A new study found that fluoxetine (Prozac) and citalopram (Celexa) treatment significantly inhibited disease progression of collagen-induced arthritis (CIA) in mice.
Research led by Sandra Sacre, Ph.D., of the Brighton and Sussex Medical School in the UK, studied the anti-arthritic potential of these drugs, known as selective serotonin reuptake inhibitors (SSRIs), most commonly used to treat depression. Both SSRIs exhibited anti-inflammatory effects and may provide drug development opportunities for arthritic conditions such as rheumatoid arthritis. The full findings of this study appear in the March issue of Arthritis & Rheumatism.
Rheumatoid arthritis is an autoimmune disease that causes inflammation in the lining of the joints. Typically, the disorder first affects hand and foot joints, and later the disease spreads to larger joints. Inflammation eventually erodes the cartilage between the joints, causing pain, stiffness, joint deformity and physical disability. According to the 2000 Global Disease Burden study by the World Health Organization, rheumatoid arthritis affects approximately 1 percent of the world population.
To understand the anti-inflammatory properties of SSRIs, the research team at The Kennedy Institute of Rheumatology investigated the use of fluoxetine and citalopram in mouse and human models of rheumatoid arthritis. Dr Sacre explained, "We were interested in SSRIs because of their reported anti-inflammatory effects. Prior studies have shown that patients with depression who respond to treatment with SSRIs display a reduction in cytokine levels [signals that can induce inflammation], suggesting a connection between SSRIs and the immune system."
In the current study, researchers used a CIA mouse model due to the similarities to human rheumatoid arthritis, including synovitis (inflammation of the joint-lining membrane), bone erosion and formation of pannus (tissue flap) in the joints. At the onset of arthritis, mice were treated daily for seven days with a dose of 10 or 25 mg/kg of fluoxetine and 25 mg/kg of citalopram.
At the lower dose of fluoxetine, the mice showed a small reduction in the clinical score (a combined measure of redness, swelling and joint mobility and deformity) and a slower increase in paw swelling. At a dose of 25 mg/kg, fluoxetine halted disease progression and no further elevation was noted in the clinical score or paw swelling.
"We observed reduced inflammation, reduced cartilage and bone erosion and a preservation of the joint structure in the mice treated with a higher dose of fluoxetine," commented Dr. Sacre.
Citalopram was not as effective as fluoxetine at inhibiting disease progression in this model.
Researchers also observed a decrease in cytokine production from cultures of human rheumatoid arthritis synovial joint tissues that were treated with SSRIs. Toll-like receptors (TLRs) are strong activators of immune cells, leading to the production of cytokines that can induce inflammation. Fluoxetine was found to inhibit the activation of TLRs more effectively than citalopram.
"While the SSRIs effectively target TLRs contributing to inflammation and could provide therapeutic benefit in [rheumatoid arthritis], they are not ideal candidates to progress into clinical trials," concluded Dr. Sacre.
The levels of the SSRIs required to halt disease progression are higher than normally prescribed for standard treatment. "Our data suggests that effective inhibition of [rheumatoid arthritis] would require levels of the drugs higher than the safe therapeutic dosages." The authors suggest further study of the role of TLRs in chronic inflammation may uncover drugs that offer an effective treatment of rheumatoid arthritis in the future.