Hostname: page-component-78c5997874-4rdpn Total loading time: 0 Render date: 2024-11-18T00:16:57.111Z Has data issue: false hasContentIssue false
  • English
  • Français

Stress, immunity, cytokines and depression

Published online by Cambridge University Press:  24 June 2014

Hymie Anisman
Hymie Anisman*
Affiliation:
Institute of Neurosciences, Carleton University, Ottawa, Ontario, Canada
Get access Rights & Permissions [Opens in a new window]

Abstract

The current issue of Acta Neuropsychiatrica presents a series of papers which together provide a broad overview relating stress, immunity, cytokine activity and depressive illness, as well as the influence of cytokines on other neurological disorders. This introduction to the issue presents a broad perspective of the impact of stressors on immune functioning in animal studies and in humans, considering the potential effects of acute, subchronic and chronic stressors, as well as the contribution of previous stressor experience in promoting neurochemical and immunological alterations. Given the supposition that cytokines may act as immunotransmitters, and immune challenge may be viewed as a stressor, a brief review is provided concerning the impact of stressors and cytokine challenges on central neurochemical functioning, with particular emphasis on the commonalties between the effects of these treatments. It is suggested that by virtue of the neurochemical changes imparted by cytokines, a depressive affect may be instigated, just as it is in response to psychogenic stressors. To this end, an overview is presented concerning the relationship between cytokines and depression, as well as the influence of cytokine treatments on behavioral changes in animal studies and among patients receiving immunotherapy. Provisionally, the data support the view that activation of the inflammatory response system may contribute to affective illness, and that cytokines may act as signaling molecules to activate central nervous system processes regulating mood states.

Keywords

stressdepressionpost-traumatic stress disorderimmunecytokineinterleukinimmunotherapy
Type
Review Article
Information
Acta Neuropsychiatrica , Volume 14 , Issue 6 , December 2002 , pp. 251 - 261
Copyright
Copyright © Acta Neuropsychiatrica 2002

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Banks, WA. Cytokines, CVSs, and the blood–brain-barrier. In: Ader, R, Felten, DL, Cohen, N, eds. Psychoneuroimmunology, vol. 2. New York: Academic Press, 2001: 483–498. Google ScholarPubMed
Blalock, JE. The syntax of immune–neuroendocrine communication. Immunol Today 1994;15: 504–511.CrossRefGoogle ScholarPubMed
Dantzer, R, Bluthe, RM, Aubert, Aet al. Cytokine actions on behavior. In: Rothwell, NJ, ed. Cytokines and the Nervous System. London: Landes, 1996: 117–144. CrossRefGoogle Scholar
Maier, SF, Watkins, LR. Cytokines for psychologists. Implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition. Psychol Rev 1998;105: 83–107.CrossRefGoogle Scholar
Quagliarello, VJ, Wisplwey, B, Long, WJ Jr,Sheld, WM. Recombinant interleukin-1 induces meningitis and blood–brain barrier injury in the rat. J Clin Invest 1991;87: 1360–1366.CrossRefGoogle ScholarPubMed
Anisman, H, Zalcman, S, Zacharko, RM. The impact of stressors on immune and central transmitter activity: Bidirectional communication. Rev Neurosci 1993;4: 147–180.CrossRefGoogle Scholar
Lopez, JF, Akil, H, Watson, SJ. Neural circuits mediating stress. Biol Psychiatry 1999;46: 461–471. CrossRefGoogle ScholarPubMed
McEwen, BS. Allostasis and allostatic load. Implications for neuropsychopharmacology. Neuropsychopharmacology 2000;22: 108–124.CrossRefGoogle ScholarPubMed
Heim, C, Nemeroff, CB. The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biol Psychiatry 2001;49: 1023–1039.CrossRefGoogle ScholarPubMed
Kalivas, P, Stewart, J. Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity. Brain Res Rev 1991;16: 223–244.CrossRefGoogle ScholarPubMed
Post, RM. Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am J Psychiatry 1992;149: 999–1010.Google ScholarPubMed
Dhabhar, FS. Acute stress enhances while chronic stress suppresses skin immunity. The role of stress hormones and leukocyte trafficking. Ann NY Acad Sci 2000;917: 876–893.CrossRefGoogle ScholarPubMed
McEwen, BS. The neurobiology of stress: from serendipity to clinical relevance. Brain Res 2000;886: 172–189.CrossRefGoogle Scholar
Sheridan, JF, Stark, JL, Avitsur, R, Padgett, DA. Social disruption, immunity, and susceptibility to viral infection. Role of glucocorticoid insensitivity and NGF. Ann NY Acad Sci 2000;917: 894–905.CrossRefGoogle ScholarPubMed
de Groot, J, Ruis, MA, Scholten, JW, Koolhaas, JM, Boersma, WJLong-term effects of social stress on antiviral immunity in pigs. Physiol Behav 2001;73: 145–158.CrossRefGoogle ScholarPubMed
Tilders, FJ, Schmidt, ED. Interleukin-1-induced plasticity of hypothalamic CRH neurons and long-term stress hyper-responsiveness. Ann NY Acad Sci 1998;840: 65–73.CrossRefGoogle Scholar
Tilders, FJ, Schmidt, ED. Cross-sensitization between immune and non-immune stressors. A role in the etiology of depression? Adv Exp Med Biol 1999;461: 179–197.CrossRefGoogle Scholar
Dhabhar, FS, Miller, AH, McEwen, BS, Spencer, RL. Differential activation of adrenal steroid receptors in neural and immune tissues of Sprague Dawley, Fischer 344, and Lewis rats. J Neuroimmunol 1995;56: 77–90.CrossRefGoogle ScholarPubMed
Lu, ZW, Song, C, Ravindran, AV, Merali, Z, Anisman, H. Influence of a psychogenic and a neurogenic stressor on several indices of immune functioning in different strains of mice. Brain Behav Immun 1998;12: 7–22.CrossRefGoogle Scholar
Cohen, S, Herbert, TB. Health psychology. psychological factors and physical disease from the perspective of human psychoneuroimmunology. Ann Rev Psychol 1996;47: 113–142. CrossRefGoogle ScholarPubMed
Cohen, S, Miller, GE, Rabin, BS. Psychological stress and antibody response to immunization: a critical review of the human literature. Psychosom Med 2001;63: 7–18.CrossRefGoogle Scholar
Kiecolt-Glaser, JK, McGuire, L, Robles, TF, Glaser, R. Emotions, morbidity, and mortality: New perspectives from psychoneuroimmunology. Ann Rev Psychol 2002;53: 83–107. CrossRefGoogle ScholarPubMed
Marsland, AL, Cohen, S, Rabin, BS, Manuck, SB. Associations between stress, trait negative affect, acute immune reactivity, and antibody response to hepatitis B injection in healthy young adults. Health Psychol 2001;20: 4–11.CrossRefGoogle ScholarPubMed
Kiecolt-Glaser, JK, Cacioppo, JT, Malarkey, WB, Glaser, R. Acute psychological stressors and short-term immune changes: what, why, for whom, and to what extent? Psychosom Med 1992;54: 680–685.CrossRefGoogle ScholarPubMed
Marucha, PT, Kiecolt-Glaser, JK, Favagehi, M. Mucosal wound healing is impaired by examination stress. Psychosom Med 1998;60: 362–365.CrossRefGoogle ScholarPubMed
Glaser, R, Kiecolt-Glaser, JK, Malarkey, WB, Sheridan, JF. The influence of psychological stress on the immune response to vaccines. Ann N Y Acad Sci 1998;840: 649–655.CrossRefGoogle ScholarPubMed
