Journal of Psychiatric Research 124 (2020) 109–114

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Journal of Psychiatric Research

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

Duloxetine and cardiovascular adverse events: A systematic review and T

meta-analysis
Kyounghoon Park, Seonji Kim, Young-Jin Ko, Byung-Joo Park∗
Department of Preventive Medicine, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, South Korea

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

Keywords: Duloxetine has been increasingly administered, but the associated cardiovascular adverse event risk is not
Duloxetine clearly understood. Therefore, we identified the association between duloxetine and cardiovascular adverse
Cardiovascular adverse events events through an analysis of heart rate and blood pressure change. We searched PubMed, EMBASE, Cochrane
Systematic review Central Register of Controlled Trials, ClinicalTrials.gov, and psycINFO in June 2019. The title, abstract, and full
Risk of Bias 2.0
text were checked in order to obtain articles. A meta-analysis was conducted with random effect model and
PRISMA harm checklist
quality of articles was evaluated using Cochrane Risk of Bias 2.0. The manuscript has been written according to
the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) harm checklist. A total of
4009 studies were screened by the title and abstract. After reviewing 186 full texts, 17 studies were finally
selected for the meta-analysis. Nine of the 17 studied duloxetine given for mood disorders and 8 for pain control.
The duration of 14 studies was under 13 weeks. Cardiovascular adverse events (hypertension, myocardial in-
farction, transient ischemic attack, tachycardia atrial fibrillation, and cerebrovascular accident) were reported.
The meta-analysis demonstrated that duloxetine increased heart rate by 2.22 beats/min (95% confidence in-
tervals [CIs]: 1.53, 2.91) and diastolic blood pressure by 0.82 mmHg (95% CI: 0.17, 1.47). Our findings may be
the signal for the safety of cardiovascular disease for short-term use of duloxetine. Well-designed pharmaco-
epidemiological studies evaluating the causal relationship between long-term use of duloxetine and cardiovas-
cular disease is still necessary.

1. Introduction the neuroanatomy of the regulatory pathways, reuptake inhibition of

Cardiovascular disease (CVD) is the number one cause of death
worldwide, causing 17.9 million deaths in 2016. It encompasses dis-
eases of the blood vessels such as coronary artery disease and cere-
brovascular disease (WHO, 2017). The known risk factors for CVD are
obesity, hyperlipidemia, hypertension, diabetes, smoking, lack of ex-
ercise, and excessive drinking (Lichtenstein et al., 2006). It has also
been established that mood disorders such as major depressive disorder
(MDD) and bipolar disorder are associated with CVD (Frasure-Smith
and Lesperance, 2005). Additionally, the prevalence of MDD is higher
in patients with CVD (Niranjan et al., 2012); therefore, risk assessment
for CVD with antidepressant use is gaining importance.
Duloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI)
that blocks serotonin and norepinephrine neuro-transporters (Chalon
et al., 2003). In 2017, duloxetine was prescribed more than 16 million
times in the U.S. and was the most widely used drug among the SNRIs
along with venlafaxine (AHRQ, 2017). Although there are differences in
serotonin and norepinephrine neurotransmission is expected to affect
both mood disorders and pain control (Goldstein et al., 2004). How-
ever, because the levels of both serotonin and norepinephrine are in-
creased with the use of SNRIs, hypertension, tachycardia, arrhythmias,
and other adverse events are more likely than with selective serotonin
reuptake inhibitors use (Piña et al., 2018).
There are several studies on the cardiovascular-related adverse
events of duloxetine. According to an analysis of eight randomized
controlled trials (RCTs), the use of duloxetine compared to placebo
significantly increased heart rate (HR) (1.6 vs. −0.6 beats/min) and
systolic blood pressure (SBP) (1.0 vs. −1.2 mmHg) (Thase et al., 2005).
In 2007, results from 42 placebo-controlled trials reported a significant
increase in HR (3.20 vs. −0.67 beats/min), SBP (0.65 vs.
−0.55 mmHg), and diastolic blood pressure (DBP) (0.88 vs.
−0.18 mmHg) (Wernicke et al., 2007). The authors concluded that the
results were statistically significant but clinically meaningless. How-
ever, the analysis was not a systematic review and many of the studies

