Anti-TNF-α Compounds as a Treatment for Depression

Abstract

Millions of people around the world suffer from psychiatric illnesses, causing unbearable burden and immense distress to patients and their families. Accumulating evidence suggests that inflammation may contribute to the pathophysiology of psychiatric disorders such as major depression and bipolar disorder. Copious studies have consistently shown that patients with mood disorders have increased levels of plasma tumor necrosis factor (TNF)-α. Given these findings, selective anti-TNF-α compounds were tested as a potential therapeutic strategy for mood disorders. This mini-review summarizes the results of studies that examined the mood-modulating effects of anti-TNF-α drugs.

Keywords: TNF-α; TNFR; bipolar disorder; depression; inflammation; pentoxifylline.

Figure 1

TNF-α and TNF-α Receptors. Transmembrane TNF-α (mTNF-α) undergoes proteolytic cleavage by TNF-α-converting enzyme (TACE) which generates the soluble form of the protein (sTNF-α). Both mTNF-α and sTNF-α are biologically active; they bind to and activate TNF receptor (TNFR) 1 and TNFR2. Arrows indicate that mTNF-α is also capable of activating TNFR1 and TNFR2.

Figure 2

TNF-α Antagonists. Clinically used selective TNF-α antagonists include recombinant TNF-α-specific monoclonal antibodies such as infliximab and adalimumab, and recombinant fusion proteins of TNFR such as etanercept which is a TNFR2 fusion protein. Pentoxifylline is a methylxanthine drug which exerts several pharmacological effects including potent inhibition of TNF-α activity (i.e., it is not a selective TNF-α antagonist). Abbreviations: ECD—extracellular domain, Fc—fragment crystallizable region, Fv—variable fragment, IgG—immunoglobulin G, TNFR2 – TNF-α receptor 2.