Psychiatric News January 7, 2005
Volume 40 Number 1
© 2005 American Psychiatric Association
p. 1
New Analysis Disputes Antidepressant, Suicide Link
Jim Rosack
Comorbid mental illness, gender, geographic location, medication
therapy, and psychotherapy are factors associated with increased rates of
suicide attempts in depressed teens.
Antidepressant medications are associated with increased incidence of
suicide attempts among youth because they are more likely to be prescribed to
more severely ill patients—not because of the medications themselves, an
innovative new analysis has determined. The analysis also found that other
factors are associated with an increased risk of suicide.
The study analyzed claims data from a cohort of more than 24,000
adolescents diagnosed with major depressive disorder and tracked patients'
treatment patterns and numerous factors that could influence patients to
attempt suicide.
The analysis found an increased incidence of suicide attempts in
adolescents treated with any antidepressnt medication, not just the serotonin
reuptake inhibitors. However, the association was not statistically
significant, and once the researchers controlled for other potentially
confounding variables, the association disappeared.
"People tend to look at that initial crude association [between
suicide and antidepressant medication] and say, `Well, it's higher for kids on
medication, and therefore the drug made them do it,'" said Robert
Valuck, Pharm.D., R.P.H., director of pharmaceutical outcomes research and an
associate professor of pharmacy at the University of Colorado Health Sciences
Center (UCHSC) in Denver. "But we tried to tease out as much as we
could, controlling for as much as we could, and when we did, that initial
relationship went away. The trend might still have been leaning [toward an
association], but if anything, I think we were stepping on severity-of-illness
markers."
Valuck was first author on the report, which was published in the December
CNS Drugs. The research was investigator initiated and funded.
"We had no outside funding for this, so no one was constraining us in
any way as to how we had to look at the question," Valuck noted.
"This is a very creative and methodologically rigorous
analysis," commented Darrel Regier, M.D., M.P.H., executive director of
the American Psychiatric Institute for Research and Education and director of
APA's Division of Research. "It goes beyond the observation that suicide
attempts appeared to be higher among those on antidepressants by demonstrating
that these same patients happen to have more severe disorders—a major
reason why they were more likely to receive medication."
Pursuing Novel Approach
Valuck and his team already had contracted for access to medical claims
records from the PharMetrics Integrated Outcomes Database, a proprietary
database of paid claims from 74 managed care plans nationwide, representing
some 58 million covered individuals.
"We already had the database put together for some other
depression-related research, and we had an open license to study whatever we
wanted to study," Valuck explained. The team had followed the U.K
government's initial concerns regarding the use of antidepressants and suicide
in teens in 2003 and began looking at a number of studies that used largely
case-control approaches.
"We thought those studies had some limitations," Valuck said.
"Those studies were informative, in their own way, but did not really
get to the real question—which was, Do the drugs themselves increase the
risk of suicide attempt?"
Rather than taking a case-control approach to the question, Valuck's group
decided to use an incidence approach to look for any association between
diagnosis, subsequent treatment patterns, and suicide attempt.
The group knew they would have to adjust for the lack of random assignment
of the patients they were studying and the resulting potential bias. To
address that inherent bias, the team created propensity or likelihood scores
for each of the 24,119 adolescents identified in the database who had an index
ICD-9 or -10 diagnosis of major depressive disorder or a
prescription for antidepressant medication (or both) between January 1997 and
March 2003. The availability of follow-up data ranged from at least six months
to as long as six years, three months. Guidelines from the Centers for Disease
Control and Prevention were used to identify individuals with a claim for a
suicide attempt.
"We determined that, once diagnosed, each individual had a certain
likelihood or not for being treated with an antidepressant. If a person was
prescribed a drug, he or she had a certain likelihood for being prescribed a
specific class of medication—an SSRI, a tricyclic, or multiple
medications," Valuck explained.
"The use of propensity analysis is quite sophisticated and state of
the art for this kind of dataset," noted Peter Jensen, M.D., the Ruane
Professor of Child Psychiatry and director of the Center for the Advancement
of Children's Mental Health at Columbia University and the New York State
Psychiatric Institute.
Antidepressant treatment was coded only if there was a claim for a
prescription filled within 30 days of the index diagnosis. Cases for which no
antidepressant claims were found at any time after diagnosis served as the
control group. Cases with claims for prescriptions filled more than 30 days
after the index diagnosis were excluded.
