|Genes Linked to Suicidal Thinking During Antidepressant
Specific variations in two genes are linked to suicidal thinking
that sometimes occurs in people taking the most commonly prescribed
class of antidepressants, according to a large study led by scientists
at the National Institutes of Health's (NIH) National Institute
of Mental Health (NIMH). Depending on the particular mix inherited,
these versions increased the likelihood of such thoughts from 2-
to15-fold, the study found. About 1 percent of adult patients were
deemed to be at high genetic risk, 41 percent at elevated risk
and 58 percent at lower risk.
If confirmed, the findings may hold promise for genetic testing,
as more such markers are identified.
Risk increased proportionately if a participant had two, as opposed
to just one of the suspect versions. Both genes code for components
of the brain's glutamate chemical messenger system (http://www.nimh.nih.gov/press/ketamine_2.cfm),
which recent studies suggest is involved in the antidepressant
Overall, about 6 percent of 1,915 patients with depression (http://www.nimh.nih.gov/healthinformation/depressionmenu.cfm)
reported that they started to have suicidal thoughts while taking
an antidepressant. This rate soared to 36 percent among the few
patients with both of the suspect gene versions; 59 percent of
the patients who had suicidal thoughts had at least one of the
Francis J. McMahon, M.D., Gonzalo Laje, M.D., NIMH Mood and Anxiety
Disorders Program, and colleagues at the National Human Genome
Research Institute (NHGRI), Mount Sinai School of Medicine, and
the University of Texas Southwestern Medical Center, report on
their findings in the October, 2007 issue of The American Journal
"These data suggest that genetics may soon help us in our quest
to individualize treatments for depression," said NIMH Director
Thomas R. Insel, M.D.
"In the future, we hope that genetic testing will help doctors
identify those few patients who are at high risk for suicidal thinking
during antidepressant therapy and need close monitoring or alternative
treatments," said McMahon. "This should help allay concerns for
the vast majority of patients. The best way to prevent suicide
is to treat depression."
In the most comprehensive study of its kind to date, McMahon and
colleagues screened genetic material from 1,915 adult participants
with major depression in level one of the NIMH-funded STAR*D (http://www.nimh.nih.gov/press/stard.cfm)
(Sequenced Treatment Alternatives for Depression) trial. Study
participants were treated with the selective serotonin reuptake
inhibitor (SSRI) citalopram. The researchers looked for associations
between self-reports of suicidal thinking and more than 700 sites
in 68 suspect genes where letters in the genetic code vary across
individuals, creating different versions of the same gene.
The researchers found that certain versions of two genes that
code for glutamate receptors — the receiving stations for the neurotransmitter's
chemical messages — were more prevalent in patients with suicidal
thinking. How the newly identified versions affect the workings
of glutamate receptors to confer increased risk remains to be discovered.
It's also not yet known whether the findings generalize to other
One percent of the study participants had a version of the kainate
receptor gene, GRIK2, that increased the odds for suicidal thinking
more than 8-fold. Forty-one percent of participants had a version
of the AMPA receptor gene, GRIA3, that raised the odds nearly 2-fold.
About one-half of 1 percent of participants had both high risk
gene versions, boosting the odds 15 fold — but this was the case
for only 11 participants, of whom four developed suicidal thinking.
Neither version was related to self-reported history of suicide
attempts. This suggests that the versions are specific to suicidal
thoughts that occur during antidepressant treatment, rather than
the much more common suicidal thoughts and behavior that occur
outside of the treatment setting.
More than 40 percent of those who developed suicidal thoughts
lacked either of the two versions, indicating that other genes
and environmental factors were also likely involved. But the potential
value of predictive testing is increasing as more genes are analyzed.
McMahon's group will report at a genetics conference in October
on identification of additional versions that emerged from a scan
of the whole genome in STAR*D patients. In July, NIMH funded researchers
at Massachusetts General Hospital reported an association (http://www.nimh.nih.gov/press/perlis_stard_genes.cfm)
between variations in the CREB1 gene and treatment-emergent suicidal
thinking among men in the STAR*D sample.
Earlier studies had shown that about 4 percent of youth treated
with antidepressants experience suicidal thinking compared with
about 2 percent of those taking placebos.
The resultant climate of concern culminated in the 2004 Food and
Drug Administration decision requiring that antidepressants carry
a black box warning about risk of suicidal thinking for children
and adolescents – and later proposing that it be extended to young
adults up to age 24. In 2004, the Centers for Disease Control recorded
the largest spike in youth suicide rates (http://www.cdc.gov/print.do?url=http%3A//www.cdc.gov/od/oc/media/pressrel/2007/r070906.htm)
in 15 years. NIMH-funded researchers recently suggested that this
may have been related to a drop in antidepressant prescriptions
for youth (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17728420&ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum).
By contrast, they note that suicide rates reached a record low
in 2004 for adults over 60, for whom antidepressant prescription
rates continued to rise; this inverse relationship held with increasing
age. A more definitive analysis must await release of 2005 U.S.
suicide rate data later this year, researchers say.
However, evidence suggests that neither suicidal thoughts, nor
the high-risk gene versions, are necessarily related to actual
suicide attempts, according to McMahon. Other studies have shown
that the rate of such attempts is higher before antidepressant
treatment begins — and suicide attempts are not always preceded
by suicidal thoughts. For example, in the current study, one of
the two participants who actually attempted suicide carried high-risk
versions, but denied experiencing suicidal thoughts.
Even if suicidal thinking does not predict suicidal behavior,
it is associated with a poorer response to antidepressant medication,
the researchers say. Only 25 percent of patients with suicidal
thinking fully recovered from their depression during the initial
phase of the STAR*D trail, compared with 42 percent of patients
not affected by such thoughts.
McMahon and colleagues hope that the newly identified versions
may prove useful in identifying patients who need closer monitoring,
alternative treatments and/or specialty care — while reassuring
those for whom antidepressants are appropriate.
Also participating in the research were: Drs. Silvia Paddock and
Husseini Manji, NIMH; Dr. A. John Rush, University of Texas Southwestern
Medical Center; Dr. Alexander Wilson, NHGRI; Dr. Dennis Charney,
Mount Sinai School of Medicine.
||People typically inherit two copies
of genes, one from each parent, so some people have two
different versions while others have two of the same version.
Only one percent of the study participants were judged
to be at high risk for developing suicidal thoughts while
taking citalopram – due to having two copies of the high
risk version of the GRIK2 gene, with or without any copies
of the GRIA3 gene version. About 41 percent of study participants
were considered at elevated risk since they had one or
two copies of the GRIA3 version, but no copies of the GRIK2
version. Most (58 percent) participants were considered
at lower genetic risk for treatment-emergent suicidal thinking,
since they carried neither high risk gene version.
Source: NIMH Mood and Anxiety Disorders Program
The National Institute of Mental Health (NIMH) mission is to reduce
the burden of mental and behavioral disorders through research
on mind, brain, and behavior. More information is available at
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advance human health through genomic research. NHGRI's Division
of Intramural Research develops and implements technology to understand,
diagnose and treat genomic and genetic diseases. Additional information
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the National Institutes of Health, is the primary U.S. agency for
conducting and supporting research on the causes, consequences,
prevention, and treatment of alcohol abuse, alcoholism, and alcohol
problems and disseminates research findings to general, professional,
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Reference: Laje G, Paddock S, Manji H, Rush AJ,
Wilson AF, Charney D, McMahon FJ. Genetic Markers of Suicidal Ideation
Emerging During Citalopram Treatment of Major Depression. Am
J Psychiatry. 2007 Oct;164(10):. PMID: