Vortioxetine improves physical and cognitive symptoms in patients with post-COVID-19 major depressive episodes

Abstract

Major Depressive Episodes (MDE) following COVID-19 are frequent, can have a characteristic clinical picture, and are associated with immune-inflammatory changes. Vortioxetine is known to improve physical and cognitive performance in patients with depression and shows anti-inflammatory and anti-oxidative activities. This study aimed to retrospectively evaluate the effects of vortioxetine after 1 and 3 months of treatment in 80 patients (44.4% males, 54±17.2 years) with post-COVID-19 MDE. The primary outcome was improvement in physical and cognitive symptoms measured by specific items of Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Rating Scale (HARS), Short Form-36 Health Survey Questionnaire (SF-36), Digit Symbol Substitution Test (DSST), Perceived Deficits Questionnaire for Depression (PDQ-D5). Changes in mood, anxiety, anhedonia, sleep, and quality of life were also investigated, as well as the underlying inflammatory status. Results show that, alongside reduction of depressive symptoms (HDRS, p<0.001), vortioxetine (mean dose: 10.1±4.1 mg/day) significantly improved physical features (all measurements p<0.001) and cognitive functioning (DDST, p=0.02; PDQ-D5, p<0.001) throughout treatment. We also observed significant reductions in inflammatory indexes. Therefore, vortioxetine might be a favorable therapeutic choice in post-COVID-19 patients with MDE because of its beneficial effects on physical complaints and cognition, features that appear to be specifically affected in relation to SARS-CoV-2 infection, and its good safety/tolerability profile. High prevalence and clinical and socioeconomic implications of COVID-19 consequences are a major public health concern and developing tailored, safe interventions is crucial to promote full functional recovery.

1. Introduction

The coronavirus disease 2019 (COVID-19) has largely affected mental health worldwide (WHO, 2022), both as the acute infection and long-term consequences. Neuropsychiatric sequelae appear to be frequent: approximately 30–40% of post-COVID-19 patients develops depressive symptoms at short, medium, and long-term follow-up after the infection, with characteristic clinical features (Renaud-Charest et al., 2021).

Alongside the central role of depressive psychopathology, cognitive and physiosomatic correlates seem to be prominent with a negative impact on overall functioning and quality of life (Mazza et al., 2022a). Although their pathogenesis is debated, the systemic immune-inflammatory response induced by SARS-CoV-2 combined with psychological stressors (Di Nicola et al., 2020) has been proposed among mechanisms underlying depressive symptomatology (Premraj et al., 2022).

The multimodal antidepressant vortioxetine is known to improve cognitive and physical symptoms in depressed patients, with a good safety and tolerability profile (Christensen et al., 2018). It also shows some anti-inflammatory and immunomodulatory activity (Talmon et al., 2018) and has been recently demonstrated to inhibit SARS-CoV-2 infection by blocking S-protein-mediated cell fusion (Xiao et al., 2020; Xiong et al., 2021).

Growing evidence has reported anti-inflammatory properties of antidepressants with recent findings on potential beneficial effects on COVID-19 outcomes (Reis et al., 2022). However, few studies investigated psychopharmacological treatments in post-COVID-19 depressive episodes and mainly focused on the effects of Selective Serotonin Reuptake Inhibitors (SSRIs) at short-term follow-up (Dobrodeeva et al., 2022; Mazza et al., 2022b).

Herein, we sought to retrospectively investigate whether vortioxetine would attenuate a combination of physical symptoms and improve cognitive performances in patients with post-COVID-19 Major Depressive Episodes (MDE). In addition to assessing mood, we were interested in evaluating outcomes with respect to anxiety, anhedonia and sleep problems, overall functioning, and quality of life, as well as the underlying inflammatory levels.

2. Experimental procedures

2.1. Participants

Patients referred to the Fondazione Policlinico Universitario “Agostino Gemelli” Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) in Rome, between April 2020 and December 2021, were retrospectively evaluated. Inclusion criteria were: age ≥18 years; fluency in spoken and written Italian; primary diagnosis of a major depressive episode (MDE), according to DSM-5 criteria (APA, 2013), emerged in the first 6 months following SARS-CoV-2 infection as confirmed by a positive polymerase chain reaction test; at least moderate symptoms according to Hamilton Depression Rating Scale (HDRS) total score ≥14; ongoing (at least three-months) treatment with a target dose of vortioxetine (5–20 mg/day, flexibly dosed). Exclusion criteria were: current primary psychiatric diagnoses other than MDE; psychotic features; current alcohol and/or substance abuse, except for smoking; concomitant intake of further antidepressants; organic brain syndromes, neurocognitive disorders or significant cognitive impairment based on a Mini-Mental State Examination (MMSE) score <26; any major medical conditions known to contribute to systemic inflammation and that were not under stable pharmacological treatment.

Continuous psychoeducational support was provided to all patients, as recently recommended for the management of psychiatric disorders in post-COVID-19 syndrome (Paez et al., 2022). The study protocol was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki (1964) and subsequent revisions and was approved by the local institutional review board.

2.2. Data collection: psychometric assessment and clinical measurements

Data were obtained from measurements and assessments performed at baseline and after 1 and 3 months of treatment (endpoint) as part of routine clinical practice.

2.2.1. Primary outcomes

Physical symptomatology was evaluated through a combination of items of HDRS and Hamilton Anxiety Rating Scale (HARS) referred to as “Physical Symptoms”, and subscales of Short Form-36 Health Survey Questionnaire (SF-36).

The physical symptoms of depression were assessed through items 4, 5, 6 (early, middle, late insomnia), 11 (somatic anxiety), 12 (gastrointestinal), 13 (general somatic), 14 (genital), and 16 (loss of weight) of HDRS, and 7 (muscular pain), 8 (sensory), 9 (cardiovascular), 10 (respiratory), 11 (gastrointestinal), 12 (genitourinary) and 13 (autonomic) of HARS, respectively (Christensen et al., 2018).

SF-36 is a 36-item, self-reported survey of patients’ health consisting of eight scaled sections, each one rated from 0 (worst health) to 100 (best health): bodily pain (BP); general health perceptions (GHP); mental health (MH); physical functioning (PF); role emotional, i.e., limitation due to emotional problems (RE); role physical, i.e., limitation due to physical health problems (RP); social functioning (SF); vitality (VT). The BP, PF, RP, and VT scales were used to evaluate physical symptomatology, with higher scores indicating less disability (Ware and Sherbourne, 1992).

Cognitive performance was assessed with the neuropsychological Digit Symbol Substitution Test (DSST) and through the Perceived Deficits Questionnaire-Depression 5-items (PDQ-D5). The pen-and-paper version of the DSST, administered according to Strauss et al. (2006) to explore cognitive skills involving attention, processing speed, spatial perception, visual scanning, and executive function, was scored through the number of correct symbols (range: 0–90), with higher scores indicating better performance. PDQ-D5 (total score: 0–20) served as a subjective measure of cognition, wherein higher scores indicate greater impairment in attention/concentration, planning/organization, retrospective and prospective memory.

2.2.2. Secondary outcomes

Depressive symptoms were assessed by the 17-item HDRS. Patients were considered responders when obtaining an improvement of at least 50% of baseline scores and remitters when achieving a total score ≤7 at endpoint. Mood relapses were defined as a new exacerbation of depressive symptoms (HDRS total score ≥14) after initial improvement.

Additional assessment included: the total HARS score to investigate anxiety levels; the self-rating Snaith-Hamilton Pleasure Scale (SHAPS), with a total score ≥3 indicating the presence of anhedonia; the Pittsburgh Sleep Quality Index (PSQI) for the evaluation of sleep disturbances, with lower scores showing a healthier sleep quality and a total score cut-off >5 defining the presence of insomnia; the World Health Organization-Five Well-Being Index (WHO-5) to self-evaluate wellbeing and quality of life.

