Journal of Affective Disorders 266 (2020) 540–548

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Journal of Affective Disorders

journal homepage: www.elsevier.com/locate/jad

Review article

Comparative efficacy of nine antidepressants in treating Chinese patients T

with post-stroke depression: A network meta-analysis
⁎
Li Xinyuana, , Zhang Congxiaob
a
Department of Neurology, the First Hospital of Jilin University, No 71 Xinmin Street, Changchun, Jilin 130021, China
b
Department of Stomatology, the First Hospital of Jilin University, Changchun, China

A R T I C LE I N FO A B S T R A C T

Keywords: Background: The efficacy ranking of antidepressants for post-stroke depression (PSD) has not been assessed
Network meta-analysis thoroughly yet due to the lack of network meta-analyses with sufficiently large sample size.
Efficacy Methods: Seven databases including PubMed, Embase, CENTRAL, CBM, CNKI, WanFang and VIP were system-
Nine antidepressants atically searched for eligible randomized controlled trials (RCTs) regarding nine antidepressants (citalopram,
Post-stroke depression
escitalopram, venlafaxine, paroxetine, duloxetine, amitriptyline, doxepin, sertraline and mirtazapine) treating
PSD patients. Stata 15 software and R software were utilized for statistical analyses.
Results: 51 RCTs were included in this NMA. For the key efficacy outcomes, escitalopram, mirtazapine, ser-
traline, citalopram, venlafaxine and paroxetine were associated with larger reduction of the Hamilton
Depression Scale (HAMD) total score compared with placebo at 2 weeks. Among the nine antidepressants, es-
citalopram ranked the best while amitriptyline was the least helpful. At 4 weeks, citalopram ranked higher than
placebo and the other eight antidepressants. In contrast, amitriptyline and doxepin were associated with
minimal reduction of HAMD score. At 8 weeks, changes in HAMD score were significantly greater in nine
antidepressants groups compared to placebo group. Besides, mirtazapine ranked higher than citalopram and
escitalopram. At endpoint, mirtazapine was related to the highest response rate, followed by venlafaxine and
escitalopram, respectively.
Limitations: No restriction was imposed on doses of every antidepressant.
Conclusions: Escitalopram was associated with a quicker relief of depression, but mirtazapine was probably the
best option when it comes to the efficacy of 8-week treatment duration. Amitriptyline and doxepin were nearly
the worst choice regardless of the duration (2, 4 or 8 weeks).

1. Introduction is therefore important to develop effective antidepressant treatments

Depression is the most frequent neuropsychiatric complication after
cerebrovascular accidents, affecting approximately one-third of all
stroke survivors (Levada and Troyan, 2018; Hackett and Pickles, 2014).
The core symptomatology is low mood (He et al., 2017), apathy, fa-
tigue, insomnia, feelings of worthlessness (Robinson and
Spalletta, 2010; Egorova et al., 2018) and even suicide (Duan et al.,
2018). In return, post-stroke depression (PSD) has a negative impact on
physical, cognitive and functional rehabilitation, leading to increased
risk of the recurrence of vascular events, poorer quality of life, lower
social participation, and higher mortality (Miranda et al., 2018;
Wang et al., 2018). Moreover, without early recognition and proper
interventions, depressive symptoms turn to be chronic, which would
put strain on medical resources and would increase healthcare costs. It
(Zhang et al., 2016).
Currently, there are a wide range of antidepressants such as tricyclic
antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selec-
tive serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine
reuptake inhibitors (SNRIs), and noradrenergic and specific ser-
otonergic antidepressants (NaSSAs) (Nabavi et al., 2014;
Niedermaier et al., 2004). However, there has not been any obvious
decrease in the percentage of post-stroke patients experiencing de-
pression, one reason is that some clinicians fail to differentiate de-
pressive symptoms from signs of normal aging and stroke, including
reduced sleep and fatigue (Lökk and Delbari, 2010), and they give
priority to antiplatelet therapy and rehabilitation training in the acute
phase of cerebral infarction. Another cause is that the guideline for
antidepressants treating PSD is lacking (Winstein et al., 2016).

