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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Identification of an association between antidepressant drug use and
suicidal thinking and behavior in some adolescents in 2004 (1), and the
regulatory public health warnings that followed (2), sparked a debate in
the clinical community regarding the potential for discouraging
appropriate use of antidepressant drugs, with the unintended consequence
of eventually exposing more patients to the suicide risk associated with
untreated depression (3). Indeed, depression is a major risk factor for
suicide in adolescents and suicide is the third leading cause of death in
this age group (4). These concerns were strengthened by an uptick in the
U.S. rate of adolescent suicide, reported annually by the Centers for
Disease Control and Prevention (CDC), which occurred in 2004 (3).
Significant decreases in the level of antidepressant drugs prescription
for pediatric patients following the regulatory actions were also reported
(2,5). Promotional spending for antidepressant drugs, which may represent
one of many possible factors influencing prescribing, also declined
significantly from the first quarter of 2004 to the first quarter of 2007
(2).
Given the reported decline in antidepressant drug prescription, it is
important to have a second look at the national trends in youth suicide.
Six years later, we present recently released data from CDC to update the
clinical community on the overall trend of rates of suicide among
adolescents. Figure-1 shows that, in spite of the observed continued
decline in use of antidepressant drugs among adolescents in the same time
frame (2,3,5), the rate of suicide decreased in the same age groups after
the unexplained increase of 2004. In 2007, the most recent year with
available data, the rates were the lowest reported in 25 years.
The findings reported in this letter underscore the limitation of
using ecological population-based approaches and especially of relying on
a single year's data to draw strong conclusions and raise what may turn
out to be premature concerns. Caution should always be exercised in
interpreting data based on this type of evidence. Ecological data could
not establish a cause-and-effect association between antidepressant drug
prescribing and suicide rates, nor could such data determine if the
changes in antidepressant prescribing were due to depression not treated
with drugs, or prescribing of fewer antidepressants for other conditions.
While it is important to be vigilant for unintended consequences of
regulatory actions on drug availability and utilization, ecological data
may not be the best guide to whether drugs are being used appropriately in
a given patient population.
References:
1- Hammad TA, Laughren T, Racoosin J. Suicidality in Pediatric
Patients Treated with Antidepressants. Arch Gen Psychiatry 2006; 63:332-9.
2- Pamer C, Hammad TA, Yu Te, Kaplan S, Rochester G, Governale L,
Mosholder AD. Changes in US antidepressant and antipsychotic prescription
patterns during a period of FDA actions. Pharmacoepidemiology and Drug
Safety 2010; 19:158-174.
3- Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK, Erkens JA,
Herings RMC, Mann JJ. Early Evidence on the Effects of Regulators'
Suicidality Warnings on SSRI Prescriptions and Suicide in Children and
Adolescents. Am J Psychiatry 2007; 164:1356-63.
4- Olfson M., Shaffer D, Marcus SC, Greenberg T. Relationship between
antidepressant medication treatment and suicide in adolescents. Arch Gen
Psychiatry 2003; 60: 978-82.
5- Libby AM, Orton HD, Valuck RJ. Persisting Decline in Depression
Treatment After FDA Warnings. Arch Gen Psychiatry 2009;66(6):633-9
Competing interests: No competing interests
Two Points Might be Taken:
(1) I have been, and remain, a critic of the FDA's managament of
antidepressants from the earliest days of Prozac until 2004. Since 2004,
however, I laud the FDA for its catch up work. Dr. Stone's (et al)
article was, in my view, the state of the data and to that end the
commentary was valuable. But its past time, now, that the FDA twisted
industry arms to do prospective suicide testing that the FDA's Dr. Paul
Leber failed to get Eli Lilly to do 20 years ago. Industry's excuse of
"ethical" barriers is getting old--as are the unresolved antidepressant
suicide questions that continue to linger.
