Illness, Cytokines, and Depression
- YIRMIYA,a,b Y. POLLAK,a M. MORAG,a A. REICHENBERG,a O. BARAK,a
- AVITSUR,a Y. SHAVIT,a H. OVADIA,c J. WEIDENFELD,c A. MORAG,d
M.E. NEWMAN,e AND T. POLLMÄCHERf
Departments of aPsychology, cNeurology, dClinical Virology, andePsychiatry, The Hebrew University and Hadassah Hospital, Jerusalem, Israel fMax Planck Institute for Psychiatry, Munich, Germany
ABSTRACT: Various medical conditions that involve activation of the immune system are associated with psychological and neuroendocrine changes that resemble the characteristics of depression. In this review we present our recent studies, designed to investigate the relationship between the behavioral effects of immune activation and depressive symptomatology. In the first set of experiments, we used a double-blind prospective design to investigate the psychological consequences of illness in two models: (1) vaccination of teenage girls with live attenuated rubella virus, and (2) lipopolysaccharide (LPS) administration in healthy male volunteers. In the rubella study, we demonstrated that, compared to control group subjects and to their own baseline, a subgroup of vulnerable individuals (girls from low socioeconomic status) showed a significant virus-induced increase in depressed mood up to 10 weeks after vaccination. In an ongoing study on the effects of LPS, we demonstrated significant LPSinduced elevation in the levels of depression and anxiety as well as memory deficits. These psychological effects were highly correlated with the levels of LPS-induced cytokine secretion. In parallel experiments, we demonstrated in rodents that immune activation with various acute and chronic immune challenges induces a depressive-like syndrome, characterized by anhedonia, anorexia, body weight loss, and reduced locomotor, exploratory, and social behavior. Chronic treatment with antidepressants (imipramine or fluoxetine) attenuated many of the behavioral effects of LPS, as well as LPS-induced changes in body temperature, adrenocortical activation, hypothalamic serotonin release, and the expression of splenic TNF- mRNA. Taken together, these findings suggest that cytokines are involved in the etiology and symptomatology of illness-associated depression.
Depression is a common, disturbing concomitant of medical conditions. The reported prevalence of major depression episodes in physically ill patients varies from 5% to more than 40%. However, because depression is often unrecognized and undertreated in sick patients, the prevalence reported in most studies is probably underestimated.1 The high prevalence of depression in various medical conditions is
bAddress for correspondence: Professor Raz Yirmiya, Department of Psychology, The Hebrew University of Jerusalem, Mount Scopus, Jerusalem 91905, Israel. Voice: 972-25883695; fax: 972-2-5881159. firstname.lastname@example.org
YIRMIYA et al.
reflected by the special psychiatric diagnostic entity “depression due to a general medical condition.”2 To make a diagnosis of this condition “the clinician should establish the presence of a general medical condition, and determine that the depression is etiologically related to the general medical condition through a physiological mechanism” (see Ref. 2, p. 367). Several lines of evidence suggest that this physiological mechanism involves the immune system—that is, the depression associated with various medical conditions is not merely a reaction to the incapacitation, pain, and losses that accompany the physical disease process, but may be directly caused by activation of the immune system.3
The physiological and psychological effects of immune activation (collectively termed sickness behavior) are mediated by cytokines derived from activated immune and other cells.4–6 Most immune challenges produce their initial effects in the periphery, but information regarding their presence is almost immediately transmitted to the brain, in a sensory-like process. Within the brain, this immune-related information activates several areas, and induces glia cells and neurons to release cytokines, such as interleukin (IL)-1 and tumor necrosis factor-alpha (TNF-α), which serve as neurotransmitters and neuroregulators.4,5 The aim of the present review is to present the current knowledge on the role of cytokines in mediating the depressive-like symptoms that accompany various medical conditions in humans and experimental models of these conditions in animals.
DEPRESSION ASSOCIATED WITH INFECTIOUS AND NONINFECTIOUS DISEASES IN HUMANS
Infectious illnesses are often associated with a range of depressive symptoms, including fatigue, psychomotor retardation, anorexia, somnolence, lethargy, muscle aches, cognitive disturbances, and depressed mood.7 The evidence for these alterations is mainly anecdotal, and only few studies examined these symptoms systematically. Experimentally induced viral infections (e.g., common cold, influenza),8,9 as well as natural occurrence of upper respiratory tract illness or influenza,10–12 produce depressed mood and other depressive symptoms, as well as various neuropsychological impairments. Similar disturbances have also been reported following chronic infections with herpesvirus, cytomegalovirus, Epstein-Barr virus, gastroenteritis, Borna disease virus and HIV.
