL (N ¼ 8453) Agomelatine cohort Total score of SDS n 7338 Mean � SD 9.0 � 7.5 Min; Max 30; 24 Work/School n 4947 Mean � SD 3.3 � 2.9 Min; Max 10; 10 Social life n 7336 Mean � SD 3.4 � 2.8 Min; Max 10; 9 Family life and home responsibilities n 7337 Mean � SD 3.3 � 2.8 Min; Max 10; 10 Days lost n 7187 Mean � SD 1.7 � 2.8 Min; Max 7; 7 Days unproductive n 7151 Mean � SD 2.6 � 2.8 Min; Max 7; 7 Note: n, Number of patients with an available baseline and at least one available value on treatment period. Laboratories, 2015; Taylor et al., 2014). The analysed population was known information on the product safety profile (Servier Labora- a large cohort of patients from six European countries (8453 pa- tories, 2015). As expected, a more frequent report of serious EAEs tients), patients' recruitment was almost balanced between psychia- was described for the group of patients who required uptitration to trists (60%) and general practitioners (40%); patients were markedly 50 mg than in patients treated with the 25 mg fixed dose, a finding ill according to CGI and had a moderate functioning impairment as likely related to the complex medical history of these patients. Similar assessed by SDS; one‐third of patients presented a suicidal risk ac- rates of EAE were reported in the whole population and in the subset cording to M.I.N.I. suicidality evaluation. Uptitration to 50 mg was of patients aged 65 years and over. Overall, the acceptability profile required for 23.9% of patients, which is in line with the ratio of agomelatine appears distinctly better than currently available observed in agomelatine clinical trials (15%–35%); Kennedy & Ems- standard treatments, with discontinuations for side effects among ley, 2006). These patients had clinical characteristics of a medically the lowest among second‐generation antidepressants (Cipriani complex population to treat, with a higher disability and number of et al., 2018). previous depressive episodes and hospitalizations, and higher suicidal A focus was made on hepatic events related to the use risk for the current episode. of agomelatine owing to the drug potential to elevate liver The mean treatment period by agomelatine was 6 months, during enzymes. As regards transaminases increases (>3 ULN), a case‐ which depressive symptoms improved according to CGI score, the under‐treatment incidence of 0.8% at 25 mg dose and 1% at 25–50 most common evaluation used in routine clinical practice (CGI‐S, mg dose were observed. These values are comparable to those mean change of 1.9 � 1.5). Functionality in daily life was not reported in the SmPC (1, 25% at 25 mg, 2, 62% at 50 mg). These affected by drug acceptability as patient SDS scores improved in the transaminases elevations (AST and/or ALT ≥ 3 ULN) were in ma- 3 domains explored (work, social life, and family life & home re- jority within the range of ]> 3–5 ULN] (54%), mainly asymptomatic, sponsibilities) and were associated with a decrease in the number of isolated and appeared mostly within the first 3 months. Unless underproductive or lost days. medical explanation (e.g., NASH, known history of liver injury), During the study, no unexpected EAEs were reported in ago- most of liver function normalized within few weeks following melatine‐treated patients: the nature and frequency of adverse treatment discontinuation. Two Hy's law cases (two patients with events reported were in accordance with previous knowledge ob- an increase in transaminases associated with cholelithiasis, both tained during clinical trials development and comparable to the not related to agomelatine) were reported, but no liver transplant, GORWOOD ET AL. - 9 of 11 no fulminant hepatitis, no case of hepatic failure, and no hepatic Nischal, & Trivedi, 2012). For all antidepressants, this risk can be disorder with fatal outcome were observed. Whatever, in most anticipated and managed clinically and there is a need for early cases, patients are clinically asymptomatic and abnormal results on follow‐up and encouraging support and supervision of patients, liver function tests are the only elements that may raise a suspi- especially in the early phase of treatment. cion of antidepressant‐induced liver injury. It should be mentioned The occurrence of cutaneous events was mentioned in the SmPC that in clinical trials, where serum transaminases are monitored at