Abstract
Aim : Affective disorders such as depression and anxiety are one of the most prevalent symptoms observed in patients following coronavirus disease 2019 (COVID-19). The aim of the TELESPHOR study was to evaluate the antidepressant effectiveness and tolerability of agomelatine therapy in daily clinical practice in patients with major depressive episodes (MDE) post-COVID-19.
Methods : This multicenter, observational study enrolled outpatients aged 18-65 years who experienced an MDE (17 item Hamilton Rating Scale for Depression [HAMD-17] total score of 8-24) within 3 months of laboratory confirmed SARS-CoV-2 infection and who had initiated treatment with agomelatine. Study visits occurred at weeks 2, 4 and 8. The primary outcome was the antidepressant effectiveness of agomelatine assessed by change in HAMD-17 total score at week 8. Secondary outcomes included changes in HAMD-17 item 10 (anxiety psychic) and item 11 (anxiety somatic), the proportion of responders (≥50% decrease in baseline HAMD-17) and remitters (HAMD-17 score ≤7 at week 8), and impact on quality of life (QoL) (Short Form Survey [SF-36] questionnaire). Tolerability was assessed at each study visit.
Results : The full analysis set comprised 103 patients of whom 73 (70.9%) were women. Median age was 45 years, and in the past 3 months 81 (78.6%) had experienced mild and 22 (21.4%) moderate COVID-19. The mean time from onset of infection to study inclusion was 2.1±0.7 months. At study entry, 55 (53.4%) had mild and 48 (46.6%) had moderate MDE. Agomelatine was associated with a significant improvement in depression severity with decreases in mean total HAMD-17 score compared with baseline of 2.6±3.3, 6.7±5.3, and 10.9±4.9 at weeks 2, 4, and 8, respectively (P<0.0001 for all). Significant reductions in anxiety psychic and anxiety somatic were also observed. Mental and physical components of SF-36 were significantly improved compared with baseline (P<0.0001). The proportion of responders was 81.4% and the proportion of remitters was 71.6%. Agomelatine was well tolerated over the 8-week follow-up.
Conclusion : Treatment with agomelatine was associated with rapid and significant antidepressive and anxiolytic effectiveness, improved QoL, and good tolerability in the treatment of patients with an MDE after COVID-19.
KEYWORDS: agomelatine, COVID-19, major depressive disorder, routine clinical practice
INTRODUCTION
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is the causative agent of coronavirus disease 2019 (COVID-19), a disease with a wide range of manifestations, from asymptomatic to severe or fatal (Wiersinga et al., 2020). In addition to the acute symptoms, a growing body of scientific and clinical evidence highlights long-term consequences that can affect multiple organ systems (Gupta et al., 2020). Depression, anxiety, fatigue, sleep difficulties, and cognitive impairment have been found to be the most common long-term neuropsychiatric consequences following COVID-19, highlighting the importance for consensus on specific neuropsychiatric needs in the multidisciplinary management of patients after the acute disease (Khraisat et al., 2022; Medvedev, 2021). In a systematic review of psychiatric sequelae in COVID-19 patients the most frequently reported symptoms were depression and/or anxiety, examined in 47 of the 66 included studies (Schou et al., 2021).  Clinically significant depression has been noted in approximately 30-40% of patients at 1, 3, and 6 months after COVID-19, suggesting that long-term depressive effects occur in many patients after the acute infection (Rogers et al., 2020; Renaud-Charest et al., 2021). A Chinese study which examined the long-term health consequences of COVID-19 following discharge from hospital reported anxiety, depression, and sleep difficulties were present in approximately one-quarter of patients in the 6 months post-discharge (Huang et al., 2021).
Depression after COVID-19 can affect survivors’ cognitive performance, symptoms of fatigue, and daily functioning, increasing the burden of noncommunicable illness associated with psychiatric disability (Rogers et al., 2020; Renaud-Charest et al., 2021). Some authors have noted the presence of continued sleep−wake cycle disturbances after recovery from COVID-19 (Salehinejad et al., 2022; Xu et al., 2022; Abuhammad et al., 2023). However, no assessment of the affective state of these patients has been made, suggesting that in some patients sleep disturbances may be part of the affective disorders
Despite the large number of affected patients, there are a paucity of data on the effectiveness of pharmacological treatments for depression disorders in post-acute COVID-19 patients. Some studies have focused on the potential antiviral properties of antidepressants such as fluoxetine (Pashaei, 2021; Hoertel et al., 2021; Dąbrowska et al., 2021) and fluvoxamine (Lenze et al., 2020; Boretti, 2023; Dobrodeeva et al., 2022), mostly during the active COVID-19 infection period. In contrast, research on the efficacy of antidepressants for post-COVID depressive disorders is limited to a few studies with selective serotonin reuptake inhibitors (SSRI) (Dobrodeeva et al., 2022; Mazza et al., 2022; Di Nicola et al., 2023).
Agomelatine is an antidepressant acting as a melatonergic MT1/MT2 receptor agonist with 5-HT2C serotonergic receptor antagonist properties. It is effective against a range of depressive symptoms in patients with moderate to severe major depressive episode (MDE) with an effect size comparable to that of other currently available antidepressive drugs (de Bodinat et al., 2010; Taylor et al., 2014; Cipriani et al., 2018). Efficacy has been demonstrated in short-term and long-term controlled studies, as well as in clinical practice and in patients with somatic diseases (Medvedev et al., 2016; Medvedev, 2018; Medvedev, 2017; Medvedev et al., 2019; Demyttenaere et al., 2013; Kennedy & Rizvi, 2010; Kennedy et al, 2016). Other aspects of clinical efficacy such as well-being, improvement of sleep disorders, daily functioning, and sexual function have also been demonstrated (Kennedy & Rizvi, 2010). The safety profile of agomelatine has been established in a number of randomized controlled trials. These have demonstrated an incidence of adverse events with agomelatine similar to that observed for placebo (agomelatine 42.4% versus placebo 42.5%) (Olié & Kasper, 2007) and sertraline (agomelatine 48.0% versus sertraline 49.1%) (Kasper et al., 2010), and lower than that observed with venlafaxine (agomelatine 51.2% versus venlafaxine 57.1%) (Lemoine et al., 2007) and escitalopram (agomelatine 66.2% versus escitalopram 81.8%) (Quera-Salva et al., 2011). Good tolerability is important for adherence and persistence with treatment and ultimately for a drug’s effectiveness. A recent network meta-analysis has confirmed the favorable safety profile of agomelatine (Cipriani et al., 2018).
Agomelatine may be a favorable therapeutic choice for use in patients with depression onset after COVID-19, but data are currently lacking on its clinical effectiveness in this population in routine clinical practice. The primary objective of the current study was therefore to describe the antidepressive effectiveness and tolerability of agomelatine in patients with a post-COVID-19 MDE in an outpatient setting.