Available via license: CC BY 4.0
Content may be subject to copyright.
Suicide risk with selective serotonin reuptake inhibitors and new-generation
serotonergic-noradrenergic antidepressants in adults: a systematic review and meta-
analysis of observational studies
Michael P Hengartner (ORCID: 0000-0002-2956-2969)1, Simone Amendola2, Jakob A Kaminski3,
Simone Kindler4, Tom Bschor5, Martin Plöderl6
1Department of Applied Psychology, Zurich University of Applied Sciences, CH-8037 Zurich,
Switzerland, 2Department of Dynamic and Clinical Psychology, Faculty of Medicine and Psychology,
Sapienza University of Rome, 00185 Roma RM, Italy, 3Charité-Universitätsmedizin Berlin, 10117
Berlin, Germany, 4Psychotherapist in private practice, CH-8400 Winterthur, Switzerland, 5Department
of Psychiatry and Psychotherapy, University Hospital, Technical University of Dresden, 01069
Dresden, Germany, 6Department of Crisis Intervention and Suicide Prevention, Christian Doppler
Clinic, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria
Summary
Background: There is ongoing controversy whether antidepressant use alters the suicide risk in adult
routine-care patients with depression and other treatment indications. The aim of this study was thus to
examine the suicide risk with antidepressants in observational studies, considering financial conflicts
of interest (fCOI) and publication bias.
Design: Systematic review and meta-analysis.
Main outcome measures: Risk of suicide, suicide attempt and/or intentional self-harm.
Data sources: We searched MEDLINE, PsycINFO, Web of Science, PsycARTICLES and SCOPUS
for case-control and cohort studies published 1990-2020.
Eligibility criteria for study selection: Cohort and case-control studies in adults (aged 18 years)
with depression and any unspecified condition reporting suicide risk for patients exposed to selective
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
serotonin reuptake inhibitors (SSRI) or new-generation serotonergic-noradrenergic antidepressants
(SNA) relative to unexposed patients.
Data extraction and analysis: Effects were aggregated with a random-effects model and reported as
relative risk estimates (RE) with 95%-confidence-intervals. We assessed heterogeneity via I2-statistics
and publication bias via funnel-plot asymmetry and trim-and-fill method. Study fCOI was defined
present when lead-authors’ professorship was industry-sponsored, they received payments from the
industry, or when the study was industry-sponsored.
Results: We included 27 original studies in the meta-analysis; 19 on depression (including other
affective and anxiety disorders) and 8 on any unspecified condition. Use of SSRI or SNA for
depression was associated with increased suicide risk (comprising both suicide and suicide attempt),
RE=1.29, 1.06-1.57. Risk estimates were significantly lower in studies with fCOI (Q=21.87, p<0.001)
and the trim-and-fill method estimated that 12 studies were missing due to publication bias; the result
with missing studies imputed was RE=1.61, 1.31-1.99. Use of SSRI or SNA for all conditions
(including depression and any unspecified condition) was associated with increased suicide risk,
RE=1.43, 1.21-1.68. Studies with fCOI reported significantly lower risk estimates (Q=34.19, p<0.001)
and the trim-fill method estimated that 13 studies were missing; after imputation of missing studies the
result was RE=1.72, 1.44-2.05. Quality of evidence was rated very low due to substantial
inconsistency of between-study results (I285%).
Conclusions: Exposure to new-generation antidepressants is associated with increased suicide risk in
adult routine-care patients with depression and other conditions. Publication bias and fCOI contribute
to systematic underestimation of risk estimates in the published literature.
Registration: Open Science Framework, https://osf.io/eaqwn/
Keywords Meta-Analysis; Antidepressant; Selective Serotonin Reuptake Inhibitor; Suicide; Self-
Harm; Cohort Study; Case-Control Study
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
Research in context
What is already known on this topic: Meta-analyses of randomised controlled trials (RCT) found
either no reduction of suicidal events or increased risk with new-generation antidepressants relative to
placebo. However, generalisability of RCT findings is limited due to narrowly preselected
participants, short study duration and treatment settings that are not representative of primary care
routine practice. A previous meta-analysis of observational studies reported significantly reduced
suicide risk in adults with depression exposed to selective serotonin reuptake inhibitors (SSRI), but it
did not include new-generation serotonergic-noradrenergic antidepressants (SNA) and did not consider
publication bias and study lead-authors’ financial conflicts of interest (fCOI).
What this study adds: Our results indicate that SSRI and SNA are associated with increased suicide
risk in adult routine-care patients with depression and other psychiatric and non-psychiatric treatment
indications. We further found empirical evidence for publication bias. Several studies with evidence of
increased suicide risk with new-generation antidepressants likely remain unpublished. Accordingly,
we found that study lead-authors with fCOI report significantly lower risk estimates than lead-authors
without fCOI.
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
Introduction
There is a longstanding and unresolved controversy whether selective serotonin reuptake inhibitors
(SSRI) and new-generation serotonergic-noradrenergic antidepressants (SNA) such as duloxetine,
venlafaxine, or mirtazapine alter the risk of suicide and suicide attempt in adults.1-4 While some
suicidologists recommend antidepressants as an important suicide-prevention strategy,5 others argue
that this strategy may increase the risk of suicide.6
The studies with the highest level of evidence - randomised controlled trials (RCT) - produced
inconsistent findings. Some meta-analyses of RCT for the acute treatment of depression and other
treatment indications in adults found significantly increased risk of suicidal events with
antidepressants relative to placebo,7-12 but others did not.13-17 Two meta-analyses of long-term RCT
have been conducted; both indicate that antidepressants may increase the risk of (attempted) suicide in
patients with depression.18 19 Remarkably, no meta-analysis of RCT found a decreased suicide risk
with antidepressants in comparison to placebo.
However, the findings from meta-analyses of RCT for depression have several caveats. A major
limitation are the extensive exclusion criteria, for example substance abuse, comorbid disorders and
acute suicidality.20 Participants included in RCT are therefore not representative of the average patient
seen in routine practice.21 22 The experimental treatment setting of RCT, with its short study duration
usually limited to a few weeks, its comprehensive assessments, close monitoring and frequent visits is
neither representative of primary care routine practice, where most antidepressants are prescribed.23 24
Finally, systematic biases in the reporting of serious adverse events such as suicides and suicide
attempts in favour of antidepressants appear to be pervasive and frequent in RCT.14 25-27
Well-designed observational studies with representative patients treated in routine practice may thus
provide ecological validity. The last meta-analysis of observational studies was published in 2009 by
Barbui et al.28 and it found that SSRI use relates to reduced suicide risk in adults with depression.
Despite being published more than a decade ago, these findings are still influential in contemporary
research, clinical guidance and scientific debate. For instance, based on the Barbui study a recent
meta-review concluded that there is “highly suggestive” evidence that antidepressants protect against
suicide in adults.29
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
The aim of this study was thus to update the meta-analysis by Barbui et al.28 and to examine, whether
incorporation of more recent evidence would support the conclusion that SSRI protect against suicide
in adults with depression. Moreover, we expanded the Barbui study by focusing not only on SSRI, but
also on SNA, and by including studies on depression and any psychiatric and non-psychiatric
treatment indication. Given the substantial impact of selective publication and financial conflicts of
interest (fCOI) in antidepressant research,30-33 we also attempted to control for these important biases.
Methods
Search strategy and selection criteria
We conducted our systematic review according to the PRISMA guideline.34 The review was registered
with PROSPERO on January 21, 2020, but as of April 29, the submission was still being processed.
As we were immediately informed that the evaluation process would take several months, the study
protocol was also registered with the Open Science Framework on February 3, 2020
(https://osf.io/eaqwn/). We searched the databases MEDLINE, PsycINFO, Web of Science,
PsycARTICLES and SCOPUS for all original studies in English published from 1990 to January
2020, using the terms “antidepressants”, “selective serotonin reuptake inhibitor”, “serotonin
norepinephrine reuptake inhibitor”, and all individual new-generation antidepressants in combination
with “suicide”, “suicide attempt”, or “self-harm”. The detailed search strategy and the Pubmed search
term are shown in the appendix.
We additionally searched MEDLINE, PsycINFO and the German database PSYNDEX for non-
English records, but found no additional studies that met our inclusion criteria. In order to find
unpublished studies, we searched observational studies registered with ClinicalTrials.gov. One study
met our inclusion criteria, but it was already included through our database search. Screening of titles
and abstracts and subsequently assessments of full-texts were conducted independently by two
investigators (SA and SK) during February and March 2020. Any discrepancies were resolved by
consensus and, if necessary, through arbitration by the lead investigator (MPH).
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
The eligibility criteria were case-control and cohort studies in adults with depression or any other
psychiatric and non-psychiatric treatment indication. We also included studies reporting risk estimates
for any unspecified antidepressant class when it was possible to infer from the data or external sources
(e.g. prescription rates for different antidepressant classes in the underlying population) that at least
75% of all prescriptions in the study sample were SSRI or SNA. We included only studies that report a
risk estimate for an exposed group in relation to an unexposed group. Therefore, we excluded studies
that compared the suicide risk with SSRI or SNA to other drugs (e.g. tricyclics) and studies that
examined variations in suicide risk across different treatment phases within exposed subjects (e.g.
suicide risk during acute therapy vs. continuation or maintenance therapy). In order to minimize
confounding by indication, we required exposed and unexposed groups to be broadly comparable in
terms of clinical and socioeconomic characteristics. We thus excluded studies that compared the
suicide risk in antidepressant users with increased baseline suicide risk (e.g. psychiatric inpatients) to
an unexposed group with low baseline risk (e.g. healthy people from the general population) if
differences in baseline risk where statistically not controlled for (e.g. via propensity score matching or
covariate adjustment). If the unexposed group consisted of patients with a baseline suicide risk
comparable to the exposed group (e.g. when both groups comprised psychiatric inpatients), then we
also included studies with unadjusted risk estimates.
Outcomes
Our primary outcomes were the risk of suicide and suicide attempt in people exposed to new-
generation antidepressants relative to an unexposed group according to the statistically best-adjusted
analysis reported in the primary study. Suicide and suicide attempt were analysed separately and, to
allow for comparability with the Barbui study,28 also as a composite outcome. We further conducted
separate analyses for depression and any treatment indication unspecified, as well as for SSRI, SNA,
and any new-generation antidepressant (comprising SSRI, SNA and any class unspecified). If studies
reported not an overall risk estimate for the entire observation period, but instead separate estimates
for mutually exclusive treatment periods (e.g. acute therapy, continuation and maintenance therapy),
we always chose the risk estimate for the earliest treatment period. This decision was specified a priori
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
in the protocol to minimise survivorship bias, as a consistent body of evidence indicates that the
suicide risk is highest at the beginning of an illness episode when patients are acutely distressed.35-38
Data analysis
To allow for comparability, study quality was rated with the same 10-point scale applied by Barbui et
al.28 This scale assesses study quality based on six domains (population framework; study design;
description of demographic data; description of clinical data; description of outcome data; and
covariate adjustment) and ranges from 0 (minimal quality) to 10 (maximal quality) points.39 40 The
scale and its rating system are shown in the appendix. The quality of evidence for each outcome was
evaluated according to the GRADE system.41 42 Study fCOI was coded present when a lead-author (i.e.
first or last author) had received payments from the pharmaceutical industry (e.g. as speaker,
consultant or adviser); when the professorship of a lead-author was funded by the pharmaceutical
industry; or when the study was sponsored by the pharmaceutical industry. For it we not only assessed
the fCOI statement made in the primary study, but also searched the internet and declarations in other
publications by the same authors.
We used an inverse variance random-effects model and computed relative risk estimates (RE) with
95% confidence intervals based on the odds ratios or hazard ratios extracted from the primary studies.
We used the Sidik-Jonkman and Hartung-Knapp adjustments recommended in the Cochrane
Handbook.43 Publication bias was inferred from funnel-plot asymmetry and tested with the trim-and-
fill method.44 Heterogeneity (inconsistency of between-study results) was estimated with I2-statistics.
All analyses were conducted with the R packages metafor and metagen. The R-code and raw data are
available online, https://osf.io/eaqwn/.
Patient involvement
Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans
of our research.
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
Results
Search results and inclusion of primary studies
The literature search identified 9542 records, which were reduced to 6676 after removal of duplicates.
After screening of titles and abstracts, further 6602 records were excluded and 74 full-text were
assessed for eligibility. A final number of 32 studies were retained. Of these, 5 focused on unique
conditions other than depression, other affective disorders or anxiety disorders. These studies were not
included in the quantitative synthesis (meta-analysis) but the results are reported qualitatively in the
appendix. Altogether 27 studies, of which 19 on depression (plus other affective disorders and anxiety
disorders) and 8 on any treatment indication unspecified were included in the meta-analysis. Included
in this dataset are also the 6 adult studies incorporated in the Barbui meta-analysis.28 The study
selection process is shown in Figure 1 and the characteristics of the primary studies included in the
meta-analysis are summarized in the appendix. Briefly, 8 studies were conducted in North America (7
in the USA and 1 in Canada), 17 studies in Europe and 2 elsewhere (1 in Australia and 1 in New
Zealand). 9 studies had fCOI (among them all 6 studies included the Barbui study) and 18 had no
fCOI. Study quality ratings ranged from 4 to 9 points (median=8, interquartile range=2). Detailed
quality ratings for all studies are shown in the appendix.
-Figure 1-
Meta-analyses for depression
The meta-analytic results for the association between exposure to new-generation antidepressants and
suicide risk in depression studies are shown in Figure 2. The summary effect estimate for suicide with
any new-generation antidepressant was RE=1.29, 0.90-1.86. For SSRI the effect estimate was
RE=1.09, 0.51-2.33 and for SNA it was RE=1.31, 0.62-2.76. The funnel-plot was asymmetrical and
the trim-and-fill method suggested 5 missing studies. Imputation of missing studies revealed a
significantly increased risk, RE=1.64, 1.14-2.36. Funnel-plots for all outcomes and Egger’s test for
funnel-plot asymmetry are shown in the appendix. Study fCOI was a significant moderator (Q=6.35,
df=1, p=0.012); studies with fCOI (RE=1.00, 0.75-1.34) reported considerably lower risk estimates
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
than studies without fCOI (RE=2.29, 0.99-5.28). Forest-plots for fCOI subgroups are shown in the
appendix.
For suicide attempt the summary effect estimate for any new-generation antidepressant was RE=1.31,
1.03-1.68 (for SSRI, RE=0.99, 0.57-1.72; for SNA, RE=1.32, 0.79-2.23). Trim-and-fill method
estimated that 8 studies were missing and with imputation of these studies the result was RE=1.61,
1.24-2.10. Study fCOI had a significant effect (Q=12.86, df=1, p<0.001); studies with fCOI (RE=0.91,
0.70-1.17) reported considerably lower risk estimates than studies without fCOI (RE=1.84, 1.31-2.58).
The summary effect estimate for suicide and suicide attempt combined (composite outcome) with any
new-generation antidepressant was RE=1.29, 1.06-1.57 (for SSRI, RE=1.03, 0.70-1.51; for SNA,
RE=1.28, 0.86-1.90). Trim-and-fill method suggested that 12 studies were missing and the result with
imputation of missing studies was RE=1.59, 1.28-1.98. Study fCOI was again a significant moderator
(Q=21.87, df=1, p<0.001); studies with fCOI showed no clear association (RE=0.91, 0.77-1.09),
whereas studies without fCOI reported significantly increased suicide risk (RE=1.94, 1.46-2.59). Of
12 studies that reported risk estimates for SSRI, 8 studies (67%) had fCOI and 4 studies (33%) had no
fCOI. By contrast, among the 8 studies reporting risk estimates for any class unspecified, none (0%)
had fCOI.
-Figure 2-
Meta-analyses for all treatment indications
The meta-analytic results for all treatment indications are shown in Figure 3. The risk estimate for
suicide with any new-generation antidepressant was RE=1.44, 1.15-1.80 (for SSRI, RE=1.33, 0.86-
2.04; for SNA, RE=1.28, 0.74-2.21). Trim-and-fill method estimated that 5 studies were missing and
the corresponding result after imputation of missing studies was RE=1.62, 1.28-2.06. Study fCOI had
a significant effect (Q=11.36, df=1, p<0.001). Studies with fCOI reported no increased risk (RE=1.08,
0.88-1.33), but studies without fCOI did (RE=1.98, 1.43-2.76).
The risk of suicide attempt with any new-generation antidepressant was RE=1.47, 1.17-1.85 (for SSRI,
RE=1.08, 0.67-1.75; for SNA, RE=1.34, 0.81-2.21). Trim-and-fill method suggested that 7 studies
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
were missing and the result after imputation of missing studies was RE=1.79, 1.40-2.28. Study fCOI
was a significant moderator (Q=21.97, df=1, p<0.001); no clear effect was shown in studies with fCOI
(RE=0.91, 0.70-1.17), but studies without fCOI revealed significantly increased risk (RE=2.05, 1.57-
2.67).