White blood cell count was extracted from charts; neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and systemic immune-inflammatory index (SII, i.e., platelets X neutrophils/lymphocytes) were calculated to measure inflammation levels before and after one and three months of treatment. These indexes are easily available and reproducible biomarkers and have been associated with systemic inflammation both in major depressive disorder (MDD; Mazza et al., 2018) and in depressive symptoms following SARS-CoV-2 infection (Mazza et al., 2021).

2.2.3. Safety and tolerability

Safety and tolerability of vortioxetine were confirmed by physical examination, measurement of body weight and vital signs, routine laboratory and instrumental clinical tests, and patients’ reports of any adverse events, as recorded in clinical charts.

2.3. Statistical analysis

Descriptive data were summarized as the number of patients and percentage (%) or mean ± standard deviation (M±SD) for categorical and continuous variables, respectively. The outcome measures - the mean changes from baseline to 1 and 3 months of each efficacy variable - were analyzed using a mixed model for repeated measurements (MMRM), including time as fixed effect, the baseline score as a continuous covariate, and the baseline score-by-time interaction, based on all available observations.

Analyses were performed on all patients with at least one valid postbaseline assessment of the variables (full-analysis set, FAS). A significance level of p<0.05 was used for each test.

All analyses were performed using IBM SPSS Statistics for Windows, v. 25 (IBM Corp., Armonk, New York, USA).

3. Results

Eighty Caucasians subjects treated with vortioxetine at dosages of 5 mg (25.8%), 10 mg (53.2%), 15 mg (14.5%), and 20 mg (6.5%) were included.

Complete sociodemographic and clinical characteristics are summarized in Table 1 .

Table 1.

Sociodemographic and clinical characteristics at baseline.

	N, %; M±SD
Overall	80
Sociodemographic features
Age (years)	54±17.2
Gender
Female Male	44 (55.6) 36 (44.4)
Education level (years)	14±4.07
Occupation (employed)	52 (65.5)
Marital status (married)	49 (61.4)
Clinical data
Psychiatric diagnosis First MDE Recurrent MDE	39 (49.2) 41 (50.8)
Age of first MDE onset (years)	45.4±18.5
Duration of illness (years)	7.64±12.5
Affective episodes lifetime	1.74±1.37
Suicide attempts	1 (1.7)
Psychiatric hospitalizations	3 (3.4)
Vortioxetine dose (mg/day)	10.1±4.10
Other psychopharmacotherapy Mood stabilizers/Anticonvulsants Antipsychotics Sedative-hypnotics/anxiolytics	53 (66.7) 30 (57.2) 11 (20.3) 31 (57.6)
Family history of psychiatric disorders	44 (55.4)
Medical comorbidities	52 (64.9)
Smoking habits	22 (26.9)
BMI	25.8±3.96
COVID-19 information
Duration (days)	25±10.3
Symptoms Mild Moderate Severe	32 (40) 13 (16.2) 30 (37.5)
Pharmacotherapy	51 (63.9)
Hospitalizations ICU	30 (37.7) 17 (21.3)
SARS-CoV-2 vaccine
No	31 (39.1)
1 dose 2 doses 3 doses	10 (13) 23 (28.3) 16 (19.6)
Days between SARS-CoV-2 infection and MDE diagnosis	79.8±34.6

Abbreviations: BMI, Body Mass Index; ICU, Intensive Care Unit; M, mean; MDE, Major Depressive Episodes; SD, Standard Deviation.

Means and standard deviations for baseline psychometric features and levels of inflammatory indexes are reported in Table 2 .

Table 2.

Effect of vortioxetine on psychiatric symptoms and inflammatory indexes (FAS, MMRM).

