Hostname: page-component-74656f9884-8rzl6 Total loading time: 0 Render date: 2026-11-05T13:25:40.785Z Has data issue: false hasContentIssue false
  • English
  • Français

Mechanisms of interferon-alpha-induced depressive symptoms

Published online by Cambridge University Press:  24 June 2014

M. C. Wichers  and
M. Maes
M. C. Wichers*
Affiliation:
Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands
M. Maes
Affiliation:
Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands
*
Department of Psychiatry and Neuropsychology, Maastricht University, PO BOX 616,6200MD Maastricht, the Netherlands. Tel. + 31-43-3871025; Fax: + 31-43-3871026; http://users.skynet.be/crc.mh/
Rights & Permissions [Opens in a new window]

Abstract

An abstract is not available for this content. As you have access to this content, full HTML content is provided on this page. A PDF of this content is also available in through the ‘Save PDF’ action button.

Information

Type
Editorial
Information
Acta Neuropsychiatrica , Volume 14 , Issue 3 , June 2002 , pp. 103 - 105
Copyright
Copyright © Acta Neuropsychiatrica 2002

Side-effects of interferon-alpha

Several studies have found a high incidence of neuropsychiatric side effects during long-term interferon-alpha (IFNα) therapy, including depressed mood, anxiety, loss of interest, slowness, severe fatigue, hypersomnia lethargy, poor appetite, irritability, short temper emotional lability, social withdrawal and lack of concentration (Reference Bonaccorso, Marino, Biondi, Grimaldi, Ippoliti and Maes1). In a study from the National Institutes of Health (Reference Renault, Hoofnagle and Park2) 10 of 58 patients (17%) with chronic viral hepatitis treated with a 4–12-month course of recombinant IFNα developed psychiatric side-effects. Furthermore, Bonaccorso et al. (Reference Bonaccorso, Marino, Biondi, Grimaldi, Ippoliti and Maes1) found that of 30 patients, 40.7% suffered of major depression according to DSM-IV criteria after treatment with IFNα for three months. Some studies even report that treatment with IFNα may lead to suicidal thoughts and suicide attempts (Reference Schafer, Messer, Wegner, Schmid-Wendtner and Volkenandt3).

The mechanisms by which IFNα is able to influence brain function are not yet clear. Some mechanisms have been proposed and will be discussed below.

Influence of IFNα on serotonin, cytokine network and HPA axis

The brain is relatively isolated from the immune system due to the presence of the blood brain barrier (BBB) (Reference Darling, Hoyle and Thomas4). However, it is thought that systemically administered IFNα is able to cross the BBB (Reference Pan, Banks and Kastin5) and that it enters the brain through areas lacking the BBB, particularly the organum vasculosum lamina terminalis (Reference Shibata and Blatteis6).

Serotonin (5-HT) plays an important role in mood regulation. Major depression is accompanied by disturbances in the 5-HT metabolism (Reference Maes, Meltzer, Bloom and Kupfer7). IFNα is able to affect the central serotonergic system. It up-regulates the transcription of the central 5-HT transporter, which enhances the reuptake of 5-HT and causes a depletion of extracellular 5-HT (Reference Morikawa, Sakai, Obara and Saito8). In addition, IFNα affects the low-affinity 5-HT1A receptor sites (Reference Abe, Hori, Suzuki, Baba, Shiraishi and Yamamoto9) and it may be able to modulate 5-HT2 receptors (Reference Kugaya, Kagaya, Uchitomi, Yokota and Yamawaki10). Furthermore, IFNα is able to modulate the 5-HT system through its effect on the enzyme indoleamine 2,3 dioxygenase (IDO), which induces the catabolism of tryptophan, the precursor of 5-HT, to kynurenine. Overstimulation of IDO leads to depletion of plasma concentrations of tryptophan and perhaps to reduced synthesis of 5-HT in the brain, as the latter depends on plasma availability of tryptophan (Reference Heyes, Saito and Crowley11). While IFNγ directly affects IDO activity, IFNα has a weak direct effect and in addition an indirect effect through a 15-kDa protein, which is a product of IFNα-treated monocytes and lymphocytes and which stimulates IDO and IFNγ production (Reference Recht, Borden and Knight12). Thus, IFNα is able to influence the central 5-HT system directly as well as by modulating peripheral tryptophan catabolism.

