■ Experimental

Baseline 2 10

Time From Vaccination (in weeks)

Figure 1. Effect of vaccination with live-attenuated rubella virus on depression scores, measured by the Children Depression Inventory in 12-years old girls with low socioeconomic status.

Monson, Sobol, Federman, & Leighton, 1991). This vulnerability may be associated with several characteristics of low SES, including higher "incidence of stressful life events, and fewer sources of social support (Adler, Boyce, Chesney, Cohen, Folkman, Khan, & Syme, 1994; Anderson & Armstead, 1995; Dohrenwend, 1973; Ranchor, Bouma, & Sanderman, 1996). As demonstrated (Cohen, 1995; Kiecolt-Glaser & Glaser, 1991), these factors modulate the responsiveness to immune challenges. Thus, even a mild viral infection can produce prolonged increase in depressive symptomatology in vulnerable individuals.

Mean (±S.E.M.) emotional depression score (A) and total depression score (B) were assessed before, and 2 and 10 weeks after vaccination. Subjects who were initially seronegative and were infected following vaccination (experimental group) had higher depression scores than subjects who were already immune to rubella before vaccination (control group), at both 2 and 10 weeks post-vaccination.

2.2. Psychological Effects of Non-Infectious Conditions Associated with Immune Activation

Chronic activation of the immune system and enhanced secretion of cytokines may be associated with several types of non-infectious conditions (Dinarello & Wolff, 1993). High incidence of depression is observed in such cases too.

Autoimmune diseases: Cytokines play an important role in the etiology and pathology of many autoimmune diseases (Cavallo, Pozzilli, & Thorpe, 1993; Dinarello & Wolff, 1993), which are also associated with a high prevalence of depression. Particularly high incidence of depression has been demonstrated in patients with multiple sclerosis (Foley, Traugott, LaRocca, Smith, Perlman, Caruso, & Scheinberg, 1992; Minden & Schiffer, 1990; Schiffer & Babigian, 1984; Schubert & Foliart, 1993; Whitlock & Siskind, 1980). According to several estimates, the prevalence of depression in MS patients is in the range of 42-54% (Joffe, Lippert, Gray, Sawa, & Horvath, 1987; Minden, Orav, & Reich, 1987; Sadovnick, Remick, Allen, Swartz, Lee, Eisen, Farquhar, Hashimoto, Hooge, Kastrukoff, Morrison, Nelson, Ogar, & Paty, 1996). Other autoimmune conditions associated with high prevalence of depression, include rheumatoid arthritis (Parker, Smarr, Anderson, Hewett, Walker, Bridges, & Caldwell, 1992; Pincus, Griffith, Pearce, & Isenberg, 1996), systemic lupus erythematosus (Denburg, Carbotte, & Denburg, 1997; Hutchinson, Nehall, & Simeon, 1996; Lim, Ron, Ormerod, David, Miller, Logsdail, Walport, & Harding, 1988; Magner, 1991; Schneebaom, Singleton, & West, 1991), and allergy (Marshal, 1993). Detailed studies of some of these conditions suggest that, rather than psychological reactions to the medical condition per-se, illness-associated depression is causally related to immune activation (see below).

Stroke and trauma: Stroke and some other types of brain traumas are associated with increased secretion of cytokines. For example, the levels of TNFa and IL-lp are dramatically increased in the brain following stroke or head trauma (Arvin, Neville, Barone, & Feuerstein, 1996). IFNa and its receptors have been identified in cerebral infarct tissues (Yamada & Yamanaka, 1995). Depression is the most common neuropsychiatric consequence of stroke, affecting up to 40% of the patients (Robinson, 1997; Schwartz, Speed, Brunberg, Brewe, Brown, & Greden, 1993). A relationship between the appearance and severity of depression to the location of the injury within the brain has been demonstrated in several cases (Robinson, 1997). However, most depressive symptoms are not explained by a direct localized neural impairment, suggesting an involvement of a more general mechanism, such as immune activation.

