Interferon-Induced Depression: How an Immune Treatment Triggers Mood Changes

Table of Contents

1. Interferon-Alpha as a Medicine
2. How Often Major Depression Developed
3. Who Was Most Likely to Become Depressed
4. Two Waves of Symptoms Over Time
5. The Proposed Tryptophan–Kynurenine Mechanism
6. What Was Measured in the Spinal Fluid
7. The Antidepressant Prevention Trials
8. What This Taught Researchers About Inflammation and Depression
9. Why the Problem Is Now Rarer
10. What Is Not Known
11. Connections
12. Key Research Papers
13. Featured Videos

Interferon-Alpha as a Medicine

Interferons are cytokines — small proteins that immune cells release to coordinate a defence against viruses and abnormal cells. Interferon-alpha was manufactured as a drug and given by injection under the skin. A 2005 review from Emory University describes it as used to treat chronic viral hepatitis and several cancers, and notes that, “although frequently effective,” it produced a range of effects on the mind and brain.

Two groups of patients account for most of the research on its psychiatric effects:

• Chronic hepatitis C. Interferon-alpha (later a long-acting “pegylated” form, peginterferon) was combined with the antiviral tablet ribavirin. Courses ran for 24 or 48 weeks. In one Italian study, patients received 3 to 6 million units under the skin three to six times a week for 6 months.
• Malignant melanoma. Some patients received high-dose interferon-alpha. The Emory paroxetine trial enrolled patients who were eligible for this high-dose treatment.

The 2005 review lists three kinds of psychiatric effect: an acute confusional state that can develop rapidly after high-dose treatment begins (with disorientation, drowsiness, slowed movement and sometimes psychotic symptoms); a depressive syndrome that develops more slowly over weeks to months; and manic states, most often marked by extreme irritability and agitation and occasionally by euphoria. The review describes severe mania as a clinical emergency. This page concerns the depressive syndrome, which was by far the most studied.

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How Often Major Depression Developed

The clearest figure for hepatitis C comes from a 2012 systematic review and meta-analysis from Barcelona. It pooled 26 prospective observational studies in which patients had no depressive episode when treatment began and were then assessed by a trained clinician during interferon-alpha and ribavirin treatment.

• The overall cumulative incidence of a major depressive episode was 25% (95% confidence interval 16% to 35%) by 24 weeks of treatment.
• It was 28% (95% confidence interval 17% to 42%) by 48 weeks.
• The authors summarised it as one in four hepatitis C patients starting interferon and ribavirin developing an induced major depressive episode.

The 2005 Emory review, which counted significant depressive symptoms rather than only full major depression, gave a range of 21% to 58% of patients receiving interferon-alpha, with symptoms typically appearing over the first several months.

In melanoma patients on high-dose interferon-alpha, the placebo group of the Emory paroxetine trial gives a direct figure: symptoms consistent with major depression developed in 9 of 20 patients (45%) during the first 12 weeks. In the German escitalopram trial in hepatitis C patients with no psychiatric history, major depression was diagnosed in 19% of the placebo group, and 59% of that group reached a depression-scale score of 13 or higher at some point.

These figures come from different doses, different diseases and different definitions of depression, which is why they do not match. What they share is that depression appeared in a substantial minority of people who were not depressed at the start.

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Who Was Most Likely to Become Depressed

The 2012 meta-analysis tested which features measured before treatment predicted a major depressive episode during it. The predictors it found were:

• A past major depressive episode — odds ratio 3.96 (95% confidence interval 2.52 to 6.21), the strongest of the group.
• Any past psychiatric disorder — odds ratio 3.18 (95% confidence interval 1.60 to 6.32).
• Mild depressive symptoms already present below the threshold for a diagnosis.
• Higher blood levels of interleukin-6, an inflammatory cytokine, before treatment.
• Female sex — odds ratio 1.40 (95% confidence interval 1.02 to 1.91).
• Fewer years of education.

The 2005 review reached a similar picture: the most replicated risk factor was mood and anxiety symptoms before treatment, with a past history of major depression, female sex, and higher interferon-alpha dose and longer treatment as less consistently replicated factors.

The interleukin-6 finding is notable. It suggests that a person’s inflammatory state before the drug was given may have shaped how their brain responded to it — a point that fed directly into the wider inflammation research described below.

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Two Waves of Symptoms Over Time

Because assessments began on the first day of treatment, researchers could track the order in which symptoms appeared. A 2002 analysis of the 40 melanoma patients in the Emory paroxetine trial found two distinct patterns:

• An early wave of neurovegetative and bodily symptoms — loss of appetite, fatigue and pain — appeared within two weeks of starting interferon-alpha in a large proportion of patients.
• A later wave of depressed mood, anxiety and problems with thinking appeared further into treatment, and mainly in the patients who went on to meet the diagnostic criteria for major depression.

The two waves also responded differently to the antidepressant. Depressed mood, anxiety, thinking problems and pain responded more to paroxetine; fatigue and loss of appetite responded less. The authors concluded that different mechanisms probably drive the different parts of cytokine-induced “sickness behaviour.”

The 2005 review describes the same split: a depression-specific syndrome of mood, anxiety and thinking complaints that responds well to serotonin-acting antidepressants, and a neurovegetative syndrome of fatigue, poor appetite, pain and slowed movement that responds much less. Across hepatitis C studies, the 2012 meta-analysis showed most of the cumulative risk building up by 24 weeks, with only a small further rise by 48 weeks.

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The Proposed Tryptophan–Kynurenine Mechanism

The leading explanation is a proposed mechanism, not a proven one. It runs through the amino acid tryptophan, which the body uses to make serotonin. Immune signals switch on an enzyme called indoleamine 2,3-dioxygenase (IDO), which breaks tryptophan down into a different molecule, kynurenine, instead. The idea is that interferon-alpha switches on indoleamine 2,3-dioxygenase, drains tryptophan away from serotonin production, and builds up kynurenine and its breakdown products, some of which act on brain cells. (The full pathway is explained on the Tryptophan and Cognitive Function page.)

What was actually measured in the blood:

• Hepatitis C, Italy (2002). In 18 patients measured before treatment and at 2, 4, 16 and 24 weeks, interferon-alpha significantly lowered blood tryptophan and blood serotonin, and raised kynurenine and the kynurenine-to-tryptophan ratio, a marker of indoleamine 2,3-dioxygenase activity. The rise in depression scores was linked to higher kynurenine and lower serotonin.
• Cancer patients, France (2002). In 16 patients receiving interleukin-2 and/or interferon-alpha, blood tryptophan fell after one week and further after one month. The size of the fall was linked to the development and severity of depressive symptoms, especially loss of appetite, pessimistic thoughts, suicidal thoughts and loss of concentration.
• Melanoma, United States (2003). In 26 patients from the paroxetine trial, every patient’s kynurenine, kynurenine-to-tryptophan ratio and neopterin (a marker of immune activation) rose during interferon-alpha, whether or not they took the antidepressant. Among patients not taking paroxetine, those who developed major depression had larger rises in kynurenine and neopterin and longer-lasting falls in tryptophan. Falls in tryptophan tracked depressive, anxious and thinking symptoms — but not fatigue, poor appetite or other bodily symptoms.

That last study also found that paroxetine did not change the kynurenine or neopterin response. The authors’ interpretation was that the antidepressant softened the behavioural effect of tryptophan depletion rather than preventing the depletion itself.

All of these are correlations in small groups. They show that the pathway is switched on during treatment and that bigger changes go with more depression; they do not on their own prove that the pathway causes the depression.

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What Was Measured in the Spinal Fluid

Blood levels say little about what happens behind the blood–brain barrier. A 2010 Emory study addressed that by sampling cerebrospinal fluid (the fluid around the brain and spinal cord) in 27 people with hepatitis C after about 12 weeks: 16 receiving interferon-alpha and 11 receiving no treatment.

• Interferon-alpha raised kynurenine in the blood and produced marked increases in kynurenine in the cerebrospinal fluid.
• The higher spinal-fluid kynurenine went with significant increases in two of its breakdown products, quinolinic acid and kynurenic acid, both of which act on nerve cells.
• Blood tryptophan fell, but tryptophan in the cerebrospinal fluid did not change.
• Increases in spinal-fluid kynurenine and quinolinic acid were linked to higher interferon-alpha and other inflammatory signals in the spinal fluid, and to more depressive symptoms.

The unchanged spinal-fluid tryptophan is an important detail. It points away from a simple “not enough tryptophan reaches the brain” explanation and toward the build-up of kynurenine and quinolinic acid inside the brain, alongside an immune response within the central nervous system itself. The study measured a single point in time in a small group, so it shows association, not cause.

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The Antidepressant Prevention Trials

Because the start date of the immune trigger was known, researchers could test whether starting an antidepressant before interferon-alpha would prevent depression. The idea came partly from laboratory animals, in which pretreatment with antidepressants lessened depression-like behaviour after a cytokine was given.

Paroxetine in melanoma (2001)

In a double-blind trial at Emory University, 40 patients with malignant melanoma about to start high-dose interferon-alpha were randomly assigned to paroxetine (20 patients) or placebo (20 patients). The study drug began 2 weeks before interferon-alpha and continued for the first 12 weeks of it.

• Major depression: 2 of 18 patients (11%) on paroxetine versus 9 of 20 (45%) on placebo (relative risk 0.24; 95% confidence interval 0.08 to 0.93).
• Stopping interferon-alpha before 12 weeks because of severe depression: 1 of 20 (5%) on paroxetine versus 7 (35%) on placebo (relative risk 0.14; 95% confidence interval 0.05 to 0.85).
• The incidence of adverse events was similar in the two groups.

Escitalopram in hepatitis C (2012)

A larger German trial at 21 university and academic hospitals enrolled 181 hepatitis C patients with no history of psychiatric disorder, the group in whom the value of prevention had been unclear. The trial gave escitalopram 10 mg a day (90 patients) or placebo (91 patients), starting 2 weeks before peginterferon-alpha-2a and continuing through 24 to 48 weeks of antiviral treatment.

• Depression by the trial’s main measure (a Montgomery–Asberg Depression Rating Scale score of 13 or higher): 32% on escitalopram versus 59% on placebo, an absolute difference of 27 percentage points.
• Major depression by diagnostic criteria: 8% versus 19%.
• Tolerability and safety measures did not differ between the groups.
• Cure of the virus (sustained virologic response): 56% versus 46%, a difference that was not statistically significant.

The authors listed limits: the results might not apply to people with previous psychiatric illness, and some patients withdrew or had temporarily raised depression scores after randomisation but before the study drug began.

The pooled picture (2014)

A 2014 meta-analysis from Barcelona combined 7 double-blind, placebo-controlled prevention trials in hepatitis C, with 591 patients (escitalopram 197, paroxetine 42, citalopram 53, placebo 299). Selective serotonin reuptake inhibitors as a group:

• reduced the incidence of a major depressive episode during treatment (odds ratio 0.53; 95% confidence interval 0.33 to 0.84);
• gave a number needed to treat of 12 — about 12 people given the antidepressant for one fewer case of major depression;
• reduced depressive symptoms at 24 weeks;
• were linked to more dizziness (odds ratio 2.65), the only side effect that differed;
• made no difference to cure of the virus.

The authors described the preventive effect as “relatively moderate” with good tolerability. The 2005 Emory review also reported that several studies found antidepressants effective in treating interferon-induced depression after it had developed, allowing most patients to complete their course.

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What This Taught Researchers About Inflammation and Depression

Interferon-alpha treatment worked, in effect, as a natural experiment: a known immune signal, given on a known day, to people who were mostly not depressed. Several lessons came out of it.

• An immune signal alone can be followed by depression. Depression appeared in roughly a quarter of hepatitis C patients with no depressive episode at the start, and in nearly half of high-dose melanoma patients on placebo.
• “Sickness behaviour” and depression overlap but are not the same. The early fatigue and poor appetite resemble the ordinary feeling of being ill; the later low mood, anxiety and thinking problems resemble depression and behaved differently in treatment.
• Vulnerability matters. Not everyone became depressed. Past depression, existing low mood and higher baseline interleukin-6 raised the odds.
• A biological pathway could be followed in people. Kynurenine rose in the blood and in the fluid around the brain, and the size of the rise went with depressive symptoms.

A 2008 review in Nature Reviews Neuroscience drew these threads into a broader model: immune cells release inflammatory cytokines that act on the brain to cause sickness behaviour, and when immune activation continues unabated — in long infections, cancer or autoimmune disease — the ongoing signalling can lead to symptoms of depression in vulnerable people. The authors proposed that this might account for the higher rate of depression in physically ill people, and described inflammation as a biological event that might increase the risk of major depressive episodes much like the more traditional psychological and social factors. Related reading on the serotonin side of this story is on Tryptophan for Mood and Serotonin and Gut-Brain Axis, Serotonin, and Mood.

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Why the Problem Is Now Rarer

For hepatitis C, the treatment itself has changed. A 2015 review in the World Journal of Hepatology describes the 2014 US Food and Drug Administration approvals of two all-tablet direct-acting antiviral regimens, and notes that until then interferon-alpha with ribavirin had remained part of the standard of care. Under the interferon regimen, the review states, psychosocial factors — including interferon-related depressive symptoms and existing psychiatric conditions — delayed as much as 70% of otherwise eligible candidates from treatment. With shorter courses, far fewer side effects and simpler regimens, the authors describe psychosocial contraindications as greatly reduced, while current psychiatric illness and interactions with psychiatric drugs still need clinical attention.

A 2023 literature review from Spain makes the same point from the psychiatric side: hepatitis C treatment was formerly based on pegylated interferon-alpha, whose neuropsychiatric adverse events contributed to the exclusion of people with severe mental illness from treatment and trials. It reports that the newer pangenotypic direct-acting antivirals have proven equally effective and safe in people with severe mental illness, and improve their quality of life. (More on the infection itself is on the Hepatitis C page.)

The sources read for this page do not describe how widely interferon-alpha is still used for melanoma or other conditions today, so this page makes no statement about that.

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What Is Not Known

• Cause versus association. The tryptophan–kynurenine findings are correlations in small studies (16 to 27 people each in the studies on this page). They show the pathway switching on and tracking symptoms, not that blocking it would prevent depression.
• Why only some people. Risk factors raise the odds, but they do not explain why one patient becomes depressed and another on the same dose does not.
• The bodily symptoms. Fatigue and poor appetite responded poorly to the serotonin-acting antidepressants tested, and the 2002 Emory analysis concluded that different mechanisms probably drive them.
• Who benefits from prevention. The escitalopram trial enrolled only people with no psychiatric history, and its authors noted the results might not apply to people with previous psychiatric disease. The pooled effect across trials was moderate, with about 12 people treated for one case prevented.
• How far the lessons carry. Interferon-alpha is a strong, deliberately given immune signal. How closely its effects match the lower-grade inflammation seen in some people with everyday depression is a question the 2008 model raises but these studies do not settle.

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Connections

• Psychiatry — the parent section
• Depression — the illness in general
• Tryptophan and Cognitive Function — the kynurenine pathway in detail
• Tryptophan for Mood and Serotonin — tryptophan and serotonin
• Hepatitis C — the infection interferon was used to treat
• Melanoma — the cancer in the paroxetine trial
• Gut-Brain Axis, Serotonin, and Mood — another route between body and mood
• Inflammation: The Cascade and How It Resolves — an animation of the inflammatory response

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Key Research Papers

1. Udina M, Castellví P, Moreno-España J, Navinés R, Valdés M, Forns X, Langohr K, Solà R, Vieta E, Martín-Santos R. Interferon-induced depression in chronic hepatitis C: a systematic review and meta-analysis. J Clin Psychiatry. 2012;73(8):1128-38. PubMed PMID: 22967776
2. Raison CL, Demetrashvili M, Capuron L, Miller AH. Neuropsychiatric adverse effects of interferon-alpha: recognition and management. CNS Drugs. 2005;19(2):105-23. PubMed PMID: 15697325
3. Capuron L, Gumnick JF, Musselman DL, Lawson DH, Reemsnyder A, Nemeroff CB, Miller AH. Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology. 2002;26(5):643-52. PubMed PMID: 11927189
4. Bonaccorso S, Marino V, Puzella A, Pasquini M, Biondi M, Artini M, Almerighi C, Verkerk R, Meltzer H, Maes M. Increased depressive ratings in patients with hepatitis C receiving interferon-alpha-based immunotherapy are related to interferon-alpha-induced changes in the serotonergic system. J Clin Psychopharmacol. 2002;22(1):86-90. PubMed PMID: 11799348
5. Capuron L, Ravaud A, Neveu PJ, Miller AH, Maes M, Dantzer R. Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry. 2002;7(5):468-73. PubMed PMID: 12082564
6. Capuron L, Neurauter G, Musselman DL, Lawson DH, Nemeroff CB, Fuchs D, Miller AH. Interferon-alpha-induced changes in tryptophan metabolism. relationship to depression and paroxetine treatment. Biol Psychiatry. 2003;54(9):906-14. PubMed PMID: 14573318
7. Raison CL, Dantzer R, Kelley KW, Lawson MA, Woolwine BJ, Vogt G, Spivey JR, Saito K, Miller AH. 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. PubMed PMID: 19918244
8. Musselman DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S, Goodkin RS, Greiner K, Nemeroff CB, Miller AH. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med. 2001;344(13):961-6. PubMed PMID: 11274622
9. Schaefer M, Sarkar R, Knop V, Effenberger S, Friebe A, Heinze L, Spengler U, Schlaepfer T, Reimer J, Buggisch P, Ockenga J, Link R, Rentrop M, Weidenbach H, Fromm G, Lieb K, Baumert TF, Heinz A, Discher T, Neumann K, Zeuzem S, Berg T. Escitalopram for the prevention of peginterferon-α2a-associated depression in hepatitis C virus-infected patients without previous psychiatric disease: a randomized trial. Ann Intern Med. 2012;157(2):94-103. PubMed PMID: 22801672
10. Udina M, Hidalgo D, Navinés R, Forns X, Solà R, Farré M, Capuron L, Vieta E, Martín-Santos R. Prophylactic antidepressant treatment of interferon-induced depression in chronic hepatitis C: a systematic review and meta-analysis. J Clin Psychiatry. 2014;75(10):e1113-21. PubMed PMID: 25373120
11. Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9(1):46-56. PubMed PMID: 18073775
12. Rowan PJ, Bhulani N. Psychosocial assessment and monitoring in the new era of non-interferon-alpha hepatitis C virus treatments. World J Hepatol. 2015;7(19):2209-13. PubMed PMID: 26380046
13. Gutiérrez-Rojas L, de la Gándara Martín JJ, García Buey L, Uriz Otano JI, Mena Á, Roncero C. Patients with severe mental illness and hepatitis C virus infection benefit from new pangenotypic direct-acting antivirals: Results of a literature review. Gastroenterol Hepatol. 2023;46(5):382-396. PubMed PMID: 35718017

PubMed Topic Searches

1. Interferon-alpha induced depression
2. Interferon, kynurenine and depression
3. Antidepressant prevention during interferon treatment for hepatitis C
4. Inflammation, cytokines and major depression

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