Psychometric assessment (M±SD)	Baseline	Mean change from baseline (SE)				SMD
		1 month	p	3 months	p	1 month	p	3 months	p
HDRS	17.8±3.80	−6.28 (0.65)	<0.001	−13.29 (0.64)	<0.001	−1.58	<0.001	−3.98	<0.001
Physical symptoms	6.23±1.96	−2.89 (0.23)	<0.001	−5.37 (0.22)	<0.001	−1.46	<0.001	−3.68	<0.001
HARS	17.5±5.49	−6.10 (0.74)	<0.001	−13.21 (0.74)	<0.001	−1.20	<0.001	−3.32	<0.001
Physical symptoms	6.57±3.28	−2.86 (0.34)	<0.001	−6.12 (0.32)	<0.001	−1.15	<0.001	−2.65	<0.001
SF-36
VT	34.1±15.6	16.56 (2.99)	<0.001	26.49 (2.98)	<0.001	0.68	<0.001	1.64	<0.001
BP	54.3±25.2	18.63 (4.42)	<0.001	24.08 (4.42)	<0.001	0.64	0.002	1.35	<0.001
PF	61.3±21.9	9.88 (2.26)	<0.001	11.55 (2.33)	<0.001	0.48	0.007	0.90	<0.001
RP	20.2±32.3	32.5 (6.47)	<0.001	54.7 (6.51)	<0.001	0.79	<0.001	1.93	<0.001
DSST	39.5±13.9	4.06 (1.34)	0.023	7.18 (1.49)	0.02	0.25	0.007	0.53	0.001
PDQ-D5	11.2±4.02	−3.8 (0.46)	<0.001	−6.44 (0.47)	<0.001	−0.83	<0.001	−1.81	<0.001
SHAPS	3.45±2.85	−0.92 (0.23)	0.001	−1.69 (0.23)	<0.001	−0.36	0.02	−1.14	<0.001
PSQI	11±3.36	−2.49 (0.50)	<0.001	−5.25 (0.51)	<0.001	−0.75	<0.001	−2.28	<0.001
WHO-5	6.65±3.53	3.69 (0.80)	<0.001	8.88 (0.78)	<0.001	0.73	<0.001	2.01	<0.001
Inflammatory indexes (M±SD)
SII	541±478	−331 (72.1)	<0.001	−124 (60.6)	0.160
NLR	2.12±1.35	−1.02 (0.23)	<0.001	−0.39 (0.19)	0.191
PLR	130±46.4	−15.2 (8.15)	0.243	−40.9 (6.42)	<0.001

Abbreviations: DSST, Digit Symbol Substitution Test; FAS, Full Analysis Set; HARS, Hamilton Anxiety Rating Scale; HDRS, Hamilton Depression Rating Scale; M, Mean; MMRM, Mixed Model for Repeated Measures; NLR, Neutrophil/Lymphocyte Ratio; p, statistical significance; PDQ-D5, Perceived Deficits Questionnaire for Depression – 5 items; PLR, Platelet/Lymphocyte Ratio; PSQI, Pittsburgh Sleep Quality Index; SD, Standard Deviation; SE, Standard Error; SMD, Standardized Mean Difference; SF-36, Short Form Health Survey Questionnaire (BP: bodily pain; PF: physical functioning; RP: role physical; VT: Vitality); SHAPS, Snaith-Hamilton Pleasure Scale; SII, Systemic Immune-inflammatory Index; WHO-5, World Health Organization-Five Well-Being Index.

At the endpoint, data were available for 65 patients. Results from MMRM and effect sizes for each efficacy variable are reported in Table 2.

All primary outcome measures significantly reduced throughout treatment.

Depressive symptoms significantly decreased, and no patient experienced a mood relapse. After one month, 12 (15%) and 3 (3.7%) patients were classified respectively as responders and remitters, while 6 (9.2%) had a significant response and 57 (87.7%) reached remission at the endpoint. Only 2 (3.1%) patients were classified as non-responders after three months.

Improvements were also observed in all secondary outcome measures and in inflammatory indexes. The rate of patients reaching the cut-off score for anhedonia (62.8% at baseline) decreased to 48.1% after one month of treatment and was as low as 3.6% at endpoint.

No significant adverse events were detected throughout treatment. Only 6 patients (7.5%) reported mild side effects at one month, i.e., nausea (5%, n=4), headache (1.25%, n=1), and dry mouth (1.25%, n=1), which gradually disappeared over time, and no one needed to discontinue vortioxetine because of tolerability concerns.

4. Discussion

In this study, patients with post-COVID-19 MDE treated with vortioxetine as part of an integrated therapeutic approach obtained a significant reduction of physical and cognitive correlates of depression, alongside the decrease of depressive symptoms, with a substantial rate of clinical remission at the endpoint. Similar progresses were observed on anxiety, anhedonia, sleep, global functioning, quality of life, and inflammatory indexes. Finally, treatment with vortioxetine was safe and well-tolerated.

The onset of symptoms such as fatigue, cognitive dysfunctions, sleep disturbances, anxiety, and depression within 3 months from SARS-CoV-2 infection is frequent (Premraj et al., 2022) and led some authors to propose the definition of “Mind Long COVID” (Llach and Vieta, 2021). Patients from our sample received a diagnosis of MDE approximately 1.5–3.5 months after the infection, possibly as part of a post-acute/ongoing symptomatic COVID-19 (i.e., from 4 to 12 weeks; n=54, 67.7%) or a chronic/post-COVID-19 syndrome (i.e., ≥12 weeks; n=26, 32.3%) (NICE, 2022), as previously described (The Lancet, 2021).

Significant physical symptoms and cognitive impairment were observed as per clinicians’ measurements, patients’ self-reports, and a neuropsychological test (i.e., DSST). In a substantial rate of patients, very low energy levels and severe limitations due to physical health problems emerged according to scores < 50 at baseline SF-36 subscales (Ware and Sherbourne, 1992). As well, DSST scores showed similar impaired cognitive performances than those detected in MDD patients before treatment (Baune et al., 2018). Patients also displayed moderate anxiety and reached the cut-off scores for anhedonia and sleep disturbances, in line with several meta-analyses reporting that insomnia and anxious symptoms are frequent following SARS-CoV-2 infection (Malik et al., 2022; Yang et al., 2022).

Fatigue and cognitive dysfunctions (mainly brain fog, memory/attention issues) have been described as key post-COVID-19 features with prevalence odds of 32% and 22% (Ceban et al., 2022), with a bi-directional relationship between such symptomatology and depression (Poletti et al., 2022), both during the acute and post-acute phases of SARS-CoV-2 infection (Al-Jassas et al., 2022), and regardless of the clinical severity of acute infection (Townsend et al., 2020). Besides, post-COVID-19 depression has been correlated with a higher risk of further persistent physical symptoms, like pain and dyspnea (Mazza et al., 2022a).

In MDE, somatic features and cognitive impairment, often persisting beyond remission of mood symptoms (Christensen et al., 2018), as well as comorbid anxiety (McIntyre et al., 2016b), have been recognized as detrimental factors for the course of illness, with more chronicity, lower probability of treatment response, heightened risk of recurrences, and reduced occupational and psychosocial performances (Malhi and Mann, 2018). Thus, the presence of additional symptomatology can result in poor quality of life and hinder full functional recovery.

Favorable effects of vortioxetine, at a dose range of 5–20 mg/day, have been demonstrated to extend beyond emotional symptoms and to involve cognitive function, physical complaints and energy, psychopathological dimensions of anhedonia and emotional blunting, overall functioning, and health-related quality of life (Cao et al., 2019b; Fagiolini et al., 2021). The multimodal mechanism of action possibly accounts for the relief of painful physical symptoms associated with depression (Christensen et al., 2018). Also, the antagonism of specific serotonin receptors (5-HT₃, 5-HT₇) might explain the improvement of insomnia and quality of sleep (De Diego et al., 2022).

It is possible that improvements in certain clinical features, i.e., cognitive functioning, might result, at least in part, from improvements in depressive symptoms; however, data from the literature suggest that vortioxetine improves cognition independently of disease severity and primarily as a direct effect of treatment (McIntyre et al., 2016a; Huang et al., 2022). Conversely, as for other MDD-related symptoms, improvement of sleep disturbances showed a linear correlation with the reduction of overall depressive symptoms severity and seemed to predict antidepressant response (Cao et al., 2019 ^a; De Diego et al., 2022).