⁎
Corresponding author.
E-mail address: xyl01180@163.com (X. Li).

https://doi.org/10.1016/j.jad.2020.02.005
Received 15 July 2019; Received in revised form 19 January 2020; Accepted 1 February 2020
Available online 03 February 2020
0165-0327/ © 2020 Elsevier B.V. All rights reserved.
X. Li and C. Zhang
Although several traditional pairwise meta-analyses evaluating the ef-
ficacy of antidepressants compared to placebo have been conducted,
the majority of clinicians still have trouble choosing a preferred option
when faced with numerous antidepressants. This is because conven-
tional meta-analyses fail to rank different classes of antidepressants
clearly based on efficacy outcomes.
Taking these into consideration, it is necessary to perform network
meta-analyses to compare relative effectiveness of various frequently-
used antidepressants. Network meta-analyses provide a statistical fra-
mework that allows direct and indirect comparisons and then create the
rank orders of different interventions (Rouse et al., 2017). To date,
there are three network meta-analyses (Sun et al., 2017; Deng et al.,
2018; Qin et al., 2018) that have been performed to evaluate relative
efficacy of antidepressants in treating PSD, however, the sample size is
very limited (less than 15 studies), which is not robust enough to inform
clinical practice. To strengthen the evidence, we thereby performed a
network meta-analysis of 51 studies to assess comparative effectiveness
of different classes of antidepressants thoroughly. Moreover, we se-
lected nine commonly prescribed antidepressants, three (mirtazapine,
amitriptyline,escitalopram) of which have not been evaluated yet in the
network meta-analyses mentioned above (Sun et al., 2017; Deng et al.,
2018; Qin et al., 2018). To our knowledge, this is the first network
meta-analysis to explore proper antidepressant management for PSD
with the largest sample size.
2. Methods
2.1. Search strategy
This network meta-analysis (NMA) was performed in accordance
with the Preferred Reporting Items for Systematic Reviews and Meta-
Analyses (PRISMA) guidelines (Moher et al., 2009). PubMed, Embase,
Cochrane Center Register of Controlled Trials (CENTRAL), Chinese
Biomedical Literature Database (CBM), China National Knowledge In-
frastructure (CNKI), WanFang Database and VIP Chinese Journal Da-
tabase were systematically searched for relevant trials concerning an-
tidepressants for post-stroke depression from inception to December 28,
2018. The key searching terms includes “post-stroke depression”,
“PSD”, “depression after stroke”, “depression after cerebrovascular
events”, “escitalopram”, “citalopram”, “duloxetine”, “paroxetine”,
“mirtazapine”, “doxepin”, “amitriptyline”, “venlafaxine”, “sertraline”,
“randomized controlled trials” and “RCT”. The detailed search strate-
gies were presented in supplementary appendix 1. All searches were
restricted to published literature and language was limited to English
and Chinese. Conference abstracts or letters to editor were excluded.
Additionally, in order not to miss any additional eligible studies, we
conducted manual searches of the reference lists from all relevant meta-
analyses and systematic reviews. A updated search was performed on
February 10, 2019 using the same strategy.
All identified articles were combined in a single reference manager
file (EndNote X9) (Bramer, 2018). Duplicates were discarded and the
titles and abstracts were reviewed to exclude studies that cannot meet
the predefined selection criteria. The full-text versions of the remaining
publications were then retrieved for inclusion. The abstract and full-text
selection process was performed by two independent authors (Xinyuan
Li and Congxiao Zhang) and any disagreement was resolved by dis-
cussion until consensus was reached.
2.2. Inclusion criteria
Inclusion criteria were as follows: (1) patients aged above 18 had a
diagnosis of stroke based on computer tomography (CT), magnetic re-
sonance imaging (MRI), or clinical criteria; (2) symptoms of depression
were diagnosed clearly according to the International Classification of
Diseases, Tenth Edition (ICD-10) (Sheehan et al., 1998), Chinese Clas-
sification of Mental Disorders (CCMD) (Zou et al., 2008) or the
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Journal of Affective Disorders 266 (2020) 540–548
Diagnosis and Statistical Manual of Mental Disorders, Fourth Edition
(DSM-IV) or later versions (American Psychiatric Association, 1994);
(3) studies were performed with a randomized controlled design; (4)
the intervention group used any of the nine antidepressants while pa-
tients in control groups received any of the other eight antidepressants
or placebo; (5) studies reported at least one of the following efficacy
outcomes: mean changes in the Hamilton Depression Scale (HAMD)
total score and/or response rate.