(2) Dr. Clayton's point on "completed suicides" as the true barometer
of risk has been the repititive theme of antidepressant advocates since
the bottomn fell out of industry and mainstream psychiatry's 15 year
argument denying the risk. I take the "completed suicide" data as fact--
but its a red herring, for two reasons. In Washington, who could question
the ridicule a tire manufacturer would receive from Congress, the media,
and the public if, in testimony before Congress, the executive
acknowledged his company's tires were involved in the most highway
accidents, but insisted nonetheless his tires were "safe" because most of
the accident victims survived. The "completed suicide" focus in the
antidepressant debate is no less disengenuous. Secondly, and most
critically here, reliance on public Coroner's reports, a common argument
made by antidepressant advocates to exonerate antidepressants in suicide
cases, e.g. "negative" findings, is more than unreliable, it is
misleading. This is not an indictment of medical examiners or
toxicologists, but recogniation that normal testing, at least in the U.S.,
is bureaucratically driven to detect drugs of abuse, and not
antidepressants, especially traces at less than "therapeutic" levels.
Most of my cases where private testing was conducted, and we knew the
decedent had likely taken the antidepressant, results were positive for
the antidepressant at tracings less than the designated "therapeutic"
range.
Competing interests:
I have represented, in over 10 years, approximately 35 plaintiffs in legal actions involving suicide and antidepressants.
Competing interests: No competing interests
In their recent paper (1) Stone and colleagues report on their
previous meta-analysis of 372 double blind placebo randomized controlled
trials (RCTs) of antidepressant medication and suicidality. While the
overall effect of antidepressant medication on the primary endpoint of
suicidal ideation or behavior was protective (OR=0.85, CI=0.71-1.02,
p<0.08), a secondary analysis based on age stratification revealed
protective effects for participants 25 years of age and older (OR=0.74,
CI=0.60-0.90, p<0.003), and in the direction of increased risk for
participants under 25 years of age (OR=1.62, CI=0.97-2.71, p<0.07). On
the basis of this finding, further analysis of suicidal behavior alone,
and their previous meta-analysis of pediatric studies (2) they conclude
that “risk of suicidality associated with use of antidepressants is
strongly age dependent.” As further support of this conclusion they refer
to case-control studies (3,4) which found increased risk of suicidality in
patients aged 18 and younger who were treated with antidepressants, but
note that these studies were subject to confounding based on differential
severity of illness between cases (i.e., patients with suicidality) and
controls. They also note that ecological studies have found inverse
associations between antidepressant treatment and completed suicide, but
are limited by the absence of person-level data.
In discussing the results of their study, Stone and colleagues
overlooked the largest person-level study that has ever been conducted in
this area (5), which examined the association between antidepressant
treatment and suicide attempts in 226,866 U.S. veterans with new episodes
of major depressive disorder. This study found an overall decreased risk
of suicide attempts in patients receiving selective serotonin reuptake
inhibitors (SSRI) monotherapy relative to those patients who did not
receive antidepressant treatment (OR=0.37, CI=0.29-0.47, p<0.0001).
When age stratified, no evidence of a relationship between differential
risk of suicide attempt with treatment and age was observed (ages 18-25
OR=0.35, CI=0.14-0.85, p<0.021; ages 26-45 OR=0.44, CI=0.29-0.65,
p<0.0001; ages 45-65 OR=0.42, CI=0.30-0.59, p<0.0001; ages >65
OR=0.38, CI=0.16-0.91, p<0.036). Similar results were obtained for non
-SSRI and tricyclic antidepressants and also for within-subject
comparisons of suicide attempt rates before and after initiation of
antidepressant treatment. Finally, within-subject comparisons showed
similar decreases in suicide attempt rates with antidepressant treatment,
both in the VA data (5) and in a large-scale medical claims database (6,7)
that is more representative of the general population (i.e., includes
women and children) than the VA population.
These findings raise serious questions regarding the generalizability
of FDA’s findings. As noted in the editorial that accompanied their paper
(8), patients who are actively suicidal are not enrolled in the RCTs
studied by FDA.
