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\begin{document}

\title{The effectiveness and tolerability of agomelatine in the treatment of
depression after COVID-19 infection in Russian daily clinical practice
(TELESPHOR study)}



\author[1]{Vladimir E. Medvedev}%
\author[2]{Anna N. Bogolepova}%
\author[3]{Denis P. Morozov}%
\author[3]{Boris Kvasnikov}%
\affil[1]{RUDN University}%
\affil[2]{Department of Neurology Neurosurgery and Medical Genetics of the Pirogov Russian National Research Medical University}%
\affil[3]{Medical affairs}%


\vspace{-1em}



  
  \date{June 02, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
\textbf{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. \textbf{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. \textbf{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\selectlanguage{ngerman}±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\textless{}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\textless{}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. \textbf{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.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{The effectiveness and tolerability of agomelatine in the
treatment of depression after COVID-19 infection in Russian daily
clinical practice (TELESPHOR study)}

Vladimir E. Medvedev \textsuperscript{1}, Anna N.
Bogolepova\textsuperscript{2}, Denis P. Morozov \textsuperscript{3},
Boris B. Kvasnikov \textsuperscript{3}

on behalf of the TELESPHOR study investigators

\emph{\textsuperscript{1} Department of Psychiatry, Psychotherapy and
Psychosomatic Pathology of the Faculty of Continuing Medical Education
of the Peoples' Friendship University of Russia (RUDN University),
Moscow, Russia}

\emph{\textsuperscript{2} Department of Neurology, Neurosurgery and
Medical Genetics of the Pirogov Russian National Research Medical
University, and Department of Cognitive Disorders of the Federal Center
of Brain and Neurotechnologies, Moscow, Russia}

\emph{\textsuperscript{3} Medical affairs, Servier JSC, Moscow, Russia}

\textbf{Correspondence}

\textbf{Denis Morozov}

Servier JSC

Moscow

Russia

Email: denis.morozov@servier.com



\textbf{Abstract}

\textbf{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.

\textbf{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.

\textbf{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\selectlanguage{ngerman}±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\textless{}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\textless{}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.

\textbf{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.

\textbf{KEYWORDS:} agomelatine, COVID-19, major depressive disorder,
routine clinical practice

\textbf{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).\textsuperscript{~} 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\selectlanguage{english}-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; D\selectlanguage{polish}ą\selectlanguage{english}browska 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\%) (Oli\selectlanguage{ngerman}é \& 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.

\textbf{METHODS}

\textbf{Study design}

TELESPHOR was a multicenter, observational study conducted in outpatient
ambulatory state and private clinics in four cities in Russia between
March 2022 and February 2023. The study included adults aged 18-65 who
experienced an MDE within 3 months of polymerase chain reaction (PCR)
confirmed SARS-CoV-2 infection in whom treatment with agomelatine was
initiated. The depressive episode was measured with the 17 item Hamilton
Rating Scale for Depression (HAMD-17) where scores of 0--7 are
considered normal, 8--16 suggest mild depression, 17--23 moderate
depression, and scores over 24 are indicative of severe depression
(Zimmerman et al., 2013). In the current study, patients with a total
HAMD-17 score of 8-24 were considered to be suffering an MDE. Patients
ineligible to participate in the study were those diagnosed with
suicidal risk (score \selectlanguage{english}[?]2 in item 3 of the HAMD-17 scale and/or according
to clinical evaluation by the investigator), psychotic symptoms
(according to clinical evaluation by the investigator), or other mental
disorder or disease; noncompensated serious somatic or neurological
disease; and COVID-19 that could not be confirmed. Agomelatine was
administered in accordance with the approved Summary of Product
Characteristics (SmPC) in Russia, local standards and guidelines.

At baseline, severity of depression, level of anxiety, and quality of
life (QoL) status in addition to clinical and sociodemographic data were
collected from all included patients. Data on the history of COVID-19
infection and its severity were collected retrospectively and extracted
from medical records. Patients were seen at baseline, with further
clinic visits at 2, 4, and 8 weeks of prospective observation. Due to
the observational nature of the study, the protocol did not mandate any
assignment of the included patients to one or another treatment
strategy. Agomelatine prescription was not decided in advance by a trial
protocol, but was determined by the current prescribing practice of the
investigating physician and was separate from the decision to include a
patient in the study. All included patients were recommended to start
treatment with agomelatine 25 mg/day taken at bedtime for at least 8
weeks. In case of insufficient effectiveness of agomelatine after 2
weeks of treatment, and based on the investigating physician's opinion,
the daily dose could be increased to 50 mg/day at bedtime.

