People with depression encounter a lot of pharmaceutical frustration. For largely unknown reasons, roughly one in three patients receive no benefit from any antidepressant. A recent study, however, suggests that something as simple as over-the-counter painkillers could play a role. Ibuprofen, aspirin and other anti-inflammatory drugs may disrupt the action of selective serotonin reuptake inhibitors (SSRIs), the most commonly prescribed type of antidepressant.

Antidepressants alter brain chemistry. SSRIs increase the amount of the neurotransmitter serotonin in the space between brain cells. Neuroscientist Jennifer L. Warner-Schmidt of the Rockefeller University and her colleagues noticed that certain proteins in the brain that interact with SSRIs had the potential to be influenced by anti-inflammatory drugs such as pain relievers.

The team embarked on a series of experiments in rodents to explore this idea. In one test, researchers measured how long it takes a mouse to overcome its fear of a new, open space and move toward food placed in the center. Mice that had been given the SSRI citalopram for two weeks approached the food more than twice as quickly as unmedicated mice. But mice given ibuprofen with the SSRI for two weeks headed for the food nearly as slowly as un­medicated mice, Warner-Schmidt and her colleagues report in the Proceedings of the National Academy of Sciences USA.

The researchers also examined information from a previous study of patients with treatment-resistant depression. The study evaluated how the participants responded to a 12-week course of citalopram and noted other medication use. Patients who had taken an anti-inflammatory drug or acetaminophen during their SSRI treatment were significantly less likely to experience relief from their symptoms than patients who had not.

The researchers are planning studies to figure out how exactly the pain medications interfere with the SSRIs and to determine how big a dose of painkillers is detrimental. But the evidence so far “is clinically important,” Warner-Schmidt says. “It’s a piece of information that doctors should keep in mind when looking at an individual who is not responding to an SSRI.”