Commentary: Can painkillers cap antidepressant effect?

Published: August, 2011

About one-third of people with depression are unable to find relief with antidepressants, even after trying several drugs. An intriguing study suggests that one reason for a disappointing response may be any of several over-the-counter drugs we use to erase a headache or knock down a fever.

Certain pain relievers — mainly nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Motrin), but also acetaminophen (Tylenol) — may reduce the benefits of selective serotonin reuptake inhibitors (SSRIs), the most commonly prescribed antidepressants.

Researchers at Rockefeller University initially conducted a series of experiments on mice genetically engineered to develop behaviors (such as helplessness) that mimic some of the symptoms of depression in people. In particular, they were looking at the activity of a protein known as p11. This protein interacts with a serotonin receptor that is decreased in animals bred to mimic human depression. And those researchers found some curious interactions between p11 activity and antidepressant response.

The study looked at the effect of two SSRIs, citalopram (Celexa) and fluoxetine (Prozac) — which the researchers gave either alone or in combination with a painkiller — on p11 levels. When SSRIs and other antidepressants were given without a painkiller, p11 activity increased in the mice. This is an indicator that the drugs were causing desirable changes in the brain. But when the mice received both an SSRI and a pain drug, p11 levels were reduced. The researchers tested two common NSAIDs — aspirin and ibuprofen — in addition to acetaminophen. All three of these medicines reduced the antidepressant action of SSRIs.

To see whether these common forms of pain relief might interfere with SSRIs in people, the Rockefeller researchers made use of data collected during the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. This federally funded investigation looked at how depression treatment is provided in the "real world." The study yielded information about how many drug trials it takes for patients, on average, to achieve significant relief from their symptoms.

The Rockefeller team added a new wrinkle, asking whether taking a pain reliever would affect a patient's chances of achieving symptom relief. They discovered that STAR*D participants who were taking pain relievers in combination with SSRIs were less likely to achieve remission during the study. For example, only 45% of STAR*D participants who took citalopram along with a pain medication achieved remission, compared with 55% who reported taking no pain medications.

This was a surprising result, because it is not a drug interaction that is at all known among clinicians. But key questions do remain. The STAR*D study did not ask participants what doses of pain reliever they used, or how long they took it. It's also possible that people who need to take both pain relievers and antidepressants at the same time constitute a unique subset of individuals who have a more severe form of depression. That is, they may have a depression that is inherently more resistant to SSRI treatment.

Although the Rockefeller University study is preliminary and needs to be confirmed by additional research, its results do remind us that the biology of depression is more complicated than the tired phrase "chemical imbalance" would lead us to believe. The brain manages mood through several complex processes involving genes, proteins, and receptor sites inside and between nerve cells. The p11 protein is just one of several objects of scientific interest. Although scientists hope that p11 will lead us to a new type of antidepressant, there are no such prospects in sight as yet.

We don't expect basic science to furnish definitive clinical advice, but this interesting study does suggest a place to look if your SSRI is not giving you relief. If you're taking a common pain reliever, it may be worth stopping it until you've completed a several-week SSRI trial. Since other types of antidepressants, such as tricyclics or bupropion, do not seem vulnerable to this interaction, it may also be worthwhile to try one of those drugs.

— Michael Craig Miller, M.D.
Editor in Chief, Harvard Mental Health Letter

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