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 Journal of Clinical Neuroscience 80 (2020) 169–181

Contents lists available at ScienceDirect

Journal of Clinical Neuroscience

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

Review article

Application of antidepressants in depression: A systematic review and

meta-analysis
Ziqi Yuan a,1, Zhenlei Chen a, Maoqiang Xue b, Jie Zhang a,⇑, Lige Leng a,2,⇑
a
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, Fujian 361102,
PR China
b
Department of Basic Medical Science, School of Medicine, Xiamen University, Xiamen, Fujian 361102, PR China

a r t i c l e i n f o a b s t r a c t

Article history: Background: The type and quantities of antidepressants are increasing, but the efficacy and safety of first-
Received 1 June 2020 line and emerging drugs vary between studies. In this article, we estimated the efficacy and safety of first-
Accepted 9 August 2020 line and emerging antidepressants (anti-inflammatory drugs and ketamine).
Method: ystematic search of EMBASE, ERIC, MEDLINE, psycARTICLES, and psycINFO without language
restriction for studies on the depression, depressive symptoms, antidepressants, fluoxetine (Prozac),
Keywords: paroxetine, escitalopram, sertraline, fluvoxamine, venlafaxine, duloxetine, NSAIDs, anti-cytokine drugs
Antidepressants
or pioglitazone published before May 1st, 2019. Information on study characteristics, depression or
MDD
SNPs
depressive symptoms, antidepressants and the descriptive statistics (including efficacy and safety of
Ketamine antidepressants) was extracted independently by 2 investigators. Estimates were pooled using
OR random-effects meta-analysis. Differences by study-level characteristics were estimated using stratified
Anti-inflammatory meta-analysis and meta-regression. The response and remission of antidepressants were used as clinical
Depression evaluation indicators, and the evaluation criteria were clinical depression scales. OR value of antidepres-
Meta-analysis sants as assessed by meta-analysis.
Results: The literature search retrieved 5529 potentially relevant articles of which 49 studies were finally
included. We compared the efficacy of antidepressants (seven first-line antidepressants (fluoxetine,
paroxetine, escitalopram, sertraline, fluvoxamine, venlafaxine, duloxetine), there kinds of anti-
inflammatory drugs(NASIDs, cytokine-inhibitor, pioglitazone) and ketamine) by comparing the OR val-
ues.
Conclusion: The three drugs with the highest OR value in response were NASID (OR = 3.62(1.58, 8.32)),
venlafaxin (OR = 3.50(1.83, 6.70)) and ketamine (OR = 3.28(1.89, 5.68)), while the highest OR value in
remission were NASID (OR = 3.17(1.60, 6.29)), ketamine (OR = 2.99(1.58, 5.67)) and venlafaxin
(OR = 2.55(1.72, 3.78)). Through reading the literature, we found 69 SNPs associated with depression.
Major depression was a debilitating disorder that could ultimately lead to enormous societal and eco-
nomical challenge [1]. The number of person which affected by depression was up to 16% of the popula-
tion worldwide. More than 300 million individuals were estimated to suffer depression these days [1,2].
Therefore, it is apparent that safety and effective treatments for depression are necessary. In the 1930 s,
the first drug for schizophrenia was discovered. This finding was a landmark for the emerging of biolog-
ical psychiatry. In the 1950 s, pharmacologists had stumbled upon the antidepressant effect of imipra-
mine. Since then, every 30 years, the use of antidepressants had made a pulsatile leap.
Selective serotonin reuptake inhibitors (SSRIs) are the most widely-prescribed psychiatric drugs for the
treatment of depression. However, the efficacy was variable and incomplete: 60%–70% of the patients do
not experience remission, while 30%–40% do not show a significant response [3,4]. Nevertheless, SSRIs,
SNRIs (selective serotonin-norepinephrine reuptake inhibitors, which can block norepinephrine at the
same time) and NaSSAs (norepinephrine and selective serotonin receptor agonist), constituted the
first-line clinical drugs.

⇑ Corresponding authors: Department: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine
Institute/University/Hospital Xiamen University Street Name & Number XiangAn South Road City, State, Postal code, Xiamen, Fujian 361102, PR China.
E-mail addresses: jiezhang@xmu.edu.cn (J. Zhang), lenglige@xmu.edu.cn (L. Leng).
1
First author
2
Lead Contact

https://doi.org/10.1016/j.jocn.2020.08.013
0967-5868/Ó 2020 Elsevier Ltd. All rights reserved.
170 Z. Yuan et al. / Journal of Clinical Neuroscience 80 (2020) 169–181

Nearly 30 years after the outbreak of SSRIs, antidepressants have ushered in a new chapter. It has been
found that anti-inflammatory drugs could also have the small and moderate antidepressant effect and it’s
widely discussed [5]. More than 40 anti-inflammatory drugs have been certificated to have antidepres-
sant effects in preclinical and clinical studies [6]. The antidepressant that has been approved for use
recently is ketamine.
There is no comprehensive comparison of the efficacy of all these drugs. In this review, we tried to esti-
mate the efficacy and safety of first-line antidepressants, anti-inflammatory drugs and ketamine.
On the other hand, with the development of GWAS, SNPs related to depression have been reported, and
the corresponding mechanisms have been elaborated, respectively. However, patients with these SNPs
have not been treated with individualized drugs according to the mechanisms. We hope to push this pro-
cess forward through the summary of this article.
Methods: Search Strategy and Study Eligibility.
Ó 2020 Elsevier Ltd. All rights reserved.

Two authors (Y.ZQ and L.LG) independently systematic search
of EMBASE, ERIC, MEDLINE, psycARTICLES, and psycINFO without
language restriction for studies on the depression, depressive
symptoms, antidepressants, fluoxetine (Prozac), paroxetine, esci-
talopram, sertraline, fluvoxamine, venlafaxine, duloxetine, NSAID,
anti-cytokine drugs or pioglitazone published before May 1st,
2019. Based on literature review and communication with clinical
psychiatrists, seven clinical drugs(fluoxetine, paroxetine, escitalo-
pram, sertraline, fluvoxamine, venlafaxine, duloxetine) were
selected as first line antidepressants[7,8].
Furthermore, the authors screened the reference lists of identi-
fied articles and corresponded with study investigators using the
approaches implied by the Preferred Reporting Items for System-
atic Reviews and Meta-analysis of Observational Studies in Epi-
demiology reporting guidelines[4,9].In order to search in the
database, terms related to antidepressants and study designs were
combined with those related to depression without language
restriction (complete details of the search strategy appear in
eMethods 1 in the Supplement). Included studies (1) reported
detailed data on antidepressants, (2) were published in peer-
reviewed journals, and (3) used a validated method to assess
depression and the safety and efficacy of antidepressants. A third
author (Z. J) resolved discrepancies by discussion and adjudication.
1. Data extraction and quality assessment
Two authors (Y.ZQ. and L.LG.) independently extracted the fol-
lowing data from each article using a standardized form: study
design; years of survey; sample size; geographic location; gender
of participants; average age of participants; diagnostic or screening
method used; outcome definition (eg, specific diagnostic criteria or
screening instrument cutoff); and reported data of depression,
depressive symptoms, or antidepressants. When there were stud-
ies involving the same author or same population of participants,
only the most comprehensive or recent publication was included.
The same 2 authors (Y.ZQ. and L.LG.) independently assessed
the risk of bias of these nonrandomized studies using a modified
version of the Newcastle-Ottawa scale[10], which assesses sample
representativeness, sample size, side effects of antidepressants,
clinical staging of depression and quality of descriptive statistics
reporting (complete details regarding scoring appear in eMethods
2 in the Supplement). Studies were judged to be at low risk of bias
(3 points) or high risk of bias (<3 points)[11]. A third author (Z.J.)
resolved discrepancies by discussion and adjudication.
2. Data synthesis and analysis
The pooled summary was expressed as odds risk (OR) with 95%
confidence interval (CI) for discontinuous variables. Heterogeneity
across trials was tested using the I2 statistic and Cochrane Q statis-
tic [12,13].
Sensitivity analyses were performed by serially excluding each
study to determine the influence of individual studies on the over-
all OR estimates. Results from studies grouped according to pre-
specified study-level characteristics were compared using
stratified meta-analysis (for diagnostic criteria or screening instru-
ment cutoff, study design, continent or region, country, and
Newcastle-Ottawa Scale components) or random-effects meta-
regression (for year of baseline survey, age, and sex).
To assess potential publication bias, a funnel plot was carried
generated. All analyses were performed using Review Manager
6.0[11,14](Cochrane Collaboration, Oxford, UK). Statistical tests
were 2-sided and used a significance threshold of P < 0 0.05.
3. Results
3.1. Study characteristics
The literature search retrieved 5529 potentially relevant articles
of which 49 studies[15–63] were finally included in this meta-
analysis (see Fig. 1f or a PRISMA diagram of literature search).
The basic characteristics of each study(author’s name, year of pub-
lication, number of participants, sex, age, antidepressants) are pre-
sented in Table 1.
The median number of participants per study was 197.84
(range, 15–833). 49 cross-sectional studies and 6 longitudinal
studies in 38 countries reported on antidepressants (eTable 1).
First, we applied a modified Newcastle-Ottawa scale to evaluate
the quality of the included articles (Newcastle-Ottawa score com-
ponents for all 49 individual studies appear in eTable 2 in the Sup-
plement). Of the 49 articles, only 2 articles rated < 3.
Response describes a gradual improvement during depression
treatment and usually implies a treatment effect [64]. Response
