Clinical Research Center for Mental Health (CRC-MH) Antwerp, Belgium
IRCCS, Istituto Fatebenefratelli, Brescia, Italy, and Department of Psychiatry, Vanderbilt University, Nashville
Contemporary models of major depression emphasize the role of hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity and of dysfunctions in the turnover of serotonin (5-HT) or catecholamines in the etiopathogenesis of major depression. Contemporary models of major depression do not incorporate the effects of the inflammatory response system (IRS), even though the IRS powerfully influences HPA-axis activity, 5-HT and catecholaminergic turnover and even though activation of the IRS may induce depression-like behavior in animals and humans. There is now evidence that major depression is accompanied by a moderate activation of the IRS (reviews: Maes, 1993; 1995; 1997; Maes, Smith, & Schärpe, 1995c; Holden, Pakula, & Mooney, 1997; Maes & Smith, 1997; Connor & Leonard, 1998; Maier & Watkins, 1998). In this paper we propose a concise IRS model of major depression.
2. INDICATORS OF IRS ACTIVATION IN DEPRESSION 2.1. IRS Activation
Indicators of IRS activation in major depression are confirmed findings of increased numbers of leukocytes, monocytes, neutrophils, activated T-lymphocytes, increased secretion of neopterin and prostaglandins. Herbert & Cohen (1993) showed,
* Mailing Address: Michael Maes, M.D., Ph.D., Director Clinical Research Center for Mental Health, Antwerp University Department of Psychiatry, 267 Lange Beeldekensstraat, 2060 Antwerp, Belgium, FAX: 32-3-4483265. e-mail: [email protected]
Cytokines, Stress, and Depression, edited by Dantzer et at. Kluwer Academic / Plenum Publishers, New York, 1999.
in a meta-analytical review, that major depression is associated with a significant increased number of leukocytes and neutrophils. There are also reports on monocytosis, increased CD4+/CD8+ T cell ratio and increased numbers of activated T cells, such as CD25+ and HLA-DR+ T cells, in depression (Muller, Ackenheil, & Hofschuster, 1989; Muller, Hofschuster, Ackenheil, Mempel, & Eckstein, 1993; Maes, Lambrechts, Bosmans, Jacobs, Suy, Vandervorst, De Jonckheere, Minner, & Raus, 1992a; Maes, Schärpe, Meitzer, & Cosyns, 1993d; Perini, Zara, Carraro, Tosin, Gava, Santucci, Valverde, & Defranchis, 1995; Seidel, Arolt, Hunstiger, Rink, Behnisch, & Kirchner, 1995; Seidel, Arolt, Hunstiger, Rink, Behnisch, & Kirchner, 1996a; Deger, Bekaroglu, Orem, Orem, Uluutku, & Soylu, 1996; review: Maes, 1997). Increased serum concentrations of the soluble interleukin-2-receptor (sIL-2R) also indicate in vivo T cell activation in depression (Maes, Bosmans, Suy, Vandervorst, Dejonckheere, Minner, & Raus, 1991a; Maes, Bosmans, Suy, Vandervorst, Dejonckheere, & Raus, 1991b; Maes, Meitzer, Bosmans, Bergmans, Vandoolaeghe, Ranjan, & Desnyder, 1995a; Nassberger & Traskman-Bendz, 1993; Sluzewska, Rybakowski, Bosmans, Sobieska, Berghmans, Maes, & Wiktorowicz, 1996a). Other direct indicators of IRS activation in depression are increased concentrations of prostaglandin E2 (PGE2) in serum, cerebro-spinal fluid (CSF), and mitogen-stimulated culture supernatant (Lieb & Karmali, 1983; Linnoila, Whorton, Rubinow, Cowdry, Ninan, & Waters, 1983; Calabrese, Skwerer, Barna, Gulledge, Valenzuela, Butkus, Subichin, & Krupp, 1986; Song, Lin, Bonaccorso, Heide, Verkerk, Kenis, Bosmans, Schärpe, Cosyns, DeJong, & Maes, 1998), and increased serum or urine secretion of neopterin (Duch, Woolf, Nichol, Davidson, & Garbutt, 1984; Dunbar, Hill, Neale, & Mellsop, 1992; Maes, Schärpe, Meitzer, Okayli, D'Hondt, & Cosyns, 1994e; Bonaccorso, Lin, Verkerk, VanHunsel, Libbrecht, Schärpe, DeClerck, Stevens, Biondi, Janca, & Maes, 1998). Neopterin, a low molecular weight not-conjugated pteridin, is produced by activated macrophages after stimulation with interferon-y (IFNy) (review: Maes et al., 1994e).
