Research

JAMA Psychiatry | Original Investigation

Association of Antidepressant Use

With Adverse Health Outcomes
A Systematic Umbrella Review
Elena Dragioti, PhD; Marco Solmi, MD, PhD; Angela Favaro, MD, PhD; Paolo Fusar-Poli, MD, PhD; Paola Dazzan, MD, PhD; Trevor Thompson, PhD;
Brendon Stubbs, PhD; Joseph Firth, PhD; Michele Fornaro, MD, PhD; Dimitrios Tsartsalis, MD, PhD; Andre F. Carvalho, MD, PhD; Eduard Vieta, MD, PhD;
Philip McGuire, MD, PhD; Allan H. Young, FRCPsych; Jae Il Shin, MD, PhD; Christoph U. Correll, MD; Evangelos Evangelou, PhD

Editorial
IMPORTANCE Antidepressant use is increasing worldwide. Yet, contrasting evidence on the Supplemental content
safety of antidepressants is available from meta-analyses, and the credibility of these findings
has not been quantified.

OBJECTIVE To grade the evidence from published meta-analyses of observational studies

that assessed the association between antidepressant use or exposure and adverse health
outcomes.

DATA SOURCES PubMed, Scopus, and PsycINFO were searched from database inception
to April 5, 2019.

EVIDENCE REVIEW Only meta-analyses of observational studies with a cohort or case-control

study design were eligible. Two independent reviewers recorded the data and assessed the
methodological quality of the included meta-analyses. Evidence of association was ranked
according to established criteria as follows: convincing, highly suggestive, suggestive, weak,
or not significant.

RESULTS Forty-five meta-analyses (17.9%) from 4471 studies identified and 252 full-text
articles scrutinized were selected that described 120 associations, including data from 1012
individual effect size estimates. Seventy-four (61.7%) of the 120 associations were nominally
statistically significant at P ⱕ .05 using random-effects models. Fifty-two associations
(43.4%) had large heterogeneity (I2 > 50%), whereas small-study effects were found for 17
associations (14.2%) and excess significance bias was found for 9 associations (7.5%).
Convincing evidence emerged from both main and sensitivity analyses for the association
between antidepressant use and risk of suicide attempt or completion among children and
adolescents, autism spectrum disorders with antidepressant exposure before and during
pregnancy, preterm birth, and low Apgar scores. None of these associations remained
supported by convincing evidence after sensitivity analysis, which adjusted for confounding
by indication.

CONCLUSIONS AND RELEVANCE This study’s findings suggest that most putative adverse
health outcomes associated with antidepressant use may not be supported by convincing
evidence, and confounding by indication may alter the few associations with convincing
evidence. Antidepressant use appears to be safe for the treatment of psychiatric disorders,
but more studies matching for underlying disease are needed to clarify the degree of
confounding by indication and other biases. No absolute contraindication to antidepressants
emerged from this umbrella review.

Author Affiliations: Author

affiliations are listed at the end of this
article.
Corresponding Author: Elena
Dragioti, PhD, Pain and Rehabilitation
Centre and Department of Medicine
and Health Sciences, Linköping
JAMA Psychiatry. doi:10.1001/jamapsychiatry.2019.2859 University, SE-581 85 Linköping,
Published online October 2, 2019. Sweden (elena.dragioti@liu.se).

