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Suicide risk with selective serotonin reuptake inhibitors and new-generation serotonergic-noradrenergic antidepressants in adults: a systematic review and meta-analysis of observational studies

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Abstract

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 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 (I2>85%). 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/
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
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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
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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.
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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
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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).
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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
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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.
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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
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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
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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).
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-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
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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
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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
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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
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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.
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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
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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
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... 7,106-108 Additionally, this relative risk needs to be considered in comparison with the greater risk associated with other substances that have been linked with suicide and suicide attempts, including recreational (e.g., acute alcohol use is strongly associated with increased likelihood of attempting suicide, OR = 6.97, 95% CI = 4.77 − 10.17) 109 and pharmaceutical drugs (e.g., benzodiazepines 110 and potentially selective serotonin reuptake inhibitors). 111,112 It is also likely the case there is a publication bias towards negative outcomes in this portion of the literature, as positive outcomes of recreational psychedelic use are rarely brought to medical attention and are therefore unlikely to be published. ...
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Use of classic psychedelics (e.g., psilocybin, ayahuasca, and lysergic acid diethylamide) is increasing, and psychedelic therapy is receiving growing attention as a novel mental health intervention. Suicidality remains a potential safety concern associated with classic psychedelics and is, concurrently, a mental health concern that psychedelic therapy may show promise in targeting. Accordingly, further understanding of the relationship between classic psychedelics and suicidality is needed. Therefore, we conducted a systematic review of the relationship between classic psychedelics (both non-clinical psychedelic use and psychedelic therapy) and suicidality. We identified a total of 64 articles, including 41 articles on the association between non-clinical classic psychedelic use and suicidality and 23 articles on the effects of psychedelic therapy on suicidality. Findings on the association between lifetime classic psychedelic use and suicidality were mixed, with studies finding positive, negative, and no significant association. A small number of reports of suicide and decreased suicidality following non-clinical classic psychedelic use were identified. Several cases of suicide in early psychedelic therapy were identified; however, it was unclear whether this was due to psychedelic therapy itself. In recent psychedelic therapy clinical trials, we found no reports of increased suicidality and preliminary evidence for acute and sustained decreases in suicidality following treatment. We identify some remaining questions and provide suggestions for future research on the association between classic psychedelics and suicidality.
... 8 An updated and expanded meta-analysis found no definite association between SSRIs and suicide risk in adult patients with depression but significantly increased risk with any new-generation antidepressant in adult patients with depression and other treatment indications. 9 Nevertheless, based on the findings from ecological studies, various authors have concluded that the increased prescription of SSRIs and other new-generation antidepressants has likely contributed to lower suicide rates in the population. 2,10,11 Such strong claims are not firmly supported by the evidence though, as the results of ecological studies are inconsistent. ...
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Background: Ecological studies have explored associations between suicide rates and antidepressant prescriptions in the population, but most of them are limited as they analyzed short-term correlations that may be spurious. The aim of this long-term study was to examine whether trends in suicide rates changed in three European countries when the first antidepressants were introduced in 1960 and when prescription rates increased steeply after 1990 with the introduction of the serotonin reuptake inhibitors (SSRIs). Methods: Data were extracted from the WHO Mortality Database. Suicide rates were calculated for people aged 10–89 years from 1951–2015 for Italy, 1955–2016 for Austria and 1951–2013 for Switzerland. Trends in suicide rates stratified by gender were analyzed using joinpoint regression models. Results: There was a general pattern of long-term trends that was broadly consistent across all three countries. Suicide rates were stable or decreasing during the 1950s and 1960s, they rose during the 1970s, peaked in the early 1980s and thereafter they declined. There were a few notable exceptions to these general trends. In Italian men, suicide rates increased until 1997, then fell sharply until 2006 and increased again from 2006 to 2015. In women from all three countries, there was an extended period during the 2000s when suicide rates were stable. No trend changes occurred around 1960 or 1990. Conclusions: The introduction of antidepressants around 1960 and the sharp increase in prescriptions after 1990 with the introduction of the SSRIs did not coincide with trend changes in suicide rates in Italy, Austria or Switzerland.