A systemic, chronic inflammation has been associated with mood symptoms in both MDD and post-COVID-19 depression (Liu et al., 2012; Mazza et al., 2021). Also, an interrelationship between fatigue, cognitive deficits, depressive symptoms, and higher pro-inflammatory markers can be found in a significant proportion of COVID-19 survivors (Ceban et al., 2022; Mazza et al., 2022a). Here, the reduction of SII, NLR and PLR levels observed at different time-points, alongside symptoms improvement, could lead to hypothesize that antidepressant response could have been associated with a decrease of low-grade systemic inflammation.

Within this framework, vortioxetine has been included among the approved drugs that can inhibit replication of coronaviruses, including SARS-CoV-2 (Xiao et al., 2020). Besides, it displays anti-inflammatory and antioxidative properties (Talmon et al., 2018) that have been partly attributed to an on-target effect on the serotonergic system together with a direct effect on cyclooxygenases (Bayram et al., 2018). Taken together, these observations suggest that vortioxetine might be useful in treating COVID-19 patients with depression (Xiong et al., 2021).

Finally, treatment with vortioxetine was safe and well-tolerated as confirmed by the absence of adverse effects and treatment dropouts in our sample, and in line with substantial evidence supporting its good safety/tolerability profile (Orsolini et al., 2017).

Some limitations must be acknowledged such as the monocentric setting of the study, the open-label, retrospective, observational design, with a partial consideration of confounding variables that might concomitantly affect the inflammatory status and depressive psychopathology, and the lack of a control group (either placebo or other antidepressants). Indeed, the antidepressant fluvoxamine, which preliminarily proved to be efficacious in managing SARS-CoV-2 infection outcomes (Boretti, 2022), turned out to show no significant effects in a subsequent placebo-controlled randomized clinical trial (McCarthy et al., 2023).

To our knowledge, this is the first study to assess vortioxetine's effectiveness at a medium-term follow-up in a well-characterized sample of adult patients who developed MDE following SARS-CoV-2 infection. Recent evidence from real-world practice in Italy highlighted that less than half of new antidepressant prescriptions have endured over 3 months, despite the recommendation of at least six months for the antidepressant therapy (Di Nicola et al., 2022), and that clinically relevant and sustained improvements were observed in depressed patients over a six-months treatment with vortioxetine (De Filippis et al., 2022). Therefore, multicentric larger case-control studies, possibly with longer follow-ups, are needed to confirm these results. Also, considering the large body of literature linking inflammatory processes with depressive symptoms and with physical and cognitive features (specifically affected in post-COVID-19 MDE), future studies with combined treatments targeting patients’ inflammatory status might explore new promising strategies to improve the efficacy of antidepressants (Fourrier et al., 2018). Given the prevalence of post-COVID-19 depression, identifying safe and effective treatments is crucial to address disease burden and promote full functional recovery.

Role of funding source

This independent investigator-initiated study was partially supported by Lundbeck Italy.

CRediT authorship contribution statement

Marco Di Nicola: Conceptualization, Methodology, Investigation, Resources, Writing – original draft, Writing – review & editing, Project administration. Maria Pepe: Conceptualization, Resources, Formal analysis, Investigation, Data curation, Writing – original draft, Writing – review & editing, Visualization. Silvia Montanari: Data curation, Writing – review & editing. Maria Chiara Spera: Data curation, Visualization. Isabella Panaccione: Validation, Formal analysis, Writing – review & editing. Alessio Simonetti: Resources, Data curation, Visualization. Gabriele Sani: Conceptualization, Supervision, Project administration.

Conflict of interest

M.D.N. is/has been a consultant and/or a speaker and/or has received research grants from: Angelini, Janssen, Lundbeck, Neuraxpharma, and Otsuka. G.S. is/has been a consultant and/or a speaker and/or has received research grants from: Angelini, Janssen, Lundbeck, Neuraxpharma, and Otsuka.