∗
Corresponding author. Department of Preventive Medicine, Seoul National University College of Medicine, 103, Daehak-ro, Jongno-gu, Seoul, 03080, South
Korea.
E-mail addresses: khoon82@snu.ac.kr (K. Park), sunji0316@snu.ac.kr (S. Kim), hyugo02@snu.ac.kr (Y.-J. Ko), bjpark@snu.ac.kr (B.-J. Park).

https://doi.org/10.1016/j.jpsychires.2020.02.022
Received 4 December 2019; Received in revised form 24 February 2020; Accepted 24 February 2020
0022-3956/ © 2020 Elsevier Ltd. All rights reserved.
K. Park, et al.
(13 of 42) were not published.
Since the indications for duloxetine have expanded and new RCTs
are being conducted, systematic reviews and meta-analyses are neces-
sary to reassess the potential cardiovascular-related adverse events of
duloxetine. Therefore, we identified RCTs that reported cardiovascular-
related adverse events after comparing duloxetine and placebo.
Changes in HR, SBP, and DBP from these studies have been quantita-
tively summarized.
2. Methods and materials
2.1. Search strategy
We searched Medline/PubMed, EMBASE, CENTRAL (Cochrane
Central Register of Controlled Trials), ClinicalTrials.gov, and PsycINFO
databases in June 2019 to find studies that met our inclusion criteria.
We constructed a PICOT-SD (Patients, Intervention, Comparison,
Outcome, Time, Setting and Design) to discover keywords. Any in-
dication for duloxetine prescription (P, I) compared with a placebo or
no medication (C), outcome-related safety (O), published after the
1990s (T), community- or hospital-based (S), and designated RCTs (D).
The outcome (O) keywords used were related to the overall safety
(safety, complication, adverse event, etc.) and included CVD. When we
conducted the pilot study, we confirmed that the search was insufficient
when the outcome keywords were limited to specific diseases or con-
ditions such as CVD, hypertension, and blood pressure. Therefore, terms
for specific diseases, conditions, and safety were included as keywords
used for searching. The keywords were created by combining keyword
subject searches (such as Medical Subject Headings) and free text words
(Table S1). The retrieved studies were sorted using EndNote X9 and
Excel. There was no language restriction.
2.2. Study selection and data collection
After removing duplicate studies, the titles and abstracts of the RCTs
related to duloxetine were searched for any information on the adverse
events of duloxetine. Thereafter, the RCTs studies that compared du-
loxetine to a placebo or to no treatment were selected through full-text
reviews. Because information on adverse events of duloxetine was often
unknown before the full texts were checked, the exclusion was not
made before the final selection of the studies through full-text reviews.
The exclusion criteria were studies that shared patient data from other
RCTs, compared duloxetine with other antidepressants or analgesics
only, open-labeled studies, and those that switched duloxetine and
placebo treatments during the study period. Unlike other databases,
ClinicalTrials.gov provided the results of clinical trials in text form
without providing abstracts or titles. Therefore, among the studies that
were searched in ClinicalTrials.gov, studies not found in other data-
bases and presented information on the adverse events of duloxetine
were included. We then collected data from the selected studies: au-
thors; publication year; indication for duloxetine; study period; number
of subjects taking duloxetine; number of subjects in the control group;
age and sex of the subjects; the daily dose of duloxetine; any reported
adverse event related to CVD during the study course (e.g., hyperten-
sion, myocardial infarction, heart failure, and stroke); and the change
from baseline of HR, SBP, and DBP for subjects taking duloxetine and
those taking a placebo.
2.3. Statistical analyses
A meta-analysis of the mean difference of HR, SBP, and DBP change
from baseline between duloxetine and placebo was performed.
Additionally, we conducted subgroup analyses of the subjects' ages and