(Reprinted) E1
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 Research Original Investigation
A
ccumulating evidence suggests a sharp growth in anti-
depressant use worldwide. Up to 8% to 10% of adults in
the United States take at least 1 antidepressant drug,
which is ranked third among prescribed and fourth among sold
medications.1,2 Antidepressants are indicated and used for de-
pressive disorders, anxiety disorders, posttraumatic stress dis-
order, premenstrual dysphoric disorder, obsessive-compulsive
disorder, bulimia nervosa, and binge-eating disorder, among
others.3-5
The safety profile of antidepressants is controversial. Since
the US Food and Drug Administration introduced the black box
warnings that associated selective serotonin reuptake inhibi-
tor (SSRI) use with a higher risk of suicidal behavior in chil-
dren and adolescents,6 the debate about the efficacy, accept-
ability, and safety profile of antidepressant medications has
gradually increased.7-11 Evidence from randomized clinical
trials (RCTs) of antidepressants’ efficacy and acceptability has
been well documented in both meta-analyses and network
meta-analyses,4,8,10,12,13 but safety assessment is inherently bi-
ased by certain methodological weaknesses of RCTs. These
weaknesses include small and unrepresentative samples, rare
and inconsistent reporting of adverse outcomes, and short du-
ration of exposures.14,15
Observational studies complement RCTs by providing evi-
dence with real-world data15 on a number of adverse health out-
comes associated with antidepressants, which is not possible in
RCTs.16 For example, observational studies can show medica-
tion safety because they include representatives of the overall
target population, such as patients with comorbid disorders or
suicidal thoughts who are often excluded from RCTs. In addition,
observational studies typically have a longer follow-up duration
compared with RCTs, providing data on the mid- or long-term
consequences of antidepressants, such as poor bone status or gas-
trointestinal bleeding, that may not arise from short-term use.16
Several meta-analyses of observational studies have been
published that assess antidepressant safety; however, to our
knowledge, no attempt has been made to quantify the credibil-
ity of their findings. This quantification is crucial considering the
uncertainty surrounding observational research results.17-19 Um-
brella reviews make it feasible to summarize the evidence from
multiple meta-analyses on the same topic20,21 and enable the
ranking of evidence (as convincing, highly suggestive, sugges-
tive, weak, or not significant) according to sample size, strength
of the association, and assessment of presence of biases.22-24
In this umbrella review, we graded the evidence from pub-
lished meta-analyses of observational studies. These studies
tested the association between antidepressant use and risk of
adverse health outcomes.
Methods
The protocol for this study was registered on PROSPERO
(CRD42018103462). We followed the Preferred Reporting Items
for Systematic Reviews and Meta-analyses (PRISMA) reporting
guideline25 and the Meta-analysis of Observational Studies in
Epidemiology (MOOSE) guidelines 26 (eAppendix 1 in the
Supplement).
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Association of Antidepressant Use With Adverse Health Outcomes
Key Points
Question Is antidepressant use associated with adverse health
outcomes, and how credible is the evidence behind this
association in published meta-analyses of real-world data?
Findings In this systematic umbrella review of 45 meta-analyses
of observational studies, convincing evidence was found for the
associations between antidepressant use and suicide attempt or
completion among individuals younger than 19 years and between
antidepressant use and autism risk among the offspring. However,
none of these associations remained at the convincing evidence
level after a sensitivity analysis that adjusted for confounding by
indication.
Meaning This study’s findings suggest that claimed adverse
health outcomes associated with antidepressants may not be
supported by strong evidence and may be exaggerated by
confounding by indication; no absolute contraindication to the use
of antidepressants was found to be currently supported by
convincing evidence.
Search Strategy and Selection Criteria
We searched PubMed, Scopus, and PsycINFO from database
inception to April 5, 2019, to identify systematic reviews with
meta-analysis of observational studies of the association be-
tween any adverse health outcome and exposure to antide-
pressants. Our search strategy used a combination of terms re-
lated to antidepressants (eg, antidepressants, selective serotonin
reuptake inhibitors), to adverse health outcomes (eg, harms,
suicide, bleeding, and autism), and to meta-analysis with no age,
sex, population, and medical condition restrictions (eAppen-
dix 2 in the Supplement). We also manually searched the cited
references of the retrieved articles and reviews.
Two of us (E.D. and M.S.) independently searched titles or
abstracts for eligibility and consulted a third reviewer (E.E.)
when we could not reach a consensus. The full texts of poten-
tially eligible articles were retrieved, and the same two of us
(E.D. and M.S.) independently scrutinized each study for eli-
gibility. Any discrepancies during this process were resolved
by our third reviewer (E.E.).
We included only peer-reviewed systematic reviews with
meta-analysis of observational studies with a cohort, case-
control, or nested case-control study design measuring any
association between antidepressant use and any adverse health
outcome in any population of any age. Whenever multiple meta-
analyses on the same adverse health outcome were performed
(ie, overlapping meta-analyses with the same outcome, type of
antidepressant used, and clinical or population setting), we
assessed only the one that included the largest data set, as pre-
viously described.22,24,27 Details of the selection between over-
lapping meta-analyses are described in the eMethods in the
Supplement. For each eligible meta-analysis, we considered the
main analysis for all primary and secondary reported outcomes.
The concordance between selected and nonselected meta-
analyses was examined in a sensitivity analysis.27
We excluded (1) meta-analyses of studies with other study
designs (eg, RCTs, cross-sectional) or that included both ob-
servational studies and RCTs in the same analysis; (2) meta-
analyses published in languages other than English; (3) meta-
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 Association of Antidepressant Use With Adverse Health Outcomes
analyses of individual patient or participant data, pooled
analyses of a nonsystematic selection of observational stud-
ies, and nonsystematic reviews; (4) meta-analyses of St John’s
wort (Hypericum perforatum) or tryptophan; and (5) meta-
analyses that provided insufficient or inadequate data for quan-
titative synthesis.
Data Extraction
Two of us (E.D. and M.S.) independently performed data ex-
traction, and disagreements were resolved by a consensus. Ad-
verse health outcomes associated with exposure to antide-
pressants were extracted as defined by the original authors.
For each meta-analysis, we recorded the standard identifier
(PMID and DOI), first author, publication year, type of antide-
pressant, study design, age of participants, adverse health out-
comes, exposure and nonexposure, illnesses examined (eg, de-
pression), number of included studies, and total sample size.
For each primary study, we recorded first author; year of
publication; study design (ie, cohort or case-control); num-
ber of cases and controls in case-control studies or total popu-
lation in cohort studies; reported adjusted (or unadjusted)
effect size (ie, relative risk, odds ratio, hazard ratio, and stan-
dardized mean difference), each with a 95% CI; and study lo-
cation. We also captured the number and nature of adjust-
ments, the length of follow-up, the study quality score, and
whether the studies were controlled for a psychiatric condi-
tion (ie, confounding by indication).18,19
The methodological quality of each included meta-
analysis was assessed by 2 of us (E.D. and M.S.) using the up-
dated AMSTAR (A Measurement Tool to Assess Systematic
Reviews) 2.28 AMSTAR 2 also accounts for the quality of stud-
ies included in the meta-analysis beyond a mere technical
methodological assessment of the included meta-analysis
(eMethods in the Supplement).16
Statistical Analysis
For each association, we extracted effect sizes of individual
studies included in each meta-analysis, and we repeated the
meta-analyses to calculate the pooled effect sizes and the
95% CIs using random-effects models to compare homoge-
neously analyzed results.29 We did not transform the initial ef-
fect sizes or modify the direction of associations presented by
the original authors to compare the results we obtained with
the reported results in the meta-analyses. Heterogeneity was
assessed with the I2 statistic.30 In addition, we calculated the
95% prediction intervals for the summary random effect
sizes, providing the possible range in which the effect sizes of
future studies were expected to fall.31
Next, we tested whether smaller studies yielded larger ef-
fect sizes compared with larger studies, an indication of small-
study effect bias.24,32-34 Small-study effect bias was indi-
cated both by the Egger regression asymmetry test (P ≤ .10) and
by the random-effects summary effect size being larger than
that of the biggest study in each association.24,32-34
We then assessed the existence of excess significance bias
by evaluating whether the observed number of studies with
nominally statistically significant results (positive studies as in-
dicated with a 1-sided P ≤ .05) was different from the expected
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Original Investigation Research
Table 1. Criteria for Credibility-of-Evidence Classification
in Observational Studies
Classification Criteria
Convincing evidence (class I) • >1000 Cases
• Significant summary associations
(P < 1 × 10−6) per random-effects
calculations
• No evidence of small-study effects
• No evidence of excess of significance bias
• Prediction intervals not including the null
value
• Largest study nominally significant
(P < .05)
• No large heterogeneity (ie, I2 < 50%)
Highly suggestive evidence • >1000 Cases
(class II) • Significant summary associations
(P < 1 × 10−6) per random-effects
calculation
• Largest study nominally significant
(P < .05)
Suggestive evidence (class III) • >1000 Cases
• Significant summary associations
(P < 1 × 10−3) per random-effects
calculations
Weak evidence (class IV) • All other associations with P ≤ .05
Nonsignificant association (NS) • All associations with P > .05
number of studies with statistically significant results.34 The ex-
pected number of statistically significant studies per association
was calculated by summing the statistical power estimates for
each component study. The power estimates of each component
study depend on the plausible effect size for the tested associa-
tion, which we assumed to be the effect size of the largest study
(ie, the smallest SE) per association.35 Excess significance bias
was set at P ≤ .10. This test was designed to assess whether the
published meta-analyses comprised an overrepresentation of
false-positive findings.34 All analyses were conducted in Stata/
MP, version 10.0 (StataCorp LLC).
Assessment of the Credibility of the Evidence
We assessed the credibility of the evidence per association
provided in meta-analyses by applying several criteria
in concordance with previously published umbrella
reviews.22,23,32,33,36,37 In brief, associations that presented
nominally significant random-effects summary effect sizes
(ie, P ≤ .05) were ranked as convincing, highly suggestive, sug-
gestive, or weak evidence according to sample size, strength
of the association, and assessment of the presence of biases
(Table 1 and eMethods in the Supplement). In addition, to pro-
vide an estimate of the epidemiologic implication of find-
ings, we calculated the prevalence of outcomes of interest from
cohort studies only (studies with case-control designs should
not be considered for prevalence estimates).
Sensitivity Analysis
We performed sensitivity analyses to assess whether the cred-
ibility of the evidence varied within both prospective and ret-
rospective cohort studies, prospective cohort studies, stud-
ies adjusted for multiple covariates and for confounding by
indication, high-quality primary studies, studies of antide-
pressant classes (SSRIs, tricyclic antidepressants [TCAs], and
other or mixed antidepressants), and locations where studies
were conducted (Europe, North America, or other regions).
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 Research Original Investigation Association of Antidepressant Use With Adverse Health Outcomes

Figure 1. Flowchart of the Literature Search and Evaluation Process

for 45 Published Meta-analyses and Systematic Reviews

4243 Records identified through 229 Records identified through

database search other sources

3762 Records screened after

duplicate removal

3510 Records excluded

252 Full-text articles assessed

207 Full-text articles excluded

121 Not a meta-analysis or systematic review with quantitative synthesis
19 Had overlapping meta-analysis or systematic review of association
between antidepressants and risk of adverse health outcomes
16 Provided insufficient or inadequate data for quantitative synthesis
13 Not a meta-analysis or systematic review of observational studies
13 Not reporting an association between antidepressants and risk of
adverse health outcomes
12 Commentaries
11 Not including only case-control and cohort studies
2 Full text could not be retrieved

45 Studies eligible for

quantitative synthesis

45 Studies from which

data were extracted

These analyses were performed only for the associations

Figure 2. Percentages of the Reported 13 Adverse Health Outcome
ranked as convincing evidence or highly suggestive evidence Domains Associated With Antidepressant Exposure in 45 Published
(ie, class I or II) in the main analysis. Meta-analyses

Suicide

Results Mortality

Maternal complications
In total, we identified 4471 studies, scrutinized 252 full-text
Malformations in the newborn
articles, and ultimately included 45 meta-analyses (17.9%) in
this umbrella review38-83 (Figure 1), corresponding to 695 stud-
Adverse Health Outcome

Fracture

ies, 1012 study estimates, and 13 putative risks (Figure 2). The Dental implications
207 excluded articles (82.1%) and the reasons for their exclu- Dementia
sion are provided in eTable 1 in the Supplement.
Cataract
Descriptive characteristics of the 45 eligible meta-analyses
Cardiovascular disorders
of observational studies can be found in eTable 2 in the Supple-
ment. All meta-analyses had a control group that was not Cancer

exposed to antidepressants except for 1 (2.2%), which com- Bleeding

pared the risk of gastrointestinal bleeding between mirtazap- Autism spectrum disorder
ine and SSRIs.47 The median number of adjustments in the Attention-deficit/hyperactivity disorder
analyses was 7 (interquartile range [IQR], 4-11), and the me-
dian duration of follow-up was 4 (IQR, 2-5) years. 0 5 10 15 20 25 30 35
Exposure to Antidepressants, %
Thirty-three meta-analyses (73.4%) met the moderate-
quality level according to the AMSTAR 2 evaluation, and 8 (17.8%)
were of low quality. Two (4.4%) were high quality, whereas 2 oth-
ers (4.4%) were of critically low quality. The 2 of us (E.D. and M.S.) outcomes associated with exposure to antidepressants
reached a high level of agreement (91%) on the quality rating. (Table 2 and eTables 2-5 in the Supplement), with a median
(IQR) number of estimates per association of 6 (4-12).
Description and Summary of Associations Seventy-four (61.7%) of the associations concerned mater-
Forty-five eligible meta-analyses described 120 associations, nal and pregnancy-related adverse health outcomes
including 1012 individual study estimates of adverse health (Figure 2). Most associations (80 [66.7%]) concerned SSRIs

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 Table 2. Class I or II Evidence in Meta-analyses of the Association Between Antidepressant Use and Risk of Adverse Health Outcomes

Prevalence No. of Criteria for Level-of-Evidence Classification

Based on Included Random-Effects No. of Cases/ P Value for
Adverse Health Exposed/ Cohort Studies per Measure, ES Total Random Heterogeneity, PI, AMSTAR 2
Source Outcome Unexposed Studies, % Association (95% CI) Result Population Effects I2 (P Value) 95% CI SSE/ESB LS CE Quality

jamapsychiatry.com
Morales et al,51 Autism spectrum Any AD users/ 0.8 7 RR: 1.48 Increased 22 877/ 6.8 × 10−8 24 (.24) 1.09 to No/NP Yes I Moderate
2018 disorders no AD users (1.29 to 1.71) risk for AD 2 400 720 2.02
(prepregnancy
maternal exposure)
Andalib et al,52 Autism spectrum SSRI/ 0.9 7 OR: 1.84 Increased 58 178/ 1.2 × 10−17 0 (.73) 1.53 to No/NP Yes I Moderate
2017 disorders (pregnancy non-SSRI users (1.60 to 2.11) risk for SSRI 5 868 692 2.20
maternal exposure;
unadjusted estimates
only)
Barbui Suicide attempt and SSRI/ 9.4 5 OR: 1.92 Increased 6531/ 1.0 × 10−7 0 (.47) 1.30 to No/NP Yes I High
et al,80 2009 completion in children non-SSRI users (1.51 to 2.44) risk for SSRI 61 522 2.84
and adolescents
Khanassov Osteoporotic fractures SSRI/ 6.5 24 RR:1.67 Increased 136 449/ 1.3 × 10−44 88 (<.001) 1.23 to No/NP Yes II Moderate
et al,42 2018 non-SSRI users (1.56 to 1.80) risk for SSRI 1 546 913 2.27
Man ADHD in children Prenatal exposure 2.4 7 RR: 1.39 Increased 57 552/ 5.1 × 10−6 79 (<.001) 0.90 to No/NP Yes II Moderate

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et al,48 2018 to AD/ (1.21 to 1.61) risk for AD 2 886 904 2.15
Association of Antidepressant Use With Adverse Health Outcomes

no AD users
Fu Cataract development TCA/nonusers or no NA 3 OR: 1.19 Increased 215 298/ 2.0 × 10−6 58 (.09) 0.50 to No/NP Yes II Moderate
et al,49 2018 users of any other (1.11 to 1.28) risk for TCA 431 171 2.52
AD
Laporte et al,55 Severe bleeding at any SSRI + SNRI/ 2.4 44 OR: 1.41 Increased 75 215/ 2.2 × 10−10 90 (<.001) 0.77 to No/no Yes II Low
2017 site non-users or no (1.27 to 1.57) risk for SSRI 1 443 029 2.59
users of any other + SNRI
AD
Jiang Postpartum Any AD 6.8 17 RR: 1.32 Increased 49 155/ 3.3 × 10−6 85 (<.001) 0.84 to No/NP Yes II Low
et al,58 2016 hemorrhage users/non-AD users (1.17 to 1.48) risk for AD 651 715 2.07
Jiang Upper GI bleeding SSRI + other 0.7 22 OR: 1.55 Increased 56 182/ 9.2 × 10−12 89 (<.001) 0.83 to No/no Yes II Moderate
et al,64 2015 non-AD/ (1.35 to 1.78) risk for SSRI 592 508 2.91
no SSRI use
only + other
non-AD
Huang Preterm birth Any AD users/ 0.8 28 RR: 1.68 Increased 24 669/ 3.6 × 10−23 44 (.008) 1.23 to Yes/NP Yes II Moderate
et al,66 2014 no AD users (1.52 to 1.86) risk for AD 3 063 709 2.30

© 2019 American Medical Association. All rights reserved.

Wu Osteoporotic fractures TCA users/ 1.4 12 RR: 1.45 Increased 178 237/ 6.2 × 10−13 76 (<.001) 1.04 to Yes/no Yes II Moderate
et al,70 2013 non-TCA users (1.31 to 1.60) risk for TCA 831 912 2.01
Ross Apgar score at 5 min Any AD users/ 2.1 15 SMD: −0.33 Increased 1473/ 7.5 × 10−7 58 (.003) −1.02 to No/no Yes II Moderate
et al,71 2013 no AD users (−0.47 to −0.20) risk for AD 71 828 0.36
76 −14
Oderda et al, Hip fracture TCA and/or SSRI 7.4 18 OR: 1.78 Increased 49 276/ 5.2 × 10 89 (<.001) 1.00 to Yes/yes Yes II Critically low
2012 users/no AD users (1.53 to 2.07) risk for TCA 210 577 3.19
or SSRI
Barbui Suicide attempt and SSRI/ 4.5 7 OR: 0.59 Decreased 7164/ 5.2 × 10−7 59 (.02) 0.33 to No/NP Yes II High
et al,80 2009 completion in adults non-SSRI users (0.48 to 0.72) risk for SSRI 147 383 1.05
Abbreviations: AD, antidepressant; ADHD, attention-deficit/hyperactivity disorder; Apgar score, appearance NP, not pertinent because of fewer-than-expected number of observed studies; OR, odds ratio; PI, prediction
(skin color), pulse (heart rate), grimace (reflex irritability), activity (muscle tone), and respiration; interval; RR, relative risk; SMD, standardized mean difference; SNRI, serotonin-norepinephrine reuptake inhibitor;
AMSTAR, A Measurement Tool to Assess Systematic Reviews; CE, class of evidence; ES, effect size; SSE, small-study effect; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.
ESB, excess significance bias; GI, gastrointestinal; LS, largest study with significant effect; NA, not applicable;

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Original Investigation Research

E5
 Research Original Investigation
or serotonin-norepinephrine reuptake inhibitors, 9 (7.5%)
TCAs, and 31 (25.8%) mixed or other antidepressants.
The median (IQR) number of the total population per
association was 1 056 374 (152 180-2 215 969). The median
(IQR) number of cases (adverse health outcomes) per asso-
ciation was 12 097 (2585-56 272), and the number of cases
was greater than 1000 for 87 associations (72.5%).
A summary of all 120 associations is presented in Table 2 and
Table 3 and eTables 3-5 in the Supplement. Seventy-four of the
120 examined associations (61.7%) were nominally statistically
significant at P ≤ .05 based on random-effects models, and only
22 (18.3%) reached a P ≤ 1 × 10−6. Almost all statistically signifi-
cant associations indicated an increased risk for antidepressants
and adverse health outcomes except for 2 associations (2.7%)
showing the protective property of SSRIs against suicide attempt
or completion in adults and in older adults.80
Fifty-two associations (43.3%) had large heterogeneity
(I2 > 50%), and the 95% prediction intervals excluded the null
value for only 24 associations (20.0%). In 63 associations
(52.5%), the effect sizes of the largest study were nominally
statistically significant at P ≤ .05. Small-study effects were
found for 17 associations (14.2%), and excess significance bias
was observed for 9 associations (7.5%).
Main Analysis Grading
Convincing Evidence
Among the 120 associations, 3 (2.5%) were supported by con-
vincing evidence, namely, the association between SSRI use
and increased risk of suicide attempt or completion in chil-
dren and adolescents80 as well as the association between ex-
posure to any antidepressant before pregnancy and SSRIs dur-
ing pregnancy and autism spectrum disorder51,52 (Table 2). The
association with suicide risk reached the high-quality level
based on AMSTAR 2, whereas the 2 associations with autism
spectrum disorder reached moderate quality.
Highly Suggestive Evidence
Eleven associations (9.2%) had highly suggestive evidence of
the association between any antidepressant use and in-
creased risk of adverse health outcomes (Table 2). The ad-
verse outcomes were attention-deficit/hyperactivity disor-
der in children, cataract development (associated with TCAs),
severe bleeding at any site, upper gastrointestinal tract bleed-
ing, postpartum hemorrhage, preterm birth, lower Apgar score
at 5 minutes, osteoporotic fractures (1 associated with TCAs
and 1 with SSRIs), and risk of hip fracture. Seven of these
associations reached the moderate-quality level based on
AMSTAR 2 (Table 2). One association with highly suggestive
evidence, however, showed a decreased risk (ie, protective
association) of suicide attempt or completion in adults,80 meet-
ing a high-quality level based on AMSTAR 2. The effect sizes
of those adverse outcomes supported by convincing and highly
suggestive evidence were small and the prevalence was on av-
erage low (range, 0.1%-9.7%) as well (Tables 2 and 3).
Suggestive, Weak, and No Evidence
Suggestive evidence was found for 21 additional associations
(17.5%) between antidepressant use and increased risk of ad-
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Association of Antidepressant Use With Adverse Health Outcomes
verse health outcomes (eTable 3 in the Supplement). For the
remaining associations, either weak evidence (n = 39 [32.5%])
or no evidence (n = 46 [38.3%] was found (ie, all associations
with P > .05) (eTables 4 and 5 in the Supplement).
Sensitivity Analyses
A sensitivity analysis limited to cohort studies, prospective co-
hort studies, studies controlled for confounding by indica-
tion, and North American studies showed that none of the as-
sociations within convincing evidence (class I) retained the
same rank (Table 3). The most important change was within
prospective cohort studies, with 1 association being up-
graded to having convincing evidence (preterm birth associ-
ated with the use of any antidepressant).
Another association was upgraded to having convincing
evidence (lower Apgar scores at 5 minutes) when the sensi-
tivity analysis was limited to SSRIs. The association between
antidepressant use and preterm birth was also upgraded to
being supported by convincing evidence when the analysis was
limited to other or mixed antidepressants (Table 3).
Findings from another sensitivity analysis, limited to ex-
cluded meta-analyses owing to overlap, agreed with the re-
sults of the main analysis (eResults and eTable 6 in the Supple-
ment). The results of each sensitivity analysis are presented
in the eResults in the Supplement, with the full list of covar-
iates in eTable 7 in the Supplement.
Discussion
We reviewed 45 meta-analyses of observational studies and
found that only a few of the 74 statistically significant asso-
ciations between antidepressants and adverse health out-
comes were supported by convincing evidence in the main and
sensitivity analyses, namely, the association between antide-
pressant use and increased suicide attempt or completion in
individuals younger than 19 years (SSRI studies),80 autism risk
in the offspring,51,52 preterm birth,66 and neonatal adaptation.71
However, the few with convincing evidence associations did
not reflect causality, and none of them remained at the con-
vincing evidence level after accounting for confounding by in-
dication. Overall, the results showed that the association be-
tween antidepressant use and adverse health outcomes was
not supported by robust evidence and that the underlying dis-
ease likely inflated the findings in a relevant way.39,44
To our knowledge, this study is the first umbrella review that
systematically assessed the potential risk of adverse health
outcomes associated with antidepressant use across a large spec-
trum of published meta-analyses of observational studies,
grading the evidence by using well-recognized criteria of
credibility.22,23,32,33,36,37 The umbrella review approach has been
applied to assess the associations between adverse health out-
comes and other medical variables, such as dietary fiber
consumption,37 serum uric acid level,23 and vitamin D
concentration.22 This approach fits in a research field that is un-
deniably complex and uncertain, as conveyed here.22,23,32,33,36,37
The large median number of participants and cases per associa-
tion allowed for robust classifications; the number of cases was
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 Table 3. Sensitivity Analysis of Class I or II Evidence in Meta-analyses of the Association Between Antidepressants and Risk of Adverse Health Outcomesa

Criteria for Level-of-Evidence Classification

Prevalence No. of
Based on Included Random Effects No. of Cases/ P Value
Exposed/ Cohort Studies per Measure to ES Total Random Heterogeneity, CES/
Source Adverse Health Outcome Unexposed Studies, % Association (95% CI) Population Effects I2 (P Value) PI, 95% CI SSE/ESB LS CE AMSTAR 2

jamapsychiatry.com
Retrospective and Prospective Cohort Studies
Andalib et al,52 2017 Autism spectrum disorders SSRI/ 0.9 3 OR: 1.65 50 494/ 2.2 × 10−7 0 (.69) 0.48 to No/no Yes I II/Moderate
(pregnancy maternal non-SSRI users (1.37 to 2.00) 5 790 186 5.68
exposure; unadjusted
estimates only)
Khanassov et al,42 Osteoporotic fractures SSRI/ 6.5 16 RR: 1.63 56 397/ 8.9 × 10−27 85 (<.001) 1.20 to No/NP Yes II II/Moderate
2018 non-SSRI users (1.49 to 1.79) 859 611 2.22
Huang et al,66 2014 Preterm birth Any AD users/ 0.8 24 RR: 1.67 24 378/ 6.5 × 10−22 49 (.004) 1.21 to Yes/no Yes II II/Moderate
no AD users (1.51 to 1.86) 3 063 012 2.33
Ross et al,71 2013 Apgar score at 5 min Any AD users/ 2.1 15 SMD: −0.33 1473/ 7.5 × 10−7 58 (.003) 1.02 to No/no Yes II II/Moderate
no AD users (−0.47 to −0.20) 71 828 0.36
Barbui et al,80 2009 Suicide attempt and SSRI/ 9.4 3 OR: 1.89 5647/ 1.8 × 10−7 0 (.46) 0.36 to No/NP Yes I II/High
completion in children and non-SSRI users (1.46 to 2.43) 59 971 9.85
adolescents

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Association of Antidepressant Use With Adverse Health Outcomes

Barbui et al,80 2009 Suicide attempt and SSRI/ 4.5 5 OR: 2.53 6458/ 5.2 × 10−7 55 (.06) 0.27 to No/NP Yes II II/High
completion in adults non-SSRI users (0.43 to 0.66) 143 340 1.04
Prospective Cohort Studies
Andalib et al,52 2017 Autism spectrum disorders SSRI/ 0.9 3 OR: 1.65 50 494/ 2.2 × 10−7 0 (.69) 0.48 to No/no Yes I II/Moderate
(pregnancy maternal non-SSRI users (1.37 to 2.00) 5 790 186 5.68
exposure; unadjusted
estimates only)
Huang et al,66 2014 Preterm birth Any AD users/ 0.4 11 RR: 1.87 2540/ 3.4 × 10−9 31 (.15) 1.17 to No/NP Yes II I/Moderate
no AD users (1.52 to 2.30) 690 121 3.00
Studies Adjusted for Multiple Covariates
Morales et al,51 2018 Autism spectrum disorders Any AD users/ 0.8 7 RR: 1.48 22 877/ 6.8 × 10−8 24 (.24) 1.09 to No/NP Yes I I/Moderate
(prepregnancy maternal no AD users (1.29 to 1.71) 2 400 720 2.02
exposure)
Barbui et al,80 2009 Suicide attempt and SSRI/ 9.4 5 OR: 1.92 6531/ 1.0 × 10−7 0 (.47) 1.30 to No/NP Yes I I/High
completion in children and non-SSRI users (1.51 to 2.44) 61 522/ 2.84
adolescents

© 2019 American Medical Association. All rights reserved.

