Articulo 2

Christensen MC, Schmidt S, Grande I.
Effectiveness of vortioxetine in patients with major depressive

disorder comorbid with generalized anxiety disorder: Results of the RECONNECT study. J
Psychopharmacol [Internet]. 2022 [citado el 16 de octubre de 2022];36(5):566–77. Disponible en:
https://pubmed.ncbi.nlm.nih.gov/35499104/
ARTICULO:
• EFFECTIVENESS OF VORTIOXETINE IN PATIENTS WITH MAJOR DEPRESSIVE
DISORDER COMORBID WITH GENERALIZED ANXIETY DISORDER: RESULTS OF
THE RECONNECT STUDY.
ALUMNO:
• MOCTEZUMA VARGAS CARLOS GABRIEL.
MATRICULA:
• A2183270051.
DOCENTE:
• DR. JAVIER PEDRAZA CHAVEZ.
GRADO Y GRUPO:
• 3°I.
ASIGNATURA:
• FARMACOLOGIA BASICA.
TEMA:
• TRATAMIENTO DE LA DEPRESION.
FECHA:
• 15 OCTUBRE 2022.
Moctezuma Vargas Carlos Gabriel 3°I

Christensen MC, Schmidt S, Grande I. Effectiveness of vortioxetine in patients with major depressive
El trastorno depresivo mayor y el trastorno de ansiedad generalizada son con frecuencia

comórbidos y las personas que los experimentan representan uno de los grupos de pacientes
más grandes dentro de la población general con trastornos de depresión mayor. se consideran
más difíciles de tratar, ya que requieren una mayor duración del tratamiento, tienen tasas más
altas de abandono del tratamiento.
La vortioxetina es un fármaco novedoso para la depresión, actúa tanto como inhibidor del
transportador de serotonina como modulador de varios subtipos de receptores 5-HT, es un
antagonista de los receptores 5-HT 3, 5-HT 7 y 5-HT 1D, un agonista parcial de los
receptores 5-HT 1B y un agonista de los receptores 5-HT 1A, así como un inhibidor de los
receptores 5-HT 1A. Es eficaz para el tratamiento de los síntomas depresivos, cognitivos,
físicos y también ha demostrado tener efectos ansiolíticos en pacientes con trastorno depresivo
mayor.
En el ensayo clínico los pacientes tenían entre 18 y 65 años con un diagnóstico de trastorno
depresivo mayor, ellos recibieron vortioxetina como primer tratamiento o cambiaban a
vortioxetina debido a una respuesta inadecuada a otro fármaco para la depresión.
Se inició el tratamiento con vortioxetina con la dosis de 10 mg/día con aumento forzado a 20
mg/día en todos los pacientes después de 1 semana. Se permitieron reducciones de dosis
posteriores en función de la tolerabilidad/respuesta individual.
Se observaron efectos significativos después de 1 semana y siguió incrementando durante el
curso del tratamiento, en la semana 8, el 35 % de los pacientes había logrado disminuir los
síntomas depresivos y el 42 % de los síntomas de ansiedad. La mejoría en los síntomas de
depresión y ansiedad estuvo acompañada por una mejoría significativa y amplia en el
funcionamiento diario de los pacientes para realizar y disfrutar de actividades de la vida diaria
Después de 8 semanas de tratamiento con vortioxetina se observaron mejoras clínica y
estadísticamente significativas en los síntomas de depresión y ansiedad evaluados por el
médico y el paciente.
En conclusión, la vortioxetina probó que logra disminuir los síntomas de depresión y ansiedad
en personas con trastorno depresivo mayor y de ansiedad generalizada ya que desde su
primera semana se logró observar una mejoría con un incremento semanalmente en su
tratamiento.
Los efectos beneficiosos observados sobre los síntomas depresivos y de ansiedad ya eran
significativos después de 1 semana y continuaron aumentando durante las 8 semanas de
tratamiento.

Original Paper
Effectiveness of vortioxetine in patients withmajor depressive

disorder comorbid with generalized anxiety disorder: Results of
the RECONNECT study
Michael Cronquist Christensen1 , Simon Schmidt1and Iria Grande2

Journal of Psychopharmacology
2022, Vol. 36(5) 566–577
© The Author(s) 2022
Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/02698811221090627
journals.sagepub.com/home/jop

Abstract
Background: Major depressive disorder (MDD) and generalized anxiety disorder (GAD) are frequently comorbid.
Aims: To assess the effectiveness of vortioxetine in patients with MDD and comorbid GAD.
Methods: Open-label, 8-week study (NCT04220996) in 100 adult outpatients with severe MDD and severe comorbid GAD receiving vortioxetine as first
treatment for the current depressive episode or switching to vortioxetine due to inadequate response to another drug for depression. Vortioxetine
starting dosage was 10 mg/day, with forced up-titration to 20 mg/day after 1 week. Response was defined as ⩾50% decrease in Montgomery–Åsberg
Depression Rating Scale (MADRS) and/or Hamilton Anxiety Rating Scale (HAM-A) total score from baseline; remission defined as MADRS and/or HAM-A
total score ⩽10.
Results: Clinically meaningful and statistically significant improvements from baseline in symptoms of depression and anxiety, and overall functioning
and health-related quality of life, were observed after 8 weeks’ vortioxetine treatment (all changes p < 0.0001 vs baseline). At week 8, rates of MADRS response
and remission were 61% and 35%, respectively. Corresponding rates of HAM-A response and remission were 55% and 42%. Response onboth the
MADRS and HAM-A scales was achieved by 52% of patients; 31% achieved remission on both scales. Vortioxetine dose up-titration was well tolerated;
no unexpected adverse events were reported.
Conclusion: Vortioxetine demonstrates effectiveness in significantly reducing symptoms of both depression and anxiety in patients with severe MDD
comorbid with severe GAD. Findings support increasing vortioxetine dosage to 20 mg/day early in the course of therapy, and show that this may be
achieved without compromising tolerability.
Keywords
Major depressive disorder, generalized anxiety disorder, vortioxetine, effectiveness, tolerability, dosage
Introduction receptor subtypes (5-HT3, 5-HT7 and 5-HT1D receptor antagonist,