Another mechanism by which IFNα may be able to produce depressive symptoms is by modulating the hypothalamic–pituitary–adrenal (HPA) axis. The main driving force behind HPA activation is hypothalamic corticotropin-releasing factor (CRF), which enhances the release of ACTH from the pituitary, which in turn stimulates the release of corticosteroids from the adrenal glands. Overactivity of the HPA axis, experimentally induced in animals by long-term central CRF-infusion, causes symptoms such as anxiety, anhedonia, anorexia, changes in sexual behavior and changes in sleeping pattern (Reference Nemeroff, Widerlov and Bissette13).

Depressed people also have an overactive HPA axis characterized by an increased number of ACTH and cortisol secretory pulses (Reference Rubin, Poland, Lesser, Winston and Blodgett14), elevated levels of CRF in the CSF (Reference Nemeroff, Widerlov and Bissette13), an increased number of CRF secreting neurons in limbic brain regions (Reference Raadsheer, Hoogendijk, Stam, Tilders and Swaab15) and a reduced number of CRF binding sites in the frontal cortex secondary to increased CRF concentration (Reference Nemeroff, Owens, Bissette, Andorn and Stanley16). Administration of dexamethasone, a synthetic glucocorticoid, reveals, in depressed patients, a relative resistance to its suppressive effect on the activity of the HPA axis (Reference Carroll17). Therefore, the hypothesis is postulated that negative feedback mechanisms through glucocorticoid receptors are impaired in depressives (Reference Carroll17).

IFNα may affect the HPA axis by its effect on the cytokine network. It stimulates the production of other proinflammatory cytokines such as interleukin (IL)-1 and IL-6 (Reference Maes, Capuron and Ravaud18). These cytokines are known to exert potent enhancing effects on the HPA axis by stimulating CRF, ACTH and the production of corticosteroids (Reference Navarra, Tsagarakis, Faria, Rees, Besser and Grossman19). A logical candidate pathway for IL-1 to influence the brain is via the vagus nerve (10th cranial nerve). First, the vagus innervates tissues known to participate in immune functions and branches of the vagus are often associated with lymph nodes that drain regions in which immune activation occurs. Secondly, the injection of IL-1β into the hepatoportal vein increases vagal electrical activity. In addition, subdiaphragmatic vagotomy blocks the neural, physiological and behavioral effects of IL-1β (Reference Maier, Goehler, Fleshner and Watkins20).

Prevention of side-effects with antidepressants

Antidepressant pharmacotherapy may be useful to prevent the depressive side-effects of administration of IFNα.

First, antidepressive agents exert an influence on the serotonergic system. Antidepressant drugs may act via their long-term ability to modulate pre- and postsynaptic serotonergic function. Furthermore, tricyclic antidepressants such as clomipramine and imipramine, selective serotonin reuptake inhibitors (SSRIs) such as sertraline, heterocyclic antidepressants such as trazodone and 5-HTP, the direct precursor of 5-HT, are found to have a significant suppressive effect on the proinflammatory cytokine IFNγ and/or a stimulatory effect on IL-10 secretion, an anti-inflammatory cytokine whole blood stimulated with polyclonal activators (Reference Kubera, Kenis, Bosmans, Scharpe and Maes21). Another study (Reference Xia, Depierre and Nassberger22) showed that the antidepressants imipramine, clomipramine and citalopram caused an inhibition of IL-2 and IFNγ release from activated T cells after polyclonal activation and a similar inhibitory pattern was seen for IL-1β, TNF-α and IL-6 release from monocytes. Thus, antidepressants may counteract the effects of IFNα on the cytokine network by its negative immunoregulatory effects.