is usually defined as a 50% improvement from baseline to end
point on depression rating scales. Response tends to occur early
on during the course of treatment (eg, after 2 weeks) and
usually precedes remission as a precondition. It is the main
categorical outcome parameter of short-term antidepressant
trial, while remission refers to a relatively symptom-free period.
If this symptom-free period prelong, it will be the recovery of
depression (The overview of the term of response, remission
and recovery were in eFigure 1). So in this article, we use
response as an indicator of the rapid efficacy of antidepressants,
while remission as an indicator of onset of continuation period
efficacy.
We then first analyzed female participants in all the literature
and found that gender(female) was the risk factor for depression
(eFigure 2)(OR. = 0.61, 95% CI(0.56, 0.65), P < 0.00001).
 Z. Yuan et al. / Journal of Clinical Neuroscience 80 (2020) 169–181
Fig. 1. Study identification and selection.
Since the literature we searched for are entirely written in Eng-
lish, the white people were also the most among the participants
(eFigure 3).More than half of the literature did not mention the
region or ethnicity of the participants.
4. Effectiveness comparison of all kinds of antidepressants
We compared the efficacy of all types of antidepressants (seven
first-line antidepressants(fluoxetine, paroxetine, escitalopram, ser-
traline, fluvoxamine, venlafaxine, duloxetine), there kinds of anti-
inflammatory drugs(NASIDs, cytokine-inhibitor, pioglitazone) and
ketamine) by comparing the OR values of all these antidepressants
in the literature, and obtained the following results: The three
drugs with the highest OR value in response were NASID
(OR = 3.62(1.58, 8.32)), venlafaxin (OR = 3.50(1.83, 6.70)) and keta-
mine (OR = 3.28(1.89, 5.68)). The three drugs with the highest OR
value in remission were NASID (OR = 3.17(1.60, 6.29)), ketamine
(OR = 2.99(1.58, 5.67)) and venlafaxin (OR = 2.55(1.72, 3.78))
(Fig. 2A, B).
4.1. Effectiveness comparison of seven first-line antidepressants (single
and combined)
Based on literature review, seven clinical drugs (fluoxetine,
paroxetine, escitalopram, sertraline, fluvoxamine, venlafaxine,
duloxetine) were selected as first-line antidepressants [7,8]. Liter-
ature was assessed by clinical effective rates of these 7 first-line
first-line antidepressants [15–40,63].
We aggregated seven clinical first-line drugs together and com-
pared them with placebos. It was clear that, whether were evalu-
ated by response or remission, these antidepressants were
171
effective (OR = 2.29, 95% CI(1.87, 2.80), P < 0.00001, response;
OR = 2.05, 95% CI(1.71, 2.46), P < 0.00001, remission) (Fig. 3A, B).
However, the heterogeneity of these different drugs is relatively
high(I2 = 70%, P < 0.00001, response; I2 = 48%, P = 0.004, remission).
Plainly, after 30 years of clinical practice, the effectiveness of these
drugs was relatively clear. We categorize ORs for different drugs,
respectively (Fig. 3A, B).By comparing these OR value, we found
that whether it’s response or remission, venlafaxine and duloxetine
were in the top two, suggesting that these two antidepressants
have better effects.
However, some literature didn’t have comparison made
between antidepressants and placebos, but comparison between
different types of antidepressants. We also conducted meta-
analysis of these literature, either (Fig. 3C, D).By comparing with
OR value, we found that whether it’s response or remission, dulox-
etine, venlafaxine and sertraline were in the top three, suggesting
that these three antidepressants have better effects, which was
consistent with the previous results in Fig. 3A, B. For each antide-
pressant studied independently, there was a slight heterogeneity
between studies of single antidepressant.
There are also some literature comparing the effects of individ-
ual antidepressant and combination use of antidepressants (Fig. 3E,
F). By comparing with OR value, we found that whether it’s
response or remission, group of combination use of drugs had a
higher OR value, suggesting that combination of antidepressants
may have more beneficial for the treatment of depression. There
was a moderate heterogeneity among the included studies
(I2 = 52%, P = 0.08, response; I2 = 15%, P = 0.32, remission).However,
the number of literature on combined drug use and the types of
combined drug use were somewhat limited, which may not be
representative.
172 Z. Yuan et al. / Journal of Clinical Neuroscience 80 (2020) 169–181