Major depressive disorder (MDD) and generalized anxiety disor- 5-HT1B receptor partial agonist and 5-HT1A receptor agonist)
der (GAD) are frequently comorbid, and individuals experien- (Gonda et al., 2019; Sanchez et al., 2015). Vortioxetine has been
cing comorbid GAD represent one of the largest patient groups shown to be effective and well tolerated for the treatment of
within the overall population with MDD (Dold et al., 2017; Hasin depressive, cognitive and physical symptoms in patients with
et al., 2018; Kessler et al., 2005; Lamers et al., 2011; Moffitt MDD across the approved dose range of 5–20 mg/day
et al., 2007; Saha et al., 2021; Zhou et al., 2017). When comor- (Christensen et al., 2018; Gonda et al., 2019), and has also dem-
onstrated anxiolytic effects in patients with MDD experiencing
bid, MDD and GAD are associated with more severe symptoms,
severe concurrent anxiety (Baldwin et al., 2016; Chokka et al.,
greater impairment in functioning and health-related quality of
2021). In patients with GAD, a short-term, randomized con-
life (HRQoL) and greater risk of suicide ideation than seen in
trolled trial demonstrated that vortioxetine 5 mg/day was signifi-
patients with either condition alone (Dold et al., 2017; Gili et al.,
cantly more efficacious than placebo for the relief of anxiety
2013; Kessler et al., 2008; Lamers et al., 2011; Pfeiffer et al.,
2009; Shepardson et al., 2019; Zhou et al., 2017). Patients with
comorbid MDD and GAD are also considered more difficult to 1H. Lundbeck A/S, Valby, Denmark
treat, requiring longer treatment duration, having higher rates of
2Bipolarand Depression Disorders Unit, Hospital Clinic, Institute
treatment withdrawal and achieving lower rates of remission than
those with either condition alone (Dold et al., 2017; Kelly and of Neurosciences, University of Barcelona, IDIBAPS, CIBERSAM,
Mezuk, 2017; Kessler et al., 2008). Barcelona, Spain
Vortioxetine is a novel drug for depression with a multimodal Corresponding author:
mechanism of action, acting both as an inhibitor of the serotonin
(5-HT) transporter as well as a modulator of several 5-HT Michael Cronquist Christensen, H. Lundbeck A/S, Ottiliavej 9, 2500
Valby, Denmark.
Email: MCRC@lundbeck.com

Christensen et al. 567
symptoms (Bidzan et al., 2012). Vortioxetine 5 or 10 mg/day has

dose of study medication (baseline), except for selective seroto-
also been shown to be efficacious and well tolerated as mainten-
nin reuptake inhibitors (SSRIs) or serotonin–norepinephrine
ance treatment for the prevention of relapse in patients with GAD
reuptake inhibitors (SNRIs), use of which was permitted until
(Baldwin et al., 2012). However, other studies in patients with
baseline. If needed, gradual dose reduction was recommended
GAD conducted entirely in US populations have yielded con-
during the screening period in order to reach the minimum thera-
flicting results (Mahableshwarkar et al., 2014a, 2014b; Rothschild
peutic dose at baseline, in line with the local prescribing informa-
et al., 2012). Geographic differences in clinical trial outcomes
tion. If switching from paroxetine, the last dose should have been
have been reported for many effective drugs for depression, in
taken no less than 1 week before the baseline visit. Fluoxetine was
particular for the US, which may arise from variation in patient
disallowed within 5 weeks before baseline.
characteristics, diagnostic and clinical practices, study design and
Concomitant use of benzodiazepines was only permitted dur-
trial setting (Chang et al., 2008; Dunlop et al., 2012; Khinet al.,
ing the study in patients who were on a stable dose before base-
2011; Niklson and Reimitz, 2001; Vieta et al., 2011; Weltenet al.,
line. Benzodiazepines were not to be taken the night before a
2015).
study visit, and episodic use was not permitted. All other drugs
Vortioxetine has been shown to have dose-dependent effects for anxiety were to be discontinued before baseline. Use of mono-
on symptoms of depression and concomitant anxiety in patients
amine oxidase inhibitors and other psychotropic agents (includ-
with MDD; greatest clinical benefits are achieved at a dosage of
ing herbal medications such as St. John’s Wort, kava kava,
20 mg/day (Baldwin et al., 2016; Christensen et al., 2021; Iovieno valerian and Ginkgo biloba) was not permitted within 2 weeks
et al., 2021; Thase et al., 2016). However, the effectiveness and before baseline or during the study period. Concomitant use of
tolerability of vortioxetine have not been demonstrated in patients
antipsychotic medication was not permitted during the study;
with a diagnosis of both MDD and GAD. This study was under- antipsychotic medications were to be discontinued at least
taken to assess the effectiveness and tolerability of vortioxetine
2 weeks before baseline (⩾6 months for depot formulations). Use
20 mg/day for the relief of symptoms of depression and anxiety in
of sedatives/hypnotics was not permitted within 1 day before
patients with MDD comorbid with GAD; patient functioning and
baseline or during the study period, with the exception of zolpi-
HRQoL were also assessed.
dem, zopiclone and zaleplon, use of which was permitted for a
maximum of two nights per week, excluding the night before a
study visit. Patients taking or likely to require any other medica-
Methods tion that could potentially interfere with study drug assessment or
the conduct or interpretation of the study were excluded from
Study design and participants
participation.
This was a multicentre, open-label effectiveness study in adult The study was conducted in accordance with the principles of
outpatients with MDD comorbid with GAD (NCT04220996). Good Clinical Practice and the Declaration of Helsinki. Local
The study included a 2-week screening period, an 8-week open- ethics committee approval was obtained at all participating sites
label, flexible-dose treatment period and a 4-week safety follow- and all patients provided written informed consent.
up period. Patients were aged 18–65 years with a primary
diagnosis of MDD (Diagnostic and Statistical Manual of Mental
Disorders (5th ed.; DSM-5) criteria (American Psychiatric Study assessments
Association, 2013), confirmed using the Mini International
Study assessments were conducted at baseline and at weeks 1, 4
Neuropsychiatric Interview); duration of current major depres-
and 8, with a follow-up safety assessment at 12 weeks.
sive episode (MDE) <12 months; comorbid GAD (diagnosed
Clinicians assessed symptom severity using the MADRS,
according to DSM-5 criteria before the current MDE);
HAM-A and Clinical Global Impression (CGI) scales, and func-
Montgomery–Åsberg Depression Rating Scale (MADRS) total
tioning using the Functioning Assessment Short Test (FAST).
score ⩾22 and Hamilton Anxiety Rating Scale (HAM-A) total
The FAST is a clinicianrated scale designed to assess patients’
score ⩾20. Patients with treatment-resistant depression (i.e. problems in daily functioning over the past 14 days across six
inadequate therapeutic response to ⩾2 previous drugs for depres- domains: autonomy, occupational functioning, cognitive func-
sion administered at the recommended dose for ⩾6 weeks) and tioning, financial issues, interpersonal relationships and leisure
those with a primary diagnosis of any other current psychiatric or time (Rosa et al., 2007). FAST total score ranges from 0 to 72
Axis I disorder were excluded. points, with higher scores indicating greater impairment in func-
Patients were receiving vortioxetine as their first treatment for tioning. Proposed ranges for mild, moderate and severe func-
the current MDE or switching to vortioxetine due to inadequate tional impairment are 12–20, 21–40 and >40 points, respectively
response to another drug for depression. Treatment with vortiox-
(Bonnín et al., 2018).
etine was initiated at the recommended starting dose of 10 mg/day,
Patients assessed anxiety and depressive symptoms using the
with forced up-titration to 20 mg/day in all patients after 1 week.
Hospital Anxiety and Depression Scale–Anxiety (HADS-A) and
Subsequent dose reductions were permitted based on individual
Hospital Anxiety and Depression Scale–Depression (HADS-D)
tolerability/response. A patient-specific log was used to track
subscales, and HRQoL using the Quality of Life Enjoyment and
study medication dispensed to and returned by patients at each
Satisfaction Questionnaire (Q-LES-Q) long-form. The Q-LES-Q
study visit. Patients considered by the investigator to be non-com-
long-form provides a comprehensive subjective assessment of
pliant with study medication were to be withdrawn from the study.
HRQoL across eight domains: physical health, subjective feel-
In patients switching to vortioxetine due to inadequate
ings, work, household duties, school/course work, leisure time
response to another drug for depression, prior treatment was to be
activities, social relationships and general activities (Endicott
discontinued at least 2 weeks before administration of the first
et al., 1993). The general activities domain of Q-LES-Q