Alzheimer's disease: Immune activation and cytokine secretion is associated with brain lesions of Alzheimer's disease and other neurodegenerative diseases (McGeer & McGeer, 1995; Rothwell, Luheshi, & Toulmond, 1996). Activated microglia cells and astrocytes that are associated with neuritic plaques produce IL-1. Moreover, IL-1 can upregulate the expression of p-amyloid precursor proteins and various other plaque-associated proteins. Moreover, this process is self propagating, because P-amyloid directly activates microglia, thus inducing further IL-1 production (Mrak, Sheng, & Griffin, 1995). Depression is very common in Alzheimer's patients. In fact, mild to severe depression is the most prevalent psychiatric symptom in these patients (Mendez, Martin, Smyth, & Whitehouse, 1990). For example, a recent study on 109 patients identified major depression in 22% and minor depression in another 27% of the patients (Lyketsos, Steele, Baker, Galik, Kopunek, Steinberg, & Warren, 1997).

Menstrual cycle and post-partum period: Women exhibit higher levels of immune activation than men (Grossman, 1985), and a high incidence of depression (DSM-IV, 1994; Parry, 1995). This relation may be attributed to many factors, but it should be noted that plasma and urinary levels of IL-1 are much higher in women than in men (Cannon & Dinarello, 1985). Moreover, in vitro production of IL-1 is much greater in unstimulated mononuclear cells derived from women is in cells derived from men (Lynch, Dinarello, & Cannon, 1994).This effect depends on the phase of the menstrual cycle; compared to men's cells, women's cells isolated during the luteal and follicular phases secreted 5-10 fold and 13-28 fold more IL-la, IL-lp, and IL-1 receptor antagonist (IL-lra), respectively (Lynch et al., 1994). Although greater absolute amounts of each species of IL-1 were secreted during the follicular phase, the ratio of agonist to antagonist secreted was greater in the luteal phase (Lynch et al., 1994). This finding is in agreement with the in vivo data, which reflected greater IL-1 bioactivity in the plasma during the luteal phase (Cannon & Dinarello, 1985). The time course of IL-1 secretion and bioactivity is correlated with the onset of depressive episodes in women, which is highest during the luteal phase, particularly several days before the menstrual flow (Abramowitz, Baker, & Fleischer, 1982; Parry, 1995). Finally, child delivery, which in some women causes post-partum depression (Parry, 1995), also triggers a marked increase in cytokine secretion (Cox, King, Casey, & Macdonald, 1993).

2.3. Psychological Effects of Cytokine Administration

Administration of cytokines in humans produces marked behavioral and neuroendocrine symptoms that are similar to those induced by viral infection. Administration of alpha interferon (IFNa) 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 (Fent & Zbinden, 1987; McDonald, Mann, & Thomas, 1987; Meyers & Valentine, 1995; Niiranen, Laaksonen, Iivanainen, Mattson, Fakkila, & Cantell, 1988; Okanoue, Sakamoto, Itoh, Minami, Yasui, Sakamoto, Nishioji, Katagishi, Nakagawa, Tada, Sawa, Mizuno, Kagawa, & Kashima, 1996; Pavol, Meyers, Rexer, Valentine, Mattis, & Talpaz, 1995; Renault, Hoofnagle, Park, Mullen, Peters, Jones, Rustgi, & Jones, 1989; Valentine, Meyers, Kling, Richelson, & Hauser, 1998). In some studies, severe depressed mood has been reported in the majority of the cytokine-administered patients (McDonald et al., 1987; Niiranen et al., 1988; Valentine et al., 1998). Depressive symptoms increased with the dose and duration of IFNa treatment (Pavol et al„ 1995; Renault et al., 1989; Valentine et al., 1998), and disappeared completely within 2-3 weeks after termination of the treatment. Patients receiving IL-2 or TNFa also exhibited flu-like symptoms and some depressive symptoms, including depressed mood, severe fatigue, weakness, lethargy, decreased concentration and confusion (Fent & Zbinden, 1987; Meyers, Valentine, Wong, & Leeds, 1994; Spriggs, Sherman, Michie, Arthur, Imamura, Wilmore, Frei, & Kufe, 1988; Walker, Walker, Heys, Lolley, Wesnes, & Eremin, 1997; Walker, Wesnes, Heys, Walker, Lolley, & Eremin, 1996). It should be noted that the effects of these cytokines on depressive symptomatology may be mediated by a cascade of other cytokines; for example, IFNa induces the expression and secretion of IL-1 and other cytokines in the periphery (Aren-zana-Seisdedos & Virelizer, 1983) and within the CNS (Licinio, Kling, & Hauser, 1998).

The findings on cytokine-induced depression have important theoretical and clinical implications. Clinical research in the "50 demonstrated that the monoamine depleting drug reserpine, which was then used as an antihypertensive drug, produces severe depression. This observation stimulated the monoamine hypothesis of depression and the development of new and effective antidepressant drugs. In the same way, the finding that exogenous administration of cytokines produces depression can stimulate the cytokinergic hypothesis of depression, and may result in the development of a new generation of effective antidepressant therapeutic procedures.

2.4. The Role of Immune Activation in Depression

2.4.1. Immune Activation and "Depression Due to a General Medical Condition." Studies on depression in randomly selected general medical inpatients indicate that more than one third report some degree of depression (Laghrissi-Thode et al., 1996; Rodin & Voshart, 1986). As discussed earlier, depression rates can be as high as 50% in certain medical conditions that are specifically associated with high levels of immune activation (e.g., autoimmune diseases, allergy, stroke) (Minden & Schiffer, 1990; Parker et al., 1992; Rodin & Voshart, 1986; Schwartz et al., 1993). 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 diagnose 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).

The depressive symptomatology that is associated with physical illness in humans may be produced directly by immune factors or may constitute a psychological reaction to the incapacitation, pain, and losses that accompany the physical disease process. It is difficult to design experiments that will directly differentiate between these two possibilities. However, several lines of evidence support the hypothesis that the direct influence of immune activation on mood and cognition is independent of, and possibly additive to, the maladaptive depressive response to the distress of having a general medical condition:

1) In a study on the neuropsychological effects of experimentally-induced influenza, cognitive disturbances were found to occur not only in sick individuals, but also in subjects with laboratory evidence of viral infection who did not have any clinical symptoms (Smith et al., 1988).

2) In some recurrent infectious conditions, the depressive symptoms precede the clinical manifestations of the disease. For example, in patients with recurrent herpes infections the depressed mood and other psychological alterations are reported by the patients 24-48hr prior to recurrence of the peripheral skin or genital lesions (Hickie & Lloyd, 1995). This finding had been interpreted as evidence for the effects of depression on the recurrence of the virus, but the temporal relationship between the immunological, psychological, and somatic alterations is more consistent with the hypothesis that viral-induced immune activation is responsible for the psychological changes.

3) The induction of depressed mood and other depressive symptoms in cytokines-treated patients, and the fact that these symptoms appear almost immediately after cytokine administration and usually disappear shortly after termination of the cytokine treatment (Fent & Zbinden, 1987; McDonald et al., 1987; Meyers & Valentine, 1995; Niiranen et al., 1988; Spriggs et al., 1988), strongly suggests a causal role for cytokines in producing the depressive symptoms. Although cytokines are usually administered in the context of a medical condition (e.g., cancer), which by itself could account for some of the depressive symptoms, at least part of the depressive symptomatology can be directly ascribed to the cytokine treatment. For example, in a controlled study on patients with chronic myelogenous leukemia, 50% of the patients had elevated levels of depression following the onset of IFNa therapy, compared to 25% following the onset of chemotherapy (Pavol et al., 1995).

4) Several studies on depression associated with autoimmune diseases suggest that the depressive symptoms reflects the action of a basic physiological mechanism, such as immune activation, rather than a psychological reaction to the consequences of the disease (e.g. functional losses). Compared to patients with other neurological diseases, MS patients showed higher levels of depressive symptoms at the time of the diagnostic interview, and higher number of depressive episodes since their diagnosis had been made (Schiffer & Babigian, 1984; Whitlock & Siskind, 1980). Furthermore, depressed MS patients are frequently characterized by the presence of vegetative symptoms and diurnal variations in mood and energy (Whitlock & Siskind, 1980). This quality of depression may suggest an "organic" rather than a "reactive" depression. In many cases the onset of depression precedes the neurological diagnosis (Schiffer & Babigian, 1984). A prospective study of MS depressed patients revealed that immune dysregulation preceded the development of depression (Foley et al., 1992). Similarly, a study that addressed the relationship of helplessness and depression to disease activity in rheumatoid arthritis (RA) patients revealed that immunological activation might moderate this relationship (Parker et al., 1992). Studies in patients with systemic lupus erythematosus (SLE) are somewhat less supportive of the immune activation hypothesis, since no differences were found in the magnitude and quality of SLE-associated depression, compared to depression associated with other chronic medical conditions (Denburg et al., 1997; Hutchinson et al., 1996; Lim et al., 1988; Magner, 1991). The authors interpreted these results as indicating reactive depression (Denburg et al., 1997). However, since many of their control patients suffered from autoimmune diseases, the involvement of immune mechanisms cannot be ruled out, both in control and in SLE patients. In fact, one study found a direct relationship between depressive manifestations and autoantibodies to ribosomal P proteins in SLE patients (Schnee-baom et al., 1991).

