Abstract

Section 1

Section 2

Section 3

Section 4

Section 5

Discussion
Board

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% (Chochinov et al., 1994), however, because depression is often unrecognized and undertreated in sick patients, the prevalence reported in most studies is probably underestimated (Katon & Sullivan, 1990). The high prevalence of depression in various medical conditions is reflected by the special psychiatric diagnostic entity of ‘depression due to a general medical condition’ (DSM IV, 1994). To be diagnosed with 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” (DSM-IV, 1994, p. 367). Several lines of evidence suggest that this physiological mechanism involves the immune system, i.e., 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.

The physiological and psychological effects of immune activation (collectively termed “sickness behavior”) are mediated by cytokines derived from activated immune and other cells (Connor & Leonard, 1998; Dantzer et al., 1996; Hart, 1988; Kent et al., 1992; Maier & Watkins, 1998 Yirmiya, 1997). 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, tumor necrosis factor-alpha (TNF-alpha), which serve as neurotransmitters and neuroregulators (Dantzer et al., 1996; Maier & Watkins, 1998). 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.

Infectious and non-infectious illnesses are associated with depression
Acute 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 (Hickie & Lloyd, 1995). 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) are associated with decreased psychomotor performance of simple reaction-time tasks and memory impairments (Smith et al., 1988). In addition, they are often associated with long term psychiatric effects, particularly depression. Experimentally-induced influenza (Smith et al., 1992), as well as natural occurrence of upper respiratory tract illness (Hall & Smith, 1996), produce a general negative mood state. Moreover, following infection with influenza, subjects showed depressive symptoms, including depressed mood, reduced appetite, sleep disturbances, sense of guilt, marked difficulty in decision making and memory impairments; these symptoms could be detected even months after the onset of the infection (Meijer et al., 1988). Similar disturbances have also been reported following infections with herpesvirus, cytomegalovirus, Epstein-Barr virus, gastroenteritis, Borna Disease virus and HIV.

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 (Morag et al., 1998). Subjects were teenager girls who were vaccinated with live attenuated rubella virus. Based on analysis of levels of antibodies to rubella, subjects were divided into two groups: An experimental group, comprised of subjects who were initially seronegative and were infected following vaccination, and a control group, comprised 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 (Morag et al., 1998). 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 (Dohrenwend, 1973; Ranchor et al., 1996), which modulate the responsiveness to immune challenges (Cohen, 1995; Kiecolt-Glaser & Glaser, 1991). Thus, even a mild viral infection can produce a prolonged increase in depressive symptomatology in vulnerable individuals.

Many non-infectious 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 (Dinarello & Wolff, 1993; Rothwell et al., 1996). High incidence of depression has been demonstrated in patients afflicted with these conditions, including multiple sclerosis (Foley et al., 1992; Minden & Schiffer, 1990), rheumatoid arthritis (Parker et al., 1992), systemic lupus erythematosus (Denburg et al., 1997), allergy (Marshal, 1993), stroke (Robinson, 1997), and Alzheimer’s disease (Lyketsos et al., 1997). When studied, immune deregulation 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.

Administration of cytokine and endotoxin 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-alpha), IL-2 or TNF-alpha 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 (McDonald et al., 1987; Meyers & Valentine, 1995; Walker et al., 1997). 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.

Together with Dr. T. Pollmacher from the Max Planck Institute of Psychiatry in Munich, Germany, we have recently conducted a study on the effects of immune activation with endotoxin on affective and cognitive variables in healthy volunteers (n=20). A within-subjects cross-over design was used, in which each subject completed an extensive battery of psychological and neuropsychological tests following endotoxin injection (0.8 ng/kg) on one day, and following saline on another day. Neither the experimenter nor the subject knew the group assignment (i.e., a double blind design). Preliminary results demonstrate that endotoxin induced clinical symptoms of illness, including a significant rise in rectal temperature, elevation in serum cortisol, and mild headache and muscle pain. Endotoxin also induced a significant elevation in negative emotions, including sadness, anxiety, stress, nervousness, and tiredness. In addition, endotoxin produced cognitive impairments, including impaired learning and memory and reduced visuo-spatial ability.

Behavioral effects of infectious diseases and cytokine administration 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 (Hart, 1988; Dantzer et al., 1996; Yirmiya, 1997; Maier and Watkins, 1998). Similar symptoms, as well as increased anxiety behavior were also reported using a mouse model of autoimmune disease (Schrott & Crnic, 1996), 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-1beta and TNF-alpha), 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 (Dantzer et al., 1996; Kozac et al., 1996; Heyser et al., 1997; Swiergiel et al., 1997; Yirmiya, 1997; Maier and Watkins, 1998).

One particularly important aspect of depression that has been recently modeled in animals is anhedonia, i.e., the diminished capacity to experience pleasure. Suppression of ICSS is a very useful animal model to study anhedonia (Willner, 1994). Endotoxin-induced suppression of ICSS has been demonstrated more than 3 decades ago (Miller, 1964). This report was recently corroborated by the findings that exogenous administration of LPS (Borowski et al., 1997) or IL-2 (Anisman et al., 1996, 1998) produce a dramatic and long-lasting decrease in ICSS. IL-1beta administration was also associated with suppression of ICSS, although the effective doses also induced other symptoms of sickness behavior. Antigenic challenge with sheep red blood cells also reduced ICSS at times that approximated the peak of immune response (Zacharko et al., 1997). The consumption of and preference for sweet solutions can also serve as a model for hedonic processes. Studies in my laboratory demonstrated that various immune challenges attenuate the consumption of and preference for sweet solutions, while having minimal effects on water drinking (Yirmiya, 1996; Yirmiya et al., 1997). Studies in other laboratories corroborate these findings, demonstrating that immune challenges reduced the intake of sweetened milk (Swiergiel et al., 1997), and abolished the reinforcing effect of cocaine (Suzuki et al., 1994).

Moreover, mice that spontaneously develop systemic autoimmune lupus-like disease, also show blunted sensitivity to sucrose, which can be reversed by an immunosuppressive treatment (Sakic et al., 1996). Finally, we have found that various immune challenges produce a dramatic decrease in libido and sexual performance of female rats (Yirmiya et al., 1995; Avitsur et al., 1997). Such a reduction in sexual interest or desire, as well as difficulties in sexual functioning are commonly associated features of depression, which are also viewed as manifestations of the general loss of interest and pleasure in activities that were previously considered pleasurable (DSM-IV, 1994). In conclusion, various immune challenges induce anhedonia and many behavioral alterations, which resemble the vegetative symptoms of depression. These findings suggest that immune activation produces a depression-like syndrome in animals.

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 conditions (Katon & Sullivan, 1990), and depression induced by IFN administration in humans (Levenson & Fallon, 1993). 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- or IL-1-induced behavioral and neuroendocrine alterations in rats. We demonstrated that chronic, but not acute imipramine treatment, completely abolished the suppressive effect of LPS on saccharine consumption (Yirmiya, 1996). Chronic, but not acute administration of imipramine (daily injection for 5 weeks) attenuated or completely abolished many other behavioral effects of LPS, including anorexia, body-weight loss, reduced social activity and suppression of locomotor and exploratory behavior in the open field test. The dissociation between the effects of acute and chronic imipramine treatment is important, since in clinical settings, imipramine is also effective in alleviating depression only following chronic, but not acute administration (Montgomery, 1994).

In subsequent experiments we showed that chronic administration (daily injections, 5 weeks) of fluoxetin also affected some, but not all the alterations produced by LPS. Fluoxetin significantly attenuated LPS-induced reduction in food consumption and body weight, but it did not affect LPS-induced decrease in social interaction and activity in the open-field test. Chronic fluoxetin treatment also attenuated LPS-induced secretion of corticosterone (Yirmiya et al., unpublished observation). The effects of fluoxetin on the behavioral and neuroendocrine alteration induced by immune activation with LPS are at least partly mediated by the effects of fluoxetin on cytokine production, becuase we found that chronic fluoxetin treatment also attenuated LPS-induced TNF-alpha and inducible nitric oxide synthase (iNOS) mRNA in splenocytes.

Immune activation and other depressive syndromes
Immune activation may be involved in depressive syndromes other than ‘depression due to a general medical condition’. Although depression has traditionally been associated with suppression of specific immune functions, recent evidence indicates that several components of the immune system are activated in patients suffering from major depression (Connor & Leonard, 1998; Maes, 1995). Depression-associated immune activation includes: 1) Increased number of blood lymphocytes, neutrophils, monocytes, and activated T-cells; 2) Increased serum levels of several soluble indicators of activated immune cells; 3) Increased serum concentrations of positive acute phase proteins (APPs) and decreased levels of negative APPs; and 4) Increased secretion of cytokines, both in vivo (particularly IL-6), and following in vitro induction by mitogens (particularly IL-1beta, IL-6, and IFN-gamma). Furthermore, immune activation is positively correlated with specific depressive symptoms and with the impaired feedback regulation of the HPA axis, found in major depression patients (Maes, 1995).

Clearly, immune activation and cytokine secretion do not account for all types of depressive disorders. However, immune factors may be involved in the pathophysiology of certain subtypes of depression (e.g., melancholia), characterized by a constellation of symptoms that are often found in virus-infected and cytokine-injected individuals. The source of immune activation in any depressive disorder other than ‘depression due to a general medical condition’ has not been identified yet. Future studies should determine whether subclinical infectious processes or viral reactivation induce a immune reaction, which in turn contributes to the depressive symptomatology in vulnerable individuals.

Conclusions
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, might be involved in the etiology and symptomatology of ‘depression due to a general medical condition’ and some other specific depressive syndromes. 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.

Back to the top.

Back to the top.

Back to the top.

Back to the top.

Back to the top.