long-form may be used as a short-form version of the Q-LES-Q

were conducted using SAS statistical software (version 9.4; SAS
(Stevanovic, 2011). Two domains assessing satisfaction with
Institute Inc., Cary, NC, USA), with significance set at p < 0.05.
medication and overall satisfaction and contentment are scored
separately. Q-LES-Q scores are expressed as a percentage of the
maximum score possible; higher scores signify better HRQoL. Results
All investigators received thorough training regarding admin-
istration and rating of the MADRS, HAM-A, CGI and FAST Study population
before being authorized to participate in the study.
This study was conducted at 17 sites in five countries (Poland,
Estonia, France, Spain and South Korea) between 27 December
Safety 2019 and 9 March 2021. At baseline, patients had on average
severe symptoms of depression (mean ± standard deviation (SD)
Treatment-emergent adverse events (TEAEs) were assessed over MADRS total score, 29.5 ± 4.7) and anxiety (HAM-A total score,
the entire study period and summarized by Medical Dictionary 28.6 ± 4.9), and severe impairment of functioning andHRQoL
for Regulatory Affairs preferred terms. The incidence of TEAEs (Table 1). Of the 102 patients enrolled, 100 received at least one
occurring on or after the day of vortioxetine dosage increase to dose of vortioxetine and were included in this analysis. Twenty-
20 mg/day was also assessed in patients who maintained this dose three patients were receiving vortioxetine as first-line treatment
until study completion or withdrawal; this was compared with the and 77 were switching to vortioxetine due to inadequate
incidence of TEAEs occurring at or after1 week for patients who response to prior therapy with another drug for depression
remained on vortioxetine 10 mg/day throughout the study. (Supplementary Table 1). Most patients were switching from an
SSRI (n = 56, most commonly escitalopram (n = 26)). Ninety-
Statistical analysis seven patients completed the study; two discontinued treatment
primarily due to adverse events (dysgeusia, n = 1; hypersensitiv-
Planned enrolment was 100 patients; with this sample size, and an ity, n = 1) and one patient withdrew consent. No patients were
assumed standard deviation of 10 points on the change in MADRS withdrawn from the study due to non-compliance with study
total score, precision with a 95% confidence interval of 4 points medication.
on the MADRS total score was expected. Effectiveness was ana- Twenty-one patients discontinued treatment with a drug for
lysed in all eligible patients who received at least one dose of vor- anxiety prior to initiating treatment with vortioxetine (five in the
tioxetine and had a valid baseline and at least one post-baseline first-treatment group and sixteen in the switch group). Five
assessment for MADRS total score (full analysis set). Safety was patients continued to take alprazolam after initiation of vortiox-
analysed in all enrolled patients who received at least one dose of etine treatment (one in the first-treatment group and four in the
vortioxetine (all treated patients set). Analyses were performed switch group). One patient in the switch group was also receiving
for the overall population and by treatment history (i.e. receiving diazepam and continued to take this after initiation of vortioxe-
vortioxetine as first-line treatment or switching to vortioxetine tine treatment. No patients initiated concomitant treatment with a
due to inadequate response to a previous drug for depression). drug for anxiety during the study.
The primary study endpoint was change from baseline to After 1 week of treatment, vortioxetine dosage was increased
week 8 in MADRS total score; secondary endpoints were the cor- to 20 mg/day in 94 patients. In all, 87 patients were receiving
responding changes in HAM-A, CGI-Severity (CGI-S), HADS- vortioxetine 20 mg/day at week 4 and continued on this dose until
D, HADS-A, FAST and Q-LES-Q scores, and CGI- study completion or withdrawal. Only four patients remained on
Improvement (CGI-I) score at each visit. Rates of response and vortioxetine 10 mg/day throughout the study. The mean ± SD
remission for MADRS and HAM-A after 8 weeks of vortioxetine dose of vortioxetine over the 8-week study period was 17.8 ± 2.6
treatment were also evaluated. Response was defined as ⩾50% mg/day.
decrease in MADRS and/or HAM-A total score from baseline;
remission was defined as MADRS and/or HAM-A total score
⩽10 at week 8. Effectiveness
For all effectiveness endpoints (except CGI-I), least-squares
Clinically and statistically significant improvements in clinician-
(LS) mean change from baseline was estimated using a mixed
and patient-assessed symptoms of depression and anxiety were
model for repeated measurements (MMRM), with week and site
observed after 8 weeks of vortioxetine treatment (p < 0.0001 for
as fixed factors and baseline score as a covariate. The interaction
all scales; Figure 1). For all scales, statistically significant
between week and baseline total score was included in the model
improvements were seen from week 1 (all p ⩽ 0.0007). Results
and an unstructured covariance matrix was applied. For CGI-I,
according to vortioxetine treatment line (first treatment or switch)
LS mean CGI-I score was estimated by a similar MMRM, but
are shown in Supplementary Figure 1 and Table 2.
with baseline CGI-S score as the baseline score covariate.
After 8 weeks of vortioxetine treatment, LS mean (standard
Descriptive and partial Pearson’s correlation coefficients
error (SE)) change in MADRS total score from baseline was
were calculated to assess correlations between HAM-A and
−16.8 (0.8) points (−19.7 (1.9) in the first-treatment group and
MADRS total scores and FAST total and Q-LES-Q general activ-
−16.1 (0.9) points in the switch group) (all p < 0.0001). At week 8,
ities scores. Partial correlation coefficients were calculated using
61% of patients achieved response and 35% achieved remis-
the baseline scores for the relevant scales as covariates. Analyses
sion based on MADRS score. The LS mean (SE) change in
HAM-A total score from baseline at week 8 was −16.1 (0.9)