A more careful examination of the Stone findings and those from the
veterans study is informative. In terms of rates of suicidal behavior in
treated patients, they are actually quite similar in young adults for the
FDA RCTs 670/100,000 and the VA study 477/100,000. What is different, is
the placebo rate of suicidal behavior observed for young adults by the FDA
(305/100,000) versus the VA study (1368/100,000). Apparently, receiving
placebo in an RCT and receiving no pharmacologic treatment in a real-world
setting are associated with quite different rates of suicidal behavior,
and can have a profound effect on the conclusions of the study (9).
Additional inspection of the FDA study results raises further
questions regarding potential reporting bias. Among young adults
randomized to placebo, the rate of suicidal ideation was 495/100,000
whereas the rate of suicidal behavior was 305/100,000. This is a ratio of
only 1.6 to 1, which seems remarkably low. Suicidal thoughts should be 5
to 10 times higher than suicidal behavior (10). This discrepancy suggests
that either there is bias in reporting suicidality in RCTs that were not
designed to study suicidality or the patient samples are simply not
representative of the general depressed patient population.
Interestingly, in adults aged 25 and over, where protective effects of
treatment were observed, the ratio of suicidal ideation to suicidal
behavior was 3.3 to 1 (i.e., 550/100,000 for ideation versus 167/100,000
for suicidal behavior). This finding suggests that the bias in reporting
and or lack of representativeness may be more profound for young adults.
It is also important to note that FDA’s finding of increased risk of
suicidality with antidepressant treatment was based solely on spontaneous
reports of suicidality both in pediatric, young adult, and adult samples.
In their pediatric analysis, prospective ratings of suicidality were
available, and showed no significant difference between treated and
placebo control subjects. In the young adult and adult studies, the
prospective ratings of suicidality were apparently not even requested.
This disconnect between the prospective ratings and retrospective review
of spontaneous adverse event reports raised considerable debate among the
original scientific advisory board, and at least in part led to several of
the members of the committee voting against the black box warning.
So which study is correct? The strength of the FDA study is that it
is based on randomization, so within each individual study, ignoring
important predictors of suicide will only lead to increased uncertainty in
the treatment effect, but should not lead to biased conclusions. The
weakness of the FDA study is that it is not representative of routine
practice, is restricted to a population that may have little resemblance
to a routine clinical sample where heightened levels of “suicidality” may
exist, and may have excluded other studies that may not have been
published. Note, however, that meta-analysis of multiple RCTs is not
equivalent to a single well controlled RCT with suicidal behavior as a
predefined endpoint. In meta-analysis, study-level differences in patient
populations, indications and types of treatment can lead to biased
conclusions and it is for this reason that meta-analysis should not be
relied upon to derive causal inferences as it is an observational study of
“studies.”. By contrast, the strength of the VA study is its
generalizability, at least to the adult male population with similar
demographic characteristics to men who have served in our nation’s
military. The weakness of the study is that it is observational in nature
and ignoring potential confounders not only leads to increased uncertainty
in the treatment effect estimate, but can also lead to biased conclusions
due to confounding by indication (i.e., severity). We note, however, that
it is reasonable to assume that patients not receiving pharmacologic
treatment would be less severely ill and if anything would have lower
suicide attempt rates than patients treated pharmacologically, if the
treatment did not have a significant benefit. We observed just the
opposite.
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. Hammad T, Laughren T, Racoosin JA. Suicidality in pediatric
patients treated with antidepressant drugs. Arch Gen Psychiatry
2006;63:332-9.
3. Olfson M, Marcus SC, Shaffer D. Antidepressant drug therapy and
suicide in severely depressed children and adults. Arch Gen Psychiatry
2006;63:865-72.
4. Martinez C, Rietbrock S, Wise L, Ashby D, Chick J, Moseley J, et
al. Antidepressant treatment and the risk of fatal and non-fatal self harm
in first episode depression: nested case-control study. BMJ 2005;330:389-
93.
5. Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK, Mann JJ. The
relationship between antidepressants and suicide: results of analysis of
the veterans health administration datasets. American Journal of
Psychiatry 2007; 164:1044–1049.