Table 1
Selected characteristics of the 49 studies of antidepressants.

Source Country No. of Age, y Gender, Race, No.

Patients No.
(Female/
Male)
Antidepressant
Allard et al. 2004 Sweden and Denmark 148 64–89 118 : 30 NA
Allgulander et al. 2004 NA 389 >=18 206 : 183 NA
Alvarez et al. 2012 11 countries (Australia, Austria, Canada, Czech Republic, 426 NA 267 : 159 NA
Finland, France, Italy, Malaysia, Slovakia, Spain, Sweden)
Baldwin et al. 2006 6 countries 325 >=18 240 : 85 NA
Binneman et al. 2008 United States,Serbia, Montenegro,the Russian Federation 89 >=18 35 : 54 NA
Bjerkenstedt et al. 2005 NA 163 18–70 129 : 34 Caucasian: 163
Blier et al. 2009 Canada 61 30–50 28 : 33 NA
Boulenger et al. 2014 13 countries (Belgium, Estonia, Finland, France, Germany, 607 18–75 400 : 207 Caucasian: 596
Latvia, Lithuania, Norway, Russia, Slovakia, South Africa,
Sweden and the Ukraine)
Brunoni et al. 2014 Brazil 120 18–65 82 : 38 NA
Coleman et al. 2001 the United States 456 NA 188 : 168 Caucasian: African American:
other = 376 : 55: 25
Corruble et al. 2013 Australia, Brazil, Canada, France, Russia, South Africa and UK 324 18–70 230 : 94 NA
Detke et al. 2002 the United States 267 >=18 184 : 83 Caucasian: Hispanic: African
American: Western Asian:
Other = 209 : 30 : 23 : 2 : 3
Detke et al. 2004 NA 367 >=18 267 : 100 Caucasian: 366
Dubé et al. 2010 India, Mexico, Romania, and the United States 469 18–65 217 : 252 West Asian : Other = 364 : 105
Fava et al. 2002 the United States 284 >=18 169 : 115 NA
Gentil et al. 2000 NA 116 18–55 94 : 22 NA
Goldstein et al. 2004 the United States 353 >=18 217 : 136 NA
Hale et al. 2010 5 countries(Argentina, Brazil, Italy, Spain, and the UK) 515 18–65 400 : 115 NA
Hedayati et al. 2017 US 193 average 52 : 141 Caucasian: African American:
58.2 other = 81 : 111 : 1
Hewett et al. 2010 NA 588 18–64 387 : 201 NA
Higuchi et al. 2011 JapanandSouth Korea 412 >=20 226 : 186 NA
Hsu et al. 2011 China 42 20–65 25 : 17 Chinese: 42
Hudson et al.1998 NA 85 18–60 77 : 8 Caucasian : 82
Hypericum Depression Trial the United States 340 >=18 224 : 116 Caucasian: African American:
Study Group. 2002 Hispanic: other:=257 : 35 : 27 : 21
Kasper et al. 2012 2 countries (Austria and Russia). 490 18–65 338 : 152 Caucasian: 487
Stein et al. 2003 Europe(France, Germany, Ireland, The Netherlands, UK) 109 18–70 51 : 58 NA
Tohen et al. 2003 13 countries. 833 >=18 525 : 308 Caucasian:688
Anti-inflammationdrug
Abbasi et al.2012 NA 40 18–50 13 : 27 NA
Aftab et al.2019 NA NA 18–70 NA NA
Akhondzadeh et al.2009 Iran 40 24–46 25 : 15 NA
Alamdarsaravi et al.2017 NA 40 NA 16 : 24 NA
Arabzadeh et al.2015 Iran 46 18–50 16 : 30 NA
Gougol et al.2015 NA 44 20–70 29 : 15 NA
Griffiths et al.2017 NA 320 18 138 : 182 Caucasian: 281
Kargar et al.2015 Iran 35 17–65 19 : 16 NA
Mousavi et al.2017 NA 40 12–18 19 : 21 NA
Müller et al.2006 NA 40 23–65 20 : 20 NA
Raison et al.2013 Atlanta, Georgia. 60 25–60 40 : 20 Caucasian:African: other = 46 : 11 :
3
Sepanjnia et al.2012 NA 40 18–50 29 : 11 NA
Zeinoddini et al.2015 NA 44 18–50 15 : 29 NA
Ketamine
Arabzadeh et al.2018 NA 81 18–60 50 : 31 NA
Grunebaum et al.2017 NA 16 NA 10 : 6 Caucasian: 14
Hu et al.2016 NA 27 18–60 17 : 10 NA
Ionescu et al.2019 NA 26 18–65 10 : 16 Caucasian: 21
Jafarinia et al.2016 NA 40 20–55 30 : 10 NA
Loo et al.2012 NA 46 18 28 : 18 NA
Ray-Griffith et al.2017 NA 16 >= 18 13 : 3 NA
Singh et al.2016a NA 67 18–64 45 : 22 Caucasian:African: other = 53 : 12 :
2
Zarate et al.2012 NA 15 18–65 8:7 NA

4.2. Effectiveness comparison of anti-inflammatory drugs as
antidepressants
So far, there are 45 anti-inflammatory drugs used to treat
depression [6]. Because of the variety and complexity of these
anti-inflammatory drugs, we roughly classify them into three
categories (NASIDs, cytokine-inhibitor, pioglitazone) for analysis
according to the number of literature searched [41–53].
We aggregated three kinds of anti-inflammatory drugs together
and compared them with placebos. It was obviously that, whether
were evaluated by response or remission, these anti-inflammatory
drugs were effective (OR = 2.86, 95% CI(2.08, 3.94), P < 0.00001,
 Z. Yuan et al. / Journal of Clinical Neuroscience 80 (2020) 169–181 173

Fig. 2. Meta-analysis of antidepressant activity of all kinds of antidepressants. (A) Effectiveness comparison of all kinds of antidepressants (response). (B) Effectiveness
comparison of all kinds of antidepressants (remission).

Fig. 3. Meta-analysis of antidepressant activity of seven first-line antidepressants. (A) Meta-analysis of seven first-line antidepressants vs.placebo (response), respectively.
(B) Meta-analysis of seven first-line antidepressants vs.placebo (remission), respectively. (C) Meta-analysis of seven first-line antidepressants vs.antidepressants (response),
respectively. (D) Meta-analysisofseven first-line antidepressants vs.antidepressants (remission), respectively. (E) Meta-analysis of antidepressants vs. combined use of
antidepressants (response), respectively. (F) Meta-analysis of antidepressants vs. combined use of antidepressants (remission), respectively.
174 Z. Yuan et al. / Journal of Clinical Neuroscience 80 (2020) 169–181
response; OR = 2.39, 95% CI(1.71, 3.33), P < 0.00001, remission)
(Fig. 4A, B). However, the heterogeneity of these different drugs
is slight high(I2 = 60%, P = 0.007, response; I2 = 54%, P = 0.02, remis-
sion). We categorize ORs for different drugs, respectively (Fig. 4A,
B).By comparing these OR value, we found that whether it’s
response or remission, NISADs had the best effect when it used
to treat depression.
However, some literature didn’t have comparison made
between anti-inflammatory drugs and placebos, but comparison
between different types of anti-inflammatory drugs. We also con-
ducted meta-analysis of these literature (Fig. 4C, D).By comparing
with OR value, we found that whether it’s response or remission,
NASIDs was in the top, which was consistent with the previous
results in Fig. 4A, B. There was a slight heterogeneity between
studies of single anti-inflammatory drug. However, the study of
pioglitazone, it may be because the quantum of studies was rare,
had a high heterogeneity.
4.3. Comparison of antidepressant effects between anti-inflammatory
drugs and clinical first-line drugs
From the comparison of OR values, anti-inflammatory drugs
had the similar anti-depression effects to clinical first-line
antidepressants, or even better than the effects of first-line
antidepressants. This may be because anti-inflammatory drugs
(like NASIDs) itself had analgesic effects, which may have a
certain antidepressant effect on the pain relief of other dis-
eases of patients. On the other hand, inflammation lacks speci-
ficity and is a common feature of almost all diseases. The
application of anti-inflammatory drugs may have a certain
therapeutic effect on a variety of pathogenic diseases in the
body to some extent.
5. Meta-analysis of ketamine effectiveness
As a new chapter in antidepressants, ketamine has just been put
into clinical trials[54–62]. It works quickly, whether it is from
response or remission, it has obvious anti-depression effect
(OR = 2.99, 95% CI(1.58,5.67), P = 0.0008, response; OR = 3.28,
95% CI(1.59, 5.68), P < 0.00001, remission) (Fig. 4E, F). The hetero-
geneity was moderate (I2 = 26%, P = 0.24, response; I2 = 63%,
P = 0.01, remission). Compared with other antidepressants, keta-
mine also had obvious advantages(OR = 2.86, 95% CI(6.21, 22.89),
P = 0.006, response; OR = 6.68 95% CI(2.23, 20.01), P = 0.0007,
remission) (Fig. 4E, F). The heterogeneity was slight (I2 = 0%,
P = 0.92, response; I2 = 0%, P = 0.68, remission).
6. Side effects comparison of all kinds of antidepressants
6.1. Side effects comparison of seven first-line antidepressants (single
and combined)
In all these studies[15–40,63], seven clinical first-line antide-
pressants had 43 items of side effects in total. We summarized
the top ten of them (Fig. 5A).These ten side effects were nau-
sea, insomnia, constipation, dry mouth, headache, dizziness,
somnolence, diarrhea, sweating and tremor. These side effects
varied from person to person and even had the opposite effect
(eg. somnolence and insomnia). Evaluating the side effects of
antidepressants as a whole, headache, nausea and insomnia
were the three highest incidences side effects of
antidepressants which incidence rates exceeded 10%(0.1842 ±
0.046; 0.1567 ± 0.0539; 0.1225 ± 0.0234). Comparisons
between these seven drugs, fluvoxamine had the highest
incidence of side effects(0.1575 ± 0.003055), while fluoxetine
had the lowest(0.08566 ± 0.01965).
6.2. Side effects comparison of anti-inflammatory drugs as
antidepressants
Anti-inflammatory drugs had 19 items of side effects in total
when used to treat depression[41–53], which were all listed in
Fig. 5B. These 19 side effects were upper respiratory infection, sore
throat, sinus congestion, nervousness, nasal congestion, myalgia,
increased appetite, fever, diarrhea, headache, tremor, fatigue, dizzi-
ness, decreased appetite, daytime drowsiness, cough, constipation
and abdominal pain. Compared with antidepressant side effects,
headache, tremor, somnolence, dizziness and constipation were
similar compare to the antidepressants. Evaluating the side effects
of anti-inflammatory drugs as a whole, headache was the highest
incidence side effects of anti-inflammatory drugs (0.2389 ± 0.214
4). Comparisons between thesedrugs, cytokine-inhibitors had the
highest incidence of side effects. So far, there have been few ran-
domized controlled trials of anti-inflammatory drugs for the treat-
ment of depression, and there have been fewer reports of side
effects of these treatments. So our analysis of existing data tried
to provide a comprehensive and convincing demonstration for
the treatment of depression with anti-inflammatory drugs.
6.3. Side effects of ketamine
Ketamine had 14 items of side effects in total when used to treat
depression[54–62], which were all listed in Fig. 5C. These 14 side
effects were upper anxiety, blurred vision, dissociation, dizziness,
headache, decreased appetite, nervousness, nausea, restlessness,
early morning awakening, cough, sweating and tremor. Compared
with antidepressant side effects, there are some common points,
which are nausea, headache, tremor and dizziness. But the side
effects of ketamine are inextricably linked to the fact that it is an
anesthetic. The incidences of headaches was over 10%(0.1253 ± 0.
07292), and the incidences of nausea, dizziness and restlessness
were over 5%(0.07544 ± 0.05388; 0.08518 ± 0.03735; 0.08648 ± 0.
06444).
6.4. SNP related to depression
Through reading the literature, we found 69 SNPs associated
with depression [65–94]. We classified these SNPs according to
the mechanism of depression (1. HPA axis [65–71,75,87–93,95],
2. Inflammation [74–85,94], 3 nervous system development
[70,72,73,87–89,94])(Fig. 6). Among them, there are 40SNPs
related to HPA, 34SNPs related to inflammation, and 35 SNPs
related to nervous system development. Most of these literatures
described the mechanisms of these SNPs and depression, but none
of these mechanisms were used to conduct clinical trials in these
patients with SNPs.
6.5. Heterogeneity within depression screening instruments
In all the literature, there are seven scales used as indicators and
instruments for the evaluation of the extent of the depression and
the efficacy of the drugs (Hamilton Depression Scale Score, HAMD/
HDRS; The Inventory of Depressive Symptomatology, IDS30;
Montgomery-Asberg Depression Rating Scale, MADRS; Quick
Inventory of Depressive Symptomatology, QIDS-C16; 16-Item
Quick Inventory Depressive Symptomatology Self-Report Version,
QIDS-SR 16; Young Manic Rating Scale score, YMRS; The Clinical
Global Impression- Improvement scale, CGI-I)(eTable 1). More than
half of the literature (28 of 49) used HAMD/HDRS as their evalua-
tion scale, 21 literatures used MADRS, while other scales involved
 Z. Yuan et al. / Journal of Clinical Neuroscience 80 (2020) 169–181 175

