Secondary Mania induced by TNF-α inhibitors: A systematic review

Abstract

A growing number of studies support a bidirectional relationship between inflammation and bipolar disorders. Tumor necrosis factor-α (TNF-α) inhibitors have recently attracted interest as potential therapeutic compounds for treating depressive symptoms, but the risk for triggering mood switches in patients with or without bipolar disorders remains controversial. Thus, we conducted a systematic review to study the anti-TNF-α medication-induced manic or hypomanic episodes. PubMed, Scopus, Medline, and Embase databases were screened for a comprehensive literature search from inception until November 2020, using The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Out of the initial 75 references, the screening resulted in the inclusion of four case reports (each describing one patient) and a cohort study (in which 40 patients out of 7600-0.53% - experienced elated mood episodes after infliximab administration). Of these 44 patients, 97.7% experienced a manic episode and 2.3% hypomania. 93.2% of patients had no history of psychiatric disorder or psychotropic treatment. Only 6.8% had a history of psychiatric disorders with the affective spectrum (4.6% dysthymia and 2.3% bipolar disorder). The time of onset of manic or hypomanic symptoms varied across TNF-α inhibitors with an early onset for Infliximab and a later onset for Adalimumab and Etanercept. These findings suggest that medications targeting the TNF-α pathway may trigger a manic episode in patients with or without affective disorders. However, prospective studies are needed to evaluate the relative risk of such side effects and identify the population susceptible to secondary mania.

Keywords: TNF inhibitors; bipolar disorders; disease-modifying antirheumatic drugs; immune system; manic switch.

Fig 1

PRISMA study flow chart.

Fig 2

TNF‐α mediated pathways are involved in a delicate balance between cell death and inflammation. TNFR, tumor necrosis factor receptor; STAT5, Signal transducer and activator of transcription 5; TGF, transforming growth factor; IL, interleukin; NF‐kB, nuclear factor kappa‐light‐chain‐enhancer of activated B cells; NAcc, nucleus accumbens; DS, dorsal striatum. TNF‐α exerts pleiotropic effects on neurons and neighboring cells in the central nervous system. TNF‐α, through the binding of TNFR‐1, initiates two multiple‐step cascades: an apoptotic one (Caspases‐mediated) and a pro‐survival one (NF‐kB‐mediated). The balance between the two signaling pathways is also regulated by ROS levels. The TNFR‐2‐mediated cascade leads to the activation of NF‐kB and STAT5, which eventually leads to the transcription of immuno‐modulatory genes (e.g., genes encoding IL‐6, IL‐10, IL‐12) and the production of neuroprotective molecules. These factors are released from the neurons and affect the neighboring microglia, eventually regulating the production and release of TNF‐α, thus closing an immuno‐modulatory loop between neurons and neighbor immune cells. Furthermore, TNF‐α exerts neuronal nuclei‐specific effects: for example, TNF‐α enhances drug reward responses through regulating NAcc neurons, whereas through the dorsal striatum neurons, it mediates an increase in locomotor activity.