The risk of suicide and suicide attempt combined with any new-generation antidepressant was
RE=1.45, 1.23-1.70 (for SSRI, RE=1.19, 0.88-1.60; for SNA, RE=1.28, 0.90-1.80). Trim-and-fill
method estimated that 14 studies were missing; the result after imputation of missing studies was
RE=1.75, 1.47-2.08. Likewise, there was a significant effect for fCOI (Q=37.17, df=1, p<0.001);
studies with fCOI reported no increased risk (RE=0.96, 0.82-1.12), but studies without fCOI showed
significantly increased risk (RE=2.02, 1.66-2.46).
The quality of evidence according to GRADE was rated very low for all outcomes due to substantial
inconsistency of between-study results (I285%, see Figures 2 and 3).
-Figure 3-
Sensitivity and subgroup analysis
Three effect estimates were found to be potential outliers. A sensitivity analysis with these potential
outlier effects excluded revealed no meaningful differences compared to the results based on the full
dataset (see supplementary material). The subgroup analyses for the composite outcome in association
with any new-generation antidepressant are reported in Table 1. No significant subgroup differences
were found for main treatment indication (depression vs. any unspecified), age (old adults vs. young
adults), study design (cohort vs. case-control), study quality (high vs. low), and covariate adjustment
(yes vs. no). There was a significant subgroup-difference for antidepressant class. Risk estimates for
SSRI (RE=1.19, 0.88-1.60) and SNA (RE=1.28, 0.90-1.80) did not differ meaningfully, but studies
that examined any class unspecified reported higher risk estimates (RE=1.87, 1.55-2.25). North
American studies (all but one from the USA) reported significantly reduced suicide risk with new-
generation antidepressants (RE=0.82, 0.68-0.99), whereas European studies showed significantly
increased risk (RE=1.82, 1.51-2.20).
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
-Table 1-
The fCOI results for all outcomes are reported in detail above and the subgroup forest-plot is shown in
Figure 4. In studies without fCOI visual inspection of the funnel-plot indicated no asymmetry. This
finding was statistically supported by Egger’s test, t=-0.8456, df=31, p=0.404. By contrast, in studies
with fCOI the funnel-plot was asymmetrical, both visually and statistically, t=-2.1368, df=26,
p=0.042. Both funnel-plots are shown in the appendix. Study fCOI and study location were related;
while 6 of 8 (75%) North American studies had fCOI, only 3 of 17 (18%) European studies had so.
Study fCOI was also related to drug class examined. While 9 of 16 studies (56%) on SSRI or SNA had
fCOI, 0 of 11 studies (0%) on any class unspecified had so. The significant subgroup differences for
drug class and study location are thus at least in part attributable to study fCOI.
-Figure 4-
Discussion
Our meta-analysis of observational studies revealed no clear association between exposure to SSRI
and suicide risk in patients with depression and therefore contradicts the reduced suicide risk reported
in the previous meta-analysis by Barbui and colleagues from 2009.28 While the Barbui study relied on
9 comparisons from 6 primary studies, our updated meta-analysis included 14 comparisons from 11
primary studies (including all 6 primary studies from the Barbui meta-analysis plus 5 new studies). It
is also important to note that all six adult studies on SSRI for depression included in Barbui et al.28
were conducted by lead-authors with fCOI. In view of the significant association between fCOI and
lower risk estimates detected in our analysis, this has likely resulted in systematically underestimated
risk estimates in the Barbui study. Moreover, our study revealed a significantly increased suicide risk
with any new-generation antidepressant in patients with depression as well as in patients with any
treatment indication unspecified. Our results are thus consistent with various meta-analyses of FDA
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
safety summaries for acute depression trials that revealed an increased suicide risk with new-
generation antidepressants as a group relative to placebo.9 10 12 45 A significantly increased risk of
suicidal events was also meta-analytically demonstrated with SSRI in general8 and specifically with
paroxetine in meta-analyses of published and unpublished placebo-controlled short-term trials.7 11 Our
results also correspond with two meta-analyses of long-term depression trials, which found an
increased risk of (attempted) suicide with antidepressants.18 19
We rated the quality of evidence very low due to substantial inconsistency of between-study results.
Effect estimates are thus very uncertain and may change substantially with publication of further
studies. Moreover, there was evidence of publication bias according to asymmetrical funnel-plots.
Smaller studies reporting reduced suicide risk with antidepressants were overrepresented, which
suggests that various studies with increased risk estimates remain unpublished. After correcting for
publication bias via trim-and-fill method, the summary effect estimates indicated a considerably
increased suicide risk with new-generation antidepressants. These findings are consistent with the
literature on selective publication of antidepressant trials33 46 and misreporting of serious adverse
events in published antidepressant trials.14 25 These biases result in systematically inflated efficacy
estimates and underestimation of harms.31 47 48 We further found that studies with fCOI reported
significantly lower risk estimates than studies without fCOI. Moreover, publication bias according to
asymmetrical funnel-plots was detected in studies with fCOI, but not in studies without fCOI. These
findings are consistent with the literature showing that fCOI systematically bias the benefit-to-risk
assessment of drugs in favour of the industry, both in psychiatry32 49-51 and in other medical fields.52-55
In our set of depression studies, two-thirds of studies focusing on SSRI had fCOI, whereas no study on
any class unspecified had so. This may explain why in depression studies no increased risk was shown
specifically for SSRI whereas significantly increased risk was found for any new-generation
antidepressant.
Limitations
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
Population-based register-linkage studies allow studying very large and representative samples and to
control for various socioeconomic and clinical covariates, which increases generalisability of findings
and which minimizes confounding by indication. Yet these studies may have important limitations,
such as incomplete assessment of exposure periods. For instance, in the cohort study by Tiihonen et
al.,56 the register used to assess antidepressant exposure contained only the purchase of medication
from pharmacies in outpatient care, but not prescriptions from hospital care. This means that suicides
occurring in hospital or shortly after discharge were necessarily ascribed to the unexposed period in
many first-episode patients, although it is likely that in these cases antidepressants were prescribed by
a hospital doctor. As the suicide risk is highest in the first weeks after hospital admission and
immediately after discharge,57 this incomplete assessment of exposure may result in an
underestimation of the suicide risk in the exposed group. On the other hand, prescription registries
record only whether drugs had been dispensed, but not whether the drugs were actually taken as
prescribed. It is known that in pharmacotherapy for chronic conditions patients show rather low
adherence rates.58 If some people redeemed a prescription but did not use the drugs for any reason, this
may result in an overestimation of the suicide risk in the exposed group.