The primary outcome was the mean change in HAMD-17 total score from
baseline to week 8 under agomelatine treatment. Key secondary
effectiveness outcomes were changes in the HAMD-17 item 10 ``anxiety
psychic'' and item 11 ``anxiety somatic'' scores, and
investigator-determined global severity of the patient's illness
assessed by the Clinical Global Impressions-Improvement of Illness Scale
(CGI-I). Patient QoL was assessed with the 36 item Short Form survey
(SF-36). Additional secondary effectiveness outcomes included the
proportion of patients with a response to agomelatine treatment (defined
as a decrease of \selectlanguage{english}[?]50\% in the baseline HAMD-17 score), as well as the
proportion of those with remission (defined as a HAMD-17 total score \selectlanguage{english}[?]7
at week 8 of the observational period). The number and proportion of
patients with reported adverse events and adverse drug reactions were
analyzed, including those that could lead to discontinuation of the drug
during the study.

The study protocol was approved by the Moscow Inter-Academic Ethics
Committee on March 17, 2022 (approval protocol \# 3) and was conducted
in compliance with the Declaration of Helsinki, and local regulatory
requirements. All participants provided their informed consent before
inclusion in the study (NCT05323994).

\textbf{2.2 Statistical considerations}

Descriptive and comparative statistics were used to present the results
of this non-interventional observational study. Continuous variables are
reported as mean +- standard deviation or median and interquartile range
(if not normally distributed). Categorical data are expressed as numbers
(percentages). Only patients for whom data on the primary outcome
(HAMD-17 score evaluation) were available at baseline and at the end of
the follow up period were included in the statistical analysis. Adjusted
means and standard errors were calculated with generalized linear
modelling to explore associations between the observed antidepressive
effectiveness of agomelatine and clinically important parameters. For
this, univariate regression modeling was performed using the following
covariates for adjustment analysis: age, sex, baseline total HAMD-17
score, severity of COVID-19 infection, time since COVID-19 infection
onset, and status of taking any antidepressants prior to the enrollment
visit. The level of statistical significance for the univariate analysis
was set at P\textless{}0.05. For each significant predictor identified
in the univariate analysis we also conducted multivariate linear
regression modelling.

To estimate required study sample size the following assumptions were
made. We calculated that approximately 28 study subjects would be
sufficient to detect at least a 3.0-point difference between the sample
and population means with 90\% power at a 0.005 one-sided significance
level. Considering the observational nature of the study a dropout rate
of approximately 30\% was assumed. A minimum number of 40 outpatients
was therefore required to be enrolled in the study.

\textbf{RESULTS}

A total of 104 patients were enrolled. One patient did not meet the
inclusion criterium for depression severity at baseline and was
excluded. Data for 103 (99.03\%) patients therefore comprised the full
analysis set (FAS). One patient in the FAS terminated participation in
the study prematurely due to a lack of treatment effect with
agomelatine, requiring the administration of another antidepressant.

Patient baseline demographic and clinical characteristics are presented
in \emph{Table 1.} Participants were mostly female (73 {[}70.9\%{]})
with a mean age of 44.0+-13.3 years. The majority was employed (79.6\%)
and none of the patients had received any prior treatment with
antidepressants. At baseline, 21.4\% of patients reported they had
suffered moderate COVID-19 infection in the past 3 months, and 78.6\%
had a history of mild COVID-19. The mean time from infection onset until
the enrollment visit was 2.1+-0.7 months. Initial assessment of the
severity of the depressive episode showed that patients were almost
equally distributed between mild (n=55, 53.4\%) and moderate (n=48,
46.6\%) depression. The mean total HAMD-17 score at baseline was
16.3+-4.7 and mean scores for the two anxiety components of the HAMD-17
scale (questions 10 and 11) were 1.4+-0.9 and 1.3+-0.8, respectively. Mean
baseline SF-36 QoL scores were 39.7+-8.4 for the physical component and
37.2+-8.7 for the mental component of the questionnaire.

\textbf{3.1 Effectiveness}

A significant improvement in depression severity assessed by the HAMD-17
scale was observed after initiation of agomelatine treatment. The mean
total HAMD-17 score decreased compared with baseline by 2.6 +- 3.3
(P\textless{}0.0001) at week 2, and by 6.7 +- 5.3 and 10.9 +- 4.9 at the
week 4 and 8 visits (P\textless{}0.0001 for both), respectively (Figure
1). Agomelatine was also associated with a significant improvement in
symptoms of anxiety. Item 10 (anxiety psychic) of the HAMD-17 score was
reduced from 1.4+-0.9 at baseline to 0.5+-0.6 at week 8 (Figure 2); the
mean change from baseline was 0.9 (95\% CI -1.1 -0.7,
P\textless{}0.0001). Item 11 (anxiety somatic) of the HAMD-17 score was
reduced from 1.3+-0.8 at baseline to 0.6+-0.6, with a mean change of 0.7
(95\% CI -0.8 -0.5; P\textless{}0.0001) at week 8 (Figure 3).

There was a significant improvement in depression severity at each study
visit based on investigators' clinical judgement. Mean CGI-I score
decreased from 3.4+-0.8 at week 2 to 2.3+-1.0 at week 4 (mean change -1.0;
P\textless{}0.0001) and to 1.3+-0.6 at week 8 (mean change -2.0 vs week 2
visit; P\textless{}0.0001) (Figure 4). At the week 8 visit, 81.4\% of
patients responded to treatment with agomelatine having at least a 50\%
decrease from baseline in total HAMD-17 score. In addition, 71.6\% of
patients had a remission of depression (total HAMD-17 score \selectlanguage{english}[?]7).

There was a significant improvement in patients' QoL reflected by an
increase in the mean scores of both the SF-36 physical (Figure 5) and
mental components (Figure 6). The physical component increased from
39.70+-8.41 at baseline to 45.80+-7.69 at week 4 (mean change -6.20+-8.64
vs baseline, P\textless{}0.0001), and to 50.50+-5.70 at week 8 (mean
change -11.10+-7.30 vs baseline, P\textless{}0.0001). The SF-36 mental
component score increased from 37.30+-8.67 at baseline to 39.80+-8.28
(week 2), 47.60+-8.55 (week 4), and 58.70+-6.91 (week 8) resulting in mean
changes of 2.70+-4.84, 10.50+-6.89, and 21.40+-8.92 at the week 2, 4 and 8
visits, respectively (P\textless{}0.0001 for all timepoints vs
baseline).

\textbf{3.2 Additional effectiveness analyses}

To explore the relations between demographic and clinical
characteristics and the observed clinical effectiveness of agomelatine
on depression we performed several linear regression analyses. The
following characteristics were selected as covariates of interest: age,
sex, severity of depressive disorder at baseline according to HAMD-17
total score, COVID-19 severity, and time passed since COVID 19 infection
onset. Univariate regression analysis showed that depression severity at
baseline (regression coefficient: -0.741; P\textless{}0.0001), moderate
severity COVID-19 (regression coefficient: -3.395; P=0.0035), and time
since onset of infection (regression coefficient: -2.395; P=0.0006) were
the parameters with a statistically significant relationship with the
observed decrease in HAMD-17 total score at the end of follow up (week 8
visit). All coefficients were negative indicating that the relations
between these parameters and the observed improvement in depression
severity were reciprocal. However, after multivariate regression
analysis the only parameter remaining significantly related to
improvement in depression severity at week 8 was baseline depression
severity expressed as total HAMD-17 score (regression coefficient:
-0.70; P\textless{}0.0001). When univariate regression analyses were
conducted to explore relations between the covariates of interest and
the effectiveness of agomelatine at reducing anxiety severity and
improving patients' QoL, mean total HAMD-17 score at baseline was again
the only parameter with a significant relation with the observed
improvement in both anxiety and patients' QoL (\emph{Table 2} ).

\textbf{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.

\textbf{DISCUSSION}The 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\selectlanguage{english}-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\textless{}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\textless{}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\textless{}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\textless{}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\textless{}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\textless{}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 (Ba\selectlanguage{polish}ş\selectlanguage{english}ol 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\textless{}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\textless{}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\textless{}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.

