The A allele in the -308 promoter region of TNF-α was specifically associated with worsening labile anger during IFN-α treatment. Labile anger was based on questions in the AIAQ about having minimal control over switches in temper; feeling normally “OK” but then suddenly feeling angry or furious with the urge to yell; or feeling so mad as to experience shaking, a pounding heart, and/or the urge to hit something.77
Of note, the A allele was specifically associated labile anger and not with irritability or increases in assault behaviors (either verbal or physical). We also did not find any association between the TNF-α polymorphism and the development of categorical MDD or worsening BDI, consistent with most prior studies.62-65
Several groups have independently described increases in hostility-related complaints in patients receiving IFN-α treatment,13-20
something very disruptive for patients.17
This phenomenon occurs whether depression develops or not,22
and is orthogonally distinct from increased depression on the symptom checklist-90.23
Aggression and depression are under genetic influence in childhood twin studies, albeit via potentially distinct pathways.79
Also, 5-HTTLPR was associated with risk for MDD during IFN-α treatment,27, 28
but not risk for labile anger. There may be a relationship between elevated peripheral interleukin-6 (IL-6) levels and MDD during IFN-α therapy,67, 80
despite no relationship between TNF-α levels and MDD. This is consistent with reports of elevated systemic IL-6 but not TNF-α in “idiopathic” MDD.81
It is entirely speculative as to what this labile-anger syndrome represents. ‘Anger attacks’ could be related to a depression subtype,9
mixed mood disorder,70, 82
or an entirely distinct syndrome. Consistent with a ‘mixed mood disorder’ hypothesis, mood dysregulation may be related to risk for bipolar disorder;83-89
bipolar disorder and elevated TNF-α levels both may predict worse response to classical antidepressants; 90, 91
and elevated TNF-α levels may occur in bipolar disorder.92
Inconsistent with a ‘mixed mood disorder’ hypothesis, we very rarely observed grandiosity, decreased sleep requirements, or increased goal-directed activities during IFN-α treatment. Future work will be required to further delineate this labile anger ‘syndrome’. An important limitation of this study is that our assessment of labile anger was limited to this single self-report questionnaire, and thus the findings should be considered preliminary.
Anger during depression has been previously examined in genetic association analyses, with possible associations with CREB1,93
monoamine oxidase A,11
and catecholamine-O-methyl transferase.96
A limitation to this study is that we also did not examine these genes or several other polymorphisms that are upstream from the TNF-α transcription start site (e.g. positions -863, -376, -244, -238). Future work will be required to more fully examine the role of genetic variation across the TNF-α gene and other candidate genes in labile anger.
We did examine whether worsening fatigue mediates the increased labile anger. Fatigue and malaise are well-known symptoms of IFN-α treatment,23, 97
and TNF-α has been associated with malaise in animal models.98
Although TNF-α genotype was associated with increased fatigue, no mediation was found. Thus, the A allele may increase sensitivity to both fatigue as well as labile anger, albeit independently.
Also, circulating levels of TNF-α were neither associated with psychiatric symptoms nor genotype. This is inconsistent with higher plasma TNF-α levels being associated with the A allele during inflammation46-48
and increased depressive symptoms correlating with lymphocyte production of TNF-α.99
Thus, our lack of associations with circulating TNF-α levels should be interpreted with caution. Nonetheless, the A-308G genotype has been associated with cognitive dysfunction in elderly subjects despite no association between genotype and peripheral TNF-α levels,58
similar to our study. It is possible that central TNF-α may be of more relevance to psychiatric symptoms.
TNF-α levels in the brain can be influenced by stress or peripheral inflammation35, 36, 38
as well as peripheral cytokines.39
Similarly, IFN-α decreases cell proliferation in the hippocampus by induction of local
Therefore, it is plausible that the A-308G polymorphism could particularly influence localized central nervous systems expression of TNF-α during IFN-α treatment. Consistent with this speculation, the A-308G polymorphism may affect the binding of some transcriptional regulators but not others.101-105
Enhanced production of quinolinic acid may mediate some psychiatric effects of IFN-α106
and elevated central TNF-α could be influential on this pathway.40
Also, increased central nervous system TNF-α can increase norepinephrine and serotonin turnover,107
possibly mediated by its effect on c-jun-N-terminal kinase.108
As TNF-α can be induced in the limbic system, any of these central TNF-α influences could be a plausible mechanism leading to labile anger. Nonetheless, the pathway by which the A allele in the TNF-α promoter region specifically leads to enhanced labile anger requires future investigation.
In summary, the risk for inflammation-related labile anger may be enhanced in subjects with the A allele in the promoter region for TNF-α. However, it should be reiterated that this study was specifically performed in patients undergoing therapy with IFN-α. Whether TNF-α is associated with labile anger in other clinical situations requires examination. A strength of the IFN-α paradigm is the ability to prospectively assess the development of symptoms; however the limitation is the lack of generalization to other “stressful” or inflammatory scenarios. Also, although hypothesis driven, these analyses had no correction for multiple testing and require replication. Regardless, the results indicate that genetic variation upstream from TNF-α may influence labile anger during a state of heightened inflammation without concomitantly influencing risk for depression.