Can Anti-TNFs Be Repurposed to Treat Depression?

Up to two-thirds of patients diagnosed with depressive symptoms have demonstrated insufficient response to first-line antidepressant medications, highlighting the need for new antidepressants acting on multiple or novel targets.

Advances in research suggest that neurotransmitters other than serotonin and noradrenaline may be involved in the pathogenesis and treatment of major depressive disorder (MDD), and have pointed to inflammation as an important factor in the development of MDD through the action of cytokines such as tumor necrosis factor (TNF) alpha. Thus, inflammation suppression may be a potential treatment for MDD through “repurposing” certain anti-inflammatory drugs, including infliximab, for treatment of MDD resistant to existing therapies, according to Mohamed Elsaed Ebada, PhD, writing in a review in the September 17, 2017, issue of Journal of Pharmacy and Pharmacology.

Ebada notes that drug repurposing may be a cost-effective way to improve remission rates for treatment-resistant depression and narrow the gap between increasing therapeutic needs and limited productivity in drug discovery.

Ebada explains that the antidepressant effect of infliximab has been noted in earlier studies of patients with Crohn’s disease and ankylosing spondylitis who were being treated with the therapy, and other studies showed that the anti—TNF agents etanercept and adalimumab also reduced secondary depressive symptoms in patients with psoriasis. Patients treated with infliximab showed an association between improved depressive symptoms and pre-treatment increased levels of high-sensitivity C-reactive protein (CRP), an inflammatory biomarker reported to be elevated in patients with treatment-resistant depression.

One of the most discussed studies of infliximab’s possibly beneficial effect in treatment-resistant depression was published in 2013 in JAMA Psychiatry by Charles L. Raison, MD, and colleagues. The study included 60 medically stable outpatients with MDD who did not have inflammatory diseases and who were randomly assigned to receive 3 infusions of infliximab versus saline (at baseline, 6 weeks, and 12 weeks). Over 50% of patients experienced major benefit, but when Dr. Raison and his colleagues “broke” the double-blinding, they found that infliximab was equivalent to placebo.

However, in a subgroup analysis of patients with greater levels of inflammation, as shown by their C-reactive protein (CRP) levels, there was a greater benefit with infliximab in those with higher CRP. Raison found that if the CRP level was greater than 5 mg/L, there was about 3-point improvement on the Hamilton Rating Scale for Depression. Because infliximab does not enter the central nervous system, the investigators hypothesized that any benefit seen in the study was based on peripheral inflammation.

Drug repurposing, for MDD or for other diseases, can involve 1 of 3 possibilities:

• Repositioning (establishing a new indication for a drug used for other indications)
• Reformulating (altering the formulation; using the same drug but in another dosage form via the same or a different route of administration)
• Combining (using 2 or more drugs together to improve their safety and efficacy)

To date, 13 drugs have been repurposed for treatment of depression or bipolar depression. By the same token, approximately 20 antidepressants have been repurposed for new indications. The advent of biosimilars for anti—TNF agents could make these therapies more available to patients with MDD.