Indicators of an acute phase response in major depression are the confirmed findings on increased serum concentrations of positive acute phase proteins, such as haptoglobin (Hp), al-antitrypsin, ceruloplasmin, al-acid glycoprotein, C-reactive protein, and al-antichymotrypsin; and lowered serum concentrations of negative acute phase proteins, such as albumin (Alb) and transferrin (Tf) (Swartz, 1990; Maes, Vandewoude, Schärpe, De Clerck, Stevens, Lepoutre, & Schotte, 1991c; Maes, Schärpe, Bosmans, Vandewoude, Suy, Uyttenbroek, Cooreman, Vandervorst, & Raus, 1992b; Maes, Schärpe, Van Grootel, Uyttenbroeck, Cooreman, Cosyns, & Suy, 1992c; Maes, De Langhe, Schärpe, Meitzer, Cosyns, Suy, & Bosmans, 1994b; Maes, Schärpe, Neels, Wauters, Van Gastel, & Cosyns, 1995b; Maes, Delanghe, Ranjan, Meitzer, Desnyder, Cooreman, & Schärpe, 1997b; Joyce, Hawes, Mulder, Sellman, Wilson, & Boswell, 1992; Song, Dinan, & Leonard, 1994; Seidel et al., 1995; Sluzewska, Rybakowski, Sobieska, & Wiktorowicz, 1996b; Van Hunsel, Wauters, Vandoolaeghe, Neels, Demedts, & Maes, 1996; Berk, Wadee, Kuschke, & O'Neill-Kerr, 1997; Kronfol, Singh, Boura, & Brown, 1998; Mikova, Stoyanova, & Tanchev, 1998). Increased serum concentrations of elastase in major depression also indicate the presence of an acute phase response (Deger et al., 1996). An acute phase response also occurs in the chronic mild stress model of depression in the rodent and the olfactory bulbectomized rat model of depression (Sluzewska, Nowakowska, Gryska, & Mackiewicz, 1994; Song & Leonard, 1994).
In depression, there are confirmed findings on increased in vivo secretion of proinflammatory cytokines, such as IL-6 and IL-8 (Maes et al., 1995a; Maes, Bosmans, De Jongh, Kenis, Vandoolaeghe, & Neels, 1997a; Sluzewska, Rybakowski, Laciak, Mackiewicz, Sobieska, & Wiktorowiz, 1995; Sluzewska et al., 1996a; Berk et al., 1997; Frommberger, Bauer, Haselbauer, Fraulin, Riemann, & Berger, 1997; Song et al., 1998) and increased mitogen-induced production of proinflammatory cytokines, such as IL-lß, IL-6, and IFNy (Maes et al., 1991a; Maes, Bosmans, Meitzer, Schärpe, & Suy, 1993a; Maes, Schärpe, Meitzer, Bosmans, Suy, Minner, Calabrese, Uyttenbroeck, Vandervorst, Raus, & Cosyns, 1993c; Maes et al., 1994e; Seidel et al., 1995; Seidel, Arolt, Hunstiger, Rink, Behnisch, & Kirchner, 1996b). In Wistar rats, an eight-week exposure to mild, unpredictable stress induces a depression-like state with an increased production of IL-1 and IL-2 by splenocytes (Kubera, Symbirtsev, Basta-Kaim, Borycz, Roman, Papp, & Claesson, 1996). Since proinflammatory cytokines induce an immune and acute phase response and since we found significant and positive correlations between cytokine production, e.g. IL-6, and indicators of immune activation, e.g. increased numbers of peripheral blood mononuclear cells (PBMC) and acute phase proteins, we have suggested that IRS activation in depression is caused by an increased production of the proinflammatory cytokines, IL-lß, IL-6, and IFNy (Maes et al., 1992a; 1993d; Maes, 1993; 1995; 1997).
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