Cohen, S, Doyle, WJ, Skoner, DP. Psychological stress, cytokine production, and severity of upper respiratory illness. Psychosom Med 1999;61: 175–180.CrossRefGoogle ScholarPubMed
Cohen, S, Frank, E, Doyle, WJ, Skoner, DP, Rabin, BS, Gwaltney, JM. Types of stressors that increase susceptibility to the common cold in healthy adults. Health Psychol 1998;17: 214–223.CrossRefGoogle ScholarPubMed
Maes, M, Van Bockstaele, DR, Gastel, Aet al. The effects of psychological stress on leukocyte subset distribution in humans: evidence of immune activation. Neuropsychobiology 1999;39: 1–9.CrossRefGoogle ScholarPubMed
Maes, M, Song, C, Lin, Aet al. The effects of psychological stress on humans: increased production of pro-inflammatory cytokines and a Th1-like response in stress-induced anxiety. Cytokine 1998;10: 313–318.CrossRefGoogle Scholar
Song, C, Kenis, G, Van Gastel, Aet al. Influence of psychological stress on immune-inflammatory variables in normal humans. Part II. Altered serum concentrations of natural anti-inflammatory agents and soluble membrane antigens of monocytes and T lymphocytes. Psychiatr Res 1999;85: 293–303. CrossRefGoogle ScholarPubMed
Kiecolt-Glaser, JK, Glaser, R, Gravenstein, S, Malarkey, WB, Sheridan, J. Chronic stress alters the immune response to influenza virus vaccine in older adults. Proc Natl Acad Sci 1996;93: 3043–3047.CrossRefGoogle ScholarPubMed
Redinbaugh, EM, MacCallum, RC, Kiecolt-Glaser, JKRecurrent syndromal depression in caregivers. Psychol Aging 1995;10: 358–368.CrossRefGoogle Scholar
Schulz, R, O'Brien, AT, Bookwala, J, Fleissner, K. Psychiatric and physical morbidity effects of dementia caregiving: prevalence, correlates, and causes. Gerontologist 1995;35: 771–791.CrossRefGoogle ScholarPubMed
Kiecolt-Glaser, JK, Dura, JR, Speicher, CE, Trask, OJ, Glaser, R. Spousal caregivers of dementia victims: longitudinal changes in immunity and health. Psychosom Med 1991;53: 345–362.CrossRefGoogle ScholarPubMed
Pearlin, LI, Mullan, JT, Semple, SJ, Skaff, MM. Caregiving and the stress process: an overview of concepts and their measures. Gerontologist 1990;30: 583–594.CrossRefGoogle Scholar
Bauer, ME, Vedhara, K, Perks, P, Wilcock, GK, Lightman, SL, Shanks, N. Chronic stress in caregivers of dementia patients is associated with reduced lymphocyte sensitivity to glucocorticoids. J Neuroimmunol 2000;103: 84–92.CrossRefGoogle Scholar
Esterling, BA, Kiecolt-Glaser, JK, Glaser, R. Psychosocial modulation of cytokine-induced natural killer cell activity in older adults. Psychosom Med 1996;58: 264–272.CrossRefGoogle Scholar
Kennedy, S, Kiecolt-Glaser, JK, Glaser, R. Immunological consequences of acute and chronic stressors: mediating role of interpersonal relationships. Br J Med Psychol 1988;61: 77–85.CrossRefGoogle ScholarPubMed
Glaser, R, Sheridan, J, Malarkey, WB, MacCallum, RC, Kiecolt-Glaser, JK. Chronic stress modulates the immune response to a pneumococcal pneumonia vaccine. Psychosom Med 2000;62: 804–807.CrossRefGoogle ScholarPubMed
Glaser, R, Kiecolt-Glaser, JK. Chronic stress modulates the virus-specific immune response to latent herpes simplex virus type 1. Ann Behav Med 1997;19: 78–82.CrossRefGoogle ScholarPubMed
Vedhara, K, Cox, NK, Wilcock, GKet al. Chronic stress in elderly carers of dementia patients and antibody response to influenza vaccination. Lancet 1999;353: 627–631.CrossRefGoogle ScholarPubMed
Irwin, M, Brown, M, Patterson, T, Hauger, R, Mascovich, A, Grant, I. Neuropeptide Y and natural killer cell activity: findings in depression and Alzheimer caregiver stress. FASEB J 1991;5: 3100–3107.Google ScholarPubMed