Khanassov et al,42 Osteoporotic fractures SSRI/ 6.5 22 RR: 1.67 96 353/ 6.6 × 10−33 88 (<.001) 1.17 to No/NP Yes II II/Moderate
2018 non-SSRI users (1.53 to 1.82) 929 936 2.38
Man et al,48 2018 ADHD in children Prenatal exposure to 2.4 7 RR: 1.39 57 552/ 5.1 × 10−6 79 (<.001) 0.90 to No/NP Yes II II/Moderate
AD/ (1.21 to 1.61) 2 886 904 2.15
no AD users
Jiang et al,64 2015 Upper GI bleeding SSRI + other 1.3 15 RR: 1.48 43 571/ 1.3 × 10−10 61 (.001) 1.00 to No/NP Yes II II/Moderate
non-AD/ (1.32 to 1.67) 08 060 2.20
no SSRI use
only + other non-AD
Wu et al,70 2013 Osteoporotic fractures TCA users/ NA 11 RR: 1.43 178 237/ 1.9 × 10−12 77 (<.001) 1.04 to Yes/no Yes II II/Moderate
non-TCA users (1.29 to 1.58) 740 768 1.97
Oderda et al76 2012 Hip fracture TCA and/or SSRI NA 14 OR: 1.76 47 762/ 1.9 × 10−11 92 (<.001) 0.96 to Yes/no Yes II II/Critically
users/no AD users (1.49 to 2.08) 198 820 3.24 low

(Reprinted) JAMA Psychiatry Published online October 2, 2019

Original Investigation Research

(continued)

E7
 E8
Table 3. Sensitivity Analysis of Class I or II Evidence in Meta-analyses of the Association Between Antidepressants and Risk of Adverse Health Outcomesa (continued)

Criteria for Level-of-Evidence Classification

Prevalence No. of
Based on Included Random Effects No. of Cases/ P Value
Exposed/ Cohort Studies per Measure to ES Total Random Heterogeneity, CES/
Source Adverse Health Outcome Unexposed Studies, % Association (95% CI) Population Effects I2 (P Value) PI, 95% CI SSE/ESB LS CE AMSTAR 2
Studies Adjusted for Confounding by Indication
Morales et al,51 2018 Autism spectrum disorders Any AD users/ 1.1 3 RR: 1.69 3016/ 1.0 × 10−7 0 (.74) 0.48 to No/no Yes I II/Moderate
(prepregnancy maternal no AD users (1.39 to 2.05) 667 431 5.94
exposure)
Research Original Investigation

Barbui et al,80 2009 Suicide attempt and SSRI/ 9.7 4 OR: 2.04 5522/ 0.006 16 (.31) 0.47 to Yes/NP No I IV/High
completion in children and non-SSRI users (1.23 to 3 to 41) 55 124 8.81
adolescents
Khanassov et al,42 Osteoporotic fractures SSRI/ 6.3 11 RR: 1.61 54 023/ 1.0 × 10−14 88 (<.001) 1.08 to No/NP Yes II II/Moderate
2018 non-SSRI users (1.43 to 1.82) 645 463 2.41
Wu et al,70 2013 Osteoporotic fractures TCA users/ NA 7 RR: 1.47 156 374/ 5.0 × 10−8 62 (.02) 0.98 to No/no Yes II II/Moderate
non-TCA users (1.23 to 1.69) 659 389 2.22
High-Quality Primary Studies
Morales et al,51 2018 Autism spectrum disorders Any AD users/ 0. 8 7 RR: 1.48 22 877/ 6.8 × 10−8 24 (.24) 1.09 to No/NP Yes I I/Moderate

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(prepregnancy maternal no AD users (1.29 to 1.71) 2 400 720 2.02

JAMA Psychiatry Published online October 2, 2019 (Reprinted)

exposure)
Andalib et al,52 2017 Autism spectrum disorders SSRI/ 0.9 7 OR: 1.84 58 178/ 1.2 × 10−17 0 (.73) 1.53 to No/NP Yes I I/Moderate
(pregnancy maternal non-SSRI users (1.60 to 2.11) 5 868 692 2.20
exposure; unadjusted
estimates only)
Barbui et al,80 2009 Suicide attempt and SSRI/ 3.6 4 OR: 1.88 5961/ 3.5 × 10−7 0 (.50) 1.10 to No/NP Yes I I/High
completion in children and non-SSRI users (1.47 to 2.40) 30 343 3.21
adolescents
Khanassov et al,42 Osteoporotic fractures SSRI/ 6.6 20 RR: 1.70 117 567/ 9.6 × 10−37 88 (<.001) 1.23 to No/NP Yes II II/Moderate
2018 non-SSRI users (1.57 to 1.85) 1 053 697 2.35
Man et al,48 2018 ADHD in children Prenatal exposure to 2.4 7 RR: 1.39 57 552/ 5.1 × 10−6 79 (<.001) 0.90 to No/NP Yes II II/Moderate
AD/no AD users (1.21 to 1.61) 2 886 904 2.15
Jiang et al,58 2016 Postpartum hemorrhage Any AD users/ 6.8 16 RR: 1.32 49 142/ 3.7 × 10−6 86 (<.001) 0.84 to No/NP Yes II II/Low
no AD users (1.17 to 1.48) 651 439 2.08
Huang et al,66 2014 Preterm birth Any AD users/ 0.3 19 RR: 1.86 5116/ 5.3 × 10−14 52 (.004) 1.16 to Yes/no Yes II II/Moderate
no AD users (1.59 to 2.19) 1 658 666 3.00

© 2019 American Medical Association. All rights reserved.

Wu et al,70 2013 Osteoporotic fractures TCA users/ NA 9 RR: 1.46 36 865/ 6.0 × 10−10 82 (<.001) 0.99 to Yes/NP Yes II II/Moderate
non-TCA users (1.30 to 1.65) 247 078 2.15
Oderda et al,76 2012 Hip fracture TCA and/or SSRI NA 6 OR: 1.59 41 227/ 2.5 × 10−7 91 (<.001) 0.82 to Yes/no Yes II II/Critically
users/no AD users (1.31 to 1.92) 159 831 3.07 low
Barbui et al,80 2009 Suicide attempt and SSRI/ 4.5 7 OR: 0.59 7164/ 5.2 × 10−7 59 (.02) 0.33 to No/NP Yes II II/High
completion in adults non-SSRI users (0.48 to 0.72) 147 383 1.05

(continued)

jamapsychiatry.com
Association of Antidepressant Use With Adverse Health Outcomes
 Table 3. Sensitivity Analysis of Class I or II Evidence in Meta-analyses of the Association Between Antidepressants and Risk of Adverse Health Outcomesa (continued)

Criteria for Level-of-Evidence Classification

Prevalence No. of
Based on Included Random Effects No. of Cases/ P Value
Exposed/ Cohort Studies per Measure to ES Total Random Heterogeneity, CES/
Source Adverse Health Outcome Unexposed Studies, % Association (95% CI) Population Effects I2 (P Value) PI, 95% CI SSE/ESB LS CE AMSTAR 2

jamapsychiatry.com
SSRI Studies
Andalib et al,52 2017 Autism spectrum disorders SSRI/ 0.9 7 OR: 1.84 58 178/ 1.2 × 10−17 0 (.73) 1.53 to No/NP Yes I I/Moderate
(pregnancy maternal non-SSRI users (1.60 to 2.11) 5 868 692 2.20
exposure; unadjusted
estimates only)
Barbui et al,80 2009 Suicide attempt and SSRI/ 9.4 5 OR: 1.92 6531/ 1.0 × 10−7 0 (.47) 1.30 to No/NP Yes I I/High
completion in children and non-SSRI users (1.51 to 2.44) 61 522 2.84
adolescents
Ross et al,71 2013 Apgar score at 5 min SSRI/ 5.7 13 SMD: −0.27 1127/ 2.1 × 10−7 35 (.10) 0.53 to No/no Yes II I/Moderate
non-SSRI users (−0.37 to −0.16) 19 695 0.01
Khanassov et al,42 Osteoporotic fractures SSRI/ 6.5 24 RR: 1.67 136 449/ 1.3 × 10−44 88 (<.001) 1.23 to No/NP Yes II II/Moderate
2018 non-SSRI users (1.56 to 1.80) 1 546 913 2.27
Huang et al,66 2014 Preterm birth SSRI/ 9.7 20 RR: 1.73 21 163/ 3.6 × 10−23 48 (.009) 1.22 to Yes/NP Yes II II/Moderate
non-SSRI users (1.53 to 1.96) 2 153 680 2.46

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Association of Antidepressant Use With Adverse Health Outcomes

Barbui et al,80 2009 Suicide attempt and SSRI/ 3.5 7 OR: 0.59 7164/ 5.2 × 10−7 59 (.02) 0.33 to No/NP Yes II II/High
completion in adults non-SSRI users (0.48 to 0.72) 147 383 1.05
TCA Studies
Fu et al,49 2018 Cataract development TCA/non-users or no NA 3 OR: 1.19 215 298/ 2.0 × 10−6 58 (.09) 0.56 to No/NP Yes II II/moderate
users of any other AD (1.11 to 1.28) 431 171 2.52
Wu et al,70 2013 Osteoporotic fractures TCA users/ 1.4 12 RR: 1.45 178 237/ 6.2 × 10−13 76 (<.001) 1.04 to Yes/no Yes II II/Moderate
non-TCA users (1.31 to 1.60) 831 912 2.01
Other or Mixed AD Studies
Morales et al,51 2018 Autism spectrum disorders Other or mixed/ 0.8 7 RR: 1.48 22 877/ 6.8 × 10−8 24 (.24) 1.09 to No/NP Yes I I/Moderate
(prepregnancy maternal no AD users (1.29 to 1.71) 2 400 720 2.02
exposure)
Huang et al,66 2014 Preterm birth Other or mixed/ 0.4 8 RR: 1.59 3506/ 3.4 × 10−7 35 (.15) 1.02 to No/NP Yes II I/Moderate
no AD users (1.31 to 1.93) 910 029 2.47
Laporte et al,55 2017 Severe bleeding at any site Other or mixed/ 6.8 44 OR: 1.41 190 016/ 2.2 × 10−10 90 (<.001) 0.77 to No/no Yes II II/Low
no AD users (1.27 to 1.57) 1 512 411 2.59

© 2019 American Medical Association. All rights reserved.

Jiang et al,58 2016 Postpartum hemorrhage Other or mixed/ 6.8 17 RR: 1.32 49 155/ 3.3 × 10−6 85 (<.001) 0.84 to No/NP Yes II II/Low
no AD users (1.17 to 1.48) 651 715 2.07
Jiang et al,64 2015 Upper GI bleeding Other 0.7 22 OR: 1.55 56 182/ 9.2 × 10−12 89 (<.001) 0.83 to No/no Yes II II/Moderate
or mixed/no AD users (1.35 to 1.78) 592 508 2.91

(continued)

(Reprinted) JAMA Psychiatry Published online October 2, 2019

Original Investigation Research

E9
 E10
Table 3. Sensitivity Analysis of Class I or II Evidence in Meta-analyses of the Association Between Antidepressants and Risk of Adverse Health Outcomesa (continued)

Criteria for Level-of-Evidence Classification

Prevalence No. of
Based on Included Random Effects No. of Cases/ P Value
Exposed/ Cohort Studies per Measure to ES Total Random Heterogeneity, CES/
Source Adverse Health Outcome Unexposed Studies, % Association (95% CI) Population Effects I2 (P Value) PI, 95% CI SSE/ESB LS CE AMSTAR 2
European Studies
Andalib et al,52 2017 Autism spectrum disorders SSRI/ 0.1 4 OR: 1.80 6394/ 1.1 × 10−13 0 (.39) 1.28 to No/no Yes I I/Moderate
(pregnancy maternal non-SSRI users (1.54 to 2.10) 5 741 029 2.53
exposure; unadjusted
Research Original Investigation

estimates only)
Khanassov et al,42 Osteoporotic fractures SSRI/ 6.5 12 RR: 1.76 92 760/ 2.3 × 10−86 67 (<.001) 1.50 to No/no Yes II II/Moderate
2018 non-SSRI users (1.68 to 1.87) 1 228 807 2.07
Jiang et al,64 2015 Upper GI bleeding SSRIs + other 0.4 14 OR: 1.60 46 594/ 4.8 × 10−7 86 (<.001) 0.80 to No/NP Yes II II/Moderate
non-AD/ (1.33 to 1.93) 236 085 3.91
no SSRI use
only + other no AD
users
Huang et al,66 2014 Preterm birth Any AD users/ 0.9 7 RR: 1.61 17 518/ 5.6 × 10−8 56 (.03) 1.02 to No/NP Yes II II/Moderate
no AD users (1.36 to 1.92) 1 984 543 2.55

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Wu et al,70 2013 Osteoporotic fractures TCA users/ NA 6 RR: 1.37 164 476/ 6.6 × 10−6 69 (.007) 0.91 to No/NP Yes II II/Moderate

JAMA Psychiatry Published online October 2, 2019 (Reprinted)

non-TCA users (1.19 to 1.56) 724 914 2.05
Oderda et al,76 2012 Hip fracture TCA and/or SSRI 2.1 8 OR: 1.74 40 196/ 1.1 × 10−6 89 (<.001) 0.88 to Yes/no Yes II II/Critically
users/no AD users (1.39 to 2.17) 159 706 3.42 low
North American Studies
Khanassov et al,42 Osteoporotic fractures SSRI/ 5.2 10 RR: 1.56 31 683/ 1.0 × 10−7 87 (<.001) 0.91 to No/NP Yes II II/Moderate
2018 non-SSRI users (1.33 to 1.84) 249 808 2.70
Huang et al,66 2014 Preterm birth Any AD users/ 0.6 17 RR: 1.70 6129/ 1.2 × 10−10 29 (.12) 1.17 to Yes/NP Yes II II/Moderate
no AD users (1.44 to 1.99) 928 528 2.45
Wu et al,70 2013 Osteoporotic fractures TCA users/ NA 6 RR: 1.54 13 761/ 7.3 × 10−8 76 (.001) 0.95 to No/No Yes II II/Moderate
non-TCA users (1.32 to 1.81) 84 583 2.51
Oderda et al,76 2012 Hip fracture TCA and/or SSRI 2.5 8 OR: 1.81 8654/ 2.8 × 10−10 82 (<.001) 1.01 to No/NP Yes II II/Critically
users/no AD users (1.51 to 2.18) 49 024 3.27 low

Abbreviations: See Table 2. CES, class of evidence after sensitivity analysis.

a
Sensitivity analysis of studies located in other regions showed no associations supported by class I and II evidence.

© 2019 American Medical Association. All rights reserved.