Many noninfectious conditions, such as autoimmune diseases, stroke, trauma, Alzheimer’s disease and other neurodegenerative diseases, are also associated with chronic activation of the immune system and secretion of cytokines. High incidence of depression has been demonstrated in patients afflicted with many of these conditions, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, allergy, stroke, and Alzheimer’s disease.3,6 When studied, immune dysregulation was found to precede the development of depression, suggesting that rather than being a psychological reaction to the medical condition per se, illness-associated depression is causally related to immune activation.
We have recently used a double-blind prospective design to investigate the immediate and prolonged psychological and physiological effects of a specific viral infection in humans.13 Subjects were teenage girls who were vaccinated with live
FIGURE 1. Effects of vaccination with live attenuated Rubella virus on psychological parameters measured in 12-year-old girls with low socioeconomic status before, and 10 weeks after, the vaccination. Compared to their own baseline and to the levels in girls who were already immune to Rubella before vaccination (control group), subjects who seroconverted following vaccination (experimental group) showed significantly increased levels of total and emotional depression, measured by the Children Depression Inventory, and significantly higher incidence of social and attention problems and delinquent behavior, assessed by the Achenbach Child Behavior Checklist. (Adapted from Morag et al.13)
attenuated rubella virus. Based on analysis of levels of antibodies to rubella, subjects were divided into two groups: an experimental group, consisting of subjects who were initially seronegative and were infected following vaccination; and a control group, consisting of subjects who were already immune to rubella before vaccination. Compared to control subjects and to their own baseline, subjects from low, but not middle or high, socioeconomic status (SES) within the experimental group exhibited more severe depressed mood, as well as more social and attention problems and delinquent behavior (see FIGURE 1).13 The particular vulnerability to immunization-induced depression may be associated with several characteristics of low SES, including higher incidence of stressful life events and fewer sources of social support, which modulate the responsiveness to immune challenges. Thus, even a mild viral infection can produce a prolonged increase in depressive symptomatology in vulnerable individuals.
ADMINISTRATION OF CYTOKINES AND LPS IN HUMANS PRODUCES DEPRESSIVE SYMPTOMS
Administration of cytokines in humans produces marked behavioral and neuroendocrine symptoms that are similar to those induced by viral infection. Administration of alpha interferon (IFN-α), IL-2, or TNF-α was found to cause flu-like symptoms as well as depressive symptoms, including depressed mood, dysphoria, anhedonia, helplessness, mild-to-severe fatigue, anorexia and weight loss, hypersomnia, psychomotor retardation, decreased concentration, and confusion.14 The fact that these symptoms appear almost immediately after cytokine administration and usually disappear shortly after termination of the cytokine treatment, strongly suggests a causal role for cytokines in producing the depressive symptoms.
To further examine the role of cytokines in the psychologcial alterations that accompany infection and inflammation, we have recently conducted a study on the effects of LPS on affective and cognitive variables in healthy volunteers. A withinsubjects cross-over design was used, in which each subject completed a battery of psychological and neuropsychological tests at various time points following LPS injection on one day, and following saline injection on another day. Neither the experimenter nor the subject knew the group assignment (i.e., a double-blind design). LPS produced a marked increase in the levels of circulating cytokines and cortisol, as well as mild fever and anorexia, but no other flu-like symptoms. The levels of anxiety and depression were significantly elevated in LPS-injected subjects. LPS produced no alterations in attention and executive functions, but it did produce a marked impairment in both verbal and nonverbal memory functions. The levels of anxiety, depression, and memory impairments were significantly and positively correlated with the levels of blood cytokines, demonstrating the important role of cytokines in mediating the emotional and cognitive responses to illness.
BEHAVIORAL EFFECTS OF INFECTIOUS AND AUTOIMMUNE DISEASES IN ANIMALS:
In animals, systemic protozoan, bacterial or viral infections are associated with anorexia and body weight loss, hypersomnia, psychomotor retardation, fatigue, and impaired cognitive abilities, exploration and social behavior.4–6 Similar symptoms, as well as increased anxiety behavior, were also reported using mouse models of autoimmune disease,15,16 indicating that behavioral changes can also accompany non-infectious conditions.