Irwin, M, Hauger, R, Patterson, TL, Semple, S, Ziegler, M, Grant, I. Alzheimer caregiver stress. basal natural killer cell activity, pituitary-adrenal cortical function, and sympathetic tone. Ann Behav Med 1997;19: 83–90.CrossRefGoogle ScholarPubMed
Uchino, BN, Cacioppo, JT, Kiecolt-Glaser, JK. The relationship between social support and physiological processes: a review with emphasis on underlying mechanisms and implications for health. Psychol Bull 1996;119: 488–531.CrossRefGoogle Scholar
Vedhara, K, Shanks, N, Anderson, S, Lightman, S. The role of stressors and psychosocial variables in the stress process: a study of chronic caregiver stress. Psychosom Med 2000;62: 374–385.CrossRefGoogle ScholarPubMed
Pike, JL, Smith, TL, Hauger, RLet al. Chronic life stress alters sympathetic, neuroendocrine, and immune responsivity to an acute psychological stressor in humans. Psychosom Med 1997;59: 447–457.CrossRefGoogle Scholar
Cacioppo, JT, Burleson, MH, Poehlmann, KMet al. Autonomic and neuroendocrine responses to mild psychological stressors: effects of chronic stress on older women. Ann Behav Med 2000;22: 140–148.CrossRefGoogle ScholarPubMed
Yehuda, R. Linking the neuroendocrinology of post-traumatic stress disorder with recent neuroanatomic findings. Sem Clin Neuropsychiatry 1999;4: 256–265. Google ScholarPubMed
Yehuda, R, McFarlane, AC. Conflict between current knowledge about post-traumatic stress disorder and its original conceptual basis. Am J Psychiatry 1995;152: 1705–1713.Google ScholarPubMed
Kawamura, N, Kim, Y, Asukai, N. Suppression of cellular immunity in men with a past history of post-traumatic stress disorder. Am J Psychiatry 2001;158: 484–488.CrossRefGoogle Scholar
Inoue-Sakurai, C, Maruyama, S, Morimoto, K. Post-traumatic stress and lifestyles are associated with natural killer cell activity in victims of the Hanshin–Awaji earthquake in Japan. Prev Med 2000;31: 467–473.CrossRefGoogle ScholarPubMed
Everson, M P, Kotler, S, Blackburn, W D Jr.Stress and immune dysfunction in Gulf War veterans. Ann NY Acad Sci 1999;876: 413–418.CrossRefGoogle Scholar
Laudenslager, ML, Aasal, R, Adler, Let al. Elevated cytotoxicity in combat veterans with long-term post-traumatic stress disorder: preliminary observations. Brain Behav Immun 1998;12: 74–79.CrossRefGoogle ScholarPubMed
Weiss, D W, Hirt, R, Tarcic, Net al. Studies in psychoneuroimmunology: psychological, immunological, and neuroendocrinological parameters in Israeli civilians during and after a period of Scud missile attacks. Behav Med 1996;22: 5–14.CrossRefGoogle ScholarPubMed
Sabioncello, A, Kocijan-Hercigonja, D, Rabatic, Set al. Immune, endocrine, and psychological responses in civilians displaced by war. Psychosom Med 2000;62: 502–508.CrossRefGoogle Scholar
Wilson, SN, Van Der Kolk, B, Burbridge, J, Fisler, R, Kradin, R. Phenotype of blood lymphocytes in PTSD suggests chronic immune activation. Psychosomatics 1999;40: 222–225.CrossRefGoogle ScholarPubMed
Matheson, K, Anisman, H. Systems of coping associated with psychological distress: a profile perspective. J Abn Psychol 2002 (in press).Google Scholar
Maes, M. Major depression and activation of the inflammatory response system. Adv Exp Med Biol 1999;461: 25–46.CrossRefGoogle ScholarPubMed
Maes, M. Evidence for an immune response in major depression. a review and hypothesis. Progr Neuro-Psychopharmacol Biol Psychiatry 1995;19: 11–38. CrossRefGoogle ScholarPubMed
Kronfol, Z, House, JD. Depression, hypothalamic–pituitary–adrenocortical activity, and lymphocyte function. Psychopharmacol Bull 1985;21: 476–478.Google ScholarPubMed