drug indications. Since the heterogeneity of each group was expected to
be high, a random effects model was used and the heterogeneity be-
tween groups was calculated as Higgins I2. We also applied Egger's test
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Journal of Psychiatric Research 124 (2020) 109–114
and created a funnel plot to determine the probability of publication
bias.
2.4. Risk of bias in individual studies
We used Cochrane ROB (Risk-of-bias tool for randomized trials)
version 2.0 from August 22, 2019, to assess for bias (Sterne et al.,
2019). This tool was developed to assess the risk of bias in RCTs and
consist of 5 domains: 1) the randomization process, 2) the intended
interventions, 3) missing outcome data, 4) the measurement of the
outcome, and 5) the reported result. Because our main concern was
safety, we evaluated outcomes accordingly.
This study was written in accordance with the PRISMA (Preferred
Reporting Items for Systematic Reviews and Meta-Analyses) harms
checklist (Zorzela et al., 2016).
Studies search, selection, data extraction, and risk of bias evaluation
were performed independently by two authors (KP and SK), and a
conclusion was reached through consensus. A conclusion was reached
through discussion with other authors in case there was a disagreement
(YJK and BJP).
3. Results
After removing 717 duplicates from the 4726 studies retrieved,
3823 studies were additionally removed after reviewing the title and
abstract because they were not RCTs involving duloxetine. For the 186
studies selected, the full texts were evaluated for eligibility. Those
sharing study samples (n = 10), those without parallel design and
open-label studies (n = 56), studies comparing duloxetine to other
antidepressants or analgesics only (n = 32), and studies whose full
texts were impossible to find (n = 8) were excluded. Additionally, 15
studies were obtained from the ClinicalTrials.gov database. In the end,
95 studies were selected. The studies were then divided, by indications,
into mood disorder, (n = 35) pain control, (n = 41) urinary incon-
tinence, (n = 12) and others (n = 9). In the end, we conducted a meta-
analysis with 17 studies (Goldstein et al., 2004; Detke et al., 2004;
Arnold et al., 2005; Raskin et al., 2005; Perahia et al., 2006, 2009;
Allgulander et al., 2008; Chappell et al., 2008; Skljarevski et al., 2009,
2010; Gaynor et al., 2011; Wu et al., 2011; Vollmer et al., 2014;
Atkinson et al., 2014; Emslie et al., 2014; Strawn et al., 2015;
Upadhyaya et al., 2019). Sixteen studies on HR change, 12 studies on
SBP change, and 13 studies on DBP change were included (Fig. 1).
3.1. General characteristics of studies included in the meta-analysis
Nine of the 17 studies were conducted for mood disorders and 8
studies for controlling pain. Fourteen of the studies lasted less than 13
weeks and the daily doses of duloxetine were 30, 60, 80, and 120 mg.
Nine studies were conducted using a single dose, and in eight studies,
the treatment dose was increased during the study. The sample size of
the study group ranged from 331 to 59. The proportion of women in all
groups was larger than men. Thirteen studies were conducted on those
aged between 30s and 50s, and four studies on 10s. Many cardiovas-
cular-related adverse events were reported. Hypertension was the most
common adverse event, but myocardial infarction, transient ischemic
attack, tachycardia, atrial fibrillation, and cerebrovascular accident
were also reported (Table 1).
3.2. Meta-analysis for HR, SBP, and DBP change from baseline compared
to a placebo
Compared to the placebo group, the duloxetine group showed a
2.22 beats/min (95% confidence interval [CI]: 1.53, 2.91) increase in
HR (Fig. 2). SBP increased by 0.62 mmHg (95% CI: -0.24, 1.52) al-
though insignificant, statistically (Fig. 3). DBP increased by 0.82 mmHg
(95% CI: 0.17, 1.47) (Fig. 4). The heterogeneity of the included studies
K. Park, et al.
Fig. 1. Flow chart of systematic review and meta-analysis.
was calculated by Higgins I2 and was not very high (HR: 27%; SBP:
21%; DBP: 24%). Meta regression was performed to estimate the as-
sociation of differences according to daily dose (if the daily dose
changed, the median value was used) and publication year. However,
there were not significant slope values with daily dose (HR: -0.01; 95%
CI: -0.04, 0.03/SBP: 0.02; 95% CI: -0.02, 0.06/DBP: -0.002; 95% CI:
-0.03, 0.03) and publication year (HR: -0.01; 95% CI: −0.19, 0.18/SBP:
-0.03; 95% CI: -0.24, 0.17/DBP: 0.02; 95% CI: -0.13, 0.17). We con-
ducted the Egger's test on each result (HR: 0.31; SBP: 0.85; DBP: 0.68),
and the Funnel plot results for the study are included in supplement
(Figs. S1–S3).
3.3. Subgroup analyses by age and indication
Subgroup analyses were performed by age and duloxetine indica-
tion. For age, the analysis was conducted in two groups—one in teen-
agers (HR: 2.31; 95% CI: 0.61, 4.02/SBP: 0.83; 95% CI: -0.41, 2.08/
DBP: 1.27; 95% CI: 0.26, 2.28) and the other in the 30s–50s age range
(HR: 2.20; 95% CI: 1.41, 2.98/SBP: 0.51; 95% CI: -0.86, 1.87/DBP:
0.63; 95% CI: -0.20, 1.46). The results obtained were similar, except for
changes in DBP. The results were similarly divided by the indication:
mood disorder (HR: 1.91; 95% CI: 0.81, 3.00/SBP: 0.58; 95% CI: -0.50,
1.66/DBP: 0.58; 95% CI: -0.11, 1.26) and pain control (HR: 2.60; 95%
CI: 1.75, 3.44/SBP: 0.76; 95% CI: -0.98, 2.51/DBP: 1.47; 95% CI: 0.01,
2.93).
3.4. Risk of bias
ROB was low in almost all the studies because they were double-
blind placebo-controlled trials. Some studies did not provide all of the
vital signs data; however, this was considered low ROB as they were not
presented because of their statistical insignificance (Table S2).
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Journal of Psychiatric Research 124 (2020) 109–114
4. Discussion
Our study showed that, compared to the control group, the use of
duloxetine increased HR and DBP. However, this change was con-
sidered clinically meaningless because it was minimal. The American
Heart Association guideline released in 2017 also reported that an in-
crease of SBP above 10 mmHg could clinically increase the risk of CVD
(Whelton et al., 2017). However, valdecoxib and sibutramine, which
were withdrawn from the market due to the risk of CVD, had an in-
crease of 1–3 mmHg in SBP or DBP compared to the control group
(Blankfield and Iftikhar, 2015). Moreover, the increases in SBP of
2 mmHg and in DBP of 1 mmHg were reported to increase the risk of
heart attack by 10% and the risk of stroke by 7% in middle-aged sub-
jects (Lewington et al., 2002). Because most RCTs were conducted
for < 13 weeks and each study group's sample size was < 350, it was
not feasible to fully observe all cardiovascular-related adverse events
caused by duloxetine. Like the Framingham risk score, assessing for the
occurrence of CVD requires long study periods (D'Agostino et al., 2008).
And according to the rule of three, with 300 study subjects, only ad-
verse events with an incidence rate of 1 percent can be found with a
probability of 95% (Eypasch et al., 1995). Our findings may provide
evidence for the short-term safety of duloxetine use with regards to
CVD adverse events. However, the long-term safety of duloxetine must
be evaluated in longer observational studies.
For the observational studies reviewed, there were conflicting re-
sults in the relationship between duloxetine and cardiovascular disease.
Xue et al. (2012) published a cohort study in 2012 that showed cardi-
ovascular-related events (acute myocardial infarction, sudden death,
hypertensive crisis, arrhythmia, and coronary revascularization) were
not related to duloxetine (incidence rate ratio: 0.51; 95% confidence
interval [CI]: 0.32, 0.81). However, another cohort study by Leong
et al. (2017) reported that SNRIs had a higher risk of acute myocardial
infarction, stroke, or cardiovascular-related adverse outcomes com-
pared to SSRIs (hazard ratio: 1.13; 95% CI: 1.06, 1.21). Leong et al.’s
cohort study had a 16-year observation period, while the cohort study
 K. Park, et al.