Fig. 4. Meta-analysis of antidepressant activity of three kinds of anti-inflammatory drugs and ketamine. (A) Meta-analysis of anti-inflammatory drugs vs. placebo (response),
respectively. (B) Meta-analysis of anti-inflammatory drugs vs. placebo (remission), respectively. (C) Meta-analysis of anti-inflammatory drug vs. antidepressants (response),
respectively. (D) Meta-analysis of anti-inflammatory drug vs. antidepressants (remission), respectively. (E) Meta-analysis of ketamine vs. placebo; ketamine vs.
antidepressants (response). (F) Meta-analysis of ketamine vs. placebo; ketamine vs. antidepressants (remission).

little literature. The most widely used criterion for remission is a
HAMD-17score of  7, which corresponds to a HAMD-7 score
of  3 [96].For the MADRS, scale cutoff scores vary from 8 to 11
[97–99].But patients with HAMD-17scores  2 (or MADRS
scores  4) show better psychosocial functioning than those with
scores of 3 to 7 (or MADRS scoresof 5 to 9) [99]. On the other hand,
a problem with the use of very stringent definitions of remission is
that healthy, non depressed individuals may be labeled depressive.
A literature review of control groups in clinical depression trials
reported a mean HAMD-17 score of 3.2 ± 3.2 (SD) among healthy
control individuals [99]. Therefore, the use of different scales, the
different cutoff scores of same scale may lead to differences in
the evaluation results. Age and sex were not significantly associ-
ated with depression prevalence among any instruments.
6.6. Assessment of publication bias
Visual inspection of the funnel plot of studies reporting on
seven fist line antidepressants, revealed no significant asymmetry
(eFigure 4 in the Supplement). There was no evidence of publica-
tion bias (P = 0.7514, response; P = 0.9791, remission, using the
Egger test). Funnel plot of studies reporting on anti-inflammatory
drugs, also showed no significant asymmetry (eFigure 5 in the Sup-
plement). No evidence of publication bias was found (P = 0.9481,
response; P = 0.5228, remission, using the Egger test). Inspection
of the funnel plot of studies reporting on ketamine, displayed no
significant asymmetry (eFigure 6 in the Supplement). There was
no evidence of publication bias (P = 0.1221, response;
P = 0.08822, remission, using the Egger test).
176 Z. Yuan et al. / Journal of Clinical Neuroscience 80 (2020) 169–181