The behavioral effects of disease processes are mediated by cytokines, as evidenced by infection-like sickness behavior symptoms following exogenous administration of cytokines (particularly IL-1β and TNF-α), which act centrally and synergistically to induce sickness behavior. Moreover, the behavioral effects of immune challenges can be attenuated by pretreatment with cytokine synthesis blockers and cytokine antagonists, as well as by manipulations in cytokine genes, such as transgenic overexpresion or gene knockout.4–6,17
One particularly important aspect of depression that has recently been modeled in animals is anhedonia—that is, the diminished capacity to experience pleasure. Suppression of intracranial self-stimulation (ICSS) is a very useful animal model to study anhedonia. LPS-induced suppression of ICSS has been demonstrated more than three decades ago.18 This report was recently corroborated by the findings that exogenous administration of IL-2 produce a specific and long-lasting decrease in ICSS.17,19 Administration of LPS,20 IL-1β,19 or antigenic challenge with sheep red blood cells21 was also associated with suppression of ICSS.
The consumption of and preference for sweet solutions can also serve as a model for hedonic processes. Studies in our laboratory, as well as others, demonstrated that various immune challenges attenuate the consumption of and preference for sweet solutions, while having minimal effects on water drinking (see FIGURE 2A).3,17,22 Autoimmune diseases in animals are also associated with anhedonia. Thus, mice that spontaneously develop systemic autoimmune lupus-like disease also show blunted sensitivity to sucrose, which can be reversed by an immunosuppressive treatment.23 Moreover, we have recently demonstrated that induction of experimental autoimmune encephalomyelitis (EAE) in SJL/J female mice by adoptive transfer of lymph node cells is associated with sickness behavior symptoms, including anorexia, loss of body weight, reduced social exploration, and decreased intake of and preference for sucrose solution (FIG. 2B).16 Interestingly, the onset and recovery of the behavioral symptoms preceded the onset and recovery of the neurological signs, respectively. Since EAE is considered as an established animal model for multiple sclerosis (MS) in humans, it is suggested that EAE-induced behavioral changes may serve as a model for the depressive symptomatology that characterizes most MS patients.
Finally, we have found that various immune challenges produce a dramatic decrease in libido and sexual performance of female rats.24,25 Such a reduction in sexual interest or desire and difficulties in sexual functioning are features commonly associated with depression, and they are also viewed as manifestations of the general loss of interest and pleasure in activities that were previously considered pleasurable.2 In conclusion, various immune challenges induce anhedonia and many behavioral alterations that resemble the core symptoms of depression. These findings suggest that immune activation produces a depression-like syndrome in animals.
FIGURE 2. Effects of various immune challenges on the consumption of sweet solutions. A. For each immune challenge, animals were presented with two graduated tubes containing a 10-mM saccharin solution or water. Data represents the mean (±SEM) saccharin solution consumption over a 24-h period in nondeprived rats, following administration of saline, HIV-1 gp120, LPS, interleukin-1β (IL-1), or Mycoplasma fermentans (MF). The intake of saccharin solution following saline was computed by averaging the intake in all the individual experiments from which this graph was derived. B. Effects of EAE on the intake of sucrose solution and water. Consumption was measured in female SJL mice presented with a dilute sucrose solution and water over a period of six hours (average of two sessions). *Significantly different from saline/control group.
ANTIDEPRESSANTS ATTENUATE THE DEPRESSIVE-LIKE SYMPTOMS INDUCED BY IMMUNE ACTIVATION IN ANIMALS
Antidepressants have been used successfully in treating depressive symptoms associated with various medical conditions1 and depression induced by IFN administration in humans.26 To further elucidate the relationship between immune activation and depression and explore the mechanisms underlying the therapeutic action of antidepressants, we employed an experimental animal model. Specifically, we examined the effects of antidepressants on LPS-induced behavioral and neuroendocrine alterations in rats. We demonstrated that chronic, but not acute, administration of the tricyclic antidepressant (TCA) imipramine (daily injection for 3–5 weeks) attenuated or completely abolished the behavioral effects of LPS, including decreased saccharine preference, anorexia, body weight loss, reduced social activity, and suppression of locomotor and exploratory behavior in the open field test (see FIGURE 3).22 The dissociation between the effects of acute and chronic imipramine treatment is important, because in clinical settings imipramine is also effective in alleviating depression only following chronic, but not acute, administration.
In subsequent experiments we showed that chronic administration of fluoxetine, a serotonin reuptake inhibitor (SSRI), also significantly attenuated LPS-induced reduction in food consumption and body weight, although it did not affect LPSinduced decrease in social interaction and activity in the open field test. Chronic fluoxetine treatment also had marked effects on changes in body temperature: in control mice LPS induced a biphasic response, characterized by initial hypothermia followed by prolonged hyperthermia; in contrast, fluoxetine-treated mice showed no hypothermic response, beginning the hyperthermic response earlier than controls. Finally, chronic treatment with fluoxetine significantly attenuated LPS-induced secretion of corticosterone.