Table 1
General characteristics of studies included in this systematic review and meta-analysis.
Year Author Indication Study duration Study group* Sample size (female)† Mean age† Reported cardiovascular-related adverse events Funding source

2004 Detke et al. (20) MDD 8 weeks 80/120/placebo 95(70)/93(70)/93(69) 43.1/44.7/43.7 Duloxetine: 3 patients HTN (80 mg) Pharmaceutical companies
1 patient HTN (120 mg)
Placebo: 1 patient HTN
2004 Goldstein et al. (6) MDD 8 weeks 40/80/placebo 86(48)/91(56)/89(57) 41/41/40 No cardiovascular-related adverse events reported Pharmaceutical companies
2005 Arnold et al. (21) fibromyalgia 12 weeks 60/120/placebo 118(118)/116(116)/120(120) 49.6 (total) Duloxetine: 1 patient HTN Pharmaceutical companies
Placebo: 1 patient HTN
2005 Raskin et al. (22) DPNP 12 weeks 60/120/placebo 116(68)/116(55)/116(63) 58.3/59/59.2 Duloxetine: 1patient atrial fibrillation (60 mg) Pharmaceutical companies
4 patients HTN (60 mg)
6 patients HTN (120 mg)
Placebo: 1 patient cerebrovascular accident
1 patient chest pain
7 patents HTN
2006 Perahia et al. (23) MDD 8 weeks 80/120/placebo 93(62)/103(77)/99(65) 46.5/44/44.7 No cardiovascular-related adverse events reported Pharmaceutical companies
§
2008 Allgulander et al. (24) GAD 10 weeks 60–120/placebo 320(−)/331(−) 41.6 (total) No cardiovascular-related adverse events reported Pharmaceutical companies
§
2008 Chappell et al. (25) fibromyalgia 27 weeks 60–120/placebo 162(149)/168(159) 50.75/50.23 HTN reported (No number presented) Pharmaceutical companies
2009 Skljarevski et al. (26) CLBP 13 weeks 20/60/120/placebo 59(36)/116(67)/112(65)/117(64) 52.9/53.3/54.9/54 Duloxetine: 1event TIA (120 mg) Pharmaceutical companies
1event MI (120 mg)
HTN reported (No number presented)
§
2009 Perahia et al. (27) MDD recurrence 52 weeks 60–120/placebo 146(100)/142(106) 47.1/48 Duloxetine: 1 patient MI Pharmaceutical companies