Irwin, M. Immune correlates of depression. Adv Exp Med Biol 1999;461: 1–24.CrossRefGoogle Scholar
Moldofsky, H. Sleep and the immune system. Int J Immunopharmacol 1995;17: 649–654.CrossRefGoogle ScholarPubMed
Cover, H, Irwin, M. Immunity and depression: Insomnia, retardation and reduction of natural killer cell activity. J Behav Med 1994;17: 217–223.CrossRefGoogle ScholarPubMed
Demitrack, MA, Dale, JK, Straus, SE, et al. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab 1991;148: 337–344. Google Scholar
Gold, PW, Licinio, J, Wong, ML, Chrousos, GP. Corticotropin releasing hormone in pathophysiology of melancholic and atypical depression and in the mechanism of action of antidepressant drugs. Ann NY Acad Sci 1995;771: 716–729.CrossRefGoogle ScholarPubMed
Levitan, RD, Kaplan, AS, Brown, GMet al. Low plasma cortisol in bulimia nervosa patients with reversed neurovegetative symptoms of depression. Biol Psychiatry 1997;41: 366–368.CrossRefGoogle ScholarPubMed
Zaharia, MD, Ravindran, AV, Griffiths, J, Merali, Z, Anisman, H. Lymphocyte proliferation among major depressive and dysthymic patients with typical or atypical features. J Affect Disord 2000;58: 1–10.CrossRefGoogle ScholarPubMed
Miller, AH, Spencer, RL, McEwen, BS, Stein, M. Depression, adrenal steroids, and the immune system. Ann Med 1993;25: 481–487.CrossRefGoogle ScholarPubMed
Anisman, H, Merali, Z. Anhedonic and anxiogenic effects of cytokine exposure. Adv Exp Med Biol 1999;461: 199–233.CrossRefGoogle ScholarPubMed
Dunn, A J. Interactions between the nervous system and the immune system. In: Bloom, FE, Kupfer, DJ, eds. Psychopharmacology: the Fourth Generation of Progress. New York: Raven Press, 1995: 719–731. Google Scholar
Dunn, AJ. Effects of cytokines and infections on brain neurochemistry. In: Ader, R, Felten, DL, Cohen, N, eds. Psychoneuroimmunology. New York: Academic Press, 2001: 649–666. Google ScholarPubMed
Lacosta, S, Merali, Z, Anisman, H. Central monoamine alterations associated with acute and repeated interleukin-2 administration. Neuroimmunomodulation 2000;9: 1–16. Google Scholar
Song, C, Merali, Z, Anisman, H. Variations of nucleus accumbens dopamine and serotonin following systemic interleukin-1, interleukin-2 or interleukin-6 treatment. Neuroscience 1999;88: 823–836.CrossRefGoogle ScholarPubMed
Licinio, J, Wong, L. The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection. Mol Psychiatry 1999;4: 317–327.CrossRefGoogle ScholarPubMed
van West, D, Maes, M. Activation of the inflammatory response system: a new look at the etiopathogenesis of major depression. Neuroendocrinol Lett 1999;20: 11–17.Google Scholar
Connor, TJ, Leonard, BE. Depression, stress and immunological activation: The role of cytokines in depressive disorders. Life Sci 1998;62: 583–606.CrossRefGoogle ScholarPubMed
Maes, M, Scharpe, S, Meltzer, HYet al. Relationships between interleukin-6 activity, acute phase proteins, and function of the hypothalamic–pituitary–adrenal axis in severe depression. Psychiatr Res 1993;49: 11–27. CrossRefGoogle ScholarPubMed
Maes, M, Lambrechts, J, Bosmans, Eet al. Evidence for a systemic immune activation during depression. Results of leukocyte enumeration by flow cytometry in conjunction with monoclonal antibody staining. Psychol Med 1992;22: 45–53.CrossRefGoogle ScholarPubMed
Muller, N, Ackenheil, M. Psychoneuroimmunology and the cytokine action in the CNS. implications for psychiatric disorders. Prog Neuropsychopharm Biol Psychiatry 1998;22: 1–33. CrossRefGoogle ScholarPubMed