2.3. Exclusion criteria
Trials were excluded if they included patients with: (1) schizo-
phrenia or any mental disorders other than depression; (2) combination
therapy such as antidepressants combined with psychotherapy or
electroconvulsive therapy; (3) a history of alcohol or any psychoactive
substance abuse or dependence within the past 6 months; (4) risk of
suicide; (5) any serious medical illness that precluded antidepressants
use; (6) sample size<40 (either treatment groups or controls). Trials
were also excluded if 17-item of HAMD total score<17 or the 24-item
version<20.
2.4. Data extraction
Two authors extracted data from included studies independently
and consensus was reached by discussion. Information was extracted as
follows: first author's name, year of publication, study design, age, sex
distribution, intervention, number of participants, treatment duration,
the evaluation scale of depression and efficacy outcome measures.
2.5. Outcome measures
The primary outcomes were mean changes in the total score of the
HAMD from baseline to 2 weeks, 4weeks, 8 weeks and endpoint. The
secondary efficacy outcome was response rate. The response rate was
defined as a decrease of≥50% in the HAMD total score from baseline to
endpoint.
2.6. Quality assessment
Two authors independently assessed the risk of bias in included
trials using Review manager 5.3 based on the Cochrane Collaboration's
Risk of Bias Tool 5.1.0 (Higgins et al., al.,2011) and disagreements were
resolved by discussion. Quality criteria were assessed based on seven
domains: random sequence generation, allocation concealment,
blinding of outcome assessment, blinding of participants and personnel,
incomplete outcome data, selective reporting, and other bias. Risk of
bias was categorized as low, high, or unclear.
2.7. Statistical analysis
We conducted a network meta-analysis to combine direct and in-
direct evidence for 9 antidepressants and placebo treatment using a
multivariate meta-analysis model implemented in STATA 15 software
(Stata Corp College Station, Texas, USA) (Statacorp, 2010). R software
(version 3.3.3) was used to perform forest plots. Mean differences
(MDs) with 95% confidence intervals (CIs) were calculated for con-
tinuous data, and odds ratios (ORs) with 95% CIs were calculated for
dichotomous variables. If the 95%CI did not include 0 (for MD) or 1 (for
OR), the difference between two comparisons can be considered sta-
tistically significant. Specifically, MDs<0 means better efficacy for an
antidepressant compared to the control, and ORs>1 for response rate
indicates better efficacy.
To rank the efficacy of various antidepressants, we used surface
under the cumulative ranking (SUCRA) probabilities, which are ex-
pressed as percentages by comparing each intervention to an imaginary
intervention that is always the best without uncertainty (Leucht et al.,
X. Li and C. Zhang
2013; Salanti et al., 2011). Thus, larger SUCRA scores reveal more ef-
fective or acceptable interventions.
The consistency between direct and indirect comparisons was as-
sessed by node-splitting method; a P value< 0.05 was deemed as in-
consistent (Donegan et al., 2013). The funnel plot was used to identify
possible publication bias when the number of included studies was
larger than 10. We conducted a comparison-adjusted funnel plot. We
also conducted sensitivity analyses to evaluate the stability of efficacy
outcomes.
3. Results
3.1. Search results
The searches identified a total of 4837 articles (PubMed:84,
Embase:618, CENTRAL:173, CBM:1120, CNKI:1535, WanFang:1270,
VIP:37). 2116 records were screened after the removal of 2721 dupli-
cates, and then 1565 irrelevant articles and reviews were excluded
based on screening of the titles and abstracts. Subsequently, 500 re-
cords were excluded after 551 articles in full-text were retrieved and
assessed thoroughly. Finally, 51 RCTs from 51 articles were identified
Fig. 1. PRISMA flow diagram of study selection process. RCTs, randomized controlled trials; HAMD, the Hamilton Depression Scale.
542
Journal of Affective Disorders 266 (2020) 540–548
and included in our NMA. Fig. 1 showed the detailed process of
screening. The details of these 51 articles were shown in supplementary
appendix 2.
3.2. Characteristics of included studies
Characteristics of 51 studies published from 2007 to 2018 were
listed in supplementary Table 1. All included trials were two arm trials
and treatment durations were between 4 and 24 weeks. Besides, the
detailed treatment conditions were examined: placebo (5 trials), esci-
talopram (12 trials), citalopram (7 trials), sertraline (10 trials), venla-
faxine (10 trials), paroxetine (10 trials), duloxetine (4 trials), ami-
triptyline (20 trials), doxepin (5 trials) and mirtazapine (6 trials).
Among these nine antidepressants, sertraline, escitalopram, citalopram
and paroxetine are referred to as SSRIs; duloxetine and venlafaxine are
classified as SNRIs; amitriptyline and doxepin are TCAs, and mirtaza-
pine is categorized as NaSSAs. A total of 5547 participants were in-
cluded in this NMA and the sample size ranged from 40 to 128.
X. Li and C. Zhang
3.3. Quality assessment
Risk of bias of the 51 RCTs was presented in supplementary ap-
pendix 3. 16 studies described random sequence generation while most
trials did not mention any concealment details. 2 trials failed to report
complete outcome data, but all the included studies exhibited a low risk
of reporting bias.
3.4. Inconsistency analysis
The consistency between direct and indirect comparisons was
evaluated by note-splitting method. All efficacy outcome parameters
were used as outcomes of interest, respectively and the inconsistency
results were presented as follows: 2-week efficacy: sertraline vs citalo-
pram (P = 0.01). 4-week mean change: citalopram vs mirtazapine
(P = 0.006), citalopram vs doxepin (P<0.001), and mirtazapine vs
doxepin (P<0.001). 8-week mean change: escitalopram vs mirtazapine
(P = 0.005), amitriptyline vs duloxetine (P = 0.024), and amitriptyline
vs mirtazapine (P = 0.005). Endpoint: citalopram vs doxepin
(P<0.001) and mirtazapine vs doxepin (P<0.001). Response rate:
venlafaxine vs doxepin (P = 0.01) and citalopram vs doxepin
(P = 0.01). However, no other inconsistencies were identified. Thus,
the inconsistency was generally unobvious between direct and indirect
comparisons.
3.5. Publication bias and sensitivity analysis
The comparison-adjusted funnel plot was basically symmetrical and
revealed no significant publication bias (See supplementary Fig. 1). The
sensitivity analysis showed stable results after one study (HAMD total
score>24 at baseline) was excluded. In addition, the removal of two
studies (the treatment duration is 24 weeks or was not available) did
not change the ranking order in SUCRA rank for efficacy. The sensi-
tivity analysis was shown in supplementary appendix 4.
Fig. 2. Network plot of treatment comparisons. The width of the lines is proportional to the number of trials comparing every pair of treatments, and the size of every
node corresponds to the number of participants (sample size). (A) Network plot for HAMD score change of 2-week duration. (B) Network plot for HAMD score change
of 4-week duration. (C) Network plot for HAMD score change of 8-week duration. (D) Network plot for HAMD score change at endpoint. (E) Network plot for
response rate after treatment completion.
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Journal of Affective Disorders 266 (2020) 540–548
3.6. NMA results
3.6.1. Mean change in HAMD score at 2 weeks
The network plot was shown in Fig. 2A. Amitriptyline was included
in the largest number of comparisons, followed by escitalopram and
paroxetine. Table 1 summarized effect sizes of direct treatment com-
parisons. In comparison with placebo, escitalopram, mirtazapine, ven-
lafaxine, sertraline, citalopram, paroxetine showed significant reduc-
tion of 2-week HAMD total score. In addition, escitalopram was
associated with a greater decrease in HAMD total score compared to the
other eight drugs. In order to further understand the results, SUCRA
values were used to rank the nine antidepressants and a higher SUCRA
value indicated larger reduction of the HAMD total score. As suggested
by Fig. 3A, the ranking of all drugs was escitalopram, mirtazapine,
sertraline, citalopram, venlafaxine, doxepin, duloxetine, paroxetine and
amitriptyline.
3.6.2. Mean change in HAMD score at 4 weeks
For 4-week mean change in the HAMD total score, the network of 38
studies was shown in Fig. 2B. A hierarchy of MDs with 95%CIs (shown
in Table 2) was used to compare direct comparisons including placebo.
The reduction of HAMD score in citalopram, sertraline, escitalopram
and mirtazapine groups was higher than that in amitriptyline group
while amitriptyline showed more obvious decrease than doxepin. Based
on SUCRA values and the cumulative probabilities, citalopram was
associated with the largest reduction of the HAMD score (Fig. 3B).
Additionally, among the remaining eight drugs, the change in the
HAMD total score was significantly greater in patients receiving mir-
tazapine compared with those that received sertraline, escitalopram or
duloxetine.
3.6.3. Mean change in HAMD score at 8 weeks
At 8 weeks from baseline, the NMA consists of 28 trials (see Fig. 2C).
All drugs were observed to be more effective than placebo according to
Table 3, which showed MDs (95%CIs) for 8-week mean changes of the
HAMD total score. Among antidepressants, sertraline seemed to be
superior to venlafaxine and paroxetine. Furthermore, as suggested by
 Table 1
Treatment comparisons for 2-week mean change in HAMD score.
Escitalopram
X. Li and C. Zhang

