Ann N Y Acad Sci. 2000;917:478-87.
Illness, cytokines, and depression
EEV: Full study is currently on evesdrift.com. It will have four of the missing graphs added to it later on today..
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.
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, and ePsychiatry, 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. email@example.com
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: