Abstract

It is firmly established that women experience major depression (MD) at roughly twice the rate of men. Contemporary research has indicated that sex hormones comprise crucial orchestrators of the differences in susceptibility associated to sex in MD, as well as in certain infectious and autoimmune diseases. Interestingly, it has been suggested that altered functioning of the immune system may be implicated in the medical morbidity of this affective disorder. To make matters more complicated, data accumulated largely during the last two decades advocate the innate inflammatory immune response as a mechanism that may contribute to the pathophysiology of MD, mainly through alterations in the ability of immune cells to secrete pro-inflammatory cytokines. Although the literature is limited, the bi-directional influences between the brain and the immune system appear to present sex-related motifs whose elucidation is far from being completely achieved but comprises a matter of intensive research. Herein, we provide a first critical glimpse into if and how sex differences in immunity may be implicated in the pathophysiology of MD. The review's major aim is to sensitize clinical scientists of different disciplines to the putative impact of immune sexual dimorphism on MD and to stimulate basic research in a need to delineate the neuroimmunological substrate in the appearance, course and outcome of this stress-related disorder.

Overview

Major depression (MD) affects both men and women, but more women than men are likely to be diagnosed with depression in any given year (Holden, 2005; Kessler, 2003; Kessler et al. 2003, 1995; Kornstein, 1997; Nemeroff et al. 2006; Somers et al. 2006; Stein et al. 2002; Steiner et al. 2005). This sex-dependent differentiation has been largely attributed to the pronounced sex differences that predominate in both the anatomy and function of the human brain, as well as to the sexually dimorphic hormonal milieu (Cosgrove et al. 2007; Kessler, 2003).

According to the World Health Organization (WHO), by 2020 MD is expected to rise to become the number two contributor to the global burden of disease (WHO, 2005). Despite the fact that our knowledge regarding the pathophysiology and the neurobiological substrate of depression has grown exponentially over the last decades, there is still a significant percentage of patients who do not tolerate or respond poorly to current antidepressant medications (Rush, 2007). The latter probably reflects the fact that the term ‘depression’ encompasses a group of disorders, each being characterized by a unique endophenotype that needs to be treated accordingly (Antonijevic, 2006; Hasler et al. 2004).

Intriguingly, a constellation of preclinical and clinical evidence supports the notion that depression and immunity are engaged in a bi-directional relationship, which is characterized by both immunosuppression and activation of the innate immune machinery (McNally et al. 2008; Miller et al. 2009). Depressed patients often show alterations in responses of both the innate and the cell-mediated arms of immunity that are associated with infectious-disease susceptibility (Zorrilla et al. 2001). On the other hand, data accumulated largely during the last two decades advocate the inflammatory immune response as a mechanism that may contribute to the pathophysiology of this affective disorder (Dantzer et al. 2008).

Contemporary research has indicated that sex hormones comprise crucial orchestrators of the differences in susceptibility to MD (Kessler, 2003), as well as during autoimmunity and in the pathogenesis of infectious diseases (Nalbandian & Kovats, 2005). To make matters more complicated, the immune system presents a sexual dimorphism of its own (Ahmed & Talal, 1990; De Leon-Nava et al. 2009; Grossman, 1984; Pilipovic et al. 2008; Stefanski & Gruner, 2006).

Paradoxically, the impact of ‘sex’ is rarely controlled for in studies screening for immune alterations in stress-related disorders (Darnall & Suarez, 2009). Thus, the present review aims to provide a glimpse into immunomodulation in MD, arguing about the fact that being male or female may comprise a critical moderator implicated in the differential sensitivity/susceptibility that the two sexes exhibit upon induction of depressive symptomatology.

Sex differences in depression: why should we bother?

The aetiology behind sex differences in depression is not entirely known but is thought to involve genetic, hormonal, biochemical and social factors. Sex differences in neurotransmitter systems (e.g. serotonergic) and neuroendocrine circuits (i.e. corticotrophin-releasing hormone; CRH) in conjunction with the sexually dimorphic hormonal milieu have been implicated in the differentiated precipitation of depressive symptomatology between men and women (Cosgrove et al. 2007; Kessler, 2003). On the other hand, from the sociocultural perspective it has been suggested that modern women struggle with role overload, while in the context of a ‘sandwich generation’ lifestyle they have to provide care to both their progeny and elders (Grigoriadis & Robinson, 2007; Stewart et al. 2006; Vigod & Stewart, 2009). Moreover, it has been postulated that genetic predisposition to the development of depressive disorders is more pronounced in women than in men since major life stressors appear to exert sex-specific detrimental effects on the female sex (Vigod & Stewart, 2009). According to some reports, MD presents a significantly higher heritability in women compared to men (42% vs. 29% respectively; Jansson et al. 2004; Kendler et al. 2006).

Notably, the expression of depressive symptomatology has been reported to present sex-related patterns. According to some studies, women seem to report increased appetite and weight gain, hypochondriasis and somatic concerns (Kornstein, 1997; Marcus et al. 2005; Young et al. 1990). On the other hand, depressed men tend to report more weight loss and are more likely to struggle with alcohol dependence and substance abuse (Breslau et al. 1995; Marcus et al. 2008).

Apart from exerting devastating influences on men and women as individuals, maternal depression has been reported to affect the child's development and is associated with children's disorders (Weissman et al. 2006). Women appear to be at higher risk for depression at specific points in their life, when sex hormones fluctuate, e.g. in puberty, when oestrogens are first rising; in the premenstrual phase; and in pregnancy or the postpartum period (McCoy et al. 2008; Wise et al. 2008). Along with hormonal fluctuations, the dysregulation of the hypothalamus–pituitary–adrenal (HPA) axis that occurs during these periods has also been implicated in stress response and incidence of depression (Nestler et al. 2002). Indeed, the cyclic release of sex hormones has been associated with profound neural influences in both women and female rodents. A recent functional magnetic resonance imaging (fMRI) study supported the view that the sex differences observed in brain activity in stress response circuitry were dependent on women's menstrual cycle phase (Goldstein et al. 2010). Moreover, hippocampal and cortical spine synapse densities vary across the oestrous cycle in rats (Chen et al. 2009; Cooke & Woolley, 2005; Prange-Kiel et al. 2009).

Preclinical research suggests that females and males respond in a different manner regarding the induction of depressive symptomatology (Dalla et al. 2005, 2008a, b, 2009; Drossopoulou et al. 2004; Kamper et al. 2009; Palanza, 2001; Pitychoutis et al. 2009a). Studies from our laboratory, as well as from other authors, underline the crucial role of sex in the manifestation of sexually dimorphic neurochemical, neurobiological, physiological, behavioural and immune responses to both the induction of depressive-like behaviour, as well as to concomitant antidepressant treatment in animal models of depression (for review see Dalla et al. 2010). Ultimately, the investigation of sex differences in the neurobiology of depression aims to improve diagnosis and hopefully will provide gender-based antidepressant pharmacotherapies (Kornstein et al. 2000).

Immunity in depression: a double-edged sword?

Immunosuppression and medical morbidity in MD

Depressed patients often show an excess in mortality rates, that according to some reports is as high as double those found in non-depressed persons (Cuijpers & Smit, 2002; Rudisch & Nemeroff, 2003). Medical morbidity of MD has been largely attributed to functional impairments in both the innate and the cell-mediated arms of immunity that may lead to the more pronounced susceptibility that depressed patients present upon infection (Leserman, 2003, 2008; Miller et al. 2009). Notably, large meta-analyses have reached the conclusion that immune function is hampered in depressed patients, while according to some reports this immune impairment is more pronounced in patients who suffer severe depression (Herbert & Cohen, 1993; Irwin, 1999; Zorrilla et al. 2001). Experimentally, immune suppression typically reflects the inhibition of several in-vitro functional immune parameters, such as the proliferative response of lymphocytes to mitogens, the cytolytic activity of natural-killer (NK) cells (CD3 CD56+ and/or CD16+ cytotoxic lymphocytes that mediate first-line defence against various types of target cells), as well as relevant alterations in white blood cell populations (Zorrilla et al. 2001).