Table 1. Patient demographics and disease characteristics at the start of vortioxetine treatment (all treated patients set).
First treatment (n = 23)a Switch (n = 77) Total (n = 100)b
Demographic characteristics
Age (years), mean ± SD 39.1 ± 12.5 43.1 ± 10.6 42.2 ± 11.1
Female, n (%) 13 (56.5) 50 (64.9) 63 (63.0)
White, n (%) 14 (60.9) 65 (84.4) 79 (79.0)
Features of current MDE
Duration (weeks), mean ± SD 13.6 ± 10.4 15.7 ± 9.1 15.2 ± 9.4
First MDE, n (%) 0 (0) 1 (1.3) 1 (1.0)
Number of prior MDEs, mean ± SD 2.9 ± 3.9 2.1 ± 2.3 2.2 ± 2.8
Vortioxetine dose (mg/day), mean ± SDc 16.7 ± 3.7 18.1 ± 2.1 17.8 ± 2.6
Clinical characteristics, mean ± SD score
MADRS total score 30.5 ± 4.0 29.2 ± 4.9 29.5 ± 4.7
HAM-A total score 30.7 ± 6.0 27.9 ± 4.3 28.6 ± 4.9
HADS-D score 13.3 ± 4.5 15.2 ± 4.2 14.7 ± 4.3
HADS-A score 15.2 ± 2.8 13.9 ± 3.5 14.2 ± 3.4
CGI-S score 5.0 ± 0.6 4.8 ± 0.6 4.9 ± 0.6
FAST total score 39.6 ± 13.2 42.8 ± 12.1 42.1 ± 12.4
Q-LES-Q general activities score (%)d 40.3 ± 14.9 38.0 ± 13.4 38.5 ± 13.7
Q-LES-Q overall satisfaction and contentment score (%)d 20.5 ± 16.6 25.6 ± 19.0 24.5 ± 18.6
CGI-S: Clinical Global Impression–Severity (score range = 1–7); FAST: Functioning Assessment Short Test (score range = 0–72); HADS-A: Hospital Anxiety and Depression
Scale–Anxiety (score range = 0–21); HADS-D: Hospital Anxiety and Depression Scale–Depression (score range = 0–21); HAM-A: Hamilton Anxiety Rating Scale (score
range = 0–56); MADRS: Montgomery–Åsberg Depression Rating Scale (score range = 0–60); MDE: major depressive episode; Q-LES-Q: Quality of Life Enjoyment and
Satisfaction Questionnaire; SD: standard deviation.
an = 22 for Q-LES-Q scores.
bn = 99 for Q-LES-Q scores.
cMean daily vortioxetine dose over the treatment period, calculated as the total dose received divided by the number of exposure days.
dTheQ-LES-Q numerical scale has been converted into a percentage scale by linear transformation of the scores into a scale of 0–100, where 0 corresponds to the worst
score and 100 to the best score on the numerical scale.
points (−18.4 (2.6) in the first-treatment group and −15.7 (0.9)

of vortioxetine treatment, the LS mean (SE) change in Q-LES-Q
points in the switch group) (all p < 0.0001). At week 8, 55% of
general activities score from baseline was 25.7% (2.5) (p < 0.0001)
patients achieved response and 42% achieved remission based on
(Table 2). Improvement in Q-LES-Q general activities score from
HAM-A score. In all, 52% of patients achieved response and 31%
baseline over the 8 weeks of vortioxetine treatment was 30.8%
achieved remission on both the MADRS and HAM-A scalesafter
(5.3) in the first-treatment group and 26.5% (2.8) in the switch
8 weeks of vortioxetine treatment.
group.
Significant improvements were also seen in CGI scores and
As shown in Table 3, changes from baseline to week 8 in
HADS-D and HADS-A subscale scores over the study period
MADRS and HAM-A total scores were significantly and strongly
(Figure 1). At week 8, LS mean (SE) change in CGI-S score from
positively correlated with FAST total score (partial r = 0.80 and
baseline was −2.1 (0.1) points (p < 0.0001). LS mean CGI-I
0.76, respectively; both p < 0.0001), and significantly and nega-
score at week 8 was 1.9 (0.1) points, with 75.3% of patients con-
tively correlated with Q-LES-Q general activities score (partial
sidered much or very much improved (CGI-I score ⩽2 points).
r = −0.65 and −0.62, respectively; both p < 0.0001).
After 8 weeks of vortioxetine treatment, LS mean (SE) changes
in HADS-D and HADS-A scores were −8.2 (0.5) and −7.2 (0.5)
points, respectively (both p < 0.0001 vs baseline). CGI-I score Safety
and improvements in CGI-S, HADS-D and HADS-A scores after In total, 46 patients (46%) reported a TEAE (Table 4). The most
8 weeks of vortioxetine treatment were generally similar in the common TEAEs (reported by >5% of patients) were nausea and
first-treatment and switch groups (Table 2).
abdominal pain. All TEAEs were of mild or moderate intensity.
Statistically significant improvements were seen in FAST total
No serious adverse events were reported.
score and across all FAST domains after 8 weeks of vortioxetine After week 1, TEAEs were reported in 17 of the 86 patients
treatment (Figure 2; all changes p < 0.0001 vs baseline). At week 8, who increased vortioxetine dosage to 20 mg/day and remained on
the LS mean (SE) change in FAST total score from baseline was this dosage to study end (most commonly, abdominal pain (five
−23.0 (1.6) points (p < 0.0001), with similar improvements seen patients) and nausea (four patients)). TEAEs were reported after
in the first-treatment and switch groups (Table 2). Statistically sig- week 1 in two of the four patients who remained on vortioxetine
nificant improvement was also seen across all Q-LES-Q long- 10 mg/day throughout the study (headache and hypersensitivity,
form domains (Figure 3; most changes p < 0.0001). After 8 weeks each reported by one patient).