\textbf{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.

\textbf{ACKNOWLEDGEMENTS}

\textbf{On behalf of the TELESPHOR investigators} : Dr.Medvedev Vladimir
(Moscow), Dr.Bogolepova Anna (Moscow), Dr.Vorobyeva Olga (Moscow),
Dr.Chaliagin Michail (Ekaterinburg), Dr. Mrykhina Veronika (Rostov on
Don), Dr.Mavani Dchaval (Rostov on Don), Dr.Pozdnyakov Stanislav
(Yaroslavl).

Editorial assistance was provided by Jenny Grice, Le Prioldy, France.

\textbf{CONFLICT OF INTEREST STATEMENT}

TELESPHOR was sponsored by Servier Russia. Denis Morozov and Boris
Kvasnikov are employees of Servier company.

\textbf{DATA AVAILABILITY STATEMENT}

The data that support the findings of this study are available from
thecorresponding author upon reasonable request

\textbf{AUTHOR CONTRIBUTIONS}

Authors DM, AB and VM designed the study and wrote the protocol. Author
DM managed the literature searches and analyses. Authors BK and DM
undertook the statistical analysis review, and author BK wrote the first
draft of the manuscript. All authors contributed to and have approved
the final manuscript.

\textbf{ORCID}

Dr. Medvedev Vladimir E., ORCID 0000-0001-8653-596X

Dr. Bogolepova Anna N., ORCID 0000-0002-6327-3546

Dr. Morozov Denis P., ORCID 0009-0007-6842-6867

Dr. Kvasnikov Boris B., ORCID 0000-0002-0806-7061

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\emph{}

\textbf{TABLE 1} Baseline sociodemographic and clinical characteristics.\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
. & \textbf{Characteristic} & \textbf{Baseline value}\tabularnewline
\midrule
\endhead
& Age (years), mean\selectlanguage{ngerman}±SD & 44.0\selectlanguage{ngerman}±13.31\tabularnewline
& Gender (n, \%) &\tabularnewline
& Male & 30 (29.1)\tabularnewline
& Female & 73 (70.9)\tabularnewline
& Working status (n, \%) &\tabularnewline
& Student & 8 (7.8)\tabularnewline
& Employed & 82 (79.6)\tabularnewline
& Unemployed & 1 (1.0)\tabularnewline
& Housewife/ Homemaker & 7 (6.8)\tabularnewline
& Retired & 5 (4.9)\tabularnewline
& Severity of COVID-19 (n, \%) &\tabularnewline
& Mild & 81 (78.6)\tabularnewline
& Moderate & 22 (21.4)\tabularnewline
& Time after COVID-19, months (mean\selectlanguage{ngerman}±SD) & 2.06\selectlanguage{ngerman}±0.68\tabularnewline
& Previous treatment with antidepressants (n, \%) &\tabularnewline
& Yes & 0\tabularnewline
& No & 103 (100)\tabularnewline
& Severity of depression (n, \%) &\tabularnewline
& Mild & 55(53.4)\tabularnewline
& Moderate & 48(46.6)\tabularnewline
& Severe & 0\tabularnewline
& HAMD-17 total score, mean\selectlanguage{ngerman}±SD & 16.3\selectlanguage{ngerman}±4.68\tabularnewline
& HAMD-17 total score item 10, mean\selectlanguage{ngerman}±SD & 1.4\selectlanguage{ngerman}±0.88\tabularnewline
& HAMD-17 total score item 11, mean\selectlanguage{ngerman}±SD & 1.3\selectlanguage{ngerman}±0.76\tabularnewline
& SF-36 Physical Component score, mean\selectlanguage{ngerman}±SD & 39.7\selectlanguage{ngerman}±8.41\tabularnewline
& SF-36 Mental Component score, mean\selectlanguage{ngerman}±SD & 37.2\selectlanguage{ngerman}±8.69\tabularnewline
& COVID-19, coronavirus disease 2019; HAMD-17, 17 item Hamilton Rating
Scale for Depression; SD, standard deviation; SF-36, Short Form survey.
. & COVID-19, coronavirus disease 2019; HAMD-17, 17 item Hamilton Rating
Scale for Depression; SD, standard deviation; SF-36, Short Form survey.
.\tabularnewline
\bottomrule
\end{longtable}

\emph{}

\textbf{TABLE 2} Univariate linear regression analyses describing
relations between covariates of interest and changes in anxiety and QoL
observed at the end of treatment with agomelatine.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Covariate of interest}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Regression coefficient}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{P value}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{P value}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Anxiety: item 10 of HAMD-17 scale}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Anxiety: item 10 of HAMD-17 scale}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Anxiety: item 10 of HAMD-17 scale}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Anxiety: item 10 of HAMD-17 scale}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Age, years\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
-0.008\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.2158\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.2158\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Sex (male)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
-0.092\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.6222\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.6222\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Baseline total HAMD-17 score\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
-0.053\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{0.0027}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{0.0027}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
COVID-19 severity (moderate)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
-0.009\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.9648\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.9648\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Time after COVID-19 onset (months)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
-0.228\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.0659\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.0659\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Anxiety: item 11 of HAMD-17 scale}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Anxiety: item 11 of HAMD-17 scale}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Anxiety: item 11 of HAMD-17 scale}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Anxiety: item 11 of HAMD-17 scale}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Age, years\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
-0.003\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.6239\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.6239\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Sex (male)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.094\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.5711\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.5711\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Baseline total HAMD-17 score\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
-0.035\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{0.0297}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{0.0297}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
COVID-19 severity (moderate)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
-0.019\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.9168\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.9168\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Time after COVID-19 onset (months)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.013\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.9042\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.9042\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{SF-36 Physical component}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{SF-36 Physical component}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{SF-36 Physical component}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{SF-36 Physical component}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Age, years\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Age, years\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
-0.007\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.8987\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Sex (male)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Sex (male)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
-1.832\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.2499\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Baseline total HAMD-17 score\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.373\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0.0149}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0.0149}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
COVID-19 severity (moderate)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.692\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.6958\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.6958\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Time after COVID-19 onset (months)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
-1.708\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.1091\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.1091\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{SF-36 Mental component} \textbf{SF-36 Mental component}
\textbf{SF-36 Mental component} Age, years -0.079 0.2392 Sex (male)
-0.693 0.7227 Baseline total HAMD-17 score 0.557 \textbf{0.0027}
COVID-19 severity (moderate) 3.428 0.1108 Time after COVID-19 onset
(months) 0.569 0.6644 COVID-19, coronavirus disease 2019; HAMD-17, 17
item Hamilton Rating Scale for Depression; SF-36, 36 item Short Form
survey. COVID-19, coronavirus disease 2019; HAMD-17, 17 item Hamilton
Rating Scale for Depression; SF-36, 36 item Short Form survey. COVID-19,
coronavirus disease 2019; HAMD-17, 17 item Hamilton Rating Scale for
Depression; SF-36, 36 item Short Form survey.\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\&\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\textbf{SF-36 Mental component} & \textbf{SF-36 Mental component} &
\textbf{SF-36 Mental component}\tabularnewline
Age, years & -0.079 & 0.2392\tabularnewline
Sex (male) & -0.693 & 0.7227\tabularnewline
Baseline total HAMD-17 score & 0.557 & \textbf{0.0027}\tabularnewline
COVID-19 severity (moderate) & 3.428 & 0.1108\tabularnewline
Time after COVID-19 onset (months) & 0.569 & 0.6644\tabularnewline
COVID-19, coronavirus disease 2019; HAMD-17, 17 item Hamilton Rating
Scale for Depression; SF-36, 36 item Short Form survey. & COVID-19,
coronavirus disease 2019; HAMD-17, 17 item Hamilton Rating Scale for
Depression; SF-36, 36 item Short Form survey. & COVID-19, coronavirus
disease 2019; HAMD-17, 17 item Hamilton Rating Scale for Depression;
SF-36, 36 item Short Form survey.\tabularnewline
\bottomrule
\end{longtable}