Smith, RS. The macrophage theory of depression. Med Hypoth 1991;35: 298–306. CrossRefGoogle Scholar
Sluzewska, A, Rybakowski, JK, Laciak, M, Mackiewicz, A, Sobieska, M, Wiktorowicz, K. Interleukin-6 serum levels in depressed patients before and after treatment with fluoxetine. Ann NY Acad Sci 1995;762: 474–476.CrossRefGoogle ScholarPubMed
Anisman, H, Ravindran, AV, Griffiths, J, Merali, Z. Endocrine and cytokine correlates of major depression and dysthymia with typical or atypical features. Mol Psychiatry 1999;4: 182–188.CrossRefGoogle Scholar
Anisman, H, Ravindran, AV, Griffiths, J, Merali, Z. Interleukin-1 beta production in dysthymia before and after pharmacotherapy. Biol Psychiatry 1999;46: 1649–1655.CrossRefGoogle ScholarPubMed
Kubera, M, Kenis, G, Bosmans, Eet al. Plasma levels of interleukin-6, interleukin-10, and interleukin-1 receptor antagonist in depression: comparison between the acute state and after remission. Pol J Pharmacol 2000;52: 237–241.Google ScholarPubMed
Hayley, S, Brebner, K, Lacosta, S, Merali, Z, Anisman, H. Sensitization to the effects of tumor necrosis factor-α;neuroendocrine, central monoamine and behavioral variations. J Neurosci 1999;19: 5654–5665.Google ScholarPubMed
Anisman, H, Kokkinidis, L, Merali, Z. Influence of interleukin-2 on responding for electrical brain stimulation from the hypothalamus. Brain Res 1996;731: 1–11.CrossRefGoogle Scholar
Yirimaya, R, Weidenfeld, J, Pollak, Yet al. Cytokines, ‘depression due to a general medical condition’, and antidepressant drugs. Adv Exp Med Biol 1999;461: 283–316.CrossRefGoogle Scholar
Reichenberg, A, Yirmiya, R, Schuld, Aet al. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry 2001;58: 445–452.CrossRefGoogle Scholar
Bonaccorso, S, Marino, V, Puzella, Aet al. 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: 86–90.CrossRefGoogle ScholarPubMed
Bonaccorso, S, Puzella, A, Marino, Vet al. Immunotherapy with interferon-alpha in patients affected by chronic hepatitis C induces an intercorrelated stimulation of the cytokine network and an increase in depressive and anxiety symptoms. Psychiatr Res 2001;105: 45–55. CrossRefGoogle ScholarPubMed
Capuron, L, Ravaud, A, Gualde, Net al. Association between immune activation and early depressive symptoms in cancer patients treated with interleukin-2-based therapy. Psychoneuroendocrinology 2001;26: 797–808.CrossRefGoogle Scholar
Capuron, L, Ravaud, A, Dantzer, R. Timing and specificity of the cognitive changes induced by interleukin-2 and interferon-alpha treatments in cancer patients. Psychosom Med 2001;63: 376–386.CrossRefGoogle ScholarPubMed
Caraceni, A, Martini, C, Belli, Fet al. Neuropsychological and neurophysiological assessment of the central effects of interleukin-2 administration. Eur J Cancer 1992;29A: 1266–1269. Google ScholarPubMed
Denicoff, KD, Rubinow, DR, Papa, MZet al. The neuropsychiatric effects of treatment with interleukin-2 and lymphokine-activated killer cells. Ann Int Med 1987;107: 293–300. CrossRefGoogle Scholar
Meyers, CA, Valentine, AD. Neurological and psychiatric adverse effects of immunological therapy. CNS Drugs 1995;3: 56–68. CrossRefGoogle Scholar
Miyaoka, H, Otsubo, T, Kamijima, K, Ishii, M, Onuki, M, Mitamura, K. Depression from interferon therapy in patients with hepatitis C. Am J Psychiatry 1999;156: 1120.Google 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
Musselman, DL, Lawson, DH, Gumnick, JFet al. Paroxetine for the prevention of the depression and neurotoxicity induced by high dose interferon alpha. N Engl J Med 2001;344: 961–966.CrossRefGoogle Scholar