Physicians prescribing selective serotonin-reuptake inhibitors (SSRIs)
should make patients aware of the possibility of gastrointestinal bleeding,
especially if they have pre-existing risk factors or are taking other drugs
that increase risk, said a University of Pennsylvania psychiatrist.
"The research shows that this is not a frequent event, but it is an
event," said robert Weinrieb, M.D., an associate professor of psychiatry
at the University of Pennsylvania School of Medicine and Philadelphia Veterans
affairs Medical Center and director of medical and consultative psychiatry at
the Hospital of the University of Pennsylvania in Philadelphia. The risk to
patients is about the same as that for ibuprofen, he said in an interview.
Weinrieb is a substance abuse specialist and backed into his interest in
the relation between SSRIs and bleeding.
"People had been using SSRIs to prevent psychiatric side effects when
interferon was used to treat patients with hepatitis C," he said. These
side effects included depression, irritability, and insomnia.
He wondered if these drugs would also work with patients on methadone, many
of whom were infected with hepatitis C. However, conventional wisdom among
doctors said that using interferon in methadone-using patients would cause
them to relapse or send them into depression or psychosis, although there were
no prospective placebo-controlled trials on the subject. He set up a pilot
experiment at the Philadelphia Veterans affairs hospital to see if the SSRI
paroxetine would prevent psychiatric side effects from developing in patients
After data gathering was completed in that study, a patient died of
gastrointestinal bleeding. The patient had several risk factors for bleeding,
but Weinrieb nevertheless did a full MEDLINE search dating back to 1966,
looking for any association of SSRIs and gastrointestinal bleeding.
In a paper published last year, Weinrieb and three colleagues found seven
retrospective analytic studies supporting an association between SSRI use and
upper gastrointestinal and perioperative bleeding. Other literature reviews
have come to the same conclusion.
U.S. Food and Drug Administration labeling requirements for some SSRIs say
that "concurrent use of an NSAID or aspirin potentiated the risk of
Combining aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) with
SSRIs appeared to increase the risk, as did concurrent use of warfarin or
low-molecular-weight heparin. The researchers estimated that SSRI use
increases risk of bleeding by 3.6 times, compared with the risk in the general
population for those who don't use SSRIs, but that there is a 12-fold risk
increase when NSAIDs and SSRIs are combined. He noted that these estimates
were drawn from retrospective studies and thus reflect some uncertainty.
"We don't know if SSRIs cause mucosal injury but they can cause
bleeding from existing lesions in the stomach," said study co-author
James Lewis, M.D., an assistant professor of medicine in the Department of
Gastroenterology at the University of Pennsylvania. SSRIs have a broad
anti-platelet effect, he said, but SSRI-related bleeding occurs mainly in the
gastrointestinal system. There's no indication that SSRIs increase risk of
bleeding strokes in the brain, for instance.
Cardiologists have hypothesized that the antiplatelet effects of SSRIs
might actually benefit patients with occlusive heart disease, even if its use
were offset by bleeding risks. At least one manufacturer also noted the
effect. The makers of one SSRI once applied to market its drug to treat
coronary artery disease because of its platelet-inhibition ability, said
Weinrieb, although the application was turned down.
Physicians prescribing SSRIs should be aware of their potential to cause
bleeding, but should not exaggerate the risk, Lewis told Psychiatric
"The relative risk is similar to that of NSAIDs, but remember that
NSAIDs are sold over the counter," said Lewis. "It's important to
balance potential benefits and harms. Usually, if there is a legitimate
indication for treatment with an SSRI, the benefits outweigh the
Physicians prescribing SSRIs should be aware of any added risk factors for
gastrointestinal bleeding, such as stomach ulcers or a history of bleeding.
They should counsel patients about the risk and tell them to call their doctor
if they have any of the signs or symptoms of bleeding, said Weinrieb. The
effects of SSRIs on bleeding are not predicted by standard blood tests but are
revealed by a platelet-aggregation test, he noted.
It is not necessary to stop the SSRIs when elevated bleeding risk is
present, said Lewis. Alternative steps are available. Patients taking aspirin
or NSAIDs for noncardiac reasons could be directed to acetaminophen to relieve
pain. Aspirin users with a history of ulcer bleeding have done well in
randomized clinical trials with a combination of aspirin and a proton pump
inhibitor to suppress stomach-acid production, said Lewis.
Weinrieb suggested that physicians caution patients who have two or more
risk factors and consider switching them to dopaminergic antidepressants (such
as bupropion) or drugs with less serotonin reuptake inhibition (such as
mirtazapine), if needed.
"Selective Serotonin Re-Uptake Inhibitors and the Risk of
Bleeding" is posted at<www.expertopin.com/doi/abs/10.1517/14740318.104.22.1687>.▪