Finally, antidepressant drugs such as desipramine, imipramine and amytriptyline (Reference Duncan, Knapp, Carson and Breese23) are able to decrease HPA activity. The fact that patients who do not respond to antidepressant treatment continue to have HPA dysregulation (Reference Maes, De Ruyter, Hobin and Suy24) supports a causal relationship between normalization of stress hormone regulation and clinical recovery. Antidepressants may be able to down-regulate HPA activity by decreasing CRH gene expression in the paraventricular nucleus of the hypothalamus (Reference Brady, Whitfield, Fox, Gold and Herkenham25) and by increasing corticosteroid receptor sites in brain regions known to mediate the inhibitory effects of glucocorticoids on subsequent HPA activity, thereby increasing the feedback inhibition over the HPA axis (Reference Rowe, Steverman and Walker26).

In addition it has been shown that they are able to reduce IFNα-induced depression. Administration of paroxetine (Reference Musselman, Lawson and Gumnick27) and imipramine (Reference Gleason and Yates28) have proven to be effective in alleviating IFNα-induced depressive symptoms in hepatitis C patients. Thus, antidepressants might be useful to prevent the development of depression in IFNα therapy.

References

Bonaccorso, S, Marino, V, Biondi, M, Grimaldi, F, Ippoliti, F, Maes, M. Major depression induced by interferon-alpha in patients affected by hepatitis C virus. J Affect Disord 2000, in press.Google Scholar
Renault, PF, Hoofnagle, JH, Park, Yet al. Psychiatric complications of long-term interferon alfa therapy. Arch Intern Med 1987;147: 1577–1580.CrossRefGoogle Scholar
Schafer, M, Messer, T, Wegner, U, Schmid-Wendtner, Mh, Volkenandt, M. [Psychiatric side effects during adjuvant therapy with interferon-alpha in patients with malignant melanoma. Clinical evaluation as well as diagnostic and therapeutic possibilities]. Hautarzt 1999;50: 654–658.Google Scholar
Darling, JJ, Hoyle, NR, Thomas, DGT. Self and non-self in the brain. Immunol Today 1981;2: 176–181. CrossRefGoogle Scholar
Pan, W, Banks, WA, Kastin, AJ. Permeability of the blood–brain and blood–spinal cord barriers to interferons. J Neuroimmunol 1997;76: 105–111.CrossRefGoogle ScholarPubMed
Shibata, M, Blatteis, CM. Human recombinant tumor necrosis factor and interferon affect the activity of neurons in the organum vasculosum laminae terminalis. Brain Res 1991;562: 323–326.CrossRefGoogle ScholarPubMed
Maes, M, Meltzer, H. The serotonin hypothesis of major depression. In: Bloom, F, Kupfer, D, eds. Psychopharmacology: the fourth generation of progress. New York: Raven Press, 1995, 933–944. Google Scholar
Morikawa, O, Sakai, N, Obara, H, Saito, N. Effects of interferon-alpha, interferon-gamma and cAMP on the transcriptional regulation of the serotonin transporter. Eur J Pharmacol 1998;349: 317–324.CrossRefGoogle ScholarPubMed
Abe, S, Hori, T, Suzuki, T, Baba, A, Shiraishi, H, Yamamoto, T. Effects of chronic administration of interferon alpha A/D on serotonergic receptors in rat brain. Neurochem Res 1999;24: 359–363.CrossRefGoogle ScholarPubMed
Kugaya, A, Kagaya, A, Uchitomi, Y, Yokota, N, Yamawaki, S. Effect of interferon-alpha on DOI-induced wet-dog shakes in rats. J Neural Transm 1996;103: 947–955.CrossRefGoogle ScholarPubMed
Heyes, MP, Saito, K, Crowley, JSet al. Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease. Brain 1992;115: 1249–1273.CrossRefGoogle ScholarPubMed