T-cell dysfunction in depression has been associated with a worse prognosis in a battery of both infectious and non-infectious medical conditions. Strikingly, a study reported that cancer patients with comorbid depressive symptomatology were 2.6 times more likely to die from cancer within 19 months following diagnosis (Stommel et al. 2002). In women with metastatic breast cancer, suppression of T-cell-mediated immunity was positively correlated with the severity of depressive symptomatology (Sephton et al. 2009). Moreover, according to a recent study, depressed patients infected with human immunodeficiency virus (HIV) were more likely to develop acquired immunodeficiency syndrome (AIDS), as well as an increased likelihood of AIDS-associated death (Leserman, 2008). In a study conducted solely in women, it was shown that in HIV infection comorbid MD was associated with reduced NK-cell cytotoxicity, but increased numbers of activated cytotoxic (CD8+) T-cells and viral load (Evans et al. 2002). In addition, MD has also been associated with a decline in memory T-cells that respond to varicella-zoster virus antigens (Irwin et al. 1998), with this immune alteration being indicative of a greater herpes zoster risk (Oxman et al. 2005). Interestingly, oxidative-related acceleration of blood leukocyte apoptosis in MD has also been proposed to affect patients’ susceptibility to a panel of different infections (Szuster-Ciesielska et al. 2008).

The inflammatory nature of MD

The notion that immune system activation is implicated in the pathophysiology of MD is supported by in clinical observations in inflammatory disorders, such as rheumatoid arthritis, multiple sclerosis, diabetes and coronary artery disease, that have been associated with increased prevalence of depression (Elenkov, 2008). Being beyond the scope of this paper to review in detail the mechanistic insights pertaining to the interactions between the brain and the immune system in depression, the interested reader is referred to several recent outstanding papers on the topic (Dantzer et al. 2008; Khairova et al. 2009; Maes, 1994; McNally et al. 2008; Miller et al. 2009; Miller, 2010).

At least a subpopulation of patients suffering from MD has been shown to exhibit inflammatory activation manifested by elevated secretion of monocyte-derived pro-inflammatory cytokines, namely interleukin-1 (IL-1), IL-6 and tumour necrosis factor-α (TNF-α), products of T-cell activation (e.g. soluble IL-2 receptors) in both the periphery and the cerebrospinal fluid, as well as acute phase proteins and adhesion molecules in the blood (Miller et al. 2009). Notably, meta-analytical approaches have exposed the peripheral blood elevations of IL-6 and C-reactive protein as the most consistent findings regarding the induction of an inflammatory state in MD (Howren et al. 2009; Mossner et al. 2007; Zorrilla et al. 2001). Moreover, it has been hypothesized that in depression the CD4+ T-helper 1/T-helper 2 (TH1/TH2) cytokine balance is impaired due to excess secretion of pro-inflammatory cytokines (i.e. IFN-γ), with this ratio being normalized upon antidepressant treatment (Myint et al. 2005). Most importantly, according to some reports depressed patients that do not respond to antidepressant pharmacotherapy are even more likely to present significant increases in blood concentrations of these inflammatory markers (Lanquillon et al. 2000).

It should be noted that the induction of an inflammatory state may not directly oppose the suppression of cellular immunity, since inflammation has been experimentally shown to both activate and suppress several immune functions through direct and compensatory mechanisms (Laroux, 2004; Naor et al. 2009; Woiciechowsky et al. 1999). For instance, in terms of immunosuppression, it has been speculated that lipopolysaccharide (LPS)-induced inflammatory activation of β-adrenergic receptors or prostanoids may exert a suppressive effect on NK-cell activity and thus increase susceptibility to experimental metastases (Harmey et al. 2002; Naor et al. 2009).

The induction of an inflammatory state by administration of cytokine inducers, such as LPS or vaccines, produces a mild state of nosothymia [from the Greek words νόσοζ (nosos) ‘disease’ and θυμικό (thymiko) ‘affective and sentimental state of an individual'], termed as ‘sickness behaviour'. Several key-features of sickness behaviour overlap with the clinical symptoms of depression, most prominent being the general suppression of motor activity, anhedonia (inability to experience pleasure), activation of the HPA axis and alterations in monoamine utilization (Dantzer, 2001; Dantzer et al. 2008; MohanKumar et al. 1999; Pitychoutis et al. 2009b; Yirmiya, 1996; Zampeli et al. 2009). Indeed, data indicate that approximately 30–50% of patients undergoing IFN-α or IL-2 immunotherapy for the treatment of several viral diseases (i.e. chronic hepatitis C or HIV infection) or certain types of cancer (e.g. malignant melanoma and renal-cell carcinoma) develop MD (Capuron et al. 2002; Capuron & Miller, 2004; Musselman et al. 2001). Of note, in the context of cytokine administration in medically ill patients, the term MD refers to a substance-induced mood disorder according to DSM-IV-TR criteria (APA, 2000; Capuron et al. 2006).

