Pharmacopsychiatry 2003; 36: 203-206
DOI: 10.1055/s-2003-45131
Original Paper
© Georg Thieme Verlag Stuttgart · New York

Neurotransmitter Changes by Interferon-Alpha and Therapeutic Implications

M. Schaefer1 , M. Schwaiger1 , M. Pich1 , K. Lieb2 , A. Heinz1
  • 1Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Campus Charité-Mitte (CCM), Berlin, Germany
  • 2Department of Psychiatry and Psychotherapy, University of Freiburg Medical School, Freiburg, Germany
Further Information

Publication History

Publication Date:
15 December 2003 (online)

Interferon alpha (IFN-α) is a cytokine that is widely used for the treatment of chronic viral infection or malignant disorders. During treatment with IFN-α, severe neuropsychiatric syndromes may occur such as depression with suicidal ideation, paranoid psychoses or confusional states. The neurobiological correlates of these side effects are widely unknown. Besides induction of other cytokines and hormonal changes, IFN-α  has been shown to modulate the opioid, serotonin, dopamine and glutamate neurotransmitter system. Positive therapeutic effects of antidepressants such as selective serotonin-reuptake-inhibitors (SSRI) or of opioid receptor antagonists support the hypothesis that neurotransmitter changes play an important role in the development of IFN-α associated neuropsychiatric side effects. We review recent research about IFN-associated neurotransmitter changes in the central nervous system and discuss treatment strategies.