Another issue is confounding by indication. Although most studies tried to minimize this bias by
controlling for important covariates such as previous suicide attempts and depression severity, unlike
RCT it cannot be excluded that patients with more severe forms of psychopathology were more likely
to receive antidepressants. On the other hand, most SSRI and SNA are prescribed by GPs,23 24 often for
mild and subclinical depression.59 60 Therefore, antidepressant use may not necessarily indicate more
severe psychopathology in people with depression. For instance, Olfson et al.24 showed that US
patients with serious psychological distress (a strong risk factor for suicide) are no more often treated
with antidepressants than patients with less serious or no distress. This resonates with our meta-
analytic finding that adjusted risk estimates were not significantly lower than unadjusted estimates.
Remarkably, the two studies that reported the strongest suicide-protective effects were both
unadjusted.61 62 Depending on the sample studied, confounding by indication could thus result in both
over- and underestimation of risk estimates. In accordance, covariate adjustment was not able to
explain the high inconsistency in between-study results. To better explain heterogeneity of risk
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
estimates, more detailed methodological aspects presumably need to be considered (e.g. concomitant
psychosocial support).
Conclusions
Our systematic review and meta-analysis of observational studies revealed that use of new-generation
antidepressants is associated with increased suicide risk in adult patients, especially after controlling
for publication bias and fCOI. Many studies showing increased suicide risk with antidepressants likely
remain unpublished. Relatedly, studies with fCOI report significantly lower risk estimates than studies
without fCOI. This has two important implications. First, contrary to prominent claims5 29 we find no
reliable evidence indicating that antidepressants protect against suicide. Instead, it appears that
antidepressant use may even increase suicide risk. Associations detected in observational studies do
not necessarily imply causality, but there is evidence of a causal relationship according to various
meta-analyses of RCT7 8 10 18 63 and challenge-dechallenge-rechallenge testing protocols.64-67 Second,
our findings underline the necessity of even more stringent research regulation to exclude possible bias
through fCOI.68-70 In accordance with the literature,32 52 53 55 our results suggest that studies with fCOI
are systematically biased. Therefore, public access to raw data and independent research on these data
conducted by authors without fCOI is warranted.
Funding: JAK is supported by the Charité Clinician-Scientist Program of the Berlin Institute of
Health. SA is supported by the Scholarships for Advanced Studies Abroad of the Sapienza University
of Rome. The sponsors had no influence on the conduct of this study. No funding was received for this
specific study.
Declaration of interests: All authors have completed the ICMJE uniform disclosure form at
http://www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the
submitted work; no financial relationships with any organisations that might have an interest in the
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
submitted work in the previous three years, no other relationships or activities that could appear to
have influenced the submitted work.
References
1. Kaminski JA, Bschor T. Antidepressants and suicidality: A re-analysis of the re-analysis. J Affect
Disord 2020;266:95-99. doi: 10.1016/j.jad.2020.01.107
2. Reeves RR, Ladner ME. Antidepressant-induced suicidality: an update. CNS Neurosci Ther
2010;16(4):227-34. doi: 10.1111/j.1755-5949.2010.00160.x
3. Teicher MH, Glod CA, Cole JO. Antidepressant drugs and the emergence of suicidal tendencies.
Drug Saf 1993;8(3):186-212. doi: 10.2165/00002018-199308030-00002
4. Wessely S, Kerwin R. Suicide risk and the SSRIs. JAMA 2004;292(3):379-81. doi:
10.1001/jama.292.3.379
5. Zalsman G, Hawton K, Wasserman D, et al. Suicide prevention strategies revisited: 10-year
systematic review. Lancet Psychiat 2016;3(7):646-59. doi: 10.1016/S2215-0366(16)30030-X
6. Hjelmeland H, Jaworski K, Knizek BL, et al. Problematic advice from suicide prevention experts.
Ethical Hum Psychol Psychiatry 2018;20(2):79-85. doi: 10.1891/1559-4343.20.2.79
7. Aursnes I, Tvete IF, Gaasemyr J, et al. Even more suicide attempts in clinical trials with paroxetine
randomised against placebo. BMC Psychiatry 2006;6:55. doi: 10.1186/1471-244X-6-55
8. Fergusson D, Doucette S, Glass KC, et al. Association between suicide attempts and selective
serotonin reuptake inhibitors: systematic review of randomised controlled trials. BMJ
2005;330(7488):396. doi: 10.1136/bmj.330.7488.396
9. Healy D, Whitaker C. Antidepressants and suicide: risk-benefit conundrums. J Psychiatry Neurosci
2003;28(5):331-7.