Intriguingly, in patients suffering from inflammatory/autoimmune disorders pharmacological interventions that aim at reducing excess inflammation have been reported to act synergistically with antidepressant drugs to the alleviation of comorbid depressive symptomatology. In two placebo-controlled trials, it has been shown that co-administration of a cyclooxygenase-2 inhibitor (celecoxib) in depressed patients treated with reboxetine or fluoxetine proved superior to either treatment alone (Akhondzadeh et al. 2009; Muller et al. 2006). Similarly, in a large double-blind, placebo-controlled trial of a TNF inhibitor (etanercept) in patients suffering from psoriasis, treatment with etanercept ameliorated depressive symptomatology, irrespective of improvement in psoriatic symptoms, such as skin clearance and joint pain (Tyring et al. 2006). Moreover, in a recent study acetylsalicylic acid co-administration resulted in significant remission in depressed patients previously non-responsive to fluoxetine monotherapy (Mendlewicz et al. 2006).

Sex differences in immunity

Sexual dimorphism in immune function is observed in vertebrates and also in a number of invertebrate species, covering an evolutionary spectrum from snakes to humans (Darnall & Suarez, 2009; De Leon-Nava et al. 2009; Saad & Shoukrey, 1988). The longer lifespan of women in many societies has been partly attributed to their enhanced resistance against certain infections and some non-infectious diseases (WHO, 2009; Nunn et al. 2009).

Interestingly, animal data suggest that female rodents have higher serum immunoglobulin (Ig) levels (especially IgM), greater and more prolonged antibody responses and shorter skin allograft rejection time (Grossman et al. 1991). Moreover, females present higher levels of IgA in lung lavage fluids, while this seems to be the case for the ocular system in males (Sullivan & Hann, 1989). The structure and cellularity of the thymus (i.e. the central T-cell pool) presents sex-associated differences. The relative thymus weight in female rats exceeds that of males, but the thymic catecholamine content is greater in males (Leposavic et al. 2008; Pilipovic et al. 2008; Pitychoutis et al. 2009a). Despite the fact that the total lymphocyte count is similar between the two sexes (Bouman et al. 2004; Giltay et al. 2000), the relative number of T-cells within the whole lymphocyte population has been reported to be lower in males (Bouman et al. 2004).

Females generally achieve higher titres of autoreactive antibodies (Ansar Ahmed et al. 1985). Interestingly, numerous diseases of autoimmune origin are much more likely to occur in women, possibly due to the enhanced immune reactivity. Indeed, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Graves’ disease, and Hashimoto's thyroiditis, show a clear female preponderance (McCombe et al. 2009). In addition, male rodents generally exhibit depressed immune responses and increased susceptibility to sepsis following trauma haemorrhage, whereas immunoreactivity in pro-oestrus females is maintained or even enhanced in view of high oestrogen concentrations (Angele et al. 2000).

Immune sexual dimorphism has been hypothesized to reflect an evolutionary preserved trait, in the context of the interesting ‘immunocompetence handicap hypothesis’ (Folstad & Karter, 1992). According to this debatable hypothesis, only highly immunocompetent males that can handle the elevated testosterone concentrations required in order to express their ornaments, are finally selected as ‘good-gene carriers’ by females (Nunn et al. 2009).

Neuroimmune sex differences in depression and stress: evidence from the clinic and from animal models

In the original expression of the ‘macrophage theory of depression', R. S. Smith hypothesized that the higher prevalence of MD in women is associated with the activating property of oestrogens on the macrophage lineage (Smith, 1991), thus considering the possibility that sex may play a causal role in the immune alterations displayed. Most importantly, this notion was expressed prior to 1993, at a time during which women were seriously under-represented in clinical trials (Uhl et al. 2007). To the best of our knowledge, relatively few studies in the literature have attempted a direct comparison between males and females regarding their immunocompetency both in humans and in experimental paradigms of depression.

In their interesting meta-analysis of numerous studies Zorrilla et al. (2001) noted that the sex ratio implemented, as well as the sex-matching of controls, or even the severity of depression, comprise factors that may affect the statistical outcome and should be ‘dissected’ in future studies. Nowadays, scant but intriguing evidence from both the clinic and animal models of depression support the notion that the bi-directional influences between the brain and the immune system in stress and depression present sex-related motifs whose elucidation is far from being completely understood but provides a fertile ground for intensive experimentation.

According to some reports, depressed men often show higher mortality rates compared to women (Penninx et al. 1999; Zheng et al. 1997), whereas others do not reach this conclusion (Cuijpers & Smit, 2002; Roberts et al. 1990). Sex appears to have a striking influence on depression-related reduction of NK activity. Despite the fact that meta-analytical approaches question whether the differences observed in the number of circulating immune cells are consistent, a decline in NK cell numbers and NK cytolytic capacity was found in men but not in women suffering from depression, compared with sex-matched healthy individuals (Evans et al. 1992).

Chronic mild stress (CMS) is considered by many researchers as one of the most valid animal models of MD and has long been associated with alterations regarding immunoreactivity (Bekris et al. 2005; Kioukia-Fougia et al. 2002; Willner, 2005). Until recently, immune alterations in the CMS model of depression were determined on either male (Azpiroz et al. 1999; Kubera et al. 1998, 2001) or female rodents (Edgar et al. 2002, 2003; Silberman et al. 2002). In a recent study from our laboratory, we screened for sex differences in cellular immunoreactivity in the CMS model. According to our results, and in contrast to those of Evans et al. (1992) in humans, CMS-treated female rats presented a relatively immunosuppressive phenotype compared to males, as evidenced by the impaired NK and lymphokine-activated killing (LAK) responses (Pitychoutis et al. 2009a). Moreover, following both CMS and chronic antidepressant treatment, thymic monoamines presented sex-related alterations, as well as intriguing associations with peripheral T-cell responses (Pitychoutis et al. 2009a).

Although cytokine-induced depression has been observed in both men and women undergoing cytokine immunotherapy for the treatment of various diseases, there is still no consensus on whether sex comprises a major differentiating factor regarding the development of MD (Raison et al. 2005). This is not unrelated to the fact that the majority of experimental studies investigating immune-related alterations both in depressed individuals and in animal models of depression have focused on either males or females and not on inter-sex differences (Dalla et al. 2010; Darnall & Suarez, 2009; Edgar et al. 2003; Eisenberger et al. 2009; Kubera et al. 1998; Wright et al. 2005). Studies with IFN-α administration in humans are dichotomized between those that do (Fontana et al. 2002; Gohier et al. 2003; Koskinas et al. 2002) and those that do not (Bonaccorso et al. 2002; Kraus et al. 2003) find the female sex to be more likely to develop depressive symptomatology. Despite the controversial findings, sex differences in ex-vivo cytokine production have also been reported in MD patients (Kim et al. 2007).

Most importantly, recent studies suggest that the mechanisms implicated in sickness behaviour may succumb to sexually dimorphic influences, with both pro- and anti-inflammatory cytokines being associated with sex-specific phenotypes. For instance, in a recent study, Eisenberger et al. (2009) reported that IL-6 elevations following LPS administration were significantly associated with depressed mood in women but not in men. In another study, female mice in which the gene for the anti-inflammatory cytokine IL-10 was ablated (IL-10 knock-out) displayed increased depressive-like behaviour in the forced swim test of behavioural despair, compared to both male IL-10 knock-out mice, as well as to their wild-type counterparts; this phenotype was reversed upon exogenous IL-10 administration (Mesquita et al. 2008). These results indicate that a sexually dimorphic regulation of the cytokine network may be associated with the manifestation of sex-specific depressive-like behavioural responses.

