Drug War: How Advil May Thwart the Benefits of Prozac

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The common painkillers known as non-steroidal anti-inflammatory drugs (NSAIDs), a class of medication that includes aspirin, naproxen (Aleve), and ibuprofen (Advil), can significantly reduce the effectiveness of certain antidepressants — cutting rates of remission from depression from 55% to 45% — according to a new study.

Researchers found that analgesics like acetaminophen (Tylenol), which belong to a different class of painkillers, also reduced the benefits of the antidepressants studied — the newer SSRIs, or selective serotonin reuptake inhibitors, which include Zoloft and Prozac.

Depressed patients who used both types of painkillers on top of their depression treatment were the worst off, with only 37% finding relief from depression with SSRIs. Prescription opioid painkillers like Vicodin were not studied.

“We think this effect is huge,” says study author Paul Greengard, a Nobel laureate and professor of neuroscience at Rockefeller University, noting that the effect of the NSAIDs is comparable to the difference seen in clinical trials between antidepressants and placebo. “It’s possible that there’s a bigger effect than is apparent from these data. It could be a reason that many people are refractory to antidepressant treatment.”

Although pain is known to worsen depression — and people using multiple types of painkillers are likely to have the worst pain — the study suggests that the effect of pain alone cannot account for the apparent reduction in benefit of the antidepressants.

“SSRIs have dramatic therapeutic effects in lots of patients,” says Greengard. “But we found both in mice and humans, if they have consumed drugs like aspirin or ibuprofen, this attenuates the therapeutic effects of antidepressants.”

In the mouse studies, researchers compared the outcome of NSAIDs plus antidepressants with the effects of antidepressants alone. The human data, meanwhile, came from a previous trial of depressed patients in which some had been taking NSAIDs or Tylenol, or both, for pain, while taking antidepressants.

The researchers have discovered a mechanism through which NSAIDs may interfere directly with the effects of SSRIs. Using genetic techniques in mice, researchers showed that the antidepressants raise levels of certain immune substances known as cytokines, which in turn raise levels of a protein called p11. That protein affects serotonin receptors, making more of them available on the surface of cells to interact with the neurotransmitter serotonin. With more receptors available, more serotonin can be transmitted, which helps lift depression.

NSAIDs, however, reduce levels of these cytokines; in turn, this prevents p11 from having its positive effect and, further, reduces the effectiveness of SSRIs. “This is really quite interesting because it contradicts other findings in depression,” says John Krystal, chair of psychiatry at Yale. He notes that previous research has found that depression itself is connected with high levels of cytokines, which is part of the body’s “inflammatory response,” a state that may be caused or exacerbated by chronic, high stress. That increases risk not only for depression, but also for conditions like heart disease and stroke.

The new findings suggest that these connections are more complicated. “It may be that certain cytokines are involved in the pathway that causes depression, and others are involved in the way that antidepressants are acting,” says Jennifer Warner-Schmidt, co-author of the paper and a research associate at Rockefeller University. Different cytokines may be involved in the body and the brain, and different concentrations of cytokines may also result in different effects. What’s more, higher levels of some cytokines may signal the brain’s attempt to heal depression, rather than being a cause of it.

“Our initial model was that perhaps the reason that cytokines are high in depression is that p11 ordinarily keeps them suppressed. It turned out that p11 raised levels of cytokines, so then our thinking adapted to the idea that, well, maybe an increase in cytokines is a compensatory effect to overcome the depressed state. And we found, in fact, that antidepressants increase the cytokines, so that became our model,” says Greengard.

“It could be that cytokines or [stress hormones like] cortisol increase p11 levels as part of resilience [in those who don’t get depressed after stress], and that SSRIs compensate for this resilience deficit. But this hypothesis has not yet been tested directly,” says Krystal.

Whatever the case, NSAIDs reduce the effectiveness only of SSRI drugs, not the antidepressants that act on other neurotransmitters beyond serotonin, such as buproprion (Wellbutrin) or the older tricyclic antidepressants.

But the effect of stopping NSAIDs in improving SSRI response could be as significant as adding a new medication, the researchers say. If the current research is replicated, depressed people who need pain relief may be advised to try non-SSRI antidepressants, and those who are already taking SSRIs may be steered toward different types of pain medications.

“It’s particularly important because in older people there is a high incidence of depression, and many people are on both types of drugs. It’s of great clinical significance for that reason,” says Greengard whose study was published in the Proceedings of the National Academy of Sciences.

Greengard and his colleagues are planning a controlled trial to look directly at the effects of NSAIDs alone versus NSAIDS with SSRI antidepressants or placebo. They plan to measure more precisely the impact of NSAIDs by controlling the doses and drugs taken.

Further research on p11 is also planned, and the researchers say that techniques or drugs that increase the protein may even be developed as new treatments for depression.

Given that depression affects some 21 million Americans and frequently co-occurs with or contributes to a variety of medical conditions such as heart disease, cancer and chronic pain, any new treatment for the mental illness may hold great potential for improving Americans’ long-term health.

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