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Background The evidence on selective serotonin reuptake inhibitors (SSRIs) for major depressive disorder is unclear. Methods Our objective was to conduct a systematic review assessing the effects of SSRIs versus placebo, ‘active’ placebo, or no intervention in adult participants with major depressive disorder. We searched for eligible randomised clinical trials in The Cochrane Library’s CENTRAL, PubMed, EMBASE, PsycLIT, PsycINFO, Science Citation Index Expanded, clinical trial registers of Europe and USA, websites of pharmaceutical companies, the U.S. Food and Drug Administration (FDA), and the European Medicines Agency until January 2016. All data were extracted by at least two independent investigators. We used Cochrane systematic review methodology, Trial Sequential Analysis, and calculation of Bayes factor. An eight-step procedure was followed to assess if thresholds for statistical and clinical significance were crossed. Primary outcomes were reduction of depressive symptoms, remission, and adverse events. Secondary outcomes were suicides, suicide attempts, suicide ideation, and quality of life. ResultsA total of 131 randomised placebo-controlled trials enrolling a total of 27,422 participants were included. None of the trials used ‘active’ placebo or no intervention as control intervention. All trials had high risk of bias. SSRIs significantly reduced the Hamilton Depression Rating Scale (HDRS) at end of treatment (mean difference −1.94 HDRS points; 95% CI −2.50 to −1.37; P < 0.00001; 49 trials; Trial Sequential Analysis-adjusted CI −2.70 to −1.18); Bayes factor below predefined threshold (2.01*10−23). The effect estimate, however, was below our predefined threshold for clinical significance of 3 HDRS points. SSRIs significantly decreased the risk of no remission (RR 0.88; 95% CI 0.84 to 0.91; P < 0.00001; 34 trials; Trial Sequential Analysis adjusted CI 0.83 to 0.92); Bayes factor (1426.81) did not confirm the effect). SSRIs significantly increased the risks of serious adverse events (OR 1.37; 95% CI 1.08 to 1.75; P = 0.009; 44 trials; Trial Sequential Analysis-adjusted CI 1.03 to 1.89). This corresponds to 31/1000 SSRI participants will experience a serious adverse event compared with 22/1000 control participants. SSRIs also significantly increased the number of non-serious adverse events. There were almost no data on suicidal behaviour, quality of life, and long-term effects. ConclusionsSSRIs might have statistically significant effects on depressive symptoms, but all trials were at high risk of bias and the clinical significance seems questionable. SSRIs significantly increase the risk of both serious and non-serious adverse events. The potential small beneficial effects seem to be outweighed by harmful effects. Systematic review registrationPROSPERO CRD42013004420.
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Objective To examine the association between the presence of individual principal investigators’ financial ties to the manufacturer of the study drug and the trial’s outcomes after accounting for source of research funding. Design Cross sectional study of randomized controlled trials (RCTs). Setting Studies published in “core clinical” journals, as identified by Medline, between 1 January 2013 and 31 December 2013. Participants Random sample of RCTs focused on drug efficacy. Main outcome measure Association between financial ties of principal investigators and study outcome. Results A total of 190 papers describing 195 studies met inclusion criteria. Financial ties between principal investigators and the pharmaceutical industry were present in 132 (67.7%) studies. Of 397 principal investigators, 231 (58%) had financial ties and 166 (42%) did not. Of all principal investigators, 156 (39%) reported advisor/consultancy payments, 81 (20%) reported speakers’ fees, 81 (20%) reported unspecified financial ties, 52 (13%) reported honorariums, 52 (13%) reported employee relationships, 52 (13%) reported travel fees, 41 (10%) reported stock ownership, and 20 (5%) reported having a patent related to the study drug. The prevalence of financial ties of principal investigators was 76% (103/136) among positive studies and 49% (29/59) among negative studies. In unadjusted analyses, the presence of a financial tie was associated with a positive study outcome (odds ratio 3.23, 95% confidence interval 1.7 to 6.1). In the primary multivariate analysis, a financial tie was significantly associated with positive RCT outcome after adjustment for the study funding source (odds ratio 3.57 (1.7 to 7.7). The secondary analysis controlled for additional RCT characteristics such as study phase, sample size, country of first authors, specialty, trial registration, study design, type of analysis, comparator, and outcome measure. These characteristics did not appreciably affect the relation between financial ties and study outcomes (odds ratio 3.37, 1.4 to 7.9). Conclusions Financial ties of principal investigators were independently associated with positive clinical trial results. These findings may be suggestive of bias in the evidence base.
