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Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials

BMJ 2005; 330 doi: https://doi.org/10.1136/bmj.330.7488.396 (Published 17 February 2005) Cite this as: BMJ 2005;330:396

Rapid Response:

Antidepressants and Suicide: Let's Keep it in Perspective

Editor:

The debate on whether antidepressants, especially SSRIs, are
responsible for provoking suicidal behaviour in patients has attracted
worldwide media reaction and generated fearfulness in many patients who
might benefit from these drugs. One of us (IS) directs a consultative
clinic that focuses on patients thought to be at high risk for suicide
and, like other colleagues, has experienced increasing patient resistance
to taking SSRIs (and indeed other antidepressants) even though these
patients are suicidally depressed and psychological treatments (including
interpersonal therapy or CBT) have failed to help them. The recent
article in your journal by Fergusson et al(1) caught our attention, as
well as the rapid response by Mitchell(2), which suggested that most of
the odds ratios given in this paper were incorrect. This prompted us to
recalculate the odds ratios for all the trials in the table in their
article. Unlike Mitchell, our calculations for the SSRIs versus placebo
studies showed odds ratios that were similar to those published by
Fergusson et al. However, we agree with Mitchell that the reported
calculations for SSRIs versus TCA's and for SSRIs versus active drugs
other than TCA's are incorrect. Fergusson et al cite an odds ratio for
completed suicides for SSRIs versus TCA's as 7.27 (95% confidence limits =
1.26 to 42.03), based on 5 deaths in an SSRI group of 6126 and 4 deaths in
a somewhat smaller TCA group of 5401. Even just glancing at the data on
which they are based should make the calculated odds ratio suspect, and
one is surprised that this result got past the authors themselves and even
more so, the reviewers. We recalculated the data ourselves as showing an
odds ratio of 1.10 (95% confidence interval = 0.30 to 4.11), which is not
significant. For fatal and non-fatal events for SSRIs versus active drugs
other than TCA's, Fergusson et al report a statistically significant odds
ratio of 1.94 (1.06 to 3.57) and, like Mitchell, we get an odds ratio of
1.54 (0.85 to 2.80), not significant. We think that, given the current
climate of anxiety among patients, to publish such blatantly misleading
analyses is unjustifiable and recommend that the authors publish an
erratum.

We suggest also that odds ratios alone (and all other indices based
on ratios) do not give an indication of absolute risk. For example,
doubling a mortality rate from 1 in 100 to 2 in 100 yields an OR of 2, but
so does doubling it from 1 in 1,000,000 to 2 in 1,000,000, even though the
responses to these two situations should be very different. It is also
necessary to examine the Number Needed to Harm (NNH), i.e. the reciprocal
of the absolute difference in the suicide rates(3). In the Fergusson et al
study, for all trials that report fatal and non-fatal events in patients
taking SSRIs vs. placebo (OR = 2.24), we calculate the NNH as 708, meaning
that this number of people must take SSRIs for there to be one excess
event (fatal or non-fatal) in the SSRI group. This actually compares quite
favourably with other examples in medicine, e.g. the NNH of 179 for fatal
or non-fatal events comparing clopidogrel versus aspirin for patients with
stroke in the CAPRIE trial(4).

Only 49% of the trials screened in this study (345 of 702 considered
eligible) reported the suicide attempts (143 in total) that occurred, and
were included in the analysis. Surely suicide attempts must have occurred
in the trials that did not report them. What guarantee do we have that
the trials that were included are representative of the total? In fact,
the authors tell us that the larger trials (those potentially more of
interest) tended to be the ones that did not report these events. Had the
comparative incidences in them been lower, the ORs reported by Fergusson
et al would have been lower too, and maybe not significant. We wonder if
the findings from the selected efficacy trials that were included can be
generalised to clinical experience at large (effectiveness).

The statistical excess of suicidal attempts reported among patients
taking SSRIs versus those on placebo has, of course, been shown before,
notably by Khan et al(5) and your editorial by Cipriani et al(6) provides
a reasonable explanation for this finding. We like also the suggestion by
Jones(7) that under reporting may be more common among placebo-treated
patients because overdoses among them would be non-toxic. One wonders
also about the randomisation process in some of the reported trials,
especially the smaller ones, and whether they were genuinely at
armslength. Clinicians are notoriously unhappy about assigning their
depressed patients to the placebo arm of a trial and are likely to subvert
the process if they can, so that their sicker cases might land up in the
active drug arm(8). In any case, the whole debate keeps losing track of
the fact that these trials were not designed to assess suicidality as an
outcome but to satisfy regulatory agencies that the drugs were efficacious
in controlling a specific disease process, hence their unreliability for
reporting of suicidal events. Suicidality (past suicidal behaviour or
present suicidal ideation) is in fact generally an exclusion criterion for
these trials. To lay these issues to rest we badly need prospective
studies with suicidality as the outcome variable of interest, but these
have very rarely been done for ethical and practical (sample size)
reasons(9). Meanwhile, the numerous, large-scale, population-based
observational studies in existence that show a fall in suicide rates
related to increased treatment of depressive illness together with
increased use of novel antidepressants including SSRIs should not be
ignored(10).

References:

[1] Fergusson D, Doucette S, Glass KC, Shapiro S, Healy D, Hebert P,
et al. Association between suicide attempts and selective serotonin
reuptake inhibitors: systematic review of randomised controlled trials.
BMJ 2005; 330: 396-9.

[2] Mitchell A. Risk of suicide using SSRIs: data appears to be incorrect.
BMJ 2005; 330: 396.

[3] Laupacis A. Sackett DL. Roberts RS. An assessment of clinically useful
measures of the consequences of treatment. New England Journal of
Medicine. 318(26):1728-33, 1988

[4] CAPRIE Steering Committee. (1996). A randomised, blinded trial of
clopidogrel versus aspirin in patients at risk of ischaemic events.
Lancet, 348, 1329-1339.

[5] 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. Archives General
Psychiatry 2000; 57: 311-7.

[6] Cipriani A, Barbui C, Geddes J. Suicide, depression, and
antidepressants: patients and clinicians need to balance benefits and
harms. BMJ 2005; 330: 373-4.

[7] Jones H. SSRI use and non-fatal self harm .BMJ 2005; 330: 396.

[8] Schulz KF. Subverting randomisation in controlled trials. JAMA
1995; 274: 1456-8.

[9] Gunnell D, Saperia J, Ashby D. Selective serotonin reuptake
inhibitors (SSRIs) and suicide in adults: meta-analysis of drug company
data from placebo-controlled randomised controlled trials submitted to the
MHRA’s safety review. BMJ 2005; 330: 385-8.

[10] Licinio J, Wong M-L. Depression, antidepressants and
suicidality: a critical appraisal. Nature Reviews/Drug Discovery 2005; 4:
165-71.

Competing interests:
None declared

Competing interests: No competing interests

01 March 2005
Isaac Sakinofsky
Professor Emeritus of Psychiatry and Public Health Sciences, University of Toronto
David L. Streiner, PhD, Professor of Psychiatry, University of Toronto; Director, Kunin-Lunenfeld Applied Research Unit, Baycrest Centre for Geriatric Care
CAMH, 250 College St, Toronto, ON, Canada, M5T 1R8