Together, these findings suggest that at least some of the depressive symptoms that accompany physical illness are not merely a reaction to the medical condition, but are at least partly produced by immune changes preceding and coincide with the appearance of clinical symptoms.

2.4.2. 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 (Herbert & Cohen, 1993), recent evidence indicates that several components of the immune system are activated in patients suffering from major depression (Connor & Leonard, 1998; Maes, 1995; Maes, Smith, & Schärpe, 1995c). Depression-associated immune activation includes: 1) Increased number of blood lymphocytes, neutrophils, monocytes, and activated T-cells (Maes, Lambrechts, Bosmans, Jacobs, Suy, Vandervorst, De Jockheere, Minner, & Raus, 1992a; Muller, Hofschuster, Ackenheil, Mempel, & Eckstein, 1993; Seidel, Arolt, Hunstiger, Rink, Behnisch, & Kirchner, 1996); 2) Increased serum levels of several soluble indicators of activated immune cells, including interleukin-2 receptor (Maes, Meitzer, Bosmans, Bergmans, Vandoolaeghe, Ranjan, & Desnyder, 1995a; Sluzewska,

Rybakowski, Bosmans, Sobieska, Berghmans, Maes, & Wiktorowicz, 1996), neopterin (Dunbar, Hill, Neale, & Mellsop, 1992; Maes, Schärpe, Meitzer, Okayli, D'Hondt, & Cosyns, 1994) and prostaglandin E2 (Lieb, & Karmali, 1983; Linnoila, Whorton, Rubinow, Cowdry, Ninan, & Waters, 1983); 3) Increased serum concentrations of positive acute phase proteins (APPs) and decreased levels of negative APPs (Maes, Schärpe, Neels,Wauters, Van Gastel, & Cosyns, 1995b; Maes, Schärpe, Van Grootel, Uyt-tenbroeck, Cooreman, Cosyns, & Suy, 1992b; Seidel, Arolt, Hunstiger, Rink, Behnisch, & Kirchner, 1995; Sluzewska et al., 1996; Song, Dinan, & Leonard, 1994); and 4) Increased secretion of cytokines, both in vivo (particularly IL-6) (Maes et al., 1995a; Maes, Bosmans, De Jongh, Kenis, Vandoolaeghe, & Neels, 1997a; Sluzewska, Rybakowski, Laciak, Mackiewicz, Sobieska, & Wiktorowicz, 1995; Sluzewska et al., 1996), and following in vitro induction by mitogens (particularly IL-lß, IL-6, and IFNy) (Maes, Bosmans, Meitzer, Schärpe, & Suy, 1993; Maes et al., 1994; Seidel et al, 1995; Seidel et al., 1996).

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 et al., 1993; Maes, 1995). Based on these findings, Maes and his colleagues hypothesized that production of interleukins contributes to the HPA hyperactivity and to the vegetative symptoms of severe major depression (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. It is possible, however, that subclinical infectious processes or viral reactivation induce immune reaction, which in turn contributes to the depressive symptomatology. This hypothesis is supported by studies reporting increased antibody titers to several viruses, particularly herpes simplex virus (HSV) in patients with major depression (Cappel, Gregoire, Thiry, & Sprecher, 1978; Lycke, Norrby, & Roos, 1974). Moreover, in a recent study (Zorzenon, Colle, Vecchio, Bertoli, Giavedoni, Degrassi, Lavaroni, & Aguglia, 1996) clear evidence was provided for active viral multiplication and elevated antibody titers to HSV in 41% of the patients with major depression. Similarly, higher serum antibodies to Borna disease virus, as well as isolation of this virus from patients with depression has been reported (Bode, Durrwald, Rantam, Ferszt, & Ludwig, 1996).

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