−2.09 (−4.30,0.13) Venlafaxine

−4.20 (−6.31,−2.09) −2.11 (−4.20,−0.03) Amitriptyline
−1.21 (−3.48,1.06) 0.88 (−1.82,3.57) 2.99 (0.71,5.27) Sertraline
−2.93 (−5.81,−0.06) −0.85 (−3.99,2.30) 1.27 (−1.38,3.92) −1.72 (−4.59,1.15) Duloxetine
−1.68 (−4.15,0.80) 0.41 (−2.10,2.92) 2.52 (0.65,4.40) −0.47 (−2.89,1.96) 1.26 (−1.74,4.25) Citalopram
−3.12 (−5.46,−0.78) −1.03 (−3.88,1.82) 1.08 (−1.41,3.57) −1.91 (−4.70,0.88) −0.19 (−2.88,2.51) −1.44 (−4.21,1.32) Paroxetine
−6.66 (−10.86,−2.47) −4.58 (−9.08,−0.08) −2.46 (−6.74,1.82) −5.45 (−9.91,−0.99) −3.73 (−8.13,0.67) −4.99 (−9.43,−0.54) −3.54 (−7.02,−0.06) Placebo
−0.42 (−3.24,2.40) −1.67 (−1.06,4.40) 3.78 (1.67,5.89) 0.79 (−2.13,3.72) 2.52 (−0.78,5.81) 1.26 (−1.15,3.66) 2.70 (−0.43,5.83) 6.25 (1.56,10.93) Mirtazapine
−2.79 (−6.62,1.03) −0.70 (−4.11,2.71) 1.41 (−2.16,4.98) −1.58 (−5.61,2.45) 0.14 (−4.18,4.47) −1.11 (−4.91,2.69) 0.33 (−3.82,4.48) 3.87 (−1.54,9.29) −2.37 (−5.92,1.18) Doxepin

Comparisons between treatments should be read from left to right, and the estimate (MD with 95%CI) is in the cell in common between the column-defining treatment and the row-defining treatment. MD lower than 0
favors the column-defining treatment. Bold results indicate statistical significance.

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Table 2
Treatment comparisons for 4-week mean change in HAMD score.
Escitalopram

−1.11 (−3.66,1.45) Venlafaxine

−2.57 (−4.92,−0.23) −1.47 (−3.60,0.67) Amitriptyline
0.57 (−2.05,3.19) 1.68 (−1.23,4.59) 3.14 (0.73,5.56) Sertraline
−0.15 (−3.44,3.14) 0.96 (−2.55,4.47) 2.42 (−0.64,5.48) −0.72 (−3.69,2.25) Duloxetine
1.44 (−1.39,4.27) 2.55 (0.05,5.05) 4.01 (1.81,6.22) 0.87 (−1.94,3.68) 1.59 (−1.91,5.09) Citalopram
−0.59 (−2.73,1.55) 0.52 (−2.32,3.35) 1.98 (−0.45,4.42) −1.16 (−4.02,1.69) −0.44 (−3.63,2.75) −2.03 (−4.93,0.87) Paroxetine
−5.36 (−8.79,−1.94) −4.26 −2.79 (−6.63,1.05) −5.93 −5.21 −6.80 −4.77 Placebo
(−8.31,−0.20) (−10.01,−1.86) (−9.62,−0.80) (−10.96,−2.65) (−8.07,−1.47)
0.68 (−2.67,4.04) 1.79 (−1.33,4.91) 3.25 (0.67,5.84) 0.11 (−3.28,3.51) 0.83 (−3.08,4.75) −0.76 (−3.64,2.12) 1.27 (−2.15,4.70) 6.05 (1.52,10.58) Mirtazapine
−7.74 (−11.39,−4.10) −6.64 −5.17 −8.31 −7.59 −9.18 −7.15 −2.38 −8.43 Doxepin
(−9.85,−3.42) (−8.35,−1.99) (−12.03,−4.60) (−11.82,−3.36) (−12.10,−6.27) (−10.90,−3.41) (−7.15,2.39) (−11.84,−5.01)

Comparisons between treatments should be read from left to right, and the estimate (MD with 95%CI) is in the cell in common between the column-defining treatment and the row-defining treatment. MD lower than 0
favors the column-defining treatment. Bold results indicate statistical significance.
Journal of Affective Disorders 266 (2020) 540–548
X. Li and C. Zhang Journal of Affective Disorders 266 (2020) 540–548

Fig. 3. Forest plot of network meta-analysis results. The nine antidepressants are listed in order of efficacy ranking based on SUCRAs. All antidepressants are
compared to placebo. (A) Summary of MDs(95%CIs) from network meta-analysis of HAMD score change at 2 weeks. (B) Summary of MDs(95%CIs) from network
meta-analysis of HAMD score change at 4 weeks. (C) Summary of MDs(95%CIs) from network meta-analysis of HAMD score change at 8 weeks. (D) Summary of MDs
(95%CIs) from network meta-analysis of HAMD score change at endpoint. (E) Summary of ORs(95%CIs) from network meta-analysis of response rate after treatment
completion. MDs,mean differences; CIs, confidence intervals; ORs, odds ratios.

