Interferon-Induced Mania

Question:

"Have you seen interferon precipitate mania in a patient?"

Charles Raison, MD:

I most definitely have. My experience in this regard is consistent with many case reports describing people who were psychiatrically normal prior to commencing therapy with the cytokine interferon (IFN)-alpha for either cancer or chronic hepatitis C virus infection. ^1-4  Our best data suggest that between 20% to 50% of people will meet criteria for major depression at some point during treatment with IFN-alpha, ⁴  and 1% to 2% will develop classic euphoric manias. ²  Many more people will develop a mixture of symptoms that defy easy categorization, but that include a mixture of irritability, racing thoughts, anxiety, fatigue, and anhedonia. The best study of this phenomenon was done by a group in Bordeaux, France. By applying strict  DSM-IV criteria they determined that most people who qualified for a mood disorder diagnosis were best classified depressive mixed states. ²

We know from many studies that IFN-alpha tends to magnify people’s baseline condition. For example, the most replicated risk factor for developing clinical depression during treatment is having any level of depressive and/or anxiety symptoms prior to starting. ^4,5 We suspect the same thing is true for treatment-emergent mania, that is that people with premorbid bipolar disorder are more likely to have them during IFN-alpha treatment, but this has never been definitively established. Similarly, no one has ever conducted a rigorous study of how to best treat IFN-alpha-induced manias, but lots of clinical experience suggests that these episodes respond to mood stabilizers/antipsychotics as do idiopathic manias. On the other hand, we have a fair amount of data for how to treat depression during IFN-alpha. Studies show that the incidence of IFN-alpha depression can be reduced by pretreatment with an antidepressant, ^6-8  but work by our group shows that antidepressant pretreatment only seems to benefit individuals with at least mild depression or anxiety symptoms prior to treatment. ⁶  Studies also suggest that antidepressants are effective in treating mood disorder symptoms once they have developed during IFN-alpha treatment. ^9,10

For the clinician, the high burden of psychiatric side effects that accompany IFN-alpha are a primary treatment challenge. For those of us who are also researchers, however, IFN-alpha has provided a truly unique opportunity to understand how the immune system contributes to the development of mood disorders. Because it is increasingly clear that psychological stress activates inflammation, ^11,12  as does sickness, findings from IFN-alpha really extend out—we suspect—to mood disorders in general, even in medically healthy individuals. What we and other research groups have found is that people who develop depression in response to IFN-alpha develop many of the same physiological changes that have been reported for mood disorders in general, including glucocorticoid resistance, flattening of the diurnal cortisol rhythm, sleep disruption and reduced slow wave sleep, impairments in the metabolism of tryptophan (leading to serotonergic changes), and the generation of excitotoxic/neurotoxic chemicals in the central nervous system. ^13-16

Not enough people develop pure manias during IFN-alpha treatment for it to be studied in the same way that depression has been studied. However, I suspect that many of the same physiological changes seen during IFN-alpha depression would also be observed during IFN-alpha-induced mania. I say this because data increasingly suggest that “regular” manias look very similar to depression in many ways. Why should IFN-alpha-induced mania be any different?

Let me close with a final practical point about manias associated with IFN-alpha. Patients seem to be at risk not only during treatment itself, but also in the weeks to months following treatment. I’ve seen this with my own eyes. We had a research participant who developed such severe depression we had to discontinue her from the study. In defiance of our advice she did not immediately go to a clinician to start an antidepressant. Two weeks after stopping the IFN-alpha she began to develop racing thoughts, mild grandiosity, increased goal directed activity, and decreased need for sleep. Fortunately, although the severity of her symptoms probably crossed the line into full mania, she did not get into trouble and the episode spontaneously resolved over the course of a week or two. The take home point here is that if you treat people undergoing therapy with IFN-alpha you really need to keep a close eye on them after they finish therapy and not just while they are in its throes.

References

1. Adams F, Fernandez F, Mavligit G.  Interferon-induced organic mental disorders associated with unsuspected pre-existing neurologic abnormalities. J Neurooncol. 1988;6(4):355-359.
2. Constant A, Castera L, Dantzer R, et al.  Mood alterations during interferon-alfa therapy in patients with chronic hepatitis C: evidence for an overlap between manic/hypomanic and depressive symptoms. J Clin Psychiatry. 2005;66(8):1050-1057.
3. Greenberg DB, Jonasch E, Gadd MA, et al.  Adjuvant therapy of melanoma with interferon-alpha-2b is associated with mania and bipolar syndromes. Cancer. 2000;89(2):356-362.
4. Raison CL, Demetrashvili M, Capuron L, Miller AH.  Neuropsychiatric adverse effects of interferon-alpha: recognition and management. CNS Drugs. 2005;19(2):105-123.
5. Raison CL, Borisov AS, Broadwell SD, et al.  Depression during pegylated interferon-alpha plus ribavirin therapy: prevalence and prediction. J Clin Psychiatry. 2005;66(1):41-48.
6. Raison CL, Woolwine BJ, Demetrashvili MF, et al.  Paroxetine for prevention of depressive symptoms induced by interferon-alpha and ribavirin for hepatitis C. Aliment Pharmacol Ther. 2007;25(10):1163-1174.
7. Musselman DL, Lawson DH, Gumnick JF, et al.  Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med. 2001;344(13):961-966.
8. Kraus MR, Schafer A, Al-Taie O, Scheurlen M.  Prophylactic SSRI during interferon alpha re-therapy in patients with chronic hepatitis C and a history of interferon-induced depression. J Viral Hepat. 2005;12(1):96-100.
9. Kraus MR, Schafer A, Schottker K, et al.  Therapy of interferon-induced depression in chronic hepatitis C with citalopram: a randomised, double-blind, placebo-controlled study. Gut. 2008;57(4):531-536.
10. Loftis JM, Hauser P.  The phenomenology and treatment of interferon-induced depression. J Affect Disord. 2004;82(2):175-190.
11. Pace TW, Mletzko TC, Alagbe O, et al.  Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am J Psychiatry. 2006;163(9):1630-1633.
12. Steptoe A, Hamer M, Chida Y.  The effect of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis. Brain Behav Immun. 2007;21(7):901-912.
13. Raison CL, Rye DB, Woolwine BJ, et al.  Chronic interferon-alpha administration disrupts sleep continuity and depth in patients with hepatitis C: association with fatigue, motor slowing, and increased evening cortisol. Biol Psychiatry. 2010;68(10):942-949.
14. Raison CL, Dantzer R, Kelley KW, et al.  CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression. Mol Psychiatry. 2010;15(4):393-403.
15. Raison CL, Borisov AS, Woolwine BJ, et al.  Interferon-alpha effects on diurnal hypothalamic-pituitary-adrenal axis activity: relationship with proinflammatory cytokines and behavior. Mol Psychiatry. 2010;15(5):535-547.
16. Raison CL, Borisov AS, Majer M, et al.  Activation of central nervous system inflammatory pathways by interferon-alpha: relationship to monoamines and depression. Biol Psychiatry. 2009;65(4):296-303.