Fig. 5. Summary of side effects of seven first-line clinical antidepressants, three kinds of anti-inflammatory drugs and ketamine. (A) Side effects of seven first-line clinical
antidepressants. (B) Side effects of three kinds of anti-inflammatory drugs. (C) Side effects of ketamine.

7. Discussion The effectiveness of antidepressants varies in different coun-

In this meta-analysis, we systematically summarize the effec-
tiveness and side effects of different types of antidepressants. For
the clinical efficacy and side effects of first-line antidepressants,
anti-inflammatory drugs and ketamine, this article covers a com-
prehensive analysis.
Through meta-analysis, we found that each of the seven first
line antidepressant was effective. By comparing these OR value,
we found that whether compare to placebo or other antidepres-
sant, venlafaxine and duloxetine had better effects.
tries and regions. This may be due to ethnic differences in the
use of antidepressants, and drug compliance may also have a cer-
tain impact on the effectiveness.
The clinical situation may be more complicated. When
prescribing, the clinicians also need to consider patient’s age,
other diseases combined, drug compliance, individual
differences and many other factors. A simple meta-analysis
does not cover complex clinical situations, but we hope to
bring some help and inspiration to clinicians through our
systematic review.
 Z. Yuan et al. / Journal of Clinical Neuroscience 80 (2020) 169–181
Fig. 6. Summary of SNPs related to depression.
The hypothalamic–pituitary–adrenal (HPA) axis has been found
closely related to depression for four decades[100–102]. One of the
most consistent biological changes in the HPA axis, which was
found in more severe depression with melancholic features, is
the increased plasma cortisol. This biological difference is due to
a combination of restraining the regulation function of glucocorti-
coid receptor-mediated feedback inhibition and excessive stress-
related cortisol release. Notably, HPA axis changes are also associ-
ated with poor clinical response and high relapse [103].
We analyzed female participants in this meta-analysis and
found that gender(female) was the risk factor for depression(sFi
gure1)(OR. = 0.61, 95% CI(0.56, 0.65), P < 0.00001). As women are
approximately twice to be diagnosed with depression, and report
greater severity and increased symptoms compared to men, the
pathophysiology of depression might also differ by sex. That may
be because women have higher cortisol levels than men. In fact,
a large-scale gene expression study revealed multiple transcription
changes in opposite directions between men and women with
major depressive disorder [8].
Inflammatory cytokines may have a crucial role in the patho-
genesis of depression and that anti-cytokine drugs may be effective
for a part of patients with depression, particularly treatment-
resistant cases characterized by increased inflammation [5]. Treat-
ment of inflammation lacks disease specificity. Increased inflam-
mation exists in the pathogenesis of many diseases in which
depression is obviously included. Therefore, it is possible that the
antidepressant effect of anti-cytokine treatment is mediated by
improvements in cytokine-induced neuro-vegetative symptoms.
In this review, we found that three kinds of anti-inflammatory
drugs were effective as antidepressants, and NASIDs had the best
antidepressant effect. Anti-inflammatory drugs had 19 items of
side effects in total when used to treat depression, which were
all listed in our article. Evaluating the side effects of anti-
inflammatory drugs as a whole, headache was the highest inci-
dence side effects of anti-inflammatory drugs. Comparisons
between these drugs, cytokine-inhibitors had the highest incidence
of side effects. Ketamine is effective and fast acting antidepressant.
177
It is because of the non-specificity of inflammation that anti-
inflammatory drugs seem to benefit a wide variety of diseases. A
large number of scholars have applied more than 45 anti-
inflammatory drugs to treat depression. Such non-specificity also
makes anti-drugs not officially enter the clinic as antidepressants,
so neither safety nor effectiveness has been systematically
combed.
Several clinical studies have shown that ketamine, an anesthetic
drug with dissociative properties, provides an astonishing rapid
and robust antidepressant effect, when used in subanesthetic
doses. Esketamine has been put into clinical practice and become
a new antidepressant drug. On one hand, it could be said certainty
that antidepressants have come to a new chapter. The antidepres-
sants no longer need to experience a few weeks to take effect, but
can bring therapeutic effect in a very short time. This characteristic
also provides drug choice for patients with refractory depression
who have suicidal tendencies.
Environment can directly impact the interpretation of genetic
information, and that some genes are activated by environmental
factors. This process has been described as the gene-environment
interaction and it is pathogenesis of depression.
Genetic sensitivity to depression may vary between individuals
[104]. We classified these SNPs according to the pathogenesis of