6. Simon GE, Savarino J, Operskalski B, Wang PS: Suicide risk during
antidepressant treatment. Am J Psychiatry 2006; 163:41–47.
7. Simon GE, Savarino J: Suicide attempts among patients starting
depression treatment with medications or psychotherapy. Am J Psychiatry
2007; 164:1029–1034
8. Geddes, J. R., Barbui, C., Cipriani, A. (2009). Risk of suicidal
behaviour in adults taking antidepressants. BMJ 2009;339: b3066-b3066.
9. Weisberg, HI, Hayden VC, and Pontes VP. Selection criteria and
generalizability within the counterfactual framework: explaining the
paradox of antidepressant-induced suicidality. Clinical Trials 2009; 6:109
-118.
10. Goldsmith SK, Pellmar TC, Kleinman AM, Bunney WE. Reducing
Suicide: A National Imperative. Washington, DC: National Academies Press;
2002:1-516.
Robert D. Gibbons Ph.D.
University of Illinois at Chicago
Sharon-Lise T. Normand Ph.D.
Harvard University
Joel B. Greenhouse Ph.D.
Carnegie Mellon University
Competing interests:
Dr Gibbons reports having served as an expert witness for the US Department of Justice, Wyeth and Pfizer Pharmaceuticals in cases involving antidepressants and suicide. His work in this area is supported by grants R01 MH8012201 from the National Institute of Mental Health and U18HS016973 from the Agency for Healthcare Research and Quality.
Competing interests: No competing interests
We agree with Dr. Tsabar. To acquire some additional assurance that
failure to identify deaths as suicide did not affect the results, we
required sponsors to identify all subjects who died from any cause within
90 days of beginning study treatment. We found no anomalies.
Competing interests:
None declared
Competing interests: No competing interests
Since death was adjudicated only by the sponsors, and since all death
cases are relevant if the main issue is safety, I believe a report of
total mortality risk should be mandatory.
Sincerely,
Nir Tsabar, MD/PhD
Competing interests:
None declared
Competing interests: No competing interests
Dear Sirs
The analysis provided by Dr Stone and colleagues in the BMJ (1) is
welcome but there are inconsistencies between this dataset and others.
Taking the data for sertraline in the Stone et al paper laid out in Table
1, we can see there is a marked difference between this and the data
submitted to the UK regulator 2 years earlier (2). While there is some
scope for differences in suicidal acts based on the coding system
specified by the regulator, it is difficult to account for differences in
completed suicides this way. It can also be noted that the data provided
by Stone and colleagues for suicides and suicidal acts on sertraline
differs markedly from the data for all other drugs listed (1). Had the
data submitted to the UK regulator, which was more in line with the data
for other drugs listed in the Stone article, been used, the conclusions
drawn might have been quite different.
Table 1:
Sertraline-Placebo Controlled Trial Data submitted to FDA 2006
Table 2:
Sertraline-Placebo Controlled Trial Data submitted to MHRA 2004
A further dataset has recently been published by Pfizer (3). This is
laid out in Table 3 and again shows a substantial increase in the risk of
suicide or suicidal acts on sertraline. But of further interest is the
data for the elderly provided in this publication (Table 4), which is at
odds with the data for the elderly in the Stone et al article. In this
most recent dataset the risk for the elderly is in fact greater than for
other age groups.
Table 3:
Sertraline-Placebo Controlled Trial Data 2009
Table 4:
Sertraline-Placebo Controlled Trial Data for Elderly 2009
It would accordingly perhaps be a mistake to think that the Stone et
al article provides the last word on the influence of age on the risks
posed by antidepressants.
David Healy MD FRCPsych
Professor of Psychiatry,
Cardiff University.
1. Stone M, Laughren T, Jones ML, Levenson M, Holland PC, Hughes A,
Hammad TA, Temple R, Rochester G (2009). Risk of suicidality in clinical
trials of antidepressants in adults: analysis of proprietary data
submitted to US Food and Drug Administration. BMJ doi 10,1136/bmj/h2880.