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Association of Antidepressant Use With Adverse Health Outcomes
 Association of Antidepressant Use With Adverse Health Outcomes
greater than 1000 for 87 of the 120 associations. Quality ratings
of the included meta-analyses with AMSTAR 2 also allowed for
the confident interpretation of the results. Sensitivity analyses
provided additional evidence from the cohort studies, high-
quality studies, and studies controlled for a psychiatric condi-
tion, thus further increasing the reliability of the results.
These results need to be considered when contemplating
the use of antidepressants in children and adolescents or in-
tegrated with efficacy data from RCTs. A network meta-
analysis of RCTs in children and adolescents showed that no
antidepressant medication was superior to placebo apart from
fluoxetine, that several antidepressants had higher discon-
tinuation rates compared with placebo, and that venlafaxine
increased the risk of suicidality even in the short-term dura-
tion of an RCT.13 However, although 1 single antidepressant,
venlafaxin (odds ratio, 7.7), was associated with an increased
risk of suicidality compared with placebo, none of the other
SSRIs or antidepressants had an association. Not only did pla-
cebo have a substantially reduced risk of suicidality (87% lower)
compared with venlafaxine, but the same was true (and with
a similar degree) for 5 antidepressants (duloxetine, escitalo-
pram, fluoxetine, imipramine, and paroxetine), with an 81%
to 86% reduced risk compared with venlafaxine; according to
the network meta-analysis, these antidepressants were safe
with regard to suicidality as an adverse effect.13 Moreover, an-
tidepressants’ lack of superiority over placebo,12 especially in
children, was associated with a high placebo response, which
has been an increasing problem in RCTs in psychiatry. In ad-
dition, the increased suicidality in children and adolescents
who use antidepressants may be associated with the unsuc-
cessful reduction of depressive symptoms in suicidal indi-
viduals rather than a direct result of antidepressant use. Fur-
thermore, the results showed that confounding by indication
probably contributes to the safety concerns of using these drugs
in children and adolescents. Besides, the risk-benefit evalua-
tion in children and adolescents is different for antidepres-
sants (predominantly SSRIs) when used for psychiatric con-
ditions, such as anxiety disorders and obsessive-compulsive
disorder.3-5,12
Conversely, we found highly suggestive evidence support-
ing the protective role of antidepressants against suicidality
in adults,80 which is consistent with results of a network meta-
analysis of RCTs in adults that showed all antidepressants were
superior to placebo in reducing depressive symptoms.10 Simi-
larly, meta-analyses support the efficacy of antidepressant use
for anxiety disorders5 and obsessive-compulsive disorder3 in
adults. In adults, the risk-benefit ratio must account for clear
efficacy of antidepressants and protection against suicide,
which should be balanced with other safety concerns that
emerged from the present umbrella review. Overall, several ad-
verse outcomes associated with antidepressant use sup-
ported by highly suggestive evidence (ie, poor bone status, gas-
trointestinal tract bleeding) can be prevented medically, as
previously reported.82 Hence, the advantages of antidepres-
sant use in adults and older adults may well trump prevent-
able safety issues given their efficacy in treating various psy-
chiatric disorders.3-5,12 Moreover, the association between
antidepressant use and certain adverse health outcomes var-
jamapsychiatry.com
© 2019 American Medical Association. All rights reserved.
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Original Investigation Research
ied within specific age groups. For instance, increased risk of
fractures applied predominantly to an older population (>65
years) already prone to poor bone status and multimorbidity84
and not to people aged 20 to 40 years.
Convincing evidence, before accounting for confounding by
indication, that supported the association between antidepres-
sant use and autism, as well as other offspring adverse health out-
comes, may call for the restriction of antidepressant use during
pregnancy among women with a high risk of relapse and severe
clinical presentations. Warnings to avoid prescribing medications
in early pregnancy have been issued.85 However, autism remains
a rare event, with a prevalence from cohort studies of less than
1% according to data pooled in this study. The convincing evi-
dence level was not confirmed when confounding by indication
was considered, suggesting that the association between anti-
depressant use and autism as well as suicidality in youth and
other outcomes may be due to the underlying disease rather than
to the use of antidepressants,39,43,44,50 as shown in a recent um-
brella review on risk factors for autism.86
Comparing 2 depression-matched groups with or with-
out antidepressant exposure may be more methodologically
accurate than adjusting analyses statistically. Several ad-
verse outcomes had small effect sizes in addition to low preva-
lence and no proof of a causal relationship between antide-
pressants and adverse health outcomes.
Hence, given that a depressive episode itself can impair
adolescents and both maternal and fetal health, individual-
ized and shared clinical decisions about the risk-benefit ratio
of antidepressant use during adolescence and pregnancy
should be implemented, but adolescence and pregnancy
should not be considered absolute contraindications to the use
of antidepressants.
Further research in RCTs and with real-world samples
matched for underlying disease is needed to confirm a pos-
sible causal association between antidepressants and ad-
verse outcomes. Such research should consider dose-effect re-
sponse; mechanistic processes; and patient-specific data such
as age, clinical diagnoses, and severity of clinical condition.
No absolute contraindication against the use of antidepres-
sants is currently supported by convincing evidence.
Limitations
This study had several limitations. First, we did not grade the
evidence from meta-analyses of RCTs, instead focusing on a
portion of available evidence. However, evidence from RCTs
was limited by the selection of healthier patients and fre-
quent short-term follow-up, among other factors.16 Many se-
vere adverse outcomes cannot be addressed in RCTs, and
observational research is the most feasible method for
low-frequency and long-term health risks.17 Nevertheless, ob-
servational studies are not free from bias, either.18,87 Their re-
sults yield associations, which do not imply causality. Sec-
ond, results from main analyses were affected by various
confounders owing to lack of randomization, potential chan-
neling bias, and confounding by indication.17,18,80 Specifi-
cally, the nature of the control groups was only insufficiently
characterized; according to the evidence, risk differences, when
matched (and not adjusted) for the underlying psychiatric dis-
(Reprinted) JAMA Psychiatry Published online October 2, 2019 E11
 Research Original Investigation Association of Antidepressant Use With Adverse Health Outcomes

order, become smaller or nonsignificant.43,44,51 Thus, the
association with suicidality may be contributed to by the an-
tidepressants’ limited efficacy in suicidal children and ado-
lescents, according to results from RCTs,19 rather than by an-
tidepressant use increasing suicidality. The association between
autism spectrum disorder and SSRI use during pregnancy52
included studies that were not adjusted for confounders, in
contrast with weak evidence of an association between any
antidepressant use during pregnancy and autism spectrum dis-
order when adjusted for confounders50 (eTable 4 in the Supple-
ment). Third, no inference can be made about newer antide-
pressants (eg, vortioxetine hydrobromide) that have not been
assessed in any of the included meta-analyses. Fourth, the data
on cardiometabolic outcomes were insufficient, which is an
emerging concern regarding the increased prescribing rates of
antidepressants and is a crucial area for future research.88 Fifth,
we used a grading system that can provide only warnings of
the potential presence of systematic biases but cannot pro-
vide evidence of the nature and extent of these biases,16,32,33
just as umbrella reviews cannot supply any comparative rank-
ing as in network meta-analyses.
Conclusions
The findings of this umbrella review are important in the con-
text of increased antidepressant use worlwide.1,2 Convincing
evidence was found for the association between antidepres-
sant use and a few adverse health outcomes, yet the preva-
lence of those outcomes was low in general, and no associa-
tion was supported by convincing evidence after confounding
by indication. Future research is needed to identify whether
a causal association exists between antidepressant use and
adverse outcomes.