depression. Despite these insights, successful translation of this
knowledge into clinically effective treatments has not occurred,
and treatments that modify HPA axis function when patients has
SNP related to HPA axis changes, such as glucocorticoid receptor
antagonists, have not worked inclinical trials [105–107]. Depres-
sive patients with inflammation-related SNP mutations do not
have individualized use of anti-inflammatory drugs as antidepres-
sants either.
8. Limitations
This study has important limitations. First, the data were
derived from studies that had different study designs, screening
178 Z. Yuan et al. / Journal of Clinical Neuroscience 80 (2020) 169–181
instruments, criteria for scale evaluation, and patients complicated
diseases and hormone levels. The substantial heterogeneity among
the studies remained largely unexplained by the variables
inspected. Second, many subgroup analyses relied on unpaired
cross-sectional data collected at different hospitals, which may
cause confounding. Third, doctors’ treatment level, preference for
drug use and comprehensive consideration of other diseases of
patients were unknown. It is also unknown whether there are false
invalidity cases. Fourth, the analysis relied on aggregated pub-
lished data. Fifth, since ketamine was just been approved by the
FDA for listing this year, there have been few retrospective studies
of the clinical effects of these new drugs. The number of other
types of research was also insufficient.
9. Future Directions
Depressive disorder (DD) and major depressive disorder (MDD)
are complex diseases influenced by both genetic contributions and
environmental risk factors. Genetic sensitivity to depression may
vary between individuals, resulting in individual differences in
the depressogenic effects. Therefore, genetic-response factors in
MDD may also underlie the aetiology of depression-linked disor-
ders with which MDD was commonly comorbid (e.g., cardiovascu-
lar diseases, diabetes, chronic pain and inflammation). The
pleiotropy and aetiology between mental and physical health con-
ditions may be due in part to genetic variants in depression. How-
ever, few genetic studies have such information and even fewer
prospective studies exist. These polymorphisms of depression sus-
ceptibility genes and genotype–diagnosis interactions may affect
individual. However, patients with these SNPs have not been trea-
ted with individualized drugs according to the mechanisms. We
hope that in the future treatment of depression, especially in the
treatment of refractory depression and MDD, we can formulate
individualized treatment plan according to the genetic polymor-
phism of patients.
10. Conclusions
The literature search retrieved 5529 potentially relevant articles
of which 49 studies were finally included. We compared the effi-
cacy of all kinds of antidepressants (seven first-line antidepres-
sants(fluoxetine, paroxetine, escitalopram, sertraline,
fluvoxamine, venlafaxine, duloxetine), there kinds of anti-
inflammatory drugs(NASIDs, cytokine-inhibitor, pioglitazone) and
ketamine) by comparing the OR values. The results suggest that
NASID, ketamine and venlafaxinwere more effective as an
antidepressant.
In this systematic review, we found that seven clinical antide-
pressants were effective, with venlafaxine and duloxetine being
more effective. Evaluating the side effects of antidepressants as a
whole, headache, nausea and insomnia were the three highest inci-
dence side effects of antidepressants which incidence rates
exceeded 10%. Comparisons between these seven drugs, fluvoxam-
ine had the highest incidence of side effects, while fluoxetine had
the lowest.
Three kinds of anti-inflammatory drugs were effective as
antidepressants, and NASIDs had the best antidepressant effect.
Anti-inflammatory drugs had 19 items of side effects in total when
used to treat depression, which were all listed in our article. Eval-
uating the side effects of anti-inflammatory drugs as a whole,
headache was the highest incidence side effects of anti-
inflammatory drugs. Comparisons between these drugs, cytokine-
inhibitors had the highest incidence of side effects.
Ketamine was effective and fast acting antidepressant. Keta-
mine had 14 items of side effects in total. Some side effects of keta-
mine were inseparable to it is an anesthetic. The incidences of
nausea and headaches were over 10%, while the incidences of
dizziness and restlessness were over 5%. SNPs related to depression
were also inductive and summarized.
Author contributions
L.LG., Y.ZQ. and J.Z. conceptualized the study and wrote the
manuscript. Y.ZQ., L.H. and X.MQ discussed and edited the manu-
script. L.LG. supervised the project. All authors reviewed and gave
final approval to the manuscript.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
Funding was provided by National Natural Science Foundation
of China (Grant 81801337 to LL); The Fundamental Research Funds
for Fujian Province University Leading Talents (Grant JAT170003 to
LL); The presidential research fund of Xiamen University(Grant
20720190075 to LL).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.jocn.2020.08.013.
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