A Pilot Study Investigating Tumor Necrosis Factor-α as a Potential Intervening Variable of Atypical Antipsychotic-Associated Metabolic Syndrome in Bipolar Disorder

Background: Strong associations exist between tumor necrosis factor-alpha (TNF-alpha) and metabolic syndrome (MetS). Although TNF-a is associated with bipolar depression (BD), its role in atypical antipsychotic (AAP)-associated MetS in BD is unclear. Here, we investigate the potential intervening role of TNF-alpha in the indirect relationship between AAP treatment and MetS in BD. Materials and Methods: Using a cross-sectional design, 99 euthymic BD volunteers were stratified by the presence or the absence of MetS (National Cholesterol Education Program Adult Treatment Panel III). Serum TNF-alpha concentration, determined via chemiluminescent immunometric assays, was compared between groups (ie, MetS or no MetS). We investigated the intervening effect of TNF-alpha on the relation between AAP treatment and MetS in BD using regression techniques. Results: Treatment with those antipsychotics believed associated with a higher risk for MetS (ie, AAPs: olanzapine, quetiapine, risperidone, paliperidone, clozapine) was found to be associated with significantly greater TNF-alpha (F-1,F-88 = 11.2, P = 0.001, mean difference of 1.7 +/- 0.51) and a higher likelihood of MetS (F-1,F-88 = 4.5, P = 0.036) than in those not receiving treatment with an AAP. Additionally, TNF-alpha was greater (trending toward significance; T-52 = 2.0, P = 0.05) in BD volunteers with MetS and was found to have a statistically significant effect on the indirect relationship between AAP treatment and elevated waist circumference in these BD volunteers. Discussion: These results identify TNF-alpha as a potential intervening variable of AAP-associated MetS in BD, not previously identified in this population. Future prospective studies could assess the predictive potential of TNF-alpha in determining risk of AAP-associated MetS in BD. Given previous evidence relating TNF-alpha and mood state in BD, this study increases the importance in understanding the role of TNF-alpha in mind-body interactions and renews discussions of the utility of research into the clinical efficacy of TNF-alpha antagonist treatment in mood disorders.