The researchers also tracked separate measures of duration of medication
therapy and patient compliance with therapy. Compliance was measured using a
medication-possession ratio, equal to the total days of medication supplied
divided by the time elapsed between the initial prescription and subsequent
refills.
Of the 24,119 adolescents identified with an index diagnosis of major
depression, 17,313 (71.8 percent) had no antidepressant prescription filled
within six months of their diagnosis.
"We thought we'd see very much the opposite," Anne Libby,
Ph.D., an assistant professor of psychiatry at UCHSC, noted. "The data
suggest the possibility of undertreatment in this cohort."
Of those on medication, the majority were on SSRIs, followed by multiple
antidepressants, "other "antidepressants, and tricyclics (see
table at top of page).
"It's important to note," Valuck pointed out, "that this
is not ideation, it's not contemplation. And it is not a measure of
completion. These are events coded as suicide attempts." The majority of
these events were coded in emergency rooms.
Strikingly, rates of suicide attempt did not significantly differ between
those on SSRIs, tricyclics, other, or multiple antidepressants. Particularly
interesting, Valuck said, "was the association of suicide attempt with
duration of medication therapy.
"[Suicide risk] was elevated during that initial short period, then
the longer an individual stayed on medication, the lower the risk became, and
it actually became, statistically significantly, a protective effect when you
got out to the guideline-based marker of 180 days."
Even after adjusting the dataset with the individually calculated
propensity scores, several variables increased an adolescent's likelihood to
attempt suicide (see table at left). Most notably, adolescents who had a
comorbid diagnosis of schizophrenia had a 3.5 higher risk of attempting
suicide; having any other psychiatric disorder, including substance abuse,
doubled the risk.
Taking an SSRI increased the risk of attempting suicide by 59 percent, and
taking multiple antidepressant medications raised the risk 43 percent;
however, neither was statistically significant. Intriguingly, the presence of
a claim for at least one psychotherapy session raised the risk by a
statistically significant 36 percent.
Echoing earlier studies, the study found that, compared with adolescents
living in the Eastern United States, adolescents living in the West were 2.7
times more likely to attempt suicide, while those in the Midwest were just
over two times more likely.
Added Libby, "Simply put, those who were more severely ill were the
ones who were most likely to attempt suicide. And they were the ones who were
more likely to be on medication—or psychotherapy for that
matter."
Thus, Valuck summed up, if people believe that the medications themselves
cause suicide, then logic dictates that "we should be out there
advocating for pulling the licenses of all those therapists."
Finding the Bottom Line
"We know that this is a very complicated issue, and there's lots of
emotion along with political and financial influences," said Libby.
"We wanted to go after a question like this because policy is being
driven by it—but policy should never be based on one study or one point
of view. We simply sought to contribute to the debate and provide whatever
evidence we could to help narrow the focus."
Valuck and his team have submitted grant applications to look at the data
in more detail. "It would be very interesting to look at to what extent
provider type mattered, or what insurance plan type, copayment type, and so on
mattered," he said, "and how each of those affect a youth's
ability to initiate treatment and then stay in treatment."
The team has also submitted research proposals to track the effects of the
black-box warnings and whether and how the warnings are changing treatment
patterns and outcomes in adolescent depression.
"It's a critical issue," said Valuck. If the drugs' use in
youth is restricted unnecessarily, "we could end up inducing problems
over the long run."
APA's Regier concluded, "This type of analysis is much more
compelling than the FDA's analysis of self-reported suicidal ideation or
attempts, which ignored the more systematic assessment data that showed a
reduction of symptoms with treatment. Media reports of the FDA hearings have
left the public with the impression that antidepressants cause suicidal
symptoms and missed the big picture that depression causes these symptoms, as
well as the finding, as supported by this study, that these medications need
to be part of a careful treatment and monitoring plan that will reduce the
overall risk of suicide."
An abstract of "Antidepressant Treatment and Risk of Suicide
Attempt by Adolescents With Major Depressive Disorder: A Propensity Adjusted
Retrospective Cohort Study," is posted online at
<www.ingentaconnect.com/content/adis/cns/2004/00000018/00000015/art00006>.
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