2. Expert Working Group on the Safety of Selective Serotonin Reuptake
Antidepressants 2004. Medical & Healthcare Products Regulatory Agency,
London. Available from:
www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE&dID=1391&noSaveAs=1&Rend....
3. Vanderburg DG, Batzar E, Fogel I, Kremer CME (2009). A pooled
analysis of suicidality in double-blind, placebo-controlled studies of
sertraline in adults. J Clin Psychiatry 70, 674-683.
Competing interests:
DH has been an expert witness in legal cases involving SSRI antidepressants and suicide, commonly on the side of the plaintiff/claimant.
Competing interests: No competing interests
Dr. Levin suggests that the occurrence of suicidal thinking or
behavior in subjects taking antidepressants is due to inadequate treatment
effect. This does not explain why the rate would be higher in the drug-
treated group than in the placebo group where all subjects received
“inadequate” treatment (i.e., no drug treatment at all). It is conceivable
that incomplete treatment of depression may cause some patients to become
actively suicidal. We would note, however, that the strongest relative
increase in suicidal behavior associated with antidepressant use found in
our study was in subjects who had conditions other than depression.
Dr. Levin’s comments about ADHD and depression are interesting. It is
true that a substantial fraction of younger patients with ADHD may, at
some time, have comorbid depression. Exactly how to treat both conditions
simultaneously is a reasonable question, but is beyond the scope of our
paper.
Dr. Levin’s statement that “When doctors accepted the FDA's black box
warning and stopped using antidepressants the teenage suicise [sic]
escalated exponentially!” is not supported by the data. The rise in
suicide rates in adolescents that occurred in 2004 preceded the warning
which was issued at the very end of 2004 and did not appear in most
labeling until 2005. Antidepressant use by children and adolescents in
2004 was essentially unchanged from 2003, and so could not explain the
2004 rise in suicide rates. Use did decline for children and adolescents
in 2005 and later years, perhaps in response to the warning. According to
the Centers for Disease Control and Prevention (National Vital Statistics
Reports, Vol. 57, No. 14, April 17, 2009), there was a decline in suicide
rates in 2005 relative to 2004 in the age 15-24 age group and a further
decline in 2006 to levels equaling the levels seen in 2001 and 2002.
Competing interests:
None declared
Competing interests: No competing interests
Dr. Clayton cites Dr. Geddes’s question as to why the article was
published but overlooks his answer: “Its objective is to make a summary of
these important results more widely available in a way similar to the
publication in the BMJ of summaries of Cochrane reviews.” The original
report was neither concise, subject to external peer review nor available
in standard searches of the medical literature. Our BMJ paper also
presents numerous analyses not contained in the original report: risk
differences in addition to odds ratios as well as presenting odds ratios
for suicidal ideation or behavior, suicidal ideation alone and suicidal
behavior alone treating age as a continuous variable.
In regards to the use of the term “suicidality”, a search using
Google Scholar identifies the term in approximately 53 000 scholarly
articles. In Dr. Clayton’s own book, The Medical Basis of Psychiatry, the
word appears 23 times, with one chapter identifying it as a “Keyword”. As
Dr. Clayton notes, we were quite clear about our definition.
Regarding the connection between suicide attempts and completed
suicide, we clearly acknowledge this as a limitation of the analysis. We
considered the question of whether antidepressants could raise the risk of
completed suicide to be unanswerable with our data; our principal interest
was in the effect of the drugs on suicidal thoughts and behavior,
important concerns in and of themselves. Nevertheless, one has to be
concerned there is some link between suicidal behaviors and completed
suicide. As Dr. Clayton points out, suicide attempts are common in young
people; a small increase in risk would result in a substantial increase in
absolute numbers of suicide attempts. Should we be reassured that “only 5
to 10%” of those who are seen in ERs for a suicide attempt eventually kill
themselves? Furthermore, there is no compelling reason to believe that
suicide attempts occurring as an adverse reaction to antidepressant drugs
should have the same low level of lethality as other attempts. As for her
complaint that we do not state how many of the eight completed suicides in
the study occurred in the antidepressant group, although the numbers are
too small for a meaningful comparison, we do report the odds ratio (2.13)
and the number of subjects in each group. Simple arithmetic would allow an
interested reader to infer that at least six of the completed suicides
occurred in the antidepressant group. Regarding the finding that suicidal
behavior is more common in adolescents than in adults, even though
completed suicides are less common, this is interesting, but not
particularly relevant. We are looking at a signal based on drug-placebo
differences within different age strata.
