Did regulators fail over selective serotonin reuptake inhibitors?BMJ 2006; 333 doi: https://doi.org/10.1136/bmj.333.7558.92 (Published 06 July 2006) Cite this as: BMJ 2006;333:92
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In his reply Dr Woods appears to distance himself from FDA by noting
that MHRA acted before FDA did as regards children, and by suggesting MHRA
warned about a risk of suicide from 2000, and by failing to comment on the
recent paper in which FDA makes all suicides on SSRIs vanish. But his
letter repeats many of the regulatory behaviours that the target article
criticizes. Did the regulators act promptly and effectively to protect
the public health? Consider this juxtaposition of Dr Wood’s statements
with the facts.
Dr Woods 1: “The MHRA moved swiftly in June 2003 to contraindicate
the use of paroxetine in children with depressive illness based on a lack
of evidence of efficacy and an increased risk of suicidal behaviour.”
Fact 1: In 1991 after the introduction of the first SSRI, fluoxetine,
and with no demonstration of efficacy in children, King and colleagues
reported self-injurious behaviour among children receiving an SSRI for OCD
warning then that “As fluoxetine and other medications are used in
increasing numbers of younger patients with a wide range of
psychopathology, vigilance is needed to detect potentially deleterious
side effects” (1).
A year earlier, Teicher and colleagues (2) had alerted the medical
community to a risk of violent thoughts and behaviours with fluoxetine:
“The purpose of this report is to suggest the surprising possibility that
fluoxetine may induce suicidal ideation in some patients.” They
recommended that “this drug be used cautiously and that the practitioner
be attentive to possible emergence of suicidal ideation, even in those
patients without a previous history of suicidal thoughts or actions.”
They reported on a further patient, a 14-year-old boy, who committed
suicide after being put on fluoxetine (3).
Dr Woods 2: “In relation to suicide risk in adults…warnings issued by
MCA in 2000 and the MHRA in 2003 “raised the possibility that SSRIs may
increase the risk of suicidal behaviour in some people.” In 2004, the CSM
Expert Working Group issued the conclusion that “available clinical trial
data could not rule out an increased risk of suicidal behaviour in adults
Fact 2: By 1991, the possibility that SSRIs could cause violent
thoughts and behaviours, including suicide and self-harm in children and
adults, regardless of the indication, had been widely reported. It is now
clear that the clinical trial data, to which only the regulators had full
access, strongly supported this possibility as of 1990/1991 (4). It took
the regulators 15 years to inform people about the risk – and the impetus
to warn did not come from the regulators.
Dr Woods 3: The regulators did not require a single study to be
undertaken to investigate the possibility that in attempting to treat
patients in an effort to prevent them from harming themselves or others,
we might actually be giving them drugs that induce some to do just that.
The reasons offered by Dr Woods for this failure are revealing. He states
that a trial designed to detect this risk “would be neither feasible nor
Taking the ethics first, MHRA’s position here appears to be that it
is fine to allow pharmaceutical companies market drugs to millions of
people suspecting they are unsafe, but it would be unethical to conduct a
study to see if the drugs are safe. On the question of feasibility, MHRA
again appears to think it is fine for pharmaceutical companies to make
billions of pounds selling the drugs, but it would be too expensive for
the companies to study whether or not they make people kill themselves.
Fact 3: Such trials could have been done quickly, simply and safely
by using re-challenge designs with instruments sensitive to the emergence
of drug-induced agitation. They would only have needed a few hundred
patients. As of 1991, the trial protocol for such a study had been
written, the instrument designed and piloted, the tablets put in blister
packs, but the regulators decided not to require the companies to go ahead
(5). The regulators did not even require companies to include this
instrument as a matter of routine in the hundreds of trials that were
undertaken after 1991. Would including this instrument in these trials
not have been feasible and ethical? Would it not have generated useful
data for regulators, and clinicians?
Dr Woods 4: Dr Woods perhaps comments all too eloquently by omission
on one of the central indicators of regulatory failure in the target
article – namely that the regulators sat by while drug companies manipulated the placebo data on suicidal acts in a manner that
was deeply misleading, and continues to be deeply misleading by virtue of
all the articles now in the public domain offering flawed datasets.
Fact 4: Dr Woods fails to mention that MHRA
have failed to prevent the drug companies' manipulation of placebo data right up to and beyond the
moment that GlaxoSmithKline posted the actual details of suicides from
their placebo controlled trials on their Website in May of this year (6).
Dr Woods 5: “The placebo-controlled trials of SSRIs reviewed in the
Expert Working Group’s report .. showed an absolute excess risk of suicide
-related events of the order of 0.1% on active treatment relative to
Fact 5: Once the misleading placebo suicides are stripped out of the
EWG report, the relative risk of suicide on active treatment compared to
placebo was 2.6 fold greater and the relative risk of any suicidal act is
2.4 fold greater and is statistically significant. However taking Dr
Woods figure of 0.1%, given the numbers of people companies claim have had
these drugs, this would result in approximately 100,000 excess suicide-
related events, a proportion of which judicious regulatory action, without
putting a dent in company sales, could surely have helped avoid. Why do
we have regulators if not to help avoid just this?
1/ King RA, Riddle MA, Chappell PB et al (1991). Emergence of self-
destructive phenomena in children and adolescents during fluoxetine
treatment. J Am Acad Child Adolesc Psychiatry 30,179-186.
2/ Teicher MA, Glod C, Cole JO (1990). Emergence of intense suicidal
preoccupation during fluoxetine treatment. Am J Psychiatry 147, 207-210.
3/ Teicher MH, Glod C, Cole JO (1990). Suicidal preoccupation during
fluoxetine treatment. Am J Psychiatry 147, 1380-1381
4/ Fergusson D, Doucette S, Cranley-Glass K, Shapiro S, Healy D,
Hebert P, Hutton B (2005). The association between suicide attempts and
SSRIs: A systematic review of 677 randomized controlled trials
representing 85,470 participants. BMJ 330, 396-399.
5/ Healy D (2004). Let Them Eat Prozac. New York University Press,
6/ See correspondence on MHRA’s handling of suicide data on
DH has links to all major pharmaceutical companies and has been an expert witness in legal cases involving antidepressants and suicide
Competing interests: No competing interests
EDITOR - Healy’s article ‘Did regulators fail over selective
serotonin reuptake inhibitors’ makes allegations about failure of MHRA to
warn about suicidal behaviour with SSRIs which require response1.
The MHRA moved swiftly in June 2003 to contraindicate the use of
paroxetine in children with depressive illness (for which it had never
been licensed) based on a lack of evidence of efficacy and an increased
risk of suicidal behaviour. The data on risk of suicidal behaviour were
clearly communicated at that time and are prominently displayed in the
Patient Information Leaflet.
In relation to suicide risk in adults, Healy states that no warnings
were issued until May 2006, and criticises regulators for “failing either
to warn or to demand suitably powered studies of the risks of treatment”.
Warnings issued by the Medicines Control Agency in 2000 and the MHRA in
2003 raised the possibility that SSRIs may increase the risk of suicidal
behaviour in some people. The Committee on Safety of Medicines’ Expert
Working Group on SSRIs was clear in its findings published in December
2004 that the available clinical trial data could not rule out an
increased risk of suicidal behaviour in adults on SSRIs compared with
placebo and advised careful and frequent monitoring of all patients taking
SSRIs as a result. In reaching its conclusions the Expert Working Group
fully recognised the limitations of statistical power in examining safety
rather than efficacy end points.
The placebo-controlled trials of SSRIs reviewed in the Expert Working
Group’s report2 showed an absolute excess risk of suicide-related events
(suicidal thoughts, non-fatal self harm or suicide) of the order of 0.1%
on active treatment relative to placebo. To reliably detect such a small
excess risk using standard statistical criteria would require extremely
large trials (tens of thousands of patients in each arm, randomised
against placebo) which would be neither feasible nor ethically defensible
for an outcome of harm. Recognising these limitations the Expert Working
Group reached its conclusions on the consistency of the evidence from
across the data sources. These include the important epidemiological
studies from the General Practice Research Database, to which Healy makes
no reference. In 146,000 patients with first-time depression there was no
evidence of increased risk of suicidal behaviour in adults prescribed
SSRIs compared to a range of other antidepressants.3
As with any question of medicines’ safety, the evidence base has
continued to evolve over time. Throughout, the Agency has published new
advice as data have become available and has published the data
underpinning that advice.
Kent Woods, chief executive,
Medicines and Healthcare products Regulatory Agency,
London SW8 5NQ
1. Did regulators fail over selective serotonin reuptake inhibitors?
Healy BMJ.2006; 333: 92-95
2.Report of the Committee on safety of medicines Expert Working Group
on the Safety of Selective Serotonin Reuptake Inhibitor Antidepressants.
3. Martinez C, Rietbrock S, Wise L, Ashby D, Chick J, Moseley J,
Evans S, Gunnell D. Antidepressant treatment and the risk of fatal and non
-fatal self harm in first episode depression: nested case-control study.
BMJ 2005; 330: 389-96.
Chief Executive, MHRA
Competing interests: No competing interests
Since the publication of this article, I have become aware of a
recent analysis of suicides from antidepressant clinical trials carried
out by the Food and Drug Administration (FDA) in the United States (1).
This new analysis reports no suicides on SSRI antidepressants in placebo
controlled trials. It differs significantly from an earlier FDA analysis
by the same authors (2) that I had cited, and it appears inconsistent with
the data provided in an analysis commissioned by Medicines' and Healthcare
Products Regulatory Agency (MHRA) in Britain in 2004 (3,4).
The MHRA data yields 8 suicides on SSRIs in placebo-controlled
trials, 12 if venlafaxine is added and 17 if mirtazapine is added, with 4
suicides on placebo (3). Hammad and colleagues in their recent analysis,
in contrast, cite no suicides on SSRIs with 3 suicides on all
antidepressants and 2 suicides on placebo (1). This is inconsistent with
their earlier analysis (2), which gives a 1.5 fold (95% C.I, 1.35, 1.66)
increase in relative risk of suicide on SSRIs compared to placebo, and
1.98 for suicides on all antidepressants compared to placebo (95% C.I,
It may be possible to eliminate all suicides on SSRIs by a careful
selection of the timeframe – the authors restrict their recent analysis to
data from trials before 2000; or by selection of the indication – these
trials are restricted to major depressive disorder trials; or by the
definition of what counts as an SSRI – excluding venlafaxine. It is
customary in science, however, to place one’s findings in context with
what has been reported previously by others, particularly if these reports
are at odds with a new analysis, and especially when the reports are at
odds with one’s own prior analysis. FDA neither mentions nor explains its
inconsistencies either with my or other papers at odds with theirs, nor
mentions its own prior analysis.
The most interesting part of the new analysis, however, lies in its
claim that there were much fewer suicides in placebo controlled than non-
placebo controlled trials, even though patients admitted to both sets of
trials were equally depressed. Most placebo controlled studies happened
in North America. This finding the authors suggest indicates the presence
of a confounder against which other results need to be adjusted.
A possible contributor to this finding of no suicides in North
American trials would seem to lie in the fact that the investigators in
one North American centre that participated in a number of these trials
ended up in jail for inventing patients (5), and a number of other
trialists were investigated for breaches of good clinical practice (GCP),
and suspended from further research. An invented patient is unlikely to
commit suicide, as this will entail later auditing of the patient’s
The appropriate adjustment to make to these data accordingly would be
to remove from the denominator all patients entered into antidepressant
trials from all centres linked to clinicians reported for breaches of GCP.
But the FDA authors of this analysis do not advert to this history as a
possible explanation of findings they otherwise spend some time trying to
This failure, along with an apparent selection of data, and flouting
of basic scientific norms, can only deepen the questions hanging over
regulatory involvement in this issue.
1/ Hammad TA, Laughren TP, Racoosin JA. Suicide rates in short term
randomised controlled trials of newer antidepressants. J Clinical
Psychopharmacology 2006; 26, 203-207.
2/ Hammad TA, Mosholder A, Boehm G, Racoosin JA, Laughren T.
Incidence of suicides in randomized controlled trials of patients with
major depressive disorder. Pharmacoepidemiol Drug Safety 2003;12(suppl
3/ Report of the CSM Expert Working Group on the safety of selective
serotonin reuptake inhibitors 2004.
(accessed 13 May 2006).
4/ Gunnell D, Saperia J, Ashby D. Selective serotonin reuptake
inhibitors (SSRIs) and suicide in adults: meta-analysis of drug company
data from placebo controlled trials submitted to the MHRA’s safety review.
BMJ 2005; 330: 385-8.
5/ Stecklow S, Johannes L (1997). Questions arise on new drug
testing. Drug Makers relied on clinical researchers who now await trial.
Wall Street Journal Aug 15th.
DH has links to all the major pharmaceutical companies and has been an expert witness in legal actions involving suicide on antidepressants
Competing interests: No competing interests
Stewart Hosie (Dundee East, Scottish National Party
I take enormous pleasure in presenting a petition on behalf of my constituent, Mr. D. Scott, from Dundee, who calls for the precautionary principle to apply to the prescription of Seroxat. He points out that many people who are prescribed Seroxat believe that they suffer side-effects, including aggression, fatigue, agitation and suicidal thoughts. Others suffer severe effects on withdrawal. He observes that a large amount of information on those side-effects is in the public domain, and he demonstrates the requirement for immediate action, including a moratorium on the prescribing of Seroxat to new patients.
Declares that there is deep concern about the side effects that many people believe that they have suffered from being prescribed the drug Seroxat.
Further declares that the Health Select Committee should carry out an investigation into the drug and its possible side effects.
The Petitioners therefore request that the House of Commons urge Her Majesty's Government to place a moratorium on the prescription of Seroxat to new patients until a review has been carried out on the large body of evidence which now exists concerning the side effects of this drug.
To lie upon the Table.
Competing interests: No competing interests