112
1 patient TIA
3 patients HTN
Placebo: 2 patients HTN
§
2010 Skljarevski et al. (28) CLBP 13 weeks 60–120/placebo 115(71)/121(73) 51.8/51.2 Duloxetine: Pharmaceutical companies
1 patient HE
1 patient TIA
Placebo: 1 patient MI
2011 Gaynor et al. (29) MDD and APPS 8 weeks 60/placebo 262(180)/266(184) 46.2/45.7 No cardiovascular-related adverse events reported Pharmaceutical companies
§
2011 Wu et al. (30) GAD 15 weeks 60–120/placebo 108(50)/102(56) 37.3/38.0 No cardiovascular-related adverse events reported Pharmaceutical companies
2014 Vollmer et al. (31) Multiple Sclerosis 6 weeks 60/placebo 118(86)/121(93) 50.8/52.7 Duloxetine: 3.3% patient diastolic HTN Pharmaceutical companies
2.6% patient systolic HTN
2.7% patient tachycardia
Placebo: 1.1% patient diastolic HTN
1.2% Systolic HTN
0.9% tachycardia
§
2014 Atkinson et al. (32) MDD 10 weeks 60–120/placebo 117(61)/103(51) 13.1/13.3 No cardiovascular-related adverse events reported Pharmaceutical companies
2014 Emslie et al. (33) MDD 10 weeks 30/60/placebo 116(47)/108(60)/122(69) 12.9/12.9/13.1 No cardiovascular-related adverse events reported Pharmaceutical companies
§
2015 Strawn et al. (34) GAD 10 weeks 30–120/placebo 135(70)/137(75) 12.6/12.2 No cardiovascular-related adverse events reported Pharmaceutical companies
§
2019 Upadhyaya et al. (35) fibromyalgia 13 weeks 30–60/placebo 91(73)/93(65) 15.74/15.33 No cardiovascular-related adverse events reported Pharmaceutical companies

MDD Major Depressive Disorder; DPNP Diabetic Peripheral Neuropathic Pain; GAD Generalized Anxiety Disorder; CLBP Chronic Low Back Pain; APPS associated painful physical symptoms; HTN hypertension; TIA
transient ischemic accident; MI myocardial infarction; HE hypertensive encephalopathy *Duloxetine daily dose(mg) †Categorized by study group §Drug dose increased in the study duration.
Journal of Psychiatric Research 124 (2020) 109–114
K. Park, et al. Journal of Psychiatric Research 124 (2020) 109–114

Fig. 2. Changes in heart rates in duloxetine vs placebo treatment.

Fig. 3. Changes in systolic blood pressure in duloxetine vs placebo treatment.

Fig. 4. Changes in diastolic blood pressure in duloxetine vs placebo treatment.

by Xue et al. was a 3-year study, supported by a pharmaceutical com-
pany. Additionally, Lee et al. (2018) conducted a signal detection study
that reported that duloxetine had signals related to cardiac disorder
(reporting odds ratios [ROR]: 3.12; 95% CI: 2.88, 3.38) and vascular
hypertensive disorders (ROR: 2.07; 95% CI: 1.91, 2.25). As many CVD
related adverse events have been identified in our study, we suggest
that more studies are conducted to determine the risk of cardiovascular-
related adverse events with duloxetine.
This study has several strengths. We applied the latest PRISMA
harms checklist to improve the transparency of the reporting and used
the risk of bias tool version 2.0 to evaluate the objectivity of study
inclusion. Also, in order to incorporate as many studies as possible, a
preliminary study was conducted to confirm the validity of our search
strategy and to modify the keywords.
Our systematic review has a limitation that there is a potential risk
of selective reporting. We have tried to conduct a comprehensive
search; however, not all published studies were included. In addition,
the included studies presented only changes for the entire group, not
individual changes. However, compared to previous studies (Thase
et al., 2005; Wernicke et al., 2007), this was a well-organized study
using the PRISMA-harms checklist that provided evidence to support
existing data regarding the short-term safety of duloxetine use.
Although vital signs were measured by other researchers when ex-
amining the cardiovascular-related adverse events of duloxetine, all
results were not published because of statistical insignificance, a major
obstacle for us in generating evidence through systematic review and
meta-analysis. It could be concluded that although many RCTs have
been conducted to evaluate the efficacy and safety of duloxetine, they
were insufficient due to their short observational periods and small
study samples. Therefore, well-designed pharmaco-epidemiological

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K. Park, et al.
studies are necessary to establish the long-term safety of duloxetine.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
No conflict of interest with any authors.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.jpsychires.2020.02.022.
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