In reference to her concerns about balance, we would note the
language of the boxed warning: “must balance this risk of suicidality with
the clinical need. Depression and certain other psychiatric disorders are
themselves associated with increases in the risk of suicide.” In addition
to discussing epidemiological data that relate a decline in suicide rates
with increasing use of antidepressants, we also state in the last
paragraph of our paper that “…depression is a serious illness that itself
is a strong predictor of suicide.” We do not question the benefits of
antidepressant treatment but that is a topic outside the scope of our
paper.
Competing interests:
None declared
Competing interests: No competing interests
Dear Sirs
The analysis provided by Dr Stone and colleagues in the BMJ (1) is
welcome but there are inconsistencies between this dataset and others.
Taking the data for sertraline in the Stone et al paper laid out in Table
1, we can see there is a marked difference between this and the data
submitted to the UK regulator 2 years earlier (2). While there is some
scope for differences in suicidal acts based on the coding system
specified by the regulator, it is difficult to account for differences in
completed suicides this way. It can also be noted that the data provided
by Stone and colleagues for suicides and suicidal acts on sertraline
differs markedly from the data for all other drugs listed (1). Had the
data submitted to the UK regulator, which was more in line with the data
for other drugs listed in the Stone article, been used, the conclusions
drawn might have been quite different.
A further dataset has recently been published by Pfizer (3). This is
laid out in Table 3 and again shows a substantial increase in the risk of
suicide or suicidal acts on sertraline. But of further interest is the
data for the elderly provided in this publication (Table 4), which is at
odds with the data for the elderly in the Stone et al article. In this
most recent dataset the risk for the elderly is in fact greater than for
other age groups.
It would accordingly perhaps be a mistake to think that the Stone et
al article provides the last word on the influence of age on the risks
posed by antidepressants.
David Healy MD FRCPsych
Professor of Psychiatry,
Cardiff University.
1. Stone M, Laughren T, Jones ML, Levenson M, Holland PC, Hughes A,
Hammad TA, Temple R, Rochester G (2009). Risk of suicidality in clinical
trials of antidepressants in adults: analysis of proprietary data
submitted to US Food and Drug Administration. BMJ doi 10,1136/bmj/h2880.
2. Expert Working Group on the Safety of Selective Serotonin Reuptake
Antidepressants 2004. Medical & Healthcare Products Regulatory Agency,
London. Available from:
www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE&dID=1391&noSaveAs=1&Rend....
3. Vanderburg DG, Batzar E, Fogel I, Kremer CME (2009). A pooled
analysis of suicidality in double-blind, placebo-controlled studies of
sertraline in adults. J Clin Psychiatry 70, 674-683.
Competing interests:
DH has been an expert witness in legal cases involving SSRI antidepressants and suicide, commonly on the side of the plaintiff/claimant.
Competing interests: No competing interests
Re: Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration
These alarming meta-analysis results, indicating up to 5 times increases in suicidality and violence in duloxetine elder users, should be further investigated regarding other antidepressants sharing similar mechanisms of action. [4]
Large part of the patient population over 60 are current antidepressant users, and if such dramatic increases in suicidality and aggression prove to be drug class effects, then clinicians might consider discontinuing all treatments.
Up to now, systematic reviews and meta-analyses uncovered only doubling of suicidality and aggression risks. [1][2][3]
References
[1] http://www.bmj.com/content/348/bmj.g3510
[2] http://www.bmj.com/content/352/bmj.i65
[3] http://nordic.cochrane.org/sites/nordic.cochrane.org/files/public/upload...
[4] http://www.bmj.com/content/355/bmj.i6103
Competing interests: No competing interests