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.