References

  • 1 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
  • 2 Blalock J E, Smith E M. Human leukocyte interferon (HuIFN-alpha): potent endorphin-like opioid activity.  Biochem Biophys Res Commun. 1981;  101 (2) 472-478
  • 3 Brown R R, Lee C M, Kohler P C, Hank J A, Storer B E, Sondel P M. Altered tryptophan and neopterin metabolism in cancer patients treated with recombinant interleukin 2.  Cancer Res. 1989;  49 4941-4944
  • 4 Capuron L, Ravaud A, Neveu P J, Miller A H, Maes M, Dantzer R. Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy.  Mol Psychiatry. 2002;  7 468-473
  • 5 Chao C C, Hu S, Sheng W S, Bu D, Bukrinsky M I, Peterson P K. Cytokine-stimulated astrocytes damage human neurons via a nitric oxide mechanism.  Glia. 1996;  16 276-284
  • 6 Dafny N. Interferon: a candidate as the endogenous substance preventing tolerance and dependence to brain opioids.  Prog Neuropsychopharmacol Biol Psychiatry. 1984;  8 351-357
  • 7 Dafny N, Prieto-Gomez B, Dong W Q, Reyes-Vazquez C. Interferon modulates neuronal activity recorded from the hypothalamus, thalamus, hippocampus, amygdala and the somatosensory cortex.  Brain Res. 1996;  734 269-274
  • 8 Dafny N, Prieto-Gomez B, Reyes-Vazquez C. Does the immune system communicate with the central nervous system? Interferon modifies central nervous activity.  J Neuroimmunol. 1985;  9 1-12
  • 9 Dafny N, Reyes-Vazquez C. Three different types of alpha-interferons alter naloxone-induced abstinence in morphine-addicted rats.  Immunopharmacology. 1985;  9 13-17
  • 10 Dafny N, Zielinksi M, Reyes-Vazquez C. Alteration of morphine withdrawal to naloxone by interferon.  Neuropeptides. 1983;  3 453-463
  • 11 De La G R, Asnis G M. The non-steroidal anti-inflammatory drug diclofenac sodium attenuates IFN-alpha induced alterations to monoamine turnover in prefrontal cortex and hippocampus.  Brain Res. 2003;  977 70-79
  • 12 De Sarro G B, Masuda Y, Ascioti C, Audino M G, Nistico G. Behavioural and ECoG spectrum changes induced by intracerebral infusion of interferons and interleukin 2 in rats are antagonized by naloxone.  Neuropharmacology. 1990;  29 167-179
  • 13 Garssadi S I, Mandi Y, Regely K, Tarodi B, Beladi I. The inhibitory effect of interferon-alpha on the serotonin-induced impairment of human NK cell activity in whole blood.  Brain Behav Immun. 1993;  7 164-175
  • 14 Hauser P, Khosla J, Aurora H, Laurin J, Kling M A, Hill J. et al . A prospective study of the incidence and open-label treatment of interferon-induced major depressive disorder in patients with hepatitis C.  Mol Psychiatry. 2002;  7 942-947
  • 15 Heinz A, Schmidt L G, Reischies F M. Anhedonia in schizophrenic, depressed, or alcohol-dependent patients-neurobiological correlates.  Pharmacopsychiatry. 1994;  27 Suppl 1 7-10
  • 16 Ho B T, Huo Y Y, Lu J G, Tansey L W, Levin V A. Opioid-dopaminergic mechanisms in the potentiation of d-amphetamine discrimination by interferon-alpha.  Pharmacol Biochem Behav. 1992;  42 57-60
  • 17 Hu S, Sheng W S, Ehrlich L C, Peterson P K, Chao C C. Cytokine effects on glutamate uptake by human astrocytes.  Neuroimmunomodulation. 2000;  7 153-159
  • 18 Jiang C L, Son L X, Lu C L, You Z D, Wang Y X, Sun L Y. et al . Analgesic effect of interferon-alpha via mu opioid receptor in the rat.  Neurochem Int. 2000;  36 193-196
  • 19 Kamata M, Higuchi H, Yoshimoto M, Yoshida K, Shimizu T. Effect of single intracerebroventricular injection of alpha-interferon on monoamine concentrations in the rat brain.  Eur Neuropsychopharmacol. 2000;  10 129-132
  • 20 Kamei S, Tanaka N, Mastuura M, Arakawa Y, Kojima T, Matsukawa Y. et al . Blinded, prospective, and serial evaluation by quantitative-EEG in interferon-alpha-treated hepatitis-C.  Acta Neurol Scand. 1999;  100 25-33
  • 21 Katafuchi T, Take S, Hori T. Roles of cytokines in the neural-immune interactions: modulation of NMDA responses by IFN-alpha.  Neurobiology (Bp). 1995;  3 319-327
  • 22 Kraus M R, Schafer A, Faller H, Csef H, Scheurlen M. Paroxetine for the treatment of interferon-alpha-induced depression in chronic hepatitis C.  Aliment Pharmacol Ther. 2002;  16 1091-1099
  • 23 Kraus M R, Schafer A, Scheurlen M. Paroxetine for the prevention of depression induced by interferon alfa.  N Engl J Med. 2001;  345 375-376
