3.3 Safety
One adverse event in one patient (0.97%) was reported during the study. This event was classified as a lack of agomelatine treatment effect and led to the withdrawal of the patient from agomelatine treatment followed by initiation of treatment with another antidepressant. No serious adverse events or drug reactions related to treatment with agomelatine were observed.
DISCUSSIONThe antidepressant effectiveness of agomelatine in patients with a post-COVID 19 depressive episode was demonstrated in this study with statistically significant improvements at each visit. At baseline, all patients had mild or moderate depression. After initiation of agomelatine, a significant improvement in the total HAMD-17 score was already observed after only 2 weeks of therapy. Improvements continued throughout the study and at 8 weeks the HAMD-17 score had decreased by 10.9 points to a mean of 5.4 (a score of 0−7 is considered normal (Zimmerman et al., 2013)). The improvement in depressive symptoms with agomelatine treatment was confirmed by the CGI-I data at week 8, which showed statistically significant improvements compared with baseline. Anxiety is common in patients with depression and is associated with a worse prognosis, increased disability and more frequent medication use. It is also a frequent neuropsychiatric symptom post-COVID 19, particularly among patients that are hospitalized during the acute infection (Premraj et al., 2022). In the current study, both HAMD-17 anxiety scores (item 10 anxiety psychic and item 11 anxiety somatic) were continuously improved following initiation of agomelatine with statistically significant decreases in score compared with baseline already apparent after 2 weeks and persisting at each study visit. The observed positive effect of treatment on all types of anxiety symptoms is consistent with the antianxiety effects of agomelatine previously reported in other observational studies in patients with more severe depression (Avedisova et al., 2013; Volel, 2015). In the EMOTION study, the mean difference in HAMD-17 item 10 (anxiety psychic) from baseline to week 6 was 0.9 (P<0.00001) (Medvedev et al., 2016). Similar dynamics were observed for the HAMD-17 item 11 score (anxiety somatic) with a mean difference from baseline to week 6 of 1.21 points (P<0.00001) (Medvedev et al., 2016). Comparable results were demonstrated in the CHRONOS study with mean differences in the anxiety psychic and anxiety somatic scores of 0.6 and 0.5, respectively, after 6 weeks of treatment with agomelatine (Ivanov & Samushiya, 2014). In both the EMOTION and CHRONOS studies, the decrease in both anxiety items was already statistically significant after 2 weeks of treatment (Medvedev et al., 2016; Ivanov & Samushiya, 2014).
In this study, sensitivity analyses with regression remodeling were performed to explore if the clinical effectiveness of agomelatine was dependent on certain parameters known to be able to influence the size of the clinical effect. The only parameter that was significantly and negatively associated with the clinical effectiveness of agomelatine was the initial severity of depression (regression coefficient -0.70, P<0.0001). The negative value of the coefficient indicates that with each 1.0 point increase in mean total HAMD-17 score at baseline, a mean reduction of 0.7 points was observed at the end of the follow-up. In other words, the more severe the depression at baseline, the more pronounced the antidepressive effectiveness of agomelatine at the end of the follow-up. Regression modelling also revealed that age, gender, baseline COVID-19 severity and time after onset of COVID-19 infection had no effect on the antianxiety effectiveness of agomelatine. The only clinical characteristic that influenced agomelatine anxiety effectiveness was again baseline HAMD-17 score with a regression coefficient of -0.053 (P=0.003) for item 10 (anxiety psychic) and -0.035 (P=0.029) for item 11 (anxiety somatic), implying that for each increase of 1 point in the total HAMD-17 score at baseline, the mean scores of items 10 and 11 decreased by 0.035 and 0.053 points, respectively. In other words, agomelatine demonstrated greater improvements in anxiety status in those patients who had more severe depression at the baseline.
Other observational studies with agomelatine conducted in routine clinical practice have shown similar findings (Medvedev et al., 2016; Ivanov & Samushiya, 2014; Smulevich et al., 2011). Patients in the EMOTION, CHRONOS and RHYTHM studies had more severe depression at baseline than those in TELESPHOR, with mean baseline total HAMD-17 of 22.1, 22.4, and 23.6, respectively, compared with 16.3 in TELESPHOR. The observed reductions in total HAMD-17 score were also larger. In the EMOTION study, the mean change in the total HAMD-17 score after 6 weeks of agomelatine therapy was 17.1 points (P<0.001) (Medvedev et al., 2016). In the CHRONOS observational study, which included patients with a first episode of depression or preexisting history of an MDE (42.7%), the mean total HAMD-17 score after 8 weeks of agomelatine treatment had decreased by 18 points (P<0.001) (Ivanov & Samushiya, 2014). In the RHYTHM prospective observational study, which included patients with preexisting depressive disorders, the overall difference in the total HAMD-17 score after 6 weeks of treatment with agomelatine was even more noticeable and reached 19.9 points (P<0.001) (Smulevich et al., 2011). In routine clinical practice, agomelatine effectiveness has therefore been demonstrated across a range of depression severity.
Evidence supports a role for 5-HT2C receptors in the induction of an anxious state, and their antagonism could play an important role in mediating the anxiolytic effects of agomelatine (Stein et al., 2021; Millan, 2022). Onset of symptoms such as depression, anxiety and sleep disturbances within 3 months of SARS-CoV-2 infection is common (Premraj et al., 2022). The precise mechanisms involved in the onset of post-COVID-19 depression are not well established. While depression and anxiety could at least partially have resulted from social isolation during the pandemic, a role for systemic inflammation caused by the acute viral infection is also likely. Indeed, it has been reported that COVID-19 can induce and promote a hyperinflammatory state, which may cause a persistent low-grade inflammation in the long term (Başol et al., 2016; Ozmen & Topsakal, 2022; Savran et al., 2020).