Behavioural responses in LPS/cytokine-induced sickness have been scarcely referenced to be differentially expressed between males and females. While female rats exhibit greater sensitivity than males to LPS and/or cytokines in several aspects of behaviour, including sexual activity and reward to mild sucrose (or saccharin) solutions (Avitsur et al. 1995, 1997; Avitsur & Yirmiya, 1999; Merali et al. 2003), ex-vivo experiments have shown that LPS-challenged macrophages derived from male mice produce higher levels of inflammatory cytokines than similarly treated female-derived cells (Marriott et al. 2006), suggesting that males may be more susceptible to bacterial sepsis than females. Furthermore, female rats develop tolerance to repeated LPS administration more quickly than male rats (Engeland et al. 2003), with this phenomenon being oestrous cycle-dependent (Engeland et al. 2006).

A recent study screened for sex differences in neurochemical patterns and behavioural manifestations in LPS-induced ‘sickness behaviour’ (Pitychoutis et al. 2009b). According to these findings, male and female rats experienced sickness in a different context, underlined by sex-differentiated sickness-associated behaviours (i.e. pain sensitivity, anorexia) and serotonergic responses in limbic brain regions implicated in the pathophysiology of MD. As commented in this study and confirmed by others, female vulnerability to LPS administration is reflected in the elevated corticosterone responses and is probably mediated by sex steroids (Frederic et al. 1993; Spinedi et al. 2002, 1994; Tonelli et al. 2008). Moreover, another study documented that repeated intranasal LPS challenge induced a sexually dimorphic increase in hippocampal TNF-α mRNA levels only in female rats, a finding that lends support to the notion that neural cytokine secretion patterns present sex-related modulation upon immune stimulation (Tonelli et al. 2008).

The type of stressor appears to be of prime importance regarding the induction of an immune response (Darnall et al. 2008; Suarez, 2008; Suarez & Krishnan, 2006). Notably, it has been shown that the pro-inflammatory cytokine secretion pattern in response to a psychosocial stressor (the Trier social stress test), presented sexual dimorphism; being boosted in women but decreased in men, alterations in cytokine levels were associated with decreased glucocorticoid sensitivity in female subjects (Rohleder et al. 2001).

Recent evidence also supports the notion that the kinetics of cytokine and antibody production varies significantly between the two sexes upon presentation of various stressors (immune, psychological, etc.; Darnall et al. 2008; Edwards et al. 2006; Pitychoutis et al. 2009b). These results point to an important time factor that dissociates inflammatory responses between the two sexes and would benefit from further clarification.

Crosstalk between the brain and the immune system: putative sex-related influences

It is widely accepted that the HPA axis interacts with the gonads to regulate sex hormone production. On the other hand, sex hormones also influence HPA axis activity. It is of special interest that the HPA axis and sex hormones play a crucial role in both the development of the immune system and the mounting of effective immune responses (Morale et al. 2001). Moreover, it has become apparent that gonadal and stress hormones may play a major role in predisposing females towards depressive disorders (Solomon & Herman, 2009). Indeed, sex-dependent HPA axis regulation following exposure to both chronic and acute stress paradigms is well-characterized (Drossopoulou et al. 2004; Iwasaki-Sekino et al. 2009; Pitychoutis et al. 2009b; Tsigos & Chrousos, 2002) and sex differences regarding immune reactivity have been largely attributed to this sexual dimorphism (Gaillard & Spinedi, 1998; Morale et al. 2001; Spinedi et al. 2002).

Sex-specific influences of housing conditions have been described in relation to HPA axis regulation and immune function (Brown & Grunberg, 1995; Grewal et al. 1997). Social instability affects females more than males (Haller et al. 1999) and crowding is stressful for males but actually calms females; basal corticosterone levels were found to be higher in isolated than in socially housed female rats, while the opposite association seems to hold true for males (Brown & Grunberg, 1995). Given the immunotropic nature of glucocorticoids, animal studies exploring neuroimmunological phenomena should take into account putative sexually dimorphic social interactions.