(a) MADRS total score (b) HAM-A total score

Time (week) Time (week)
0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8
0 0
-2 -2
LS mean change from baseline

-4 p<0.0001 -4 p<0.0001
-6 -6
-8 -8
-10 -10
-12 -12
-14 -14
-16 -16
-18 -18
-20 -20
(c) HADS-D subscale score (d) HADS-A subscale score

Time (week) Time (week)
00 1 2 3 4 5 6 7 8 00 1 2 3 4 5 6 7 8
-1 -1
-2 -2
-3 -3
p<0.0001 p<0.0001
-4 -4
-5 -5
-6 -6
-7 -7
-8 -8
-9 -9
-10 -10
(e) CGI-S score (f) CGI-I score

Time (week)
0 1 2 3 4 5 6 7 8 -3.0
0.0 -
2.
0
mean change from baseline
-0.5
p<0.0001 -
2.5
-1.0
-1.5

Christensen et al. 4.0 571
3.5
3.0
p
LS mean score
2.5 <
0
2.0
.
1.5 0
0
1.0 0
1
0.5
0.0
0
1
2
3
4
5
6
7
8
T
i
m
e
(
w
e
e
k
)
Figure 1. Panels (a) to (e): LS mean (SE) change from baseline for (a) MADRS total score, (b) HAM-A total score, (c) HADS-D subscale score, (d)
HADS-A subscale score and (e) CGI-S score; panel (f): LS mean (SE) CGI-I score (full analysis set). For panels (a) to (e), p-values are at week 8 vs
baseline; for panel (f), p-value is at week 8 based on a test of CGI-I score = 4 (no improvement).
CGI-I: Clinical Global Impression–Improvement; CGI-S: Clinical Global Impression–Severity; HADS-A: Hospital Anxiety and Depression Scale–Anxiety; HADS-D: Hospital Anxi-
ety and Depression Scale–Depression; HAM-A: Hamilton Anxiety Rating Scale; LS: least-squares; MADRS: Montgomery–Åsberg Depression Rating Scale; SE: standard error.

Table 2. Results of the mixed-model repeated measurements analyses for key effectiveness outcomes after 8 weeks of vortioxetine treatment (full analysis
set). For all values except CGI-I, LS mean (SE) change from baseline is shown; for CGI-I, LS mean (SE) score is shown.
Outcomea First treatment Switch Total
Patients included in model, n 20 77 97

MADRS total score
LS mean (SE) −19.7 (1.9) −16.1 (0.9) −16.8 (0.8)
(95% CI) (−23.7, −15.7) (−17.9, −14.4) (−18.4, −15.3)
p-value <0.0001 <0.0001 <0.0001
HAM-A total score
LS mean (SE) −18.4 (2.6) −15.7 (0.9) −16.1 (0.9)
(95% CI) (−23.7, −13.0) (−17.5, −13.9) (−17.8, −14.3)
p-value <0.0001 <0.0001 <0.0001
HADS-D score
LS mean (SE) −6.7 (1.3) −8.5 (0.6) −8.2 (0.5)
(95% CI) (−9.6, −3.9) (−9.7, −7.3) (−9.2, −7.1)
p-value 0.0002 <0.0001 <0.0001
HADS-A score
LS mean (SE) −7.5 (1.2) −7.0 (0.5) −7.2 (0.5)
(95% CI) (−9.9, −5.0) (−8.0, −5.9) (−8.2, −6.2)
p-value <0.0001 <0.0001 <0.0001
CGI-S score
LS mean (SE) −2.4 (0.3) −2.0 (0.1) −2.1 (0.1)
(95% CI) (−2.9, −1.9) (−2.3, −1.8) (−2.4, −1.9)
p-value <0.0001 <0.0001 <0.0001
CGI-I score
LS mean (SE) 1.8 (0.2) 2.0 (0.1) 1.9 (0.1)
(95% CI) (1.3, 2.2) (1.7, 2.2) (1.7, 2.2)
p-value <0.0001 <0.0001 <0.0001
FAST total score
LS mean (SE) −24.1 (2.9) −23.4 (1.8) −23.0 (1.6)
(95% CI) (−30.5, −17.7) (−27.0, −19.9) (−26.2, −19.8)
p-value <0.0001 <0.0001 <0.0001
Q-LES-Q general activities score (%)b
LS mean (SE) 30.8 (5.3) 26.5 (2.8) 25.7 (2.5)
(95% CI) (19.1, 42.6) (21.0, 32.0) (20.7, 30.7)
p-value 0.0002 <0.0001 <0.0001
Q-LES-Q overall satisfaction and contentment score (%)b
LS mean (SE) 44.0 (7.9) 38.5 (3.6) 38.3 (3.4)
(95% CI) (26.4, 61.5) (31.3, 45.8) (31.5, 45.2)
p-value 0.0002 <0.0001 <0.0001
CGI-I: Clinical Global Impression–Improvement; CGI-S: Clinical Global Impression–Severity; CI: confidence interval; FAST: Functioning Assessment Short Test; HADS-A:
Hospital Anxiety and Depression Scale–Anxiety; HADS-D: Hospital Anxiety and Depression Scale–Depression; HAM-A: Hamilton Anxiety Rating Scale; LS: least-squares;
MADRS: Montgomery–Åsberg Depression Rating Scale; Q-LES-Q: Quality of Life Enjoyment and Satisfaction Questionnaire; SE: standard error.
LS means and 95% CI were estimated using a mixed-model repeated measurements analysis with week and site as fixed factors and baseline score as a covariate. The
interaction between week and baseline total score was included in the model and an unstructured covariance matrix was applied with week, site and week, and baseline
score interaction as fixed factors, and baseline score as a covariate.
aFor all outcomes except CGI-I, p-values are at week 8 versus baseline; for CGI-I, p-value is at week 8 based on a test of CGI-I score = 4 (no improvement).
bTheQ-LES-Q numerical scale has been converted into a percentage scale by linear transformation of the scores into a scale of 0–100, where 0 corresponds to the worst
score and 100 to the best score on the numerical scale.
Discussion effects were already observed after 1 week and continued to

increase over the treatment course. At week 8, 35% of patients had
Vortioxetine demonstrated effectiveness in significantly reducing
achieved remission from depressive symptoms and 42% had
both depressive and anxiety symptoms in this population of
achieved remission from anxiety symptoms. The improvement in
patients with severe MDD and severe comorbid GAD, the major-
symptoms of depression and anxiety was accompanied by signifi-
ity of whom showed inadequate response to prior treatment with
cant and broad improvement in patients’ daily functioning and
another drug for depression. Significant and clinically meaningful
their self-perceived ability to perform and enjoy a broad range of

50 Baseline CFB (Week 8) Week 8
42.3
40
30
FAST total and domain scores
19.3
20
11.0
9.9 9.8
10
5.6 5.7
4.6 4.1 4.5
2.2 1.6 2.3
0.5
0
-1.1
-2.2
-3.4
-5.3 -5.7 -5.3
-10
-20
-23.0
-30
Total Autonomy Occupational Cognitive Financial Interpersonal Leisure
issues relationships
functioning function
Figure 2. FAST total and domain scores at baseline and change (SE) from baseline after 8 weeks of treatment with vortioxetine (full analysis set;
patients with a corresponding baseline score). p < 0.0001 for all changes from baseline.
FAST: Functioning Assessment Short Test; CFB: change from baseline; SE: standard error.
activities of daily life. Clinically meaningful improvement in

adverse events was not increased in patients who received vorti-
symptoms of depression and anxiety, as well as functioning and
oxetine 20 mg/day compared with those who received 10 mg/day
HRQoL, was seen in patients receiving vortioxetine as first-line
(Christensen et al., 2021). In a recent open-label study with flex-
treatment and in those who were switching to vortioxetine due to
ible vortioxetine dosing in patients with MDD and inadequate
inadequate response to prior therapy. However, greatest improve-
response to prior treatment with another drug for depression
ments were generally seen when vortioxetine was used as a first-
(Fagiolini et al., 2021), vortioxetine dosage was increased to
line therapy. Per protocol, vortioxetine dosage was to be up-titrated
20 mg/day after 1 week in 38/143 patients (27%), only three of
to 20 mg/day from the starting dose of 10 mg/day after 1 week of
whom had their dosage subsequently decreased. Half of all
treatment. Almost all patients (94%) had their vortioxetine dosage
patients were receiving vortioxetine 20 mg/day at study end.
increased at that time, and treatment with vortioxetine 20 mg/day
The observed improvement in symptoms of both depression
was generally well tolerated.
and anxiety in patients receiving treatment with vortioxetine in
Vortioxetine is the only drug for depression with a demon- this study is noteworthy as patients with MDD and comorbid
strated dose–response relationship across the full therapeuticdose
GAD are generally considered difficult to treat, typically achiev-
range (5–20 mg/day) (Baldwin et al., 2016; Christensenet al.,
ing poorer treatment outcomes than those with either condition
2021; Iovieno et al., 2021; Thase et al., 2016), as isacknowledged
alone (Dold et al., 2017; Kelly and Mezuk, 2017; Kessler et al.,
in the EU Summary of Product Characteristics (European
2008). Assessment of the clinical effectiveness of drugs for
Medicines Agency, 2020). Available data indicate that an early
depression in patients with a diagnosis of both MDD and GAD is
increase in vortioxetine dosage from 10 to 20 mg/day isgenerally
rare; however, evidence of effectiveness in this patient popula-
well tolerated and does not prompt a need for subsequent dosage
tion is clinically relevant given how frequently these two condi-
reduction or treatment withdrawal. In a pooled analysis of data
tions are comorbid (Montgomery, 2019; Saha et al., 2021).
from three randomized, controlled, flexible-dosestudies, 48% of
The beneficial effects of vortioxetine against symptoms of
vortioxetine-treated patients had their dosage increased to 20
depression and anxiety are most likely due to its multimodal
mg/day after the first week of treatment and 64% were receiving mechanism of action. Vortioxetine has been shown to be a 5-HT3,
vortioxetine 20 mg/day at their last study visit (Christensen et al.,
5-HT7 and 5-HT1D receptor antagonist, a 5-HT1B receptor partial
2021). Importantly, vortioxetine dose up-titra-tion did not appear
agonist and a 5-HT1A receptor agonist, as well as an inhibitor of
to compromise tolerability; the incidence of
the 5-HT transporter (Bang-Andersen et al., 2011;

80 Baseline CFB (Week 8) Week 8

74.1
70
Q-LES-Q (long-form) domain score (%)
65.6 66.4
64.0 63.7
62.3
60.2 60.5
60 57.8
55.8
50
38.3
40.9
40 36.3
38.3 38.3 38.0
35.9
34.8 34.2
29.3
28.0 28.1 28.2 33.1
29.8
30 26.2
25.7
25.4
24.0
20 17.5
10
Figure 3. Q-LES-Q long-form domain scores at baseline and change (SE) from baseline after 8 weeks of treatment with vortioxetine (full analysis
set, patients with a corresponding baseline score). The Q-LES-Q numerical scale has been converted into a percentage scale by linear transformation
of the scores into a scale of 0–100, where 0 corresponds to the worst score and 100 to the best score on the numerical scale. p < 0.0001 for all
changes from baseline.
CFB: change from baseline; Q-LES-Q long-form: Quality of Life Enjoyment and Satisfaction Questionnaire long-form; SE: standard error.
Table 3. Correlation analysis of change from baseline to week 8 in key endpoints (full analysis set).
HAM-A total score MADRS total score FAST total score
HAM-A total score 1 – –

MADRS total score 0.86 (0.90) 1 –
FAST total score 0.63 (0.76) 0.69 (0.80) 1
Q-LES-Q general activities score −0.62 (−0.62) −0.70 (−0.65) −0.68 (−0.67)
FAST: Functioning Assessment Short Test; HAM-A: Hamilton Anxiety Rating Scale; MADRS: Montgomery–Åsberg Depression Rating Scale; Q-LES-Q: Quality of Life Enjoyment
and Satisfaction Questionnaire.
Pearson’s (partial) correlation coefficients are shown. All p-values < 0.0001.
Pearson’s (partial) correlation coefficients p > (r) under H0: (partial) correlation = 0.
Mørk et al., 2012; Sanchez et al., 2015). As such, vortioxetine

To fully appreciate the results of this study, it is relevant to
modulates several neurotransmitter systems relevant to the neu-
consider the results observed in earlier studies with vortioxetine
robiology of depression and anxiety, including not only the sero-
in patients with a diagnosis of either MDD or GAD alone. The
toninergic system, but probably also the norepinephrine,
observed improvement in depressive symptoms (reduction in
dopamine, histamine, acetylcholine, gamma-aminobutyric acid,
MADRS total score, −16.8 points) is comparable to that reported
and glutamate systems (Riga et al., 2016; Stahl, 2015). The
in fixed-dose, randomized controlled trials of vortioxetine 10 or
effects of vortioxetine on 5-HT1A, 5-HT3 and 5-HT7 receptors
20 mg/day in patients with MDD alone (Boulenger et al., 2014;
and the 5-HT transporter, in particular, are considered responsi-
Inoue et al., 2020; Jacobsen et al., 2015; Mahableshwarkar et al.,
ble for its anxiolytic-like effects.
2015; McIntyre et al., 2014; Nishimura et al., 2018), and is of a
Table 4. Overview of TEAEs occurring in ⩾2% of patients during the 8-week treatment period (all treated patients set).
First treatment (n = 23) Switch (n = 77) Total (n = 100)
Any TEAE, n (%) 15 (65.2) 31 (40.3) 46 (46.0)

Nausea 8 (34.8) 13 (16.9) 21 (21.0)
Abdominal pain 0 6 (7.8) 6 (6.0)
Anxiety 1 (4.3) 2 (2.6) 3 (3.0)
Back pain 0 3 (3.9) 3 (3.0)
Dizziness 0 3 (3.9) 3 (3.0)
Decreased appetite 1 (4.3) 1 (1.3) 2 (2.0)
Headache 0 2 (2.6) 2 (2.0)
Middle insomnia 0 2 (2.6) 2 (2.0)
Vomiting 2 (8.7) 0 2 (2.0)
TEAE: treatment-emergent adverse event.
similar magnitude to that seen in flexible-dose studies of vorti-

have been reported in community samples of healthy individuals
oxetine 10–20 mg/day in patients with MDD without comorbid
with no history of mental illness (Rapaport et al., 2005; Schechter
GAD who had inadequate response to prior therapy with another
et al., 2007). Improvements in Q-LES-Q general activities scores
drug for depression (Fagiolini et al., 2021; Montgomery et al.,
of 11.9% and 6.8% have been suggested as minimum clinically
2014).
important changes in patients with bipolar depressive disorder
With regard to anxiety symptoms, the improvement in HAM- and GAD, respectively, treated with quetiapine for 8 weeks
A total score after 8 weeks of vortioxetine treatment in thisstudy (Endicott et al., 2007; Wyrwich et al., 2009). The LS mean
(−16.1 points) is greater than that reported in a randomized improvement in Q-LES-Q general activities score seen in patients
controlled trial in patients with GAD alone treated with vortiox-
with MDD comorbid with GAD after 8 weeks of vortioxetine
etine 5 mg/day (−14.3 points) (Bidzan et al., 2012). The reduction
treatment in this study (25.7%) was greater than these proposed
in HAM-A total score of −15.7 points seen in patients switching thresholds and similar to that previously reported in patients with
to vortioxetine in this study is also greater than that reported in a either condition alone following treatment with escitalopram
randomized, flexible-dose study of vortioxetine 10–20 mg/day in
(Demyttenaere et al., 2008).
patients with MDD and significant anxiety symptoms who had
The Q-LES-Q was described by its developers as a question-
inadequate response to prior therapy (−11.7 points) (Montgomery
naire that “evaluates patients’ enjoyment and satisfaction with
et al., 2014). Our findings support earlier evidence of a dose–
different aspects of their lives” (Endicott et al., 1993). However,
response effect for vortioxetine for the treatment of anxiety
it is clear that the scale captures more than these aspects of
symptoms (Baldwin et al., 2016), as also reported for depressive
HRQoL; indeed, it probes in detail about patients’ physical health
symptoms (Baldwin et al., 2016; Christensen et al., 2021; Iovieno
and their ability to perform activities of daily living and engage
et al., 2021; Thase et al., 2016).
in work and social activities. The long-form questionnaire com-
Substantial and broad improvements were observed in prises 93 items eliciting information on physical health, subjec-
patients’ daily functioning, as comprehensively assessed by the tive feelings, work, household duties, school/course work, leisure
investigator using the FAST scale. The FAST captures not only time activities, social relationships and general activities. For
how well patients are functioning at home, work and in their instance, the 13 questions covering physical health explore
social life, but also their ability to take care of personal finances whether patients have ‘been free of visual problems’, ‘completely
and cognitive functioning. Patients had severe functional impair- free of aches, pains, or discomfort’ and ‘felt your memory was
ment at baseline, and only mild impairment after 8 weeks of vor- functioning well’. The 13 questions covering the work domain
tioxetine treatment (FAST total score, 42.1 vs 20.1 points). The include ‘solved work problems or dealt with them without undue
observed change in FAST total score (−23.0 points) is greater stress’, ‘been decisive about work, or made decisions’ and ‘com-
than that reported in a randomized controlled trial in working municated and interacted with ease with others while working’.
patients with MDD over 8 weeks of fixed-dose treatment with In the subjective feelings domain, the 14 questions assess aspects
vortioxetine 10 mg/day or paroxetine 20 mg/day (−13.0 and such as feeling ‘clearheaded’, ‘able to travel about to get things
−11.0 points, respectively, vs −8.3 points for placebo) (Baune done’ and ‘able to communicate with others’. The marked
et al., 2018). The significant and substantial improvements seen improvement across all domains of the Q-LES-Q long-form in
across all domains on the FAST scale in this study are particu- this study substantiates the clinical relevance of the significant
larly noteworthy, as domains such as work functioning do not improvements in symptoms of depression and anxiety seen over
necessarily show meaningful improvement after only 8 weeks of the 8 weeks of vortioxetine treatment.
treatment.
This study was conducted in routine practice conditions in a
Although patients had significantly impaired HRQoL at base- representative population of patients with MDD and comorbid
line (mean Q-LES-Q general activities score, 38.5%), significant GAD and therefore provides new clinically relevant information
improvements in all HRQoL domains were seen after 8 weeks
about vortioxetine in this patient group. Potential limitations
(mean Q-LES-Q general activities score at week 8, 62.5%).Mean
include those generally associated with open-label studies due to
Q-LES-Q general activities scores of approximately 80%
lack of blinding, the lack of a placebo or active-comparator arm,

and the relatively short duration of treatment (8 weeks). As American Psychiatric Association (2013) Diagnostic and Statistical
patients with mood and anxiety disorders generally require long- Manual of Mental Disorders (5th edn). Washington, DC: American
term treatment, studies involving longer durations of vortioxetine Psychiatric Association.
treatment in this patient population would be of clinical interest.
Notably, results of a previous study in patients with GAD found
vortioxetine 5 or 10 mg/day to be significantly more effective
than placebo for the prevention of relapse over a period of up to
56 weeks (Baldwin et al., 2012).
Conclusion
In summary, results of this study demonstrate the effectiveness of
vortioxetine 20 mg/day for the treatment of symptoms of both
depression and anxiety in patients with severe MDD comorbid with
severe GAD. The observed beneficial effects on depressive and
anxiety symptoms were already significant after 1 week and contin-
ued to increase over the 8 weeks of treatment. The improvements in
symptoms of depression and anxiety were significantly correlated
with broad improvements in overall functioning and HRQoL.
Findings also support increasing vortioxetine dosage to 20 mg/day
early in the course of therapy, and show that this is well tolerated.
Acknowledgements
Editorial assistance in the preparation of this manuscript was provided by
Jennifer Coward of Piper Medical Communications, funded by H.
Lundbeck A/S.
Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with
respect to the research, authorship and/or publication of this article:
M.C.C. and S.S. are employees of H. Lundbeck A/S. I.G. is an adviser,

consultant and/or speaker for Lundbeck, Otsuka, Angelini, Casen
Recordati, Ferrer and Janssen Cilag, and has received research funding
from the Instituto de Salud Carlos III, Ministry of Economy and
Competitiveness, Spain.
Funding
The author(s) disclosed receipt of the following financial support for the
research, authorship and/or publication of this article: The RECONNECT
study was funded by H. Lundbeck A/S.
ORCID iD
Michael Cronquist Christensen https://orcid.org/0000-0002-
3605-7223
Data availability statement

The authors confirm that the data supporting the findings of this study
areavailable within the article. The authors may be contacted for further
datasharing.
Supplemental material
Supplemental material for this article is available online.
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Christensen MC, Schmidt S, Grande I.

Effectiveness of vortioxetine in patients with major depressive

Moctezuma Vargas Carlos Gabriel 3°I

El trastorno depresivo mayor y el trastorno de ansiedad generalizada son con frecuencia

Moctezuma Vargas Carlos Gabriel 3°I

Effectiveness of vortioxetine in patients withmajor depressive

Michael Cronquist Christensen1 , Simon Schmidt1and Iria Grande2

© The Author(s) 2022

Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/02698811221090627

Moctezuma Vargas Carlos Gabriel 3°I

Introduction receptor subtypes (5-HT3, 5-HT7 and 5-HT1D receptor antagonist,

Moctezuma Vargas Carlos Gabriel 3°I

symptoms (Bidzan et al., 2012). Vortioxetine 5 or 10 mg/day has

Moctezuma Vargas Carlos Gabriel 3°I

long-form may be used as a short-form version of the Q-LES-Q

Moctezuma Vargas Carlos Gabriel 3°I

First treatment (n = 23)a Switch (n = 77) Total (n = 100)b

an = 22 for Q-LES-Q scores.

bn = 99 for Q-LES-Q scores.

points (−18.4 (2.6) in the first-treatment group and −15.7 (0.9)

Moctezuma Vargas Carlos Gabriel 3°I

(a) MADRS total score (b) HAM-A total score

LS mean change from baseline

(c) HADS-D subscale score (d) HADS-A subscale score

(e) CGI-S score (f) CGI-I score

Moctezuma Vargas Carlos Gabriel 3°I

Moctezuma Vargas Carlos Gabriel 3°I

Outcomea First treatment Switch Total

Patients included in model, n 20 77 97

Discussion effects were already observed after 1 week and continued to

Moctezuma Vargas Carlos Gabriel 3°I

50 Baseline CFB (Week 8) Week 8

activities of daily life. Clinically meaningful improvement in

Moctezuma Vargas Carlos Gabriel 3°I

80 Baseline CFB (Week 8) Week 8

HAM-A total score MADRS total score FAST total score

HAM-A total score 1 – –

Mørk et al., 2012; Sanchez et al., 2015). As such, vortioxetine

First treatment (n = 23) Switch (n = 77) Total (n = 100)

Any TEAE, n (%) 15 (65.2) 31 (40.3) 46 (46.0)

TEAE: treatment-emergent adverse event.

similar magnitude to that seen in flexible-dose studies of vorti-

Moctezuma Vargas Carlos Gabriel 3°I

Declaration of conflicting interests

M.C.C. and S.S. are employees of H. Lundbeck A/S. I.G. is an adviser,

Data availability statement

Moctezuma Vargas Carlos Gabriel 3°I

Baune BT, Sluth LB and Olsen CK (2018) The effects of vortioxetine

Bidzan L, Mahableshwarkar AR, Jacobsen P, et al. (2012) Vortioxetine

Bonnín CM, Martínez-Arán A, Reinares M, et al. (2018) Thresholds for

Chokka P, Ge H, Bougie J, et al. (2021) Anxiety symptoms in work-

Christensen MC, Florea I, Lindsten A, et al. (2018) Efficacy of vortiox-

Christensen MC, McIntyre RS, Florea I, et al. (2021) Vortioxetine 20

Demyttenaere K, Andersen HF and Reines EH (2008) Impact of esci-

Dold M, Bartova L, Souery D, et al. (2017) Clinical characteristics and

Moctezuma Vargas Carlos Gabriel 3°I

Gonda X, Sharma SR and Tarazi FI (2019) Vortioxetine: A novel antide-

Inoue T, Sasai K, Kitagawa T, et al. (2020) Randomized, double-blind,

Iovieno N, Papakostas GI, Feeney A, et al. (2021) Vortioxetine versus