10. Hengartner MP, Plöderl M. Newer-generation antidepressants and suicide risk in randomized
controlled trials: A re-analysis of the FDA database. Psychother Psychosom 2019;88(4):247-
48. doi: 10.1159/000501215
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
11. Barbui C, Furukawa TA, Cipriani A. Effectiveness of paroxetine in the treatment of acute major
depression in adults: a systematic re-examination of published and unpublished data from
randomized trials. CMAJ 2008;178(3):296-305. doi: 10.1503/cmaj.070693
12. Plöderl M, Hengartner MP, Bschor T, et al. Commentary to "Antidepressants and suicidality: A re-
analysis of the re-analysis". J Affect Disord 2020;in press
13. Jakobsen JC, Katakam KK, Schou A, et al. Selective serotonin reuptake inhibitors versus placebo
in patients with major depressive disorder. A systematic review with meta-analysis and Trial
Sequential Analysis. BMC Psychiatry 2017;17(1):58. doi: 10.1186/s12888-016-1173-2
14. Sharma T, Guski LS, Freund N, et al. Suicidality and aggression during antidepressant treatment:
systematic review and meta-analyses based on clinical study reports. BMJ 2016;352:i65. doi:
10.1136/bmj.i65
15. Stone M, Laughren T, Jones ML, et al. Risk of suicidality in clinical trials of antidepressants in
adults: analysis of proprietary data submitted to US Food and Drug Administration. BMJ
2009;339:b2880. doi: 10.1136/bmj.b2880
16. Khan A, Warner HA, Brown WA. Symptom reduction and suicide risk in patients treated with
placebo in antidepressant clinical trials - An analysis of the food and drug administration
database. Arch Gen Psychiat 2000;57(4):311-17. doi: 10.1001/archpsyc.57.4.311
17. Storosum JG, van Zwieten BJ, van den Brink W, et al. Suicide risk in placebo-controlled studies of
major depression. Am J Psychiatry 2001;158(8):1271-5. doi: 10.1176/appi.ajp.158.8.1271
18. Baldessarini RJ, Lau WK, Sim J, et al. Suicidal risks in reports of long-term controlled trials of
antidepressants for major depressive disorder II. Int J Neuropsychopharmacol
2017;20(3):281-84. doi: 10.1093/ijnp/pyw092
19. Braun C, Bschor T, Franklin J, et al. Suicides and suicide attempts during long-term treatment with
antidepressants: A meta-analysis of 29 placebo-controlled studies including 6,934 patients
with major depressive disorder. Psychother Psychosom 2016;85(3):171-9. doi:
10.1159/000442293
20. Zimmerman M, Clark HL, Multach MD, et al. Have treatment studies of depression become even
less generalizable? A review of the inclusion and exclusion criteria used in placebo-controlled
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
antidepressant efficacy trials published during the past 20 years. Mayo Clin Proc
2015;90(9):1180-6. doi: 10.1016/j.mayocp.2015.06.016
21. Wisniewski SR, Rush AJ, Nierenberg AA, et al. Can phase III trial results of antidepressant
medications be generalized to clinical practice? A STAR*D report. Am J Psychiatry
2009;166(5):599-607. doi: 10.1176/appi.ajp.2008.08071027
22. Zimmerman M, Chelminski I, Posternak MA. Generalizability of antidepressant efficacy trials:
differences between depressed psychiatric outpatients who would or would not qualify for an
efficacy trial. Am J Psychiatry 2005;162(7):1370-2. doi: 10.1176/appi.ajp.162.7.1370
23. Haller E, Watzke B, Blozik E, et al. Antidepressant prescription practice and related factors in
Switzerland: a cross-sectional analysis of health claims data. BMC Psychiatry 2019;19(1):196.
doi: 10.1186/s12888-019-2178-4
24. Olfson M, Blanco C, Marcus SC. Treatment of adult depression in the United States. JAMA Intern
Med 2016;176(10):1482-91. doi: 10.1001/jamainternmed.2016.5057
25. de Vries YA, Roest AM, Beijers L, et al. Bias in the reporting of harms in clinical trials of second-
generation antidepressants for depression and anxiety: A meta-analysis. Eur
Neuropsychopharmacol 2016;26(11):1752-59. doi: 10.1016/j.euroneuro.2016.09.370
26. Hughes S, Cohen D, Jaggi R. Differences in reporting serious adverse events in industry sponsored
clinical trial registries and journal articles on antidepressant and antipsychotic drugs: a cross-
sectional study. BMJ Open 2014;4(7):e005535. doi: 10.1136/bmjopen-2014-005535
27. Wieseler B, Wolfram N, McGauran N, et al. Completeness of reporting of patient-relevant clinical
trial outcomes: comparison of unpublished clinical study reports with publicly available data.
PLoS Med 2013;10(10):e1001526. doi: 10.1371/journal.pmed.1001526
28. Barbui C, Esposito E, Cipriani A. Selective serotonin reuptake inhibitors and risk of suicide: a
systematic review of observational studies. CMAJ 2009;180(3):291-7. doi:
10.1503/cmaj.081514
29. Dragioti E, Solmi M, Favaro A, et al. Association of antidepressant use with adverse health
outcomes: A systematic umbrella review. JAMA Psychiatry 2019 doi:
10.1001/jamapsychiatry.2019.2859
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
30. Amsterdam JD, McHenry LB, Jureidini JN. Industry-corrupted psychiatric trials. Psychiatr Pol
2017;51(6):993-1008. doi: 10.12740/PP/80136
31. Hengartner MP. Methodological flaws, conflicts of interest, and scientific fallacies: Implications
for the evaluation of antidepressants' efficacy and harm. Front Psychiatry 2017;8:275. doi:
10.3389/fpsyt.2017.00275
32. Tungaraza T, Poole R. Influence of drug company authorship and sponsorship on drug trial
outcomes. Br J Psychiatry 2007;191:82-3. doi: 10.1192/bjp.bp.106.024547
33. Turner EH, Matthews AM, Linardatos E, et al. Selective publication of antidepressant trials and its
influence on apparent efficacy. N Engl J Med 2008;358(3):252-60. doi:
10.1056/NEJMsa065779
34. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-
analyses: the PRISMA statement. BMJ 2009;339:b2535. doi: 10.1136/bmj.b2535
35. Coupland C, Hill T, Morriss R, et al. Antidepressant use and risk of suicide and attempted suicide
or self harm in people aged 20 to 64: cohort study using a primary care database. BMJ
2015;350:h517. doi: 10.1136/bmj.h517
36. Schneeweiss S, Patrick AR, Solomon DH, et al. Variation in the risk of suicide attempts and
completed suicides by antidepressant agent in adults: a propensity score-adjusted analysis of 9
years' data. Arch Gen Psychiatry 2010;67(5):497-506. doi:
10.1001/archgenpsychiatry.2010.39
37. Sondergard L, Kvist K, Andersen PK, et al. Do antidepressants prevent suicide? Int Clin
Psychopharmacol 2006;21(4):211-8.