FIGURE 3. Effects of chronic imipramine treatment on LPS-induced behavioral suppression. Saccharin preference, food consumption, and social exploration (SE) were measured following an acute injection with LPS in rats that were treated chronically with either saline or imipramine (daily injections of 10 mg/kg for 3–5 weeks). *Significantly different from all other groups. (Adapted from Yirmiya.22)
FIGURE 4. Effects of chronic clomipramine treatment on LPS-induced changes in serotonin (5-HT) concentration within the hypothalamus. Following chronic treatment (five weeks of daily injections) with either saline (n = 11) or clomipramine (n = 7), the concentration of 5-HT within the anterior hypothalamus was measured by an in vivo microdialysis system. Measurements (fractions) were taken every 30 min, four times before and five times after an i.p. injection with LPS (100 µg/kg).
Several mechanisms may underlie the effects of antidepressants on LPS-induced behavioral suppression. One possibility is that antidepressants attenuate LPSinduced cytokine secretion. Indeed, several recent reports have demonstrated that TCAs and SSRIs can attenuate the in vitro secretion of cytokines by cells taken from either rodents or humans.27,28 To further explore these effects, we recently measured LPS-induced expression of TNF-α and IL-1β mRNA in splenocytes of rats and mice treated chronically with antidepressants. In collaboration with Professor E. Weihe and Dr. M. Bette from the Department of Anatomy and Cell Biology, University of Marburg, Germany, we demonstrated, using in situ hybridization, that chronic treatment with fluoxetine, but not imipramine, produced a small attenuation of LPSinduced increase in TNF-α mRNA expression. Neither fluoxetine nor imipramine produced any attenuation in LPS-induced increase in IL-1β mRNA levels. Similar results were obtained in our laboratory using PCR analysis.6 These findings suggest that suppression of cytokine production is not a general mechanism by which antidepressants modulate the responses to LPS.
To begin to explore the possibility that antidepressants attenuate the effects of immune challenges on neurochemical systems within the brain, we recently examined the effects of chronic treatment with the TCA clomipramine on LPS-induced secretion of brain serotonin (5-HT). On the last day of antidepressant treatment, rats were implanted with a dialysis probe into the hypothalamus, and the effect of LPS on 5-HT concentrations was assessed 24 h later in freely moving rats. In rats that were chronically treated with saline, LPS produced a significant elevation in hypothalamic 5-HT concentration. This effect was completely abolished by chronic clomipramine treatment, suggesting that antidepressants can attenuate the serotonergic activation induced by an immune challenge (see FIGURE 4).
FIGURE 5. Immune activation and depression due to a general medical condition: possible mechanisms for modulation by antidepressants.
Accumulating evidence indicates that immune activation during various medical conditions is associated with a depressive syndrome in both humans and experimental animals. Taken together with the reports that brain cytokines influence the neurochemical systems involved in depression, these findings support the hypothesis that immune activation, via the release of peripheral and brain cytokines, may be involved in the etiology and symptomatology of “depression due to a general medical condition” (see FIGURE 5). This hypothesis has direct implications for antidepressant therapy. Future research should examine the effects of antidepressant drugs on immune functions and cytokine secretion, as well as the effects of cytokine synthesis blockers and antagonists on depressive disorders associated with medical conditions.
This work was supported by a grant from the German Israeli Foundation for Research and Development and by Grant 97-204 from the United States–Israel Binational Science Foundation.
- KATON, W., & M.D. SULLIVAN. 1990. Depression and chronic medical illness. J. Clin. Psychiatry 51: 3–11.
- DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edit.
American Psychiatric Association. Washington, DC.
- YIRMIYA, R. 1997. Behavioral and psychological effects of immune activation: implications for “depression due to a general medical condition.” Curr. Opinion Psychiatry 10: 470–476.
- MAIER, S.F. & L.R. WATKINS. 1998. Cytokines for psychologists: implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition. Psychol. Rev. 105: 83–107.
- DANTZER, R., A. AUBERT et al. Mechanisms of the effects of cytokines. In Cytokines, Stress and Depression. R. Dantzer, E.E. Wollman & R. Yirmiya, Eds.: 83–106. Kluwer Academic/Plenum Publishers. New York.
- YIRMIYA, R., J. WEIDENFELD et al. Cytokines, “depression due to a general medical condition,” and antidepressant drugs. In Cytokines, Stress and Depression. R. Dantzer, E.E. Wollman & R. Yirmiya, Eds.: 283–316. Kluwer Academic/Plenum Publishers. New York.