Peripheral and central influences of sex hormones appear to be the major candidates regarding the sex differences observed in both cytokine-induced sickness and immune alterations in depression (Fig. 1). These hormones exert significant immunotropic influences by acting both directly or via compensatory routes and ultimately producing sex-related effects on immune function. Oestrogens have been reported to enhance both humoral and cell-mediated in vivo and in vitro immune functions, vs. androgens and progestins that are primarily immunosuppressive (Olsen & Kovacs, 1996). Although the modulation of peripheral immune responses by sex steroids is complex and far from being elucidated, these hormones are able to regulate a number of processes regarding immunoreactivity, including maturation and selection of thymocytes and T- and B-cell effectors’ functions, the differentiation and function of antigen-presenting cells, as well as cytokine production by immune cells (Olsen & Kovacs, 1996). As far as mature T-cells are concerned, oestrogens may induce a biphasic effect on TH1 and TH2 functions; low doses promote TH1, while high doses promote TH2 responses (Pernis, 2007). Moreover, these hormones have been reported to regulate the expression of several chemokine receptors and thus to influence T-cell trafficking, possibly in a sex-related manner (Lengi et al. 2007; Pernis, 2007).

Fig. 1

An overview of putative neuroimmune interactions in major depression: sex hormones influence this crosstalk on all its levels. (a) In major depression, the bi-directional communication between affected neurotransmitter systems and the hypothalamus–pituitary–adrenal (HPA) axis results in enhanced secretion of glucocorticoids (GCs) by the adrenal cortex; the sympathetic nervous system (SNS) also modulates immune function directly (i.e. catecholamine secretion in the microenvironment of immune cells), as well as indirectly (i.e. thymus innervation). (b) In immune cells, GCs interact with nuclear receptors and exert major immunosuppressive influences that have been associated with the increased susceptibility of depressed patients to both infectious and non-infectious diseases. (c) On the other hand, chronic inflammatory conditions, several stressors and pathogen-associated molecular patterns (PAMPs) result in enhanced peripheral pro-inflammatory cytokine secretion; during an inflammatory episode a ‘replica’ of the peripheral immune response is created within the CNS by cytokines and inflammatory mediators that signal the brain via different routes and consequently stimulate the in-situ production of prostaglandins and cytokines. (d) Induction of pro-inflammatory mediators by glial cells affects neurotransmitter metabolism (e.g. serotonin and glutamate) and HPA axis reactivity, as well as neuronal integrity and synaptic plasticity, by hampering brain-derived neurotrophic factor (BDNF) signalling in stress-sensitive regions such as the hippocampus. (e) Neural inflammatory activation by causing a wide spectrum of neuroimmune, neurochemical and neuroendocrine effects, ultimately leads to the induction of depressive symptomatology (e.g. anhedonia, and fatigue). BDNF, Brain-derived neurotrophic factor; CAs, catecholamines; CRP, c-reactive protein; DA, dopamine; GABA, gamma-aminobutyric acid; GCs, glucocorticoids; Glu, glutamate; HPA, hypothalamus–pituitary–adrenal; NA, noradrenaline; NK, natural killer cells; PAMPs, pathogen-associated molecular patterns; SNS, sympathetic nervous system; 5-HT, serotonin.

Fig. 1

An overview of putative neuroimmune interactions in major depression: sex hormones influence this crosstalk on all its levels. (a) In major depression, the bi-directional communication between affected neurotransmitter systems and the hypothalamus–pituitary–adrenal (HPA) axis results in enhanced secretion of glucocorticoids (GCs) by the adrenal cortex; the sympathetic nervous system (SNS) also modulates immune function directly (i.e. catecholamine secretion in the microenvironment of immune cells), as well as indirectly (i.e. thymus innervation). (b) In immune cells, GCs interact with nuclear receptors and exert major immunosuppressive influences that have been associated with the increased susceptibility of depressed patients to both infectious and non-infectious diseases. (c) On the other hand, chronic inflammatory conditions, several stressors and pathogen-associated molecular patterns (PAMPs) result in enhanced peripheral pro-inflammatory cytokine secretion; during an inflammatory episode a ‘replica’ of the peripheral immune response is created within the CNS by cytokines and inflammatory mediators that signal the brain via different routes and consequently stimulate the in-situ production of prostaglandins and cytokines. (d) Induction of pro-inflammatory mediators by glial cells affects neurotransmitter metabolism (e.g. serotonin and glutamate) and HPA axis reactivity, as well as neuronal integrity and synaptic plasticity, by hampering brain-derived neurotrophic factor (BDNF) signalling in stress-sensitive regions such as the hippocampus. (e) Neural inflammatory activation by causing a wide spectrum of neuroimmune, neurochemical and neuroendocrine effects, ultimately leads to the induction of depressive symptomatology (e.g. anhedonia, and fatigue). BDNF, Brain-derived neurotrophic factor; CAs, catecholamines; CRP, c-reactive protein; DA, dopamine; GABA, gamma-aminobutyric acid; GCs, glucocorticoids; Glu, glutamate; HPA, hypothalamus–pituitary–adrenal; NA, noradrenaline; NK, natural killer cells; PAMPs, pathogen-associated molecular patterns; SNS, sympathetic nervous system; 5-HT, serotonin.

