Labile Anger During Interferon Alfa Treatment is Associated With a Polymorphism in Tumor Necrosis Factor α

Abstract

Objective-Inflammatory cytokines may influence both labile anger and depression. Both psychiatric conditions can occur during interferon-alpha (IFN-α) based treatments. Evidence also indicates a central nervous system role for TNF-α, whose expression may be increased by IFN-α. A polymorphism in the promoter region of TNF-α has been associated with various inflammatory illnesses. We therefore hypothesized that this TNF-α polymorphism would influence susceptibility to psychiatric symptoms during IFN-α therapy.Methods-105 patients with hepatitis C, initially without active major depression (MDD), were treated with IFN-α and then prospectively monitored using the Structured Clinical Interview for DSM-IV, the Beck Depression Inventory-II (BDI), the Anger Irritability and Assault Questionnaire, and circulating TNF-α levels. The A-308G polymorphism (rs1800629) was determined using the 5′-nuclease assay. Repeated-measure mixed-effect analyses compared changes in symptoms over time.Result-BDI increased during IFN-α therapy (F = 6.2; p<0.001), with 27% developing MDD. The TNF-α A allele was associated with worsened labile anger (F = 2.5; p<0.05) and fatigue (F = 2.9; p<0.05) during treatment, but not with major depression incidence (X 2 = 0.0; p=0.99) or increased BDI (F = 1.2; p=0.31). Labile anger was not predicted by the serotonin transporter polymorphism (F = 0.8; p=0.59).Discussion-During treatment with an exogenous cytokine, vulnerability to worsening labile anger --distinct from major depression --is associated with genetic variability in TNF-α. This has implications both for patients being treated with IFN-α, as well as our understanding of genetic vulnerability for different subtypes of dysphoric and mood disorders.

Brain-Derived Neurotrophic Factor Serum Levels and Genotype: Association with Depression during Interferon-α Treatment

“…Consistent with this, we have found that polymorphisms affecting TNF-a and IL-28b are associated with specific mood-related symptom clusters in individuals receiving IFN-a (Lotrich et al, 2010;Lotrich et al, 2011). Also, we have found that a serotonin reuptake promoter polymorphism (5-HTTLPR) is associated with increased Beck Depression Inventory scores during IFN-a therapy ), but another group did not find an association using the Hospital Anxiety Depression Scale (Kraus et al, 2007).…”

“…Several quantitative assessments, rather than a categorical outcome of MDD, were selected because of increasing evidence that many genetic vulnerabilities may be associated with specific symptom clusters during IFN-a therapy (Lotrich et al, 2010;Lotrich et al, 2011;Su et al, 2010). Subjects were given the opportunity to either mail in questionnaire results or complete them on routine clinic days.…”

Correlations of inflammatory gene pathways, corticolimbic functional activities, and aggression in pediatric bipolar disorder: A preliminary study

“…LPS-stimulated TNFα expression was positively correlated with physical aggression, verbal aggression, and hostility. In other studies, LPS-induced increases in TNFα correlated with stress-induced emotion arousal,(Moons et al, 2010; Suarez et al, 2006) and interferon-induced labile anger (Lotrich et al, 2010). …”

A review of the neuro- and systemic inflammatory responses in post concussion symptoms: Introduction of the “post-inflammatory brain syndrome” PIBS

“…The 2010 work of Lotrich et al has demonstrated that presence of a polymorphism of the TNF-a gene, previously associated with increased TNF-a response to inflammation, is associated with a greater increase in labile anger with interferon treatment. This is speculated by the authors to be mediated by central TNF-a levels as there was no correlation with circulating levels of TNF-a (Lotrich et al, 2010). In addition, baseline ratios of arachidonic acid (an x-6 fatty acid) to eicosapentaenoic acid and docosahexaenoic acid (x-3 fatty acids) are correlated with increased labile anger after interferon treatment and subjects with a higher ratio had significantly more labile anger and irritability after interferon treatment.…”