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Objective To study serious harms associated with selective serotonin and serotonin-norepinephrine reuptake inhibitors. Design Systematic review and meta-analysis. Main outcome measures Mortality and suicidality. Secondary outcomes were aggressive behaviour and akathisia. Data sources Clinical study reports for duloxetine, fluoxetine, paroxetine, sertraline, and venlafaxine obtained from the European and UK drug regulators, and summary trial reports for duloxetine and fluoxetine from Eli Lilly’s website. Eligibility criteria for study selection Double blind placebo controlled trials that contained any patient narratives or individual patient listings of harms. Data extraction and analysis Two researchers extracted data independently; the outcomes were meta-analysed by Peto’s exact method (fixed effect model). Results We included 70 trials (64 381 pages of clinical study reports) with 18 526 patients. These trials had limitations in the study design and discrepancies in reporting, which may have led to serious under-reporting of harms. For example, some outcomes appeared only in individual patient listings in appendices, which we had for only 32 trials, and we did not have case report forms for any of the trials. Differences in mortality (all deaths were in adults, odds ratio 1.28, 95% confidence interval 0.40 to 4.06), suicidality (1.21, 0.84 to 1.74), and akathisia (2.04, 0.93 to 4.48) were not significant, whereas patients taking antidepressants displayed more aggressive behaviour (1.93, 1.26 to 2.95). For adults, the odds ratios were 0.81 (0.51 to 1.28) for suicidality, 1.09 (0.55 to 2.14) for aggression, and 2.00 (0.79 to 5.04) for akathisia. The corresponding values for children and adolescents were 2.39 (1.31 to 4.33), 2.79 (1.62 to 4.81), and 2.15 (0.48 to 9.65). In the summary trial reports on Eli Lilly’s website, almost all deaths were noted, but all suicidal ideation events were missing, and the information on the remaining outcomes was incomplete. Conclusions Because of the shortcomings identified and having only partial access to appendices with no access to case report forms, the harms could not be estimated accurately. In adults there was no significant increase in all four outcomes, but in children and adolescents the risk of suicidality and aggression doubled. To elucidate the harms reliably, access to anonymised individual patient data is needed.
Article
Background: A recent study by Hengartner and Plöderl describes a strong increase for suicides (odds ratio (OR) of 2.83, 95% CI=1.13-9.67) and suicide attempts (OR=2.38 95%, CI=1.63-3.61) in antidepressant treated patients as compared to placebo. The authors re-analyzed data presented by Khan et al. who found no drug-placebo differences in suicide and suicide attempt rates. Hengartner and Plöderl base their findings on calculating the OR from a 2×2 table of the sum of the events and the totals of the sample sizes across studies. We here argue that pooling data from all drugs may not be the adequate approach. Methods: We applied a meta-analytical approach to account for between-drug variance and conducted several statistical analyses as a sensitivity analysis. We argue that a more suitable approach for finding an overall effect from several observations is a meta-analytical approach namely the Mantel-Haenszel method without continuity correction. Results: Our analysis leads to different conclusions as opposed to Hengartner and Plöderl. With the recommended method we estimate an OR of 1.98, 95% CI 0.71-5.50 for suicides and 1.63 (95%CI=1.09-2.43) for suicide attempts. Limitations: The conducted analysis was restricted to the data available from the previous studies. Possibly, a more extensive search of the literature would lead to different results. However, we showed that re-analysing the re-analysis with several different approaches underlines the necessity of sensitivity analysis. Conclusion: We could show that, in the case of rare events, the data is very sensitive to different analytical approaches underlining the importance of further investigations.
Article
Based on a 10-year systematic review of suicide prevention strategies, “29 suicide prevention experts from 17 European countries” recommend 4 allegedly evidence-based strategies to be included in national suicide prevention programs. One of the recommended strategies is pharmacological treatment of depression. This recommendation is problematic for several reasons. First, it is based on a biased selection and interpretation of available evidence. Second, the authors have failed to take into consideration the widespread corruption in the research on antidepressants. Third, the many and serious side effects of antidepressants are not considered. Thus, the recommendation may have deleterious consequences for countless numbers of people, and, in fact, contribute to an increase in the suicide rate rather than a decrease.
