Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration
BMJ 2009; 339 doi: https://doi.org/10.1136/bmj.b2880 (Published 11 August 2009) Cite this as: BMJ 2009;339:b2880
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If you mean "Risk of Suicide", please say so..... Leave Gerundised
Nouns where they belong - in the Trash (Rubbish) Can (Bin). Have a Nice
Day (Thank you). Good Job, man! (Well Done!).
I feel like Suicidalising myself, know what I mean?
Competing interests:
None declared
Competing interests: No competing interests
The controversial thrust of this article (1) is that the young are
more prone to suicide ideation than the old as a result of anti-
depressant prescription. Any statistical approach, however sophisticated
it may seem, is fundamentally handicapped; it can point (always
tentatively, given the lurking confounders) to a connection, but not to
the actual medical cause. At the level of neuron and axon and
neurotransmitter, why are anti-depressants able to disturb, not soothe,
mood?
Table 2 has an odds ratio for the under 25s that just misses
Fisherian significance at 0.07, but the risk difference is just within the
Fisherian threshold at 0.03. The statistical point is that the 5%
significance level is only a guideline, and to stick to it strictly
without medical interpretation is a blind way of proceeding. David Healey
observed how there have been signals linking antidepressant to
suicidality, even if the signals did not have precise statistical
significance(2).
The forest plot here (fig.2) is unusual in that it is not back
transformed logarithmically, so that the odds ratio confidence intervals
are skewed, not symmetrical. In my always inadequate view, there is an
element of bad practice in not having a consistent x- axis (perhaps a log
one of 0.1 to 10) for all forest plots in evidence based medicine.
Different sorts of x- axis produce visual confusion when we try with
difficulty to compare effect sizes across forest plots.
Being young and taking anti- depressants can be dangerous. But why?
The statisticians must now pass the baton on to the doctors and medical
researchers- who have so far failed to find the cause in the brain for
this
age- related anomaly. As an older person, who is considerably grey and
wrinkled, I am puzzled. Surely anti- depressants should be just as
dangerous for us elderly ones?
REFERENCES:
(1) Risk of suicidality in clinical trials of antidepressants in
adults: analysis of proprietary data submitted to US Food and Drug
Administration. Marc Stone et al. BMJ 2009;339:b2880.
(2) The antidepressant tale: figures signifying nothing? David Healy.
Advances in Psychiatric Treatment (2006), vol. 12,320-328.
Competing interests:
None declared
Competing interests: No competing interests
It is well known that many depressed patient on antidepressants claim
they are better but very few claim they are fine.Very few doctors monitor
the doses with a rating scale(Hamilton). If they did it would be obvious
how few are on optimal treatment. These patients on an antidepressant who
are not responding still have their depression fostering suicide
concepts.It is not the antidepressant to be blamed.
Many teenageers and young adults with non diagnosed ADHD become
depressed. The condition has a built in "suicider!" Hasty impulsive
emotional doing or saying without thinking.THey would perhaps have their
depression recognised but not the cause of their depression which is ADHD.
They would not respond to antidepressants alone. Giving them
antidepressants and stimulants at the same time ,but in optimal doses,
would give sometimes a dramatic positive responce! Optimal treatment of
both conditions is essential to reduce the suicise tendency. Do not blame
the innocent antidepressants which reduce suicide.
When doctors accepted the FDA's black box warning and stopped using
antidepressants the teenage suicise escalated exponentially!
Competing interests:
None declared
Competing interests: No competing interests
Dear Sir,
It was surprising to see the recent article by Stone et al (1) in the
August issue of the British Medical Journal. As the editorial by Geddes
(2) so nicely questions, why, since the data have not been updated since
the initial publication more than two years ago and the present report
only selectively reports the fuller analysis, was it published in the BMJ
now?
I am concerned that the report and discussion of the selective data
in this publication are misleading. While the authors do define the word
suicidality as “suicidal thoughts and actions,” it is not a word that, to
my knowledge, is defined in the dictionary. Furthermore, the manuscript
fails to define for the reader the distinction between completed suicide
and suicidal thoughts and attempts. Even when those who are seen in the
emergency room for a suicide attempt are followed for the next 20 years,
only five to ten percent of them actually die by suicide (3). Contrary to
what this article implies, suicide attempts are not synonymous with
completed suicide.