38. Valenstein M, Kim HM, Ganoczy D, et al. Higher-risk periods for suicide among VA patients
receiving depression treatment: prioritizing suicide prevention efforts. J Affect Disord
2009;112(1-3):50-8. doi: 10.1016/j.jad.2008.08.020
39. Bhutta AT, Cleves MA, Casey PH, et al. Cognitive and behavioral outcomes of school-aged
children who were born preterm: a meta-analysis. JAMA 2002;288(6):728-37. doi:
10.1001/jama.288.6.728
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
40. Etminan M, Takkouche B, Isorna FC, et al. Risk of ischaemic stroke in people with migraine:
systematic review and meta-analysis of observational studies. BMJ 2005;330(7482):63. doi:
10.1136/bmj.38302.504063.8F
41. Atkins D, Best D, Briss PA, et al. Grading quality of evidence and strength of recommendations.
BMJ 2004;328(7454):1490. doi: 10.1136/bmj.328.7454.1490
42. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of
evidence and strength of recommendations. BMJ 2008;336(7650):924-6. doi:
10.1136/bmj.39489.470347.AD
43. Higgins JPT, Thomas J, Chandler J, et al., editors. Cochrane Handbook for Systematic Reviews of
Interventions Version 6.0: The Cochrane Collaboration, 2019.
44. Duval S, Tweedie R. Trim and fill: A simple funnel-plot-based method of testing and adjusting for
publication bias in meta-analysis. Biometrics 2000;56(2):455-63. doi: 10.1111/j.0006-
341x.2000.00455.x
45. Laughren TP. The scientific and ethical basis for placebo-controlled trials in depression and
schizophrenia: an FDA perspective. Eur Psychiatry 2001;16(7):418-23. doi: 10.1016/s0924-
9338(01)00600-9
46. Melander H, Ahlqvist-Rastad J, Meijer G, et al. Evidence b(i)ased medicine--selective reporting
from studies sponsored by pharmaceutical industry: review of studies in new drug
applications. BMJ 2003;326(7400):1171-3. doi: 10.1136/bmj.326.7400.1171
47. Bschor T, Kilarski LL. Are antidepressants effective? A debate on their efficacy for the treatment
of major depression in adults. Expert Rev Neurother 2016;16(4):367-74. doi:
10.1586/14737175.2016.1155985
48. Eyding D, Lelgemann M, Grouven U, et al. Reboxetine for acute treatment of major depression:
systematic review and meta-analysis of published and unpublished placebo and selective
serotonin reuptake inhibitor controlled trials. BMJ 2010;341:c4737. doi: 10.1136/bmj.c4737
49. Ebrahim S, Bance S, Athale A, et al. Meta-analyses with industry involvement are massively
published and report no caveats for antidepressants. J Clin Epidemiol 2016;70:155-63. doi:
10.1016/j.jclinepi.2015.08.021
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
50. Kelly RE, Jr., Cohen LJ, Semple RJ, et al. Relationship between drug company funding and
outcomes of clinical psychiatric research. Psychol Med 2006;36(11):1647-56. doi:
10.1017/S0033291706008567
51. Perlis RH, Perlis CS, Wu Y, et al. Industry sponsorship and financial conflict of interest in the
reporting of clinical trials in psychiatry. Am J Psychiatry 2005;162(10):1957-60. doi:
10.1176/appi.ajp.162.10.1957
52. Ahn R, Woodbridge A, Abraham A, et al. Financial ties of principal investigators and randomized
controlled trial outcomes: cross sectional study. BMJ 2017;356:i6770. doi: 10.1136/bmj.i6770
53. Fugh-Berman A, McDonald CP, Bell AM, et al. Promotional tone in reviews of menopausal
hormone therapy after the Women's Health Initiative: an analysis of published articles. PLoS
Med 2011;8(3):e1000425. doi: 10.1371/journal.pmed.1000425
54. Lundh A, Lexchin J, Mintzes B, et al. Industry sponsorship and research outcome. Cochrane
Database Syst Rev 2017;2:MR000033. doi: 10.1002/14651858.MR000033.pub3
55. Wang AT, McCoy CP, Murad MH, et al. Association between industry affiliation and position on
cardiovascular risk with rosiglitazone: cross sectional systematic review. BMJ
2010;340:c1344. doi: 10.1136/bmj.c1344
56. Tiihonen J, Lonnqvist J, Wahlbeck K, et al. Antidepressants and the risk of suicide, attempted
suicide, and overall mortality in a nationwide cohort. Arch Gen Psychiatry 2006;63(12):1358-
67. doi: 10.1001/archpsyc.63.12.1358
57. Qin P, Nordentoft M. Suicide risk in relation to psychiatric hospitalization: evidence based on
longitudinal registers. Arch Gen Psychiatry 2005;62(4):427-32. doi:
10.1001/archpsyc.62.4.427
58. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005;353(5):487-97. doi:
10.1056/NEJMra050100
59. Dowrick C, Frances A. Medicalising unhappiness: new classification of depression risks more
patients being put on drug treatment from which they will not benefit. BMJ 2013;347:f7140.
doi: 10.1136/bmj.f7140
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
60. Mojtabai R. Clinician-identified depression in community settings: concordance with structured-
interview diagnoses. Psychother Psychosom 2013;82(3):161-9. doi: 10.1159/000345968
61. Gibbons RD, Brown CH, Hur K, et al. Relationship between antidepressants and suicide attempts:
an analysis of the Veterans Health Administration data sets. Am J Psychiatry
2007;164(7):1044-9. doi: 10.1176/ajp.2007.164.7.1044
62. Rahme E, Dasgupta K, Turecki G, et al. Risks of suicide and poisoning among elderly patients
prescribed selective serotonin reuptake inhibitors: a retrospective cohort study. J Clin
Psychiatry 2008;69(3):349-57. doi: 10.4088/jcp.v69n0303
63. Hengartner MP, Plöderl M. Reply to the letter to the editor: "Newer-generation antidepressants and
suicide risk: Thoughts on Hengartner and Ploderl's re-analysis". Psychother Psychosom
2019;88(6):373-74. doi: 10.1159/000502485
64. Breggin PR. Suicidality, violence and mania caused by selective serotonin reuptake inhibitors
(SSRIs): A review and analysis. Int J Risk Saf Med 2004;16:31-49.