Article
Background: Clinical research affecting how doctors practice medicine is increasingly sponsored by companies that make drugs and medical devices. Previous systematic reviews have found that pharmaceutical-industry sponsored studies are more often favorable to the sponsor's product compared with studies with other sources of sponsorship. A similar association between sponsorship and outcomes have been found for device studies, but the body of evidence is not as strong as for sponsorship of drug studies. This review is an update of a previous Cochrane review and includes empirical studies on the association between sponsorship and research outcome. Objectives: To investigate whether industry sponsored drug and device studies have more favorable outcomes and differ in risk of bias, compared with studies having other sources of sponsorship. Search methods: In this update we searched MEDLINE (2010 to February 2015), Embase (2010 to February 2015), the Cochrane Methodology Register (2015, Issue 2) and Web of Science (June 2015). In addition, we searched reference lists of included papers, previous systematic reviews and author files. Selection criteria: Cross-sectional studies, cohort studies, systematic reviews and meta-analyses that quantitatively compared primary research studies of drugs or medical devices sponsored by industry with studies with other sources of sponsorship. We had no language restrictions. Data collection and analysis: Two assessors screened abstracts and identified and included relevant papers. Two assessors extracted data, and we contacted authors of included papers for additional unpublished data. Outcomes included favorable results, favorable conclusions, effect size, risk of bias and whether the conclusions agreed with the study results. Two assessors assessed risk of bias of included papers. We calculated pooled risk ratios (RR) for dichotomous data (with 95% confidence intervals (CIs)). Main results: Twenty-seven new papers were included in this update and in total the review contains 75 included papers. Industry sponsored studies more often had favorable efficacy results, RR: 1.27 (95% CI: 1.17 to 1.37) (25 papers) (moderate quality evidence), similar harms results RR: 1.37 (95% CI: 0.64 to 2.93) (four papers) (very low quality evidence) and more often favorable conclusions RR: 1.34 (95% CI: 1.19 to 1.51) (29 papers) (low quality evidence) compared with non-industry sponsored studies. Nineteen papers reported on sponsorship and efficacy effect size, but could not be pooled due to differences in their reporting of data and the results were heterogeneous. We did not find a difference between drug and device studies in the association between sponsorship and conclusions (test for interaction, P = 0.98) (four papers). Comparing industry and non-industry sponsored studies, we did not find a difference in risk of bias from sequence generation, allocation concealment, follow-up and selective outcome reporting. However, industry sponsored studies more often had low risk of bias from blinding, RR: 1.25 (95% CI: 1.05 to 1.50) (13 papers), compared with non-industry sponsored studies. In industry sponsored studies, there was less agreement between the results and the conclusions than in non-industry sponsored studies, RR: 0.83 (95% CI: 0.70 to 0.98) (six papers). Authors' conclusions: Sponsorship of drug and device studies by the manufacturing company leads to more favorable efficacy results and conclusions than sponsorship by other sources. Our analyses suggest the existence of an industry bias that cannot be explained by standard 'Risk of bias' assessments.
Article
Background: It is unclear whether antidepressants can prevent suicides or suicide attempts, particularly during long-term use. Methods: We carried out a comprehensive review of long-term studies of antidepressants (relapse prevention). Sources were obtained from 5 review articles and by searches of MEDLINE, PubMed Central and a hand search of bibliographies. We meta-analyzed placebo-controlled antidepressant RCTs of at least 3 months' duration and calculated suicide and suicide attempt incidence rates, incidence rate ratios and Peto odds ratios (ORs). Results: Out of 807 studies screened 29 were included, covering 6,934 patients (5,529 patient-years). In total, 1.45 suicides and 2.76 suicide attempts per 1,000 patient-years were reported. Seven out of 8 suicides and 13 out of 14 suicide attempts occurred in antidepressant arms, resulting in incidence rate ratios of 5.03 (0.78-114.1; p = 0.102) for suicides and of 9.02 (1.58-193.6; p = 0.007) for suicide attempts. Peto ORs were 2.6 (0.6-11.2; nonsignificant) and 3.4 (1.1-11.0; p = 0.04), respectively. Dropouts due to unknown reasons were similar in the antidepressant and placebo arms (9.6 vs. 9.9%). The majority of suicides and suicide attempts originated from 1 study, accounting for a fifth of all patient-years in this meta-analysis. Leaving out this study resulted in a nonsignificant incidence rate ratio for suicide attempts of 3.83 (0.53-91.01). Conclusions: Therapists should be aware of the lack of proof from RCTs that antidepressants prevent suicides and suicide attempts. We cannot conclude with certainty whether antidepressants increase the risk for suicide or suicide attempts. Researchers must report all suicides and suicide attempts in RCTs.