Recht, M, Borden, EC, Knight, E JrA human 15-kDa IFN-induced protein induces the secretion of IFN-gamma. J Immunol 1991;147: 2617–2623.Google ScholarPubMed
Nemeroff, CB, Widerlov, E, Bissette, Get al. Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 1984;226: 1342–1344.CrossRefGoogle ScholarPubMed
Rubin, RT, Poland, RE, Lesser, IM, Winston, RA, Blodgett, AL. Neuroendocrine aspects of primary endogenous depression. I. Cortisol secretory dynamics in patients and matched controls. Arch General Psychiatry 1987;44: 328–336. CrossRefGoogle ScholarPubMed
Raadsheer, FC, Hoogendijk, WJ, Stam, FC, Tilders, FJ, Swaab, DF. Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology 1994;60: 436–444.CrossRefGoogle ScholarPubMed
Nemeroff, CB, Owens, MJ, Bissette, G, Andorn, AC, Stanley, M. Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims. Arch Gen Psychiatry 1988;45: 577–579.CrossRefGoogle ScholarPubMed
Carroll, BJ. Clinical applications of the dexamethasone suppression test for endogenous depression. Pharmacopsychiatria 1982;15: 19–25.CrossRefGoogle ScholarPubMed
Maes, M, Capuron, L, Ravaud, Aet al. Lowered serum dipeptidyl peptidase IV activity is associated with depressive symptoms and cytokine production in cancer patients receiving interleukin-2-based immunotherapy. Neuropsychopharmacology 2001;24: 130–140.CrossRefGoogle ScholarPubMed
Navarra, P, Tsagarakis, S, Faria, MS, Rees, LH, Besser, GM, Grossman, AB. Interleukins-1 and -6 stimulate the release of corticotropin-releasing hormone-41 from rat hypothalamus in vitro via the eicosanoid cyclooxygenase pathway. Endocrinology 1991;128: 37–44.CrossRefGoogle ScholarPubMed
Maier, SF, Goehler, LE, Fleshner, M, Watkins, LR. The role of the vagus nerve in cytokine-to-brain communication. Ann NY Acad Sci 1998;840: 289–300.CrossRefGoogle Scholar
Kubera, M, Kenis, G, Bosmans, E, Scharpe, S, Maes, M. Effects of serotonin and serotonergic agonists and antagonists on the production of interferon-gamma and interleukin-10. Neuropsychopharmacology 2000;23: 89–98.CrossRefGoogle Scholar
Xia, Z, Depierre, JW, Nassberger, L. Tricyclic antidepressants inhibit IL-6, IL-1 beta and TNF-alpha release in human blood monocytes and IL-2 and interferon-gamma in T cells. Immunopharmacology 1996;34: 27–37.CrossRefGoogle Scholar
Duncan, GE, Knapp, DJ, Carson, SW, Breese, GR. Differential effects of chronic antidepressant treatment on swim stress- and fluoxetine-induced secretion of corticosterone and progesterone. J Pharmacol Exp Ther 1998;285: 579–587.Google ScholarPubMed
Maes, M, De Ruyter, M, Hobin, P, Suy, E. Repeated dexamethasone suppression test in depressed patients. J Affect Disord 1986;11: 165–172.CrossRefGoogle ScholarPubMed
Brady, LS, Whitfield, HJ Jr,Fox, RJ, Gold, PW, Herkenham, M. Antidepressant drugs regulate corticotropin-releasing factor and tyrosine hydroxylase messenger RNAs in rat brain. J Clin Invest 1991;87: 831–837.CrossRefGoogle Scholar
Rowe, W, Steverman, A, Walker, Met al. Antidepressants restore hypothalamic-pituitary-adrenal feedback function in aged, cognitively-impaired rats. Neurobiol Aging 1997;18: 527–533.CrossRefGoogle Scholar
Musselman, DL, Lawson, DH, Gumnick, JFet al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med 2001;344: 961–966.CrossRefGoogle ScholarPubMed
Gleason, OC, Yates, WR. Five cases of interferon-alpha-induced depression treated with antidepressant therapy. Psychosomatics 1999;40: 510–512.CrossRefGoogle ScholarPubMed