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
The figures for suicides on SSRIs from placebo controlled trials
produced by David Gunnell and colleagues in this article may not be all
they seem. In the Expert Working Group report on SSRIs (EWG)(1), the
table for citalopram trials suggests there was no suicide in the placebo
group. Data on paroxetine are not available from the EWG report, but my
reading of prior submissions on paroxetine suggests there were 4 suicides
on paroxetine in placebo controlled trials (2). The authors note 3
suicides on placebo in the withdrawal phase of these trials. The Safety
Review of paroxetine conducted by M Brecher in 1991 does not suggest these
suicides happened in the withdrawal phase of placebo-controlled trials
(3). Unless the authors can confirm from their own inspection of the raw
data that there were in fact 3 suicides in the withdrawal phase, as
opposed to relying on a company submission, these figures must be in some
doubt.
Based on the above, there may therefore have been 12 suicides in
23,804 SSRI patients versus 6 suicides in 17,022 placebo patients, an odds
ratio of 1.43, or possibly 12 SSRI suicides versus 3 placebo suicides, an
odds ratio of 2.86. Given the confusion about paroxetine, if it is left
out, the figures become 8 suicides in 15,323 SSRI patients versus 3
suicides in 11,214 placebo patients, an odds ratio of 1.96. Adding in
suicides on venlafaxine and mirtazapine from the EWG gives 16 suicides in
23,885 antidepressant patients versus 3 in 14,564 placebo patients, an
odds ratio of 3.1.
Given that antidepressants may reduce the risk of suicide in some
patients, even an odds ratio of 1.0 points to a risk. As things stand at
present, therefore, we have a very clear signal of risk from both clinical
accounts of the problem and clinical trials. Against this background
Gunnell and colleagues call for more research is compelling. But their
suggestion as regards the numbers needed to recruit to an RCT to establish
a drugs ability to reduce the risk of suicide is likely to deter further
research. In contrast, an RCT with a challenge-dechallenge design and a
rating scale sensitive to suicidal ideation, might need less than a
hundred patients to establish conclusively whether there are patients at
risk of induced suicidality. Eli Lilly designed such an RCT in
conjunction with FDA in 1990. The details are available for posting on
the BMJ website.
2 CSM Expert Working Group on the Safety of SSRIs. Risk:Benefit
Evaluation of paroxetine. Williams J, Wise L, Dunne J, Day S, Davies C,
October 2003.
3. Brecher M (1991). Review and evaluation of clinical data original
NDA 20-031. Paroxetine safety review. Department Heath & Human
Services, Washington, Center for Drug Evaluation and Research, Freedom of
Information File F99-22360
Competing interests:
Extensive links to all the major pharmaceutical companies making antidepressants, and expert witness in antidepressant linked legal cases
Rapid Response:
Risk of Suicide
Dear Sirs
The figures for suicides on SSRIs from placebo controlled trials
produced by David Gunnell and colleagues in this article may not be all
they seem. In the Expert Working Group report on SSRIs (EWG)(1), the
table for citalopram trials suggests there was no suicide in the placebo
group. Data on paroxetine are not available from the EWG report, but my
reading of prior submissions on paroxetine suggests there were 4 suicides
on paroxetine in placebo controlled trials (2). The authors note 3
suicides on placebo in the withdrawal phase of these trials. The Safety
Review of paroxetine conducted by M Brecher in 1991 does not suggest these
suicides happened in the withdrawal phase of placebo-controlled trials
(3). Unless the authors can confirm from their own inspection of the raw
data that there were in fact 3 suicides in the withdrawal phase, as
opposed to relying on a company submission, these figures must be in some
doubt.
Based on the above, there may therefore have been 12 suicides in
23,804 SSRI patients versus 6 suicides in 17,022 placebo patients, an odds
ratio of 1.43, or possibly 12 SSRI suicides versus 3 placebo suicides, an
odds ratio of 2.86. Given the confusion about paroxetine, if it is left
out, the figures become 8 suicides in 15,323 SSRI patients versus 3
suicides in 11,214 placebo patients, an odds ratio of 1.96. Adding in
suicides on venlafaxine and mirtazapine from the EWG gives 16 suicides in
23,885 antidepressant patients versus 3 in 14,564 placebo patients, an
odds ratio of 3.1.
Given that antidepressants may reduce the risk of suicide in some
patients, even an odds ratio of 1.0 points to a risk. As things stand at
present, therefore, we have a very clear signal of risk from both clinical
accounts of the problem and clinical trials. Against this background
Gunnell and colleagues call for more research is compelling. But their
suggestion as regards the numbers needed to recruit to an RCT to establish
a drugs ability to reduce the risk of suicide is likely to deter further
research. In contrast, an RCT with a challenge-dechallenge design and a
rating scale sensitive to suicidal ideation, might need less than a
hundred patients to establish conclusively whether there are patients at
risk of induced suicidality. Eli Lilly designed such an RCT in
conjunction with FDA in 1990. The details are available for posting on
the BMJ website.
1 Report on the CSM Expert Working Group on the Safety of Selective
Serotonin Reuptake Inhibitor Antidepressants.
www.mhra.gov.uk/news/2004/SSRIfinal.pdf
2 CSM Expert Working Group on the Safety of SSRIs. Risk:Benefit
Evaluation of paroxetine. Williams J, Wise L, Dunne J, Day S, Davies C,
October 2003.
3. Brecher M (1991). Review and evaluation of clinical data original
NDA 20-031. Paroxetine safety review. Department Heath & Human
Services, Washington, Center for Drug Evaluation and Research, Freedom of
Information File F99-22360
Competing interests:
Extensive links to all the major pharmaceutical companies making antidepressants, and expert witness in antidepressant linked legal cases
Competing interests: No competing interests