In support of the authors, they do state on page 7 of 10 that, “this
study can do little to resolve whether antidepressants affect the risk of
death by suicide, even in a population of tens of thousands, there was
only a handful of cases.” A major problem with this report is that there
were eight completed suicides in the whole study of about 100,000, but the
authors never tell us how the number is divided between the drug- and
placebo-treated groups. It is fair to conclude that in their meta-analysis
of 372 double-blind randomized short term placebo-controlled trials of
antidepressants, the FDA showed no evidence of an increase in suicide in
any age group.
Their analysis shows a slight, but significant, increase in suicidal
behavior or ideation among adolescents and young adults treated with
antidepressants compared to those treated with a placebo. The reader
should be told, however, that such attempts are especially common among
this age group. For example, according to the 2006 Centers for Disease
Control (CDC) data, self-harm reports for those 15 to 19 years old are
323/100000, while the suicide rate in this age group is 7.3/100000. This
is in contrast to adults 25 and older, for whom the self-harm rates are
148/100000 and the suicide rate is 14.75. In other words, suicide attempts
are more common among teens, but teens’ completed suicide rate is half
that of adults’ –again, the relationship between the two is unclear.
It is certainly important for clinicians and caretakers to be aware
of this safety issue when antidepressants are prescribed. And it is
essential for both groups to closely monitor such treatment in young
people, especially at the beginning of treatment. It is also a good idea
to implement other safety planning measures. However, it is equally as
important that clinicians and caretakers not be frightened of the use of
such medications when they are appropriately indicated. Depression is
clearly an illness for which appropriate treatment with antidepressants is
not only effective in resolving the condition, but may in fact be
lifesaving. It is most important, however, that these data be reported in
an informative, clear and balanced way in published research articles.
I notice that the Editorial by Geddes, Barbui and Cipriani was
commissioned by the BMJ. It may be worthy of the BMJ to consider
commissioning a paper by the noted statistician Joel Greenhouse of the
University of Pittsburgh, who has recently examined the meta-analysis of
treatment data underlying the black box labeling of antidepressants. Such
a paper would be a service to all.
Thank you for considering the concerns I express to you in this
letter.
Sincerely,
Paula J Clayton MD
Medical Director, American Foundation for Suicide Prevention
New York, New York
References
1. Stone MB, Laughren T, Jones ML, Levenson M, Holland PC, Hughes A,
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.
2. Geddes JR, Barbui C, Cipriani A. Editorial : Risk of suicidal
behaviour in adults taking antidepressants. BMJ 2009;339:b3066.
3. Jenkins et al. Suicide rate 22 years after parasuicide: cohort
study. BMJ 2002;325(7373):1155.
Competing interests:
None declared
Competing interests: No competing interests
Beware of pharmaceutical company bias.
The meta-analysis by Stone et al further confirms the fact that
antidepressant drugs are associated with increased suicidality in young
persons(1).The concerns have been raised since 1990 but drug companies
managed to keep the issue under the carpet until 2003 by selectively
publishing the only positive data. Even when they did publish the data
they tried to spin the conclusions in their favour (2, 3).Paroxetine
(Seroxat), manufactured by GlaxoSmithKline dominated the headlines in
2003/04 as they did not reveal the data showing increased suicidal risks
in children. In 2008 Turner et al compared the published trials of 12
antidepressant drugs submitted to FDA. They found that on one hand
majority of the positive studies were published whilst on the other hand
majority of the negative trials were not published. The above discrepancy
led to overestimation of the effect size (4). This paper once again
emphasised the importance of availability of all trials data irrespective
of the outcomes. The negative, failed or unpublished trials are also as
important as published, positive trials .Lastly; we should not take
trials, done by pharmaceutical companies, at their face value.
1. Stone MB, Laughren T, Jones ML, Levenson M, and Holland PC, Hughes
A, 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.
2. Teicher MH, Glod C, Cole JO.Selective Publication of
Antidepressant Trials and Its Influence on Apparent Efficacy. Am J
Psychiatry. 1990 Feb;147(2):207-10
3. Healy D. The antidepressant tale: figures signifying nothing?
Advances in Psychiatric Treatment (2006) 12: 320-327
4.Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R.
Selective publication of antidepressant trials and its influence on
apparent efficacy N Engl J Med. 2008 Jan 17;358(3):252-6
Competing interests:
None declared
Competing interests: No competing interests