Nonsteroidal anti-inflammatory drugs (NSAIDs) have been among the most commonly prescribed medications worldwide. NSAIDs act by inhibiting cyclooxygenase (COX) enzymes, which convert the fatty acid arachidonic acid to prostaglandins (particularly prostaglandin H2), eicosanoids, and thromboxanes, which in turn increase pain, fever, and both local and systemic inflammation. Most COX inhibitors are nonselective inhibitors of COX-1 and -2 enzymes (e.g., aspirin and ibuprofen). Selective COX-2 inhibitors, such as celecoxib and rofecoxib, were developed to reduce side effects, particularly gastric ulceration and bleeding (1). By the year 2000, there were more than 75 million prescriptions for NSAIDs in the United States alone and over $3 billion in sales for celecoxib (2). However, by the mid-2000s, data emerged indicating that COX inhibitors (both selective and nonselective agents) increase risk for cardiovascular disease, stroke, and heart failure, which has reduced sales of at least the COX-2 selective inhibitors. Celecoxib is the only COX-2 inhibitor that remains on the market in the United States, and its use has declined considerably since 2005. At the same time, the use of naproxen has held steady, and the use of both ibuprofen and meloxicam have increased (3). Any significant interaction between antidepressants and COX inhibitors would be very important given the high degree of comorbidity of depression with the inflammatory diseases treated with these drugs.