Food and Behaviour Research

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Anger induced by interferon-alpha is moderated by ratio of arachidonic acid to omega-3 fatty acids

Lotrich FE, Sears B, McNamara RK. (2013)  J Psychosom Res. 2013 75(5) 475-83. doi: 10.1016/j.jpsychores.2013.07.012. 

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Anger worsens in some patients during interferon-alpha (IFN-α) therapy. Elevated anger has also been associated with lower long-chain omega-3 (LCn-3) fatty acid levels. We examined whether fatty acids could influence vulnerability to anger during IFN-α exposure.


Plasma arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) levels were determined prior to IFN-α therapy by mass spectroscopy. Repeated-measure analyses examined the relationship between AA/EPA+DHA and the subsequent development of labile anger and irritability in 82 subjects who prospectively completed the Anger, Irritability, and Assault Questionnaire (AIAQ) during the first eight weeks of IFN-α therapy.


Prior to IFN-α therapy, AA/EPA+DHA did not correlate with either labile anger or irritability. Pre-treatment AA/EPA+DHA did correlate with the subsequent maximal increase in labile anger during IFN-α therapy (r=0.33; p=0.005). Over time, labile anger increased more in subjects with above median AA/EPA+DHA ratios (p<0.05). Of the 17 subjects ultimately requiring psychiatric intervention for anger, 14/17 had above-median AA/EPA+DHA ratios (p=0.009). There was also an interaction with the tumor necrosis factor-alpha (TNF-α) promoter polymorphism (A-308G), such that only those with both elevated AA/EPA+DHA and the A allele had increased labile anger (p=0.001). In an additional 18 subjects, we conversely observed that selective serotonin reuptake inhibitor treatment was associated with increased irritability during IFN-α therapy.


LCn-3 fatty acid status may influence anger development during exposure to elevated inflammatory cytokines, and may interact with genetic risk for increased brain TNF-α. LCn-3 supplements may be one strategy for minimizing this adverse side effect of IFN-α.

© 2013.


Treatment with interferon-alpha (IFN-α) - a powerful immune system modulator that increases inflammation - is known to induce low or volatile mood states - if not clinical depression - in some people.

In this study, low blood levels of long-chain omega-3 (EPA and DHA) relative to omega-6 (AA) pre-treatment were found to predict vulnerability to interferon-induced anger and irritability; and this association appeared to be driven by a subgroup with a specific genetic marker.

These findings add to the existing evidence that for some people, relative deficiencies of omega-3 LC-PUFA can adversely affect mood via an immune-mediated mechanism - and conversely, that higher blood levels of these omega-3 may protect such individuals from interferon-induced depression.