  • 24 Kumai T, Tateishi T, Tanaka M, Watanabe M, Shimizu H, Kobayashi S. Effect of interferon-alpha on tyrosine hydroxylase and catecholamine levels in the brain of rats.  Life Sci. 2000;  67 663-669
  • 25 Kuriyama K, Hori T, Mori T, Nakashima T. Actions of interferon alpha and interleukin- 1 beta on the glucose-responsive neurons in the ventromedial hypothalamus.  Brain Res Bull. 1990;  24 803-810
  • 26 Levenson J L, Fallon H J. Fluoxetine treatment of depression caused by interferon-alpha.  Am J Gastroenterol. 1993;  88 760-761
  • 27 Makino M, Kitano Y, Komiyama C, Hirohashi M, Kohno M, Moriyama M. et al . Human interferon-alpha induces immobility in the mouse forced swimming test: involvement of the opioid system.  Brain Res. 2000;  852 482-484
  • 28 Makino M, Kitano Y, Komiyama C, Hirohashi M, Takasuna K. Involvement of central opioid systems in human interferon-alpha induced immobility in the mouse forced swimming test.  Br J Pharmacol. 2000;  130 1269-1274
  • 29 Mendoza-Fernandez V, Andrew R D, Barajas-Lopez C. Interferon-alpha inhibits long-term potentiation and unmasks a long-term depression in the rat hippocampus.  Brain Res. 2000;  885 14-24
  • 30 Menkes D B, MacDonald J A. Interferons, serotonin and neurotoxicity.  Psychol Med. 2000;  30 259-268
  • 31 Menzies R A, Patel R, Hall N R, O’Grady M P, Rier S E. Human recombinant interferon alpha inhibits naloxone binding to rat brain membranes.  Life Sci. 1992;  50 L227-232
  • 32 Meyers C A, Scheibel R S, Forman A D. Persistent neurotoxicity of systemically administered interferon-alpha.  Neurology. 1991;  41 672-676
  • 33 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
  • 34 Musselman D L, Lawson D H, Gumnick J F, Manatunga A K, Penna S, Goodkin R S. et al . Paroxetine for the prevention of depression induced by high-dose interferon alfa.  N Engl J Med. 2001;  344 961-966
  • 35 Nakashima T, Murakami T, Murai Y, Hori T, Miyata S, Kiyohara T. Naloxone suppresses the rising phase of fever induced by interferon-alpha.  Brain Res Bull. 1995;  37 61-66
  • 36 Naranjo C A, Tremblay L K, Busto U E. The role of the brain reward system in depression.  Prog Neuropsychopharmacol Biol Psychiatry. 2001;  25 781-823
  • 37 Pavol M A, Meyers C A, Rexer J L, Valentine A D, Mattis P J, Talpaz M. Pattern of neurobehavioral deficits associated with interferon alfa therapy for leukemia.  Neurology. 1995;  45 947-950
  • 38 Schaefer M, Engelbrecht M A, Gut O, Fiebich B L, Bauer J, Schmidt F. et al . Interferon alpha (IFNalpha) and psychiatric syndromes: a review.  Prog Neuropsychopharmacol Biol Psychiatry. 2002;  26 731-746
  • 39 Schafer M, Schmidt F, Amann B, Schlosser S, Loeschke K, Grunze H. Adding low-dose antidepressants to interferon alpha treatment for chronic hepatitis C improved psychiatric tolerability in a patient with schizoaffective psychosis.  Neuropsychobiology. 2000;  42 Suppl 1 43-45
  • 40 Schmidt K, Nolte-Zenker B, Patzer J, Bauer M, Schmidt L G, Heinz A. Psychopathological correlates of reduced dopamine receptor sensitivity in depression, schizophrenia, and opiate and alcohol dependence.  Pharmacopsychiatry. 2001;  34 66-72
  • 41 Schramm T M, Lawford B R, Macdonald G A, Cooksley W G. Sertraline treatment of interferon-alfa-induced depressive disorder.  Med J Aust. 2000;  173 359-361
  • 42 Shuto H, Kataoka Y, Horikawa T, Fujihara N, Oishi R. Repeated interferon-alpha administration inhibits dopaminergic neural activity in the mouse brain.  Brain Res. 1997;  747 348-351
  • 43 Sugiyama K, Brunori A, Mayer M L. Glial uptake of excitatory amino acids influences neuronal survival in cultures of mouse hippocampus.  Neuroscience. 1989;  32 779-791
  • 44 Suter C C, Westmoreland B F, Sharbrough F W, Hermann R C, Jr. Electroencephalographic abnormalities in interferon encephalopathy: a preliminary report.  Mayo Clin Proc. 1984;  59 847-850

Martin Schaefer, MD

Charité - University Medicine Berlin

Campus Charité-Mitte (CCM)

Department of Psychiatry and Psychotherapy

Schumannstr. 20/21

10117 Berlin

Germany

Phone: (+49) 030-450 517011

Fax: (+49) 030-450 517922

Email: martin.schaefer@charite.de

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