One of the most debated drug-safety controversies in recent years is
whether antidepressant drugs cause some people to have suicidal ideation.
After analyzing DNA samples from almost 2,000 patients who received
citalopram, researchers found two genetic markers with strong links to
suicidal ideation in patients who developed it only after they started taking
the drug. This finding may be a "smoking gun" that at least
contributes to this uncommon but disturbing potential side effect of
Researchers at the Genetic Basis of Mood and Anxiety Disorders Unit of the
Mood and Anxiety Program at the National Institute of Mental Health (NIMH)
tested the blood samples of 1,915 participants of the Sequenced Treatment
Alternatives to Relieve Depression (STAR*D) clinical trial to look
for any genetic difference between 1,742 participants who did not have any
treatment-emergent suicidal ideation and 120 participants who did. In the
study, treatment-emergent suicidal ideation was defined as any thoughts about
suicide that were absent at baseline (before taking citalopram) but were
reported within the 12 weeks of the treatment period. Two genetic markers were
significantly more common in those who had treatment-emergent suicidal
ideation. The study was funded by the National Institutes of Health and the
Swedish Research Council.
The two markers were identified through a massive screening of 768 single
nucleotide polymorphisms (SNPs) that were selected from a library of common
variations in 68 genes. SNPs are point mutations involving just one"
misspelled letter" in a strand of DNA sequence. These 68 genes
were chosen because they code for proteins that are known to be involved in
certain neurotransmission pathways and suspected to be affected, directly or
indirectly, by antidepressants.
Both of the genetic markers identified as being linked to
treatment-emergent suicidal ideation are related to the glutamate signaling
system and located in genes that code for ionotropic glutamate receptors,
which control the flow of ions in and out of neurons. This supports recent
research implicating the glutamate pathways in certain antidepressants'
mechanism of action. Those who carry both genetic markers seemed to be at even
higher risk of suicidal ideation, compared with patients who carry one of the
markers, and the effect appeared to be at least additive.
"We were a little surprised by the magnitude of association between
the genetic markers and the suicidal ideation," Gonzalo Laje, M.D., a
psychiatrist and a clinical research fellow at the Genetic Basis of Mood and
Anxiety Disorders program at NIMH and the lead author of the study, told
Psychiatric News. "The two markers seem highly specific, which
is rare in genetic testing in psychiatry. The study shows that we are on the
right path to understanding this phenomenon."
He cautioned, however, that these results need to be independently
replicated by other studies involving other patient populations and other
The British regulatory agency and the U.S. have required strong warnings in
the prescribing information of all antidepressants, which may have influenced
adequate depression care for a large number of patients. The rise in suicide
rates, which coincides with the warnings and the drop in antidepressant
prescribing, has caused much concern among psychiatrists (Psychiatric
News, October 5).
The STAR*D clinical trial is the largest on the treatment of
depression to date, according to NIMH, and lasted for seven years. The study
enrolled adult outpatients from clinical sites around the country. The large
number of participants who consented to genetic testing provides a rare
opportunity for researchers to systematically and prospectively study
treatment-emergent suicidal ideation, which occurs only in a small percentage
of the population who take antidepressants. All patients received stepwise
treatment for depression, starting with citalopram 20 mg/day, and adjusted
according to pre-established algorithm. All participants took citalopram for
at least 12 weeks.
In addition to the genetic markers, the authors also presented some curious
clinical observations. Compared with those who had no treatment-emergent
suicidal ideation, participants who developed suicidal ideation tended to
require a higher maximum citalopram dose and were significantly less likely to
go into remission. Over 90 percent of these patients reported suicidal
ideation within the first month of starting the treatment. Only one
participant in the DNA study population actually attempted suicide, as
reported by the authors of this study (two persons did so in the entire
STAR*D study), according to the authors. The patient consistently
denied suicidal ideation but did carry both of the genetic markers. "The
markers.. .do not appear to be related to a general tendency toward suicide
but rather to suicidal thoughts specifically emerging during antidepressant
treatment," the authors wrote. "This [phenomenon] is consistent
with [case] reports to regulatory agencies, in which the patients with
antidepressant-emergent suicidal ideation did not actually attempt
suicide," said Laje. "None of the participants who reported
treatment-emergent suicidal ideation had a history of suicidal
A separate genetic study on the same group of STAR*D
participants was published in the June Archives of General
Psychiatry. Roy Perlis, M.D., and colleagues identified two SNPs that
were associated with treatment-emergent suicidal ideation in men. In that
study, the researchers focused their search on known SNPs in one particular
gene, CREB1, which codes for cyclic adenosine monophosphate response element
binding (CREB) protein, and the DNA sequence near this gene (where the two
identified SNPs reside). The sex-specific nature of this association is yet to
As more meaningful genetic markers are discovered, a clearer picture begins
to emerge explaining why some people have unusual responses to certain drugs.
Pharmacogenetics has already explained a range of adverse drug reactions that
are specific to only a segment of the population. For example, genetic
variations are responsible for population differences in the liver enzyme
system, cytochrome P450, which metabolizes most drugs. This is why codeine is
metabolized much faster in some people (known as "ultrarapid
metabolizers") than others; these ultrarapid metabolizers in turn have a
sharper rise in morphine blood concentration and experience exaggerated side
effects. A similar mechanism may apply to the emergence of suicidal ideation
with antidepressants in a minority of patients.
"The long-term goal of psychiatrists is to adequately treat patients
with depression," Laje emphasized. "The best way to prevent
suicide is to treat the disease."
The genetic markers discovered in this study have been licensed to
Neuromark, a private company that plans to market the genetic test.
AJP editors learned of the arrangement after the study was printed
and will publish an addendum in an upcoming issue to disclose the additional
"Genetic Markers of Suicidal Ideation Emerging During
Citalopram Treatment of Major Depression" is posted at<http://ajp.psychiatryonline.org/cgi/content/full/164/10/1530>.▪