cumulative probabilities, mirtazapine and doxepin were among the best
(96.2% and 85.5%, independently), followed by sertraline, citalopram,
escitalopram, duloxetine, paroxetine and venlafaxine, respectively. In
contrast, amitriptyline seemed to be the least helpful one (11.5%). The
forest plot for the hierarchy of the antidepressants was shown in
Fig. 3C.
3.6.4. Mean change in HAMD score after treatment completion
The network of treatment comparisons (48 trials) for the mean
change in HAMD total score from baseline to endpoint was shown in
Fig. 2D. Interestingly, there was no significant difference between
doxepin and placebo (MD= −2.24, 95%CI: −6.18, 1.70), but all of the
other eight drugs were more significant than placebo. In addition, the
MDs (shown in Table 4) indicated that nearly all drugs performed better
than amitriptyline in terms of reducing the HAMD total score except
doxepin. Moreover, the results of cumulative probabilities and SUCRA
values (shown in Fig. 3D) revealed the following hierarchy among the
nine active interventions: mirtazapine, sertraline, citalopram, escitalo-
pram, duloxetine, paroxetine, venlafaxine, amitriptyline, doxepin.
3.6.5. Response rate from baseline to endpoint
In the assessment of response rate, the network plot (Fig. 2E) in-
cluded 26 nodes/ trearments. The MDs (95%CIs) of direct comparisons
between two interventions were presented in Table 5. Compared to
placebo, all drugs were illustrated to be more efficacious. Among the
active treatments, doxepin was inferior compared with the other eight
antidepressants. Mirtazapine showed the highest percentage of re-
sponders with a SUCRA value of 94%. According to ranking prob-
abilities and SUCRA values (Fig. 3E), the ranking of the remaining
antidepressants was evaluated as follows: venlafaxine, escitalopram,
paroxetine, citalopram, sertraline, duloxetine, amitriptyline and dox-
epin.
4. Discussion
This NMA aimed to rank the effectiveness of nine commonly pre-
scribed antidepressants in treating Chinese patients with PSD measured
with mean changes in the HAMD total score as well as response rate.
With regard to the former, there were some substantial differences
among the results evaluated after 2 weeks, 4 weeks, 8 weeks and
treatment completion. At 2 weeks, Escitalopram was superior to ser-
traline and citalopram with faster relief from depressive symptoms. The
result was in line with previous reviews. Although escitalopram is
commonly referred to as SSRIs, it has allosteric properties. Different
from traditional SSRIs, escitalopram (S-citalopram) interacts with or-
thosteric and allosteric binding sites at the serotonin transporter
(Sanchez et al., 2014). In this way, escitalopram may be the first choice
for an early improvement.
However, the rank orders varied significantly at 4 weeks.
Citalopram was the best option compared to the other eight anti-
depressants. It should be noted escitalopram was not better than cita-
lopram, which may be attributed by decreased antidepressant action
with time. It was well-documented that the washout half-life of cita-
lopram is longer than escitalopram, leading to higher steady-state
concentrations (Ng et al., 2016). Besides, sertraline showed superior
advantages to escitalopram probably because of the bias of allowing
sertraline to be flexibly doses (50–200 mg/day) compared to nearly
fixed dose of escitalopram at 10 mg/day. Interestingly, Deng et al. ’s

545
 Table 3
Treatment comparisons for 8-week mean change in HAMD score.
Escitalopram
X. Li and C. Zhang

−1.30 (−2.99,0.38) Venlafaxine

−3.05 (−4.70,−1.40) −1.75 (−3.25,−0.25) Amitriptyline
1.09 (−0.58,2.76) 2.39 (0.36,4.43) 4.14 (2.36,5.93) Sertraline
−0.56 (−2.75,1.64) 0.75 (−1.66,3.16) 2.50 (0.32,4.67) −1.65 (−3.70,0.41) Duloxetine
0.28 (−2.20,2.76) 1.59 (−1.17,4.34) 3.33 (0.76,5.91) −0.81 (−2.94,1.33) 0.84 (−1.95,3.62) Citalopram
−0.72 (−2.10,0.66) 0.58 (−1.26,2.43) 2.33 (0.74,3.92) −1.81 (−3.34,−0.28) −0.17 (−2.08,1.74) −1.00 (−3.28,1.28) Paroxetine
−9.45 (−12.24,−6.66) −8.15 −6.40 −10.54 −8.90 −9.73 −8.73 Placebo
(−11.19,−5.10) (−9.29,−3.51) (−13.28,−7.80) (−11.97,−5.82) (−12.53,−6.94) (−11.22,−6.24)
3.87 (1.17,6.57) 5.17 (2.31,8.03) 6.92 (4.28,9.56) 2.78 (−0.17,5.73) 4.42 (1.20,7.64) 3.59 (0.10,7.07) 4.59 (1.77,7.41) 13.32 Mirtazapine
(9.60,17.03)
2.91 (−1.60,7.41) 4.21 (−0.39,8.81) 5.96 (1.49,10.43) 1.82 (−2.84,6.48) 3.46 (−1.37,8.30) 2.63 (−2.39,7.64) 3.63 (−0.95,8.21) 12.36 −0.96 Doxepin
(7.18,17.54) (−4.56,2.64)

Comparisons between treatments should be read from left to right, and the estimate (MD with 95%CI) is in the cell in common between the column-defining treatment and the row-defining treatment. MD lower than 0
favors the column-defining treatment. Bold results indicate statistical significance.