65. Masand P, Gupta S, Dewan M. Suicidal ideation related to fluoxetine treatment. N Engl J Med
1991;324(6):420. doi: 10.1056/nejm199102073240616
66. Rothschild AJ, Locke CA. Reexposure to fluoxetine after serious suicide attempts by three
patients: the role of akathisia. J Clin Psychiatry 1991;52(12):491-3.
67. Wirshing WC, Van Putten T, Rosenberg J, et al. Fluoxetine, akathisia, and suicidality: is there a
causal connection? Arch Gen Psychiatry 1992;49(7):580-1. doi:
10.1001/archpsyc.1992.01820070074012
68. Fava GA. Financial conflicts of interest in psychiatry. World Psychiatry 2007;6(1):19-24.
69. Moynihan R, Bero L, Hill S, et al. Pathways to independence: towards producing and using
trustworthy evidence. BMJ 2019;367:l6576. doi: 10.1136/bmj.l6576
70. Steinbrook R, Kassirer JP, Angell M. Justifying conflicts of interest in medical journals: a very bad
idea. BMJ 2015;350:h2942. doi: 10.1136/bmj.h2942
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
Table 1: Risk of suicide and suicide attempt combined in association with exposure to new-generation
antidepressants
Number of
comparisons
Summary
estimate
95% Confidence
interval
Hetero
-
geneity
S
ubgroup
difference
k
RE
CIL
B
CIU
B
I
2
Drug class
SSRI
SNA
Any unspecified
19
21
21
1.19
1.28
1.87
0.88
0.90
1.55
1.60
1.80
2.25
96.0
96.2
89.3
Q =
9
.3
9
p = 0.009
Main t
reatment
indication
Depression
Any unspecified
41
20
1.
3
5
1.65
1.
10
1.26
1.
6
5
2.17
95.
6
93.1
Q = 1.
53
p = 0.217
Location
North America
Europe
Other
21
36
4
0.82
1.82
1.73
0.68
1.51
0.84
0.99
2.20
3.57
65.5
95.7
10.8
Q = 3
9
.
95
p < 0.001
Old
er
adult sample
(65 years)
Yes
No
Missing data
4
54
3
1.67
1.44
0.35
1.21
7.86
1.71
94.7
95.0
Q = 0.
09
p = 0.764
Study Design
Cohort
Case-control
37
24
1.59
1.22
1.27
1.00
1.99
1.50
96.4
79.7
Q =
3
.1
6
p = 0.076
Study quality
High
(
7
points)
Low (<7 points)
4
9
12
1.3
6
1.92
1.
15
1.21
1.
61
3.03
9
4
.
4
96.5
Q = 2.
3
8
p = 0.123
Covariate
adjustment
Yes
No
5
1
10
1.
40
1.71
1.1
9
0.96
1.6
5
3.04
94.
1
97.2
Q =
0
.
54
p = 0.460
fCOI
Yes
No
28
33
0.96
2.02
0.82
1.66
1.12
2.46
86.1
94.3
Q = 3
7
.1
7
p < 0.001
SSRI: selective serotonin reuptake inhibitors; SNA: new-generation serotonergic-noradrenergic
antidepressants (includes serotonin norepinephrine reuptake inhibitors, e.g. duloxetine and
venlafaxine, and atypical antidepressants, e.g. mirtazapine and bupropion); fCOI: financial conflicts of
interest; RE: risk estimate; CILB: confidence interval lower bound; CIUB: confidence interval upper
bound
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
Figure 1: PRISMA flow chart
Figure 2: Forest-plots for suicide risk in patients with depression (including other affective disorders
and anxiety disorders). SSRI: selective serotonin reuptake inhibitor; SNA: new-generation
serotonergic-noradrenergic antidepressant (includes serotonin norepinephrine reuptake inhibitor, e.g.
duloxetine and venlafaxine, and atypical antidepressants, e.g. mirtazapine and bupropion); S: Suicide;
SA: Suicide attempts; RE: risk estimate
Figure 3: Forest-plots for suicide risk in patients with any treatment indication (including depression
and any unspecified psychiatric and non-psychiatric condition). SSRI: selective serotonin reuptake
inhibitor; SNA: new-generation serotonergic-noradrenergic antidepressant (includes serotonin
norepinephrine reuptake inhibitor, e.g. duloxetine and venlafaxine, and atypical antidepressants, e.g.
mirtazapine and bupropion); S: Suicide; SA: Suicide attempts; RE: risk estimate
Figure 4: Forest-plot for suicide risk by financial conflicts of interest (fCOI) subgroups. SSRI:
selective serotonin reuptake inhibitor; SNA: new-generation serotonergic-noradrenergic antidepressant
(includes serotonin norepinephrine reuptake inhibitor, e.g. duloxetine and venlafaxine, and atypical
antidepressants, e.g. mirtazapine and bupropion); S: Suicide; SA: Suicide attempts; RE: risk estimate
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2020. .https://doi.org/10.1101/2020.05.11.20098178doi: medRxiv preprint