the time of agomelatine launch. Results of the present cohort regularly, the risk is adequately minimized (Perlemuter et al., 2016) confirm that the frequency of these events did not differ according to with no emergence of severe symptomatic cases. As consequence, the dose prescribed (1.4% at 25–50 mg vs. 1.8% at 25 mg) or the age the monitoring of transaminases values required since 2012 with of patients (2.1%, ≥65 years). Based on these cohort data, the respect of contra indications are the most effective ways of mini- European Medical Agency (EMA) decided not to consider any more mising hepatic risk. In general health care, such measures are skin events as a potential risk for agomelatine. considered adapted to ensure an optimal follow‐up of depressed Cutaneous side effects have been described with all psychotropic patients (Voican et al., 2016). A recent analysis in a cohort drugs; they are variable and numerous and usually benign, but may comprising 3.2 million new users of antidepressants has shown occasionally carry significant morbidity (Bliss & Warnock, 2013; that, in routine clinical practice, agomelatine did not increase the Mitkov, Trowbridge, Lockshin, & Caplan, 2014). risk of hospitalisation due to acute liver injury when compared to The sustained adherence observed in this cohort study is in line citalopram (Pladevall‐Vila et al., 2019). As risk minimisation mea- with the recommendations supporting duration of at least 6 months sures (compliance with relevant contra‐indications, precautions of of the treatment period to achieve a sufficient improvement of use, and biological liver testing before and during treatment) were symptoms and prevent the chronic evolution of the disease in place in the populations studied, this might contribute to the (ANAES, 2002; Davidson, 2010; Mitchell, 2006; Qaseem, Snow, lower risk found for agomelatine versus citalopram. Denberg, Forciea, & Owens, 2008; Wade, Despiegel, & Heldbo, All antidepressant drugs may potentially cause hepatotoxic side 2006). It may be hypothesized that the level of adherence and the events, even at therapeutic doses, but antidepressant‐induced hep- observed efficacy of the agomelatine treatment are directly linked atotoxicity has been underestimated in the scientific literature, so the to the good acceptability of the treatment by patients, hypothesis evidence is insufficient for rigorous conclusions to be drawn about supported by a low rate of treatment discontinuation due to AE in the prevalence and severity of these events. Several antidepressants the study. including imipramine, amitriptyline, duloxetine, bupropion, trazo- A first limitation of this prospective study was that physicians done, and agomelatine are associated with greater risks, whereas who accepted the study, compared to those who never answered or citalopram, escitalopram, paroxetine, and fluvoxamine seem to have refused, were probably more prone to work in accordance with the least potential for hepatotoxicity (Voican, Corruble, Naveau, & recommendations of treatment for depression or product SmPC. Perlemuter, 2014). In real‐life practice, there is no evidence of an Second, it cannot be ruled out that the duration of exposure has been increased risk of serious liver injury following initiation of SNRIs inflated by the recruitment of patients who were more compliant or (venlafaxine, milnacipran, duloxetine) or other antidepressants more concerned by the disease, and as such might more easily adhere (mianserin, mirtazapine, tianeptine and agomelatine) compared with to the study medication. Finally, as a result of the non‐interventional SSRIs (fluoxetine, citalopram, paroxetine, sertraline, fluvoxamine, and design, investigations were limited, thus no detailed information was escitalopram; Billioti de et al., 2018). collected regarding the evolution of the different symptoms associ- A thorough evaluation of the patient's suicide risk has been ated with depression. performed during the study. The incidence did not differ according to The results of this international, observational, prospective, non‐ the age of the patients (0.7% for patients aged <30 years or ≥65 interventional study confirm under daily practice conditions the years vs. 1.0% for patients aged <65 years) but was numerically more safety profile of agomelatine given at the therapeutic recommended elevated in the group of patients who required uptitration to 50 mg doses. While patients' functioning and symptomatic distress were (1.5% vs. 0.7% at 25 mg), a difference that can be due to more severe improved by the treatment, collected safety data did not reveal any depression characteristics at the start of treatment in the 25–50 mg new risk compared to those described in the SmPC and allowed a group. The two completed suicides were not considered related to more accurate assessment of potential risks in usual practice. These agomelatine. findings obtained in a large representative population of out‐patients In general, it is assumed that antidepressants are beneficial for all suffering from MDD confirm the favourable tolerability profile of symptoms of depression, including suicidality. Some evidence sug- agomelatine. gests that antidepressant, including SSRIs, may cause worsening of suicidal ideas in vulnerable patients, though systematic reviews and CO N F L I C T O F I N T E R E S T S pooled analysis of experimental, observational, and epidemiological Philip Gorwood received during the last 5 years fees for pre- studies failed to provide a clear relationship between their use and sentations at congresses or participation in scientific boards from increased suicidal ideation and behaviour in adults (Nischal, Tripathi, Alcediag‐Alcen, Angelini, GSK, Janssen, Lundbeck, Otsuka, SAGE and 10 of 11 - GORWOOD ET AL. Servier; Jacques Benichou received during the last 10 years fees for Cipriani, A., Furukawa, T. A., Salanti, G., Chaimani, A., Atkinson, L. Z., participation in scientific boards from Astra Zeneca, Pierre Fabre, Ogawa, Y., … Egger, M. (2018). Comparative efficacy and accept- ability of 21 antidepressant drugs for the acute treatment of adults IRIS and Research Triangle Institute; Nicholas Moore has received with major depressive disorder: A systematic review and network Honoraria for Servier study scientific committee; Enric Álvarez meta‐analysis. Lancet, 391, 1357–1366. Martínez has received consulting and educational honoraria from Eli Davidson, J. R. (2010). Major depressive disorder treatment guidelines in Lilly, Lundbeck, Pfizer, Sanofi‐Aventis and Otsuka; has participated as America and Europe. Journal of Clinical Psychiatry, 71(Suppl. E1), e04. Ferrari, A. J., Somerville, A. J., Baxter, A. J., Norman, R., Patten, S. B., Vos, principal local investigator in clinical trials sponsored by Eli Lilly, T., & Whiteford, H. A. (2013). Global variation in the prevalence and Bristol‐Myrers Squibb, Sanofi‐Aventis and AB·Biotics; and has served incidence of major depressive disorder: A systematic review of the as national coordinator of clinical trials sponsored by Servier and epidemiological literature. Psychological Medicine, 43, 471–481. Lundbeck. Joost Mertens declared no conflict of interest, Eugenio Guardiola‐Lemaitre, B., de, B. C., Delagrange, P., Millan, M. J., Munoz, C., & Mocaer, E. (2014). Agomelatine: Mechanism of action and pharma- Aguglia has received during the last 2 years, fees participation in cological profile in relation to antidepressant properties. British scientific boards from Angelini, Glaxo, Lundbeck, Luisa Figueira has Journal of Pharmacology, 171, 3604–3619. received consulting and educational honoraria from Eli Lilly, Lund- Guy, W. (1976). ECDEU assessment manual for psychopharmacology. Rock- beck, Pfizer, Servier and Astra‐Zéneca; has participated as principal ville MD: US Department of Health, Education and Welfare publi- local investigator in clinical trials sponsored by Eli Lilly, Servier, cation ADM 76‐338.National Institute of Mental Health. ISPE. (2008). Guidelines for good pharmacoepidemiology practices (GPP). Astra‐Zéneca Janssen; and has served as national coordinator of Pharmacoepidemiology and Drug Safety, 17, 200–208. clinical trials sponsored by Servier and Eli Lilly, Peter Falkai has Kennedy, S. H., & Emsley, R. (2006). Placebo‐controlled trial of agomelatine received research support and honoraria for lectures or advisory in the treatment of major depressive disorder. European Neuro- activities from Abbott, Janssen, Lundbeck, Otsuka, Recordati, psychopharmacology, 16(2), 93–100. https://doi.org/10.1016/j.euro neuro.2005.09.002 Richter, Servier and Takeda. Valérie Olivier, Marine Wattez, Kennedy, S. 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