546
Table 4
Treatment comparisons for the mean change in HAMD score from baseline to endpoint.
Escitalopram

−0.73 (−3.13,1.67) Venlafaxine

−3.04 (−5.23,−0.85) −2.31 Amitriptyline
(−4.25,−0.37)
0.80 (−1.55,3.14) 1.53 (−1.01,4.06) 3.84 (1.83,5.84) Sertraline
−0.44 (−3.83,2.94) 0.29 (−3.23,3.81) 2.60 (−0.55,5.74) −1.24 (−4.22,1.74) Duloxetine
0.38 (−2.16,2.93) 1.11 (−1.05,3.28) 3.42 (1.33,5.52) −0.41 (−2.92,2.10) 0.83 (−2.70,4.36) Citalopram
−0.60 (−2.67,1.47) 0.13 (−2.47,2.73) 2.44 (0.22,4.66) −1.39 (−3.70,0.91) −0.15 (−3.34,3.03) −0.98 (−3.57,1.61) Paroxetine
−10.04 (−12.81,−7.27) −9.31 −7.00 −10.83 −9.59 −10.42 −9.44 Placebo
(−12.62,−6.00) (−10.13,−3.87) (−14.09,−7.58) (−13.62,−5.57) (−13.65,−7.19) (−12.31,−6.57)
1.11 (−1.83,4.05) 1.84 (−1.01,4.69) 4.15 (1.66,6.64) 0.31 (−2.70,3.33) 1.55 (−2.32,5.43) 0.72 (−2.06,3.51) 1.71 (−1.37,4.79) 11.15 Mirtazapine
(7.43,14.86)
−7.79 (−11.09,−4.50) −7.07 −4.75 −8.59 −7.35 −8.18 −7.20 2.24 −8.90 Doxepin
(−9.82,−4.31) (−7.71,−1.80) (−11.93,−5.25) (−11.50,−3.21) (−10.95,−5.41) (−10.59,−3.81) (−1.70,6.18) (−12.18,−5.62)

Comparisons between treatments should be read from left to right, and the estimate (MD with 95%CI) is in the cell in common between the column-defining treatment and the row-defining treatment. MD lower than 0
favors the column-defining treatment. Bold results indicate statistical significance.
Journal of Affective Disorders 266 (2020) 540–548
X. Li and C. Zhang Journal of Affective Disorders 266 (2020) 540–548

Comparisons between treatments should be read from left to right, and the estimate (OR with 95%CI) is in the cell in common between the column-defining treatment and the row-defining treatment. OR higher than 1
NMA (Deng et al., 2018) suggested duloxetine was more helpful for PSD

Doxepin
than citalopram and sertraline based on the evaluation of 4-week effi-
cacy, which was inconsistent with our results.
After 8 weeks of treatment, an unexpected finding was that mirta-
zapine became the most effective one among the nine antidepressants.

1.98 (1.37,2.87)
Mirtazapine, classified as a NaSSA, has a unique pharmacological pro-

Mirtazapine
file. Specifically, it acts by antagonizing the adrenergic alpha 2-auto-
receptors, alpha 2-heteroreceptors, and by blocking 5-HT2 and 5-HT3
receptors. In this way, mirtazapine has minimal effects on monoamine
reuptake (Anttila and Leinonen, 2001; Watanabe et al., 2011). This is
why it is superior to venlafaxine and duloxetine. Besides, in our NMA,
mirtazapine was observed to be more efficacious than paroxetine, ser-
0.14 (0.06,0.32)
0.28 (0.12,0.64)

traline and citalopram, which is consistently reported in several RCTs

(Behnke et al., 2003; Leinonen et al., 1999; Schatzberg et al., 2002) and
Placebo

a systemic review (Watanabe et al., 2011). It was interesting to find that

citalopram and sertraline performed better than duloxetine after both
4-week and 8-week treatment duration. On the contrary, duloxetine
was previously reported to be more significant in Deng et al's NMA of
5.71 (2.69,12.13)

only 15 studies (Deng et al., 2018). The underestimated efficacy of ci-

1.60 (1.16,2.22)
0.81 (0.61,1.06)

talopram and sertraline may be caused by the bias of very limited

Paroxetine

sample size.
At endpoint, the ranking of antidepressants was similar to what was
observed at 8 weeks. The only exception was doxepin (ranking last)
possibly due to the wider variation in treatment durations ranging from
4 weeks to 12 weeks. Amongst these trials, only one study reported 8-
5.71 (2.62,12.46)

week change in HAMD score, which meant that the effectiveness of

1.60 (1.21,2.12)
1.00 (0.82,1.22)

