It just might be one of the most complicated issues psychiatric researchers
have faced, and one that affects clinical-practice decisions almost every day.
Yet despite a voluminous—and ever expanding—body of research, no
consensus appears to be in sight.
A recent epidemiological/observational study has concluded that counties
across the United States with higher prescribing rates of antidepressant
medications have significantly lower rates of youth suicide, compared with
counties with lower prescribing rates (see story at right).
Even so, in an editorial accompanying that report in the November
American Journal of Psychiatry, Greg Simon, M.D., M.P.H., director of
the Center for Health Studies at the Group Health cooperative in Seattle,
asks, "How can we know whether antidepressants increase suicide
Simon told Psychiatric News, "I'm one of the people who does
these studies for a living, so I can sit back and say that, yes, this is a
really interesting and complicated problem. But that's not very helpful to my
Since the mid-1980s, when the first hints of a link between antidepressant
medications and self-harming or suicidal thoughts and acts appeared,
researchers have been struggling to design a study that could effectively
address the concern.
Now, 20 years later and with a large body of conflicting and inconclusive
reports, investigators across the globe continue to pursue what some see as
the Holy Grail of psychiatric research.
"I think it is very likely that we will eventually discover that
there are important differences between [antidepressant] medications and
vitally important differences between individual patients who take
them," Simon said.
However, at the heart of the debate is the fundamental question of how to
identify those differences in individual medications and how to predict higher
risk in particular subsets of patients. Because suicide is such a rare event,
a double-blind, placebo-controlled, randomized trial looking at one specific
antidepressant and the risk of suicide, compared with placebo, "would
need to include several hundred thousand patients. Such a trial will never
occur," Simon said in his editorial. Observational or epidemiological
studies can include very large populations, but they are subject to any number
of confounding factors that could bias outcomes, he added.
Thomas Laughren, M.D., director of the Division of Psychiatry Products at
the U.S. Food and Drug Administration (FDA), agreed: "I think most in
the psychiatric community would now agree that there is at least some subset
of people who appear to be susceptible to an increased risk of suicidality
when taking these medications. Observational studies might be able to look
deeper to figure out what particular factors might make an individual more
susceptible," Laughren told Psychiatric News. "But we
need to look much deeper at individual details and design and implement much
better observational methods to identify those individual patient traits
linked to higher risk."
The FDA continues to analyze patient-level data from more than 50 clinical
trials of antidepressants in adults—using the same analytic methods as
the agency used for its pediatric analysis of suicidality and antidepressant
medications. Laughren declined to speculate as to when that analysis might be
completed. However, also paralleling the pediatric analysis, the FDA"
will almost certainly hold an advisory committee meeting to discuss the
"At this point," Simon told Psychiatric News,"
it is difficult to even make a solid statement that `on average, this
whole group of drugs either increases or decreases risk of suicide.' But
obviously, when you are sitting with an individual patient, the pertinent
question isn't about averages; it's about one particular medication for one
"My own view," he continued, "is that if there is going
to be a clear explanation for this phenomenon—in terms of why some
patients have wonderful results with antidepressants, while others have a
terrible reaction—it's going to be in the patients' DNA. That's got to
be where the explanation lies."
In Simon's editorial, he concluded with a suggested conversation clinicians
should have with patients for whom they are prescribing antidepressant
medications. The conversation addresses the conflicting and complex evidence
base and is straightforward and critical, Simon noted, to protect the patient
as well as the clinician.
"Even if antidepressants help most people who take them, some people
may have very negative reactions," Simon tells his patients when he
prescribes an antidepressant. "Thus, it is important that we have
regular contact over the next few weeks."
"From a clinical perspective," said 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, "the summary
provided by Dr. Simon at the end of the editorial provides the type of
practical guidance needed for physicians managing the treatment of young
patients with depression."
In the meantime, clinicians are left waiting for the FDA's adult
suicidality analysis while researchers pursue new avenues in an attempt to
give clinicians and their patients more precise information.
"How Can We Know Whether Antidepressants Increase Suicide
Risk?" is posted at<www.ajp.psychiatryonline.org/cgi/content/full/163/11/1861>.▪