\&\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\textbf{SF-36 Mental component} & \textbf{SF-36 Mental component} &
\textbf{SF-36 Mental component}\tabularnewline
Age, years & -0.079 & 0.2392\tabularnewline
Sex (male) & -0.693 & 0.7227\tabularnewline
Baseline total HAMD-17 score & 0.557 & \textbf{0.0027}\tabularnewline
COVID-19 severity (moderate) & 3.428 & 0.1108\tabularnewline
Time after COVID-19 onset (months) & 0.569 & 0.6644\tabularnewline
COVID-19, coronavirus disease 2019; HAMD-17, 17 item Hamilton Rating
Scale for Depression; SF-36, 36 item Short Form survey. & COVID-19,
coronavirus disease 2019; HAMD-17, 17 item Hamilton Rating Scale for
Depression; SF-36, 36 item Short Form survey. & COVID-19, coronavirus
disease 2019; HAMD-17, 17 item Hamilton Rating Scale for Depression;
SF-36, 36 item Short Form survey.\tabularnewline
\bottomrule
\end{longtable}

\&\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\textbf{SF-36 Mental component} & \textbf{SF-36 Mental component} &
\textbf{SF-36 Mental component}\tabularnewline
Age, years & -0.079 & 0.2392\tabularnewline
Sex (male) & -0.693 & 0.7227\tabularnewline
Baseline total HAMD-17 score & 0.557 & \textbf{0.0027}\tabularnewline
COVID-19 severity (moderate) & 3.428 & 0.1108\tabularnewline
Time after COVID-19 onset (months) & 0.569 & 0.6644\tabularnewline
COVID-19, coronavirus disease 2019; HAMD-17, 17 item Hamilton Rating
Scale for Depression; SF-36, 36 item Short Form survey. & COVID-19,
coronavirus disease 2019; HAMD-17, 17 item Hamilton Rating Scale for
Depression; SF-36, 36 item Short Form survey. & COVID-19, coronavirus
disease 2019; HAMD-17, 17 item Hamilton Rating Scale for Depression;
SF-36, 36 item Short Form survey.\tabularnewline
\bottomrule
\end{longtable}



\textbf{Hosted file}

\verb`image1.emf`  available at \url{https://authorea.com/users/772670/articles/858057-the-effectiveness-and-tolerability-of-agomelatine-in-the-treatment-of-depression-after-covid-19-infection-in-russian-daily-clinical-practice-telesphor-study}

\emph{}

\textbf{FIGURE 2} Mean changes in HAMD-17 item 10 scores at each study
visit. HAMD-17, 17 item Hamilton Rating Scale for Depression.

\textbf{Hosted file}

\verb`image2.emf`  available at \url{https://authorea.com/users/772670/articles/858057-the-effectiveness-and-tolerability-of-agomelatine-in-the-treatment-of-depression-after-covid-19-infection-in-russian-daily-clinical-practice-telesphor-study}

\textbf{FIGURE 3} Mean changes in HAMD-17 item 11 scores at each study
visit. HAMD-17, 17 item Hamilton Rating Scale for Depression.

\textbf{Hosted file}

\verb`image3.emf`  available at \url{https://authorea.com/users/772670/articles/858057-the-effectiveness-and-tolerability-of-agomelatine-in-the-treatment-of-depression-after-covid-19-infection-in-russian-daily-clinical-practice-telesphor-study}

\textbf{FIGURE 4} Mean changes in CGI-I scores. CGI-I, Clinical Global
Impressions-Improvement of Illness Scale.

\textbf{Hosted file}

\verb`image4.emf`  available at \url{https://authorea.com/users/772670/articles/858057-the-effectiveness-and-tolerability-of-agomelatine-in-the-treatment-of-depression-after-covid-19-infection-in-russian-daily-clinical-practice-telesphor-study}

\emph{}

\textbf{FIGURE 5} Mean changes in SF-36 Physical Component scores.

\textbf{Hosted file}

\verb`image5.emf`  available at \url{https://authorea.com/users/772670/articles/858057-the-effectiveness-and-tolerability-of-agomelatine-in-the-treatment-of-depression-after-covid-19-infection-in-russian-daily-clinical-practice-telesphor-study}

\textbf{FIGURE 6} Mean changes in SF-36 Mental Component scores. SF-36,
36 item Short Form survey.

\textbf{Hosted file}

\verb`image6.emf`  available at \url{https://authorea.com/users/772670/articles/858057-the-effectiveness-and-tolerability-of-agomelatine-in-the-treatment-of-depression-after-covid-19-infection-in-russian-daily-clinical-practice-telesphor-study}

\selectlanguage{english}
\FloatBarrier
\end{document}