0.81 (0.63,1.04)

doxepin at 8 weeks was overrated. Additionally, all antidepressants

Citalopram

were more effective in comparison with placebo except doxepin, which

was generally in accordance with several studies.
When it comes to response rate before and after the whole treatment
duration, the rank orders of the antidepressant effect differed slightly
from mean changes in the HAMD total score. However, mirtazapine still
5.49 (2.50,12.04)

showed significant superiority to the other drugs. Especially, it ranked

1.54 (1.06,2.24)
0.96 (0.72,1.27)
0.96 (0.77,1.20)

0.78 (0.56,1.08)

higher than all SSRIs (sertraline, escitalopram, citalopram and parox-

Duloxetine

etine), which was supported by Watanabe et al's cochrane review

(Watanabe et al., 2011).
This NMA was subject to the following limitations. Firstly, no re-
striction on drug doses and the treatment duration may result in bias.
Most studies had variable drug doses according to the severity of de-
5.69 (2.60,12.43)

pression or adverse reactions. To detect or minimize possible bias

1.60 (1.11,2.30)
1.04 (0.77,1.39)
0.99 (0.77,1.29)
0.99 (0.81,1.23)

0.81 (0.59,1.10)

arising from the length of treatment, we performed NMA in 2, 4, and 8

favors the column-defining treatment. Bold results indicate statistical significance.

weeks, respectively. We also conducted sensitivity analyses by re-

Sertraline

moving two trials based on treatment duration. Secondly, a higher

proportion of unclear risk of bias across individual trials suggested that
most studies exhibited methodological shortages and were in relatively
low quality. Thirdly, we did not estimate whether the severity of de-
5.05 (2.34,10.91)

pression affects the efficacy as no data were available. But we at-

1.42 (1.04,1.93)
0.89 (0.71,1.11)
0.92 (0.73,1.17)
0.88 (0.74,1.06)
0.88 (0.75,1.04)

0.72 (0.57,0.90)

tempted to overcome this limitation by performing sensitivity analysis

Amitriptyline

and the results showed that the efficacy ranking of the nine anti-
depressants did not change after the removal of one study for severe
Treatment comparisons for response rate at endpoint.

depression.
In conclusion, our NMA provided reliable recommendations for the
efficacy of frequently used antidepressants in treating PSD.
5.86 (2.67,12.86)

Escitalopram was associated with a faster relief of depression.

1.65 (1.25,2.17)
1.16 (0.95,1.41)
1.03 (0.78,1.36)
1.07 (0.80,1.43)
1.03 (0.86,1.22)
1.03 (0.82,1.28)

0.83 (0.63,1.10)

Mirtazapine was probably the best option in terms of efficacy of

Venlafaxine

medium-term duration while amitriptyline and doxepin were nearly the

worst choice. As a consequence, the findings help clinicians to de-
termine which antidepressant to prescribe and the extent to which
every agent alleviates depression. However, the selection of a phar-
macologic agent should be an appropriate balance between efficacy,
5.88 (2.72.12.72)

acceptability, and tolerability. Unfortunately, the majority of included

1.65 (1.17,2.34)
1.00 (0.78,1.29)
1.16 (0.95,1.44)
1.03 (0.85,1.26)
1.07 (0.82,1.41)
1.03 (0.81,1.31)
1.03 (0.87,1.33)

0.83 (0.61,1.13)

trials did not report overall discontinuation rate or discontinuation due

Escitalopram

to adverse effects, and thus we were unable to investigate the toler-

ability or acceptability of these antidepressants.
Table 5

Therefore, in order to satisfy clinical application, more high-quality

studies should be conducted to evaluate the tolerability, acceptability

547
X. Li and C. Zhang
and safety of the nine antidepressants described in our NMA, and fur-
ther explore the association between efficacy and the severity of de-
pression.
Author statement
Contributors
Xinyuan Li designed the study and wrote the draft of the manu-
script. Xinyuan Li and Congxiao Zhang managed the literature searches.
Xinyuan Li undertook the statistical analysis and interpretation.
Xinyuan Li revised the manuscript. All authors contributed to and have
approved the final manuscript.
Role of the funding source
None.
Declaration of Competing Interest
None.
Acknowledgements
None.
Supplementary materials
Supplementary material associated with this article can be found, in
the online version, at doi:10.1016/j.jad.2020.02.005.
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