- HICKIE, I. & A. LLOYD. 1995. Are cytokines associated with neuropsychiatric syndromes in humans? Int. J. Immunopharmacol. 17: 677–683.
- SMITH, A.P., D.A.J. TYRRELL et al. The effects of experimentally induced respiratory virus infections on performance. Psychiatr. Med. 18: 65–71.
- SMITH, A.P., D.A.J. TYRRELL et al. Mood and experimentally induced respiratory virus infections and illness. Psychol. Health 6: 205–212.
- HALL, S. & A.P. SMITH. 1996. Investigating the effects and aftereffects of naturally occurring upper respiratory tract illnesses on mood and performance. Physiol. Behav. 59: 569–577.
- CAPURON, L. D. LAMARAQUE et al. Attentional and mnemonic deficit associated with infectious disease in humans. Psychol. Med. 29: 291–297.
- MEIJER, A., Z. ZAKAY-RONES & A. MORAG. 1988. Post-influenzal psychiatric disorder in adolescents. Acta Psychiatr. Scand. 78: 176–181.
- MORAG, M., R. YIRMIYA et al. Influence of socioeconomic status on behavioral, emotional, and cognitive effects of rubella vaccination: a prospective, double blind study. Psychoneuroendocrinology 23: 337–351.
- MEYERS, C.A. 1999. Mood and cognitive disorders in cancer patients receiving cytokine therapy. In Cytokines, Stress and Depression. R. Dantzer, E.E. Wollman & R. Yirmiya, Eds.: 75–82. Kluwer Academic/Plenum Publishers. New York.
- SCHROTT, L.M. & L.S. CRNIC. 1996. Anxiety behavior, exploratory behavior, and activity in NZB X NZW F1 hybrid mice: role of genotype and autoimmune disease progression. Brain Behav. Immun. 10: 260–274.
- POLLAK, Y., H. OVADIA et al. Behavioral aspects of experimental autoimmune encephalomyelitis (EAE). J. Neuroimmunol. 104: 31–36.
- ANISMAN, H. & Z. MERALI. 1999. Anhedonic and anxiogenic effects of cytokine exposure. In Cytokines, Stress and Depression. R. Dantzer, E.E. Wollman & R. Yirmiya, Eds.: 199–233. Kluwer Academic/Plenum Publishers. New York.
- MILLER, N.E. 1964. Some psychophysiological studies of motivation and of the behavioral effects of illness. Bull. Br. Psychiatr. Soc. 17: 1–20.
- ANISMAN, H., L. KOKKINIDIS et al. Differential effects of interleukin (IL)–1, IL-2, and IL-6 on responding for rewarding lateral hypothalamic stimulation. Brain Res. 779: 177–187.
- BOROWSKI, T., L. KOKKINIDIS et al. Lipopolysaccharide, central in vivo biogenic amine variations, and anhedonia. NeuroReport 9: 3797–3802.
- ZACHARKO, R.M., S. ZALCMAN et al. Differential effects of immunologic challenge on self-stimulation from the nucleus accumbens and the substantia nigra. Pharmacol. Biochem. Behav. 58: 881–886.
- YIRMIYA, R. 1996. Endotoxin produces a depressive-like syndrome in rats. Brain Res. 711: 163–174.
- SAKIC, B., J.A. DENBURG et al. Blunted sensitivity to sucrose in autoimmune MRL-lpr mice: a curve shift study. Brain Res. Bull. 41: 305–311.
- YIRMIYA, R., R. AVITSUR et al. Interleukin-1 inhibits sexual behavior in female but not in male rats. Brain Behav. Immun. 9: 220–33.
- AVITSUR, R. & R. YIRMIYA. 1999. The immunobiology of sexual behavior: gender differences in the suppression of sexual activity during illness. Pharmacol. Biochem. Behav. 64: 787–796.
- LEVENSON, J.L. & H.J. FALLON. 1993. Fluoxetine treatment of depression caused by interferon-alpha. Am. J. Gastroenterol. 88: 760–761.
- XIA, Z., J.W. DEPIERRE & L. NASSBERGER. 1996. Tricyclic antidepressants inhibit IL6, IL-1β and TNF-α release in human blood monocytes and IL-2 and interferon-γ in T-cells. Immunobiology 34: 27–37.
- MAES, M., C. SONG et al. Negative immunoregulatory effects of antidepressants:
inhibition of interferon-gamma and stimulation of interleukin-10 secretion. Neuropsychopharmacology 20: 370–379.