Notably, the cyclic release of oestrogens has been shown to exert significant effects on immunity. For instance, it has been shown that the ability of murine lymphocytes to proliferate in response to mitogens (e.g. concanavalin A or LPS) is oestrous cycle-dependent (Krzych et al. 1981), while as noted by Cannon (1998), circulating and tissue concentrations of pro-inflammatory cytokines (i.e. IL-1β), vary temporally through the menstrual cycle and pregnancy in women.

Oestrogens have also been shown to act on all glial cell types, including microglia and astrocytes (Arevalo et al. 2009; Sierra et al. 2008). In MD, the aforementioned cellular types present functional dysregulations including alterations in cytokine secretion patterns (McNally et al. 2008). It is of interest that the depletion of oestrogens has been found to increase the levels of pro-inflammatory cytokines (Bismar et al. 1995), while in studies implementing murine microglial cells, these hormones were found to increase IL-10 levels in vitro (Dimayuga et al. 2005). Oestrogens have been associated with neuroprotection mainly through their ability to induce growth factors by all glial cell types that promote neuronal survival (Arevalo et al. 2009). In accordance, recent studies have indicated that oestrogens not only elicit antidepressant-like actions (Halbreich & Kahn, 2001) but also improve the therapeutic outcome when co-administered with antidepressants that target the serotonergic system (Estrada-Camarena et al. 2006a, b; Soares et al. 2001).

Sex differences in neural inflammatory signalling cascades generated upon transduction of the peripheral cytokine signal within the brain have also received attention. NF-κB, a crucial transcription factor positively implicated in multiple aspects of the inflammatory machinery, has been proposed as a possible orchestrator of these neuroimmune sex differences (Eisenberger et al. 2009). In support of this, mononuclear NF-κB activation was markedly enhanced in women but not in men following a night of sleep loss, which is considered an acute stressor known to increase pro-inflammatory cytokines (Irwin et al. 2008).

Obesity can be considered a subclinical inflammatory condition that has been associated with depression (Luppino et al. 2010). Notably, it has been suggested that men and women differ substantially in adiposity (Heyward & Stolarczyk, 1996) and that distortion of the HPA axis function in depression may favour fat accumulation (Adam & Epel, 2007). Given that the adipose tissue comprises an endocrine organ that provides about 30% of total IL-6 (Bastard et al. 2006; Mohamed-Ali et al. 1998), its interaction with sex hormones and the HPA axis could provide a playground for a sexually dimorphic neuroimmune milieu in the periphery.

Elegant genomic research highlights the fact that numerous immune-related genes located on the X chromosome encode receptors, chaperones, transcription factors and other molecules that may be implicated in immune sexual dimorphism (Fish, 2008; Migeon, 2007). Given that certain polymorphisms in pro-inflammatory cytokine genes have been associated with mood disorders (Clerici et al. 2009), it could be speculated that the sexually dimorphic responsiveness of the immune system in MD may be related to polymorphisms in immune-related genes that ‘behave’ in a different manner between the two sexes; however, to the best of our knowledge evidence regarding this matter has yet to come forward. In this context, and despite the elusive functional significance, it has been shown that the IFN-γ promoter contains putative oestrogen response elements (EREs) and that a genetic variation within this promoter creates an ERE-like element that is capable of binding oestrogen receptor-α (ER-α; Fox et al. 1991; Gonsky et al. 2006; Pernis, 2007). Besides genetic predisposition, other risk factors related to health-associated behaviours that have been reported to present sex-related motifs in depressed patients, such as appetite, exercise, smoking habits and alcohol dependence, may also be implicated in the sex differences observed in immunity (Grant et al. 2