The antidepressive and anxiolytic effectiveness of agomelatine in this study may be additionally explained by its antioxidant, anti-inflammatory, immunomodulatory and anti-cytokine properties (Millan, 2022; Gupta et al., 2017). Agomelatine decreases production of interleukin-1-beta (IL-1-beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha), the main mediators of the ”cytokine storm” and septic shock). It also depresses the activity of NLRP3 inflammasome, induces autologous processes, prevents macrophage infiltration and microglial cell activation, and decreases cell apoptosis by its effect on the NF-kappa-signaling cascade (Molteni et al., 2013; Hyeon et al., 2017; Kalkman & Feuerbach, 2016). It is hypothesized that the above properties may underlie the antidepressive effectiveness of agomelatine against MDEs occurring after COVID-19. However, further studies examining the relationship between the anti-inflammatory pleiotropic properties of agomelatine and its antidepressive effectiveness are required to provide more assertive and definitive conclusions.
In the TELESPHOR study, agomelatine was also associated with an improvement in patients’ QoL with positive and significant changes in SF-36 Physical and Mental component scores. These improvements had already achieved statistical significance after 4 weeks of treatment and remained statistically robust until the end of the follow-up period. The observed findings imply that agomelatine therapy is able to rapidly improve mental and somatic status as well as QoL in patients with initially mild-to-moderate depression in a real-life setting. Other agomelatine studies have demonstrated similar results in a broad range of outpatients. In the PULSE study, treatment with agomelatine was associated with significant changes in both the SF-36 Physical and Mental components from week 3 to week 12 (P<0.00001) (Medvedev, 2017). In the EMOTION study, patients’ well-being was self-assessed with a visual analog scale (VAS), which revealed a significant increase from 19.7 points at baseline to 73.3 points (P<0.00001) after a 6-week period of treatment with agomelatine (Medvedev et al., 2016). Assessment of patients’ work capacity also revealed a significant improvement, reflected in an observed increase in VAS score from 14.3 to 70.4 (P<0.00001).
A high percentage of patients (81.4%) in the TELESPHOR study responded to therapy with agomelatine and 71.6% of participants achieved remission of depression at the end of the follow-up period. The observed high numbers of responders and remitters are consistent with those from other observational studies conducted with agomelatine, in which the proportion of patients responding to treatment ranged from 60% to 97%, while the proportion considered to be remitters ranged from 32% to 81% (Medvedev et al., 2016; Medvedev, 2017; Avedisova et al., 2013; Volel, 2015; Ivanov & Samushiya, 2014; Smulevich et al., 2011; Vorob’eva, 2012; Tsygankov et al., 2011; Yakno & Voznesenskay, 2012). Treatment with agomelatine was safe and well-tolerated as confirmed by the absence of serious adverse events and treatment discontinuations due to adverse drug reactions. Only one adverse event (drug ineffectiveness) occurred in one patient (0.97%). These data are consistent with results from a large systematic review and network meta-analysis of the effectiveness and acceptability of 21 antidepressants which showed that patients receiving agomelatine and fluoxetine had a significantly decreased risk of premature treatment termination compared with either placebo or other antidepressants (Cipriani et al., 2018). Agomelatine is also associated with a low drug−drug interaction profile, which is an important characteristic for patients with COVID-19 who may need to take concomitant antiviral, anti-inflammatory and other medicines (Cipriani et al., 2018).
Emerging data on the effectiveness of agomelatine as well as other antidepressants for post-COVID-19 depression, coupled with their effect on the pathogenesis of viral infection, suggest they may not only be useful to treat long-term post-COVID-19 depression, but also depression in the acute COVID-19 period (University of Liverpool, 2024; Mas et al., 2022; Borovcanin et al., 2022; Firouzabadi et al., 2022).
Observational studies provide important data on the effectiveness and safety of drugs used in everyday clinical practice, which supplement benefit/risk profiles evaluated in randomized clinical studies. However, some limitations related to the observational nature of this study must be acknowledged. First, the study design does not permit any comparative conclusions to be drawn with other antidepressants as it was a single-group study. Second, agomelatine adherence data for outpatients treated in a routine clinical setting were not collected, although it is acknowledged that such data would be of special interest to practicing physicians. Third, despite having performed sensitivity analyses to explore relations between some important demographic and clinical characteristics and the observed agomelatine clinical effectiveness, it remains possible that some unidentified confounding factors could have influenced the antidepressive effectiveness of agomelatine observed in this study.
CONCLUSION
In the TELESPHOR study, treatment with agomelatine was associated with rapid and significant antidepressive and anxiolytic effectiveness in patients with a post-COVID-19 MDE. The demonstrated clinical effectiveness of agomelatine also resulted in statistically significant and clinically meaningful positive changes in patients’ QoL. Sensitivity analyses revealed that baseline severity of depression was a significant positive predictor of drug effectiveness in patients with post-COVID-19 depression. The results of this study supplement our knowledge on the antidepressive effectiveness of agomelatine and suggest that it could be a valuable option to treat patients developing MDE post-COVID-19.