ARTICLE INFORMATION
Accepted for Publication: June 21, 2019.
Published Online: October 2, 2019.
doi:10.1001/jamapsychiatry.2019.2859
Author Affiliations: Pain and Rehabilitation Centre,
Department of Medicine and Health Sciences,
Linköping University, Linköping, Sweden (Dragioti);
Department of Hygiene and Epidemiology, School
of Medicine, University of Ioannina, University
Campus, Ioannina, Greece (Dragioti, Evangelou);
Department of Neuroscience, University of Padua,
Padua, Italy (Solmi, Favaro); Padova Neuroscience
Center (PNC), University of Padua, Padua, Italy
(Solmi, Favaro); Early Psychosis: Interventions and
Clinical-Detection (EPIC) Lab, Department of
Psychosis Studies, Institute of Psychiatry,
Psychology and Neuroscience, King's College
London, London, United Kingdom (Solmi,
Fusar-Poli, McGuire); OASIS Service, South London
and Maudsley NHS (National Health Service)
Foundation Trust, London, United Kingdom
(Fusar-Poli); Department of Brain and Behavioral
Sciences, University of Pavia, Pavia, Italy
(Fusar-Poli); Section of Imaging, Neurobiology,
and Psychosis, Department of Psychosis Studies,
Institute of Psychiatry, Psychology, and
Neuroscience, King's College London, London,
United Kingdom (Dazzan); National Institute for
Health Research (NIHR) Mental Health Biomedical
Research Centre at South London and Maudsley
NHS Foundation Trust, London, United Kingdom
(Dazzan); Department of Psychology, Social Work
and Counselling, University of Greenwich,
Greenwich, United Kingdom (Thompson);
Physiotherapy Department, South London and
Maudsley NHS Foundation Trust, London, United
Kingdom (Stubbs); Department of Psychological
Medicine, Institute of Psychiatry, Psychology and
Neuroscience, King's College London, London,
United Kingdom (Stubbs, Young); NICM Health
Research Institute, School of Science and Health,
University of Western Sydney, Sydney, Australia
(Firth); Division of Psychology and Mental Health,
Faculty of Biology, Medicine and Health, University
of Manchester, Manchester, United Kingdom
(Firth); Centre for Youth Mental Health, University
of Melbourne, Melbourne, Australia (Firth);
Department of Neuroscience, Reproductive
Sciences and Dentistry, Federico II University,
Naples, Italy (Fornaro); Department of Clinical
Physiology, Linköping University, Linköping,
Sweden (Tsartsalis); Centre for Addiction and
Mental Health and Department of Psychiatry,
University of Toronto, Toronto, Ontario, Canada
(Carvalho); Department of Psychiatry and
Psychology, Hospital Clinic, Institute of
Neuroscience, University of Barcelona, IDIBAPS,
the Spanish Ministry of Science and Innovation
(CIBERSAM), Barcelona, Catalonia, Spain (Vieta);
South London and Maudsley NHS Foundation Trust,
Bethlem Royal Hospital, Beckenham, Kent, United
Kingdom (Young); Department of Pediatrics, Yonsei
University College of Medicine, Seoul, Republic of
Korea (Shin); Department of Psychiatry, Zucker
Hillside Hospital, Glen Oaks, New York (Correll);
Department of Psychiatry and Molecular Medicine,
Hofstra Northwell School of Medicine, Hempstead,
New York (Correll); Center for Psychiatric
Neuroscience, Feinstein Institute for Medical
Research, Manhasset, New York (Correll); Campus
Virchow-Klinikum, Charité-Universitätsmedizin
Berlin, Department of Child and Adolescent
Psychiatry, Berlin Institute of Health, Berlin,
Germany (Correll); Department of Epidemiology
and Biostatistics, Imperial College London, London,
United Kingdom (Evangelou).
Author Contributions: Drs Dragioti and Solmi
contributed equally to the manuscript as joint first
authors. Drs Dragioti and Solmi had full access to all
of the data in the study and take responsibility for
the integrity of the data and the accuracy of the
data analysis.
Concept and design: Dragioti, Solmi, Favaro,
Fusar-Poli, Stubbs, Firth, Tsartsalis, Vieta, McGuire,
Young, Correll, Evangelou.
Acquisition, analysis, or interpretation of data:
Dragioti, Solmi, Fusar-Poli, Dazzan, Thompson,
Stubbs, Fornaro, Carvalho, Vieta, Shin, Correll,
Evangelou.
Drafting of the manuscript: Dragioti, Solmi, Dazzan,
Thompson, Stubbs, Firth, Fornaro, Tsartsalis, Vieta.
Critical revision of the manuscript for important
intellectual content: Dragioti, Solmi, Favaro,
Fusar-Poli, Dazzan, Thompson, Stubbs, Fornaro,
Tsartsalis, Carvalho, Vieta, McGuire, Young, Shin,
Correll, Evangelou.
Statistical analysis: Dragioti, Solmi, Fusar-Poli,
Fornaro, Carvalho, Young, Shin, Evangelou.
Obtained funding: McGuire.
Administrative, technical, or material support:
Dragioti, Stubbs, Firth, Vieta, McGuire.
Supervision: Dragioti, Favaro, Fusar-Poli, Dazzan,
Stubbs, Tsartsalis, Vieta, McGuire, Young, Shin,
Correll, Evangelou.
Approval of protocol: Thompson.
Conflict of Interest Disclosures: Dr Fusar-Poli
reported receiving grants and personal fees from
Lundbeck outside the submitted work. Dr Vieta
reported receiving grants and serving as a
consultant, advisor, or continuing medical
education speaker for the following entities:
AB-Biotics, Abbott, Allergan, Angelini, AstraZeneca,
Bristol-Myers Squibb, Dainippon Sumitomo
Pharma, Farmindustria, Ferrer, Forest Research
Institute, Galenica, Gedeon Richter,
GlaxoSmithKline, Janssen, Lundbeck, Otsuka,
Pfizer, Roche, SAGE, Sanofi, Servier, Shire,
Sunovion, Takeda, the Brain and Behaviour
Foundation, CIBERSAM, the Seventh European
Framework Programme and Horizon 2020, and the
Stanley Medical Research Institute. Dr Young
reported receiving grants and personal fees from
Janssen; receiving personal fees from Lundbeck,
Allegan, Sunovion, Livanova, Johnson & Johnson,
and Bionomics outside the submitted work; being
employed by King's College London and an
honorary consultant for SLaM (NHS United
Kingdom); receiving fees for lectures and service on
advisory boards for the following companies with
drugs for affective and related disorders:
AstraZeneca, Eli Lilly, Lundbeck, Sunovion, Servier,
Livanova, Janssen, Allegan, and Bionomics; being a
consultant to Johnson & Johnson and Livanova; not
having share holdings in pharmaceutical
companies; being lead investigator for the
Embolden Study (AstraZeneca), BCI Neuroplasticity
Study, and Aripiprazole Mania Study and
participating in investigator-initiated studies from
AstraZeneca, Eli Lilly, Lundbeck, Wyeth, and
Janssen; and receiving past and present grant
funding from the National Institute of Mental
Health, Canadian Institutes of Health Research,
National Alliance for Research on Schizophrenia and
Depression, Stanley Medical Research Institute,
Medical Research Council, Wellcome Trust, Royal
College of Physicians, British Medical Association,
Vancouver General Hospital and University of
Bristish Columbia Hospital Foundation, Western
Economic Diversification Canada, Canadian Cancer

E12 JAMA Psychiatry Published online October 2, 2019 (Reprinted) jamapsychiatry.com

© 2019 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by Sean Cho on 10/06/2019

 Association of Antidepressant Use With Adverse Health Outcomes
Society Depression Research Fund, Michael Smith
Foundation for Health Research, National Institute
for Health Research (NIHR), and Janssen. Dr Correll
reported receiving personal fees from Alkermes,
Allergan, Angelini, Boehringer-Ingelheim, Gedeon
Richter, Indivior, LB Pharma, Lundbeck,
MedAvante-ProPhase, Merck, Neurocrine, Noven,
Otsuka, Pfizer, Recordati, Rovi, Servier, Sumitomo
Dainippon, Sunovion, and Supernus; receiving
grants and personal fees from Janssen/Johnson &
Johnson and Teva outside the submitted work;
serving on a data safety monitoring board for
Boehringer-Ingelheim, Lundbeck, Rovi, Supernus,
and Teva; providing expert testimony for
Bristol-Myers Squibb, Janssen, and Otsuka;
receiving royalties from UpToDate and grant
support from Janssen and Takeda; and being
shareholder of LB Pharma. No other disclosures
were reported.
Funding/Support: This independent research was
funded by the NIHR Biomedical Research Centre at
South London and Maudsley NHS Foundation Trust
and King’s College London. Dr Firth was supported
by a Blackmores Institute Fellowship. Dr Stubbs
holds a clinical lectureship supported by Health
Education England and the NIHR Integrated Clinical
Academic (ICA) Programme (ICA-CL-2017-03-001)
and was supported in part by the Maudsley Charity
and the NIHR Collaboration for Leadership in
Applied Health Research and Care South London at
King’s College Hospital NHS Foundation Trust.
Role of the Funder/Sponsor: The funders had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review,
or approval of the manuscript; and decision to
submit the manuscript for publication.
Disclaimer: The views expressed here are those of
the authors and do not necessarily reflect those of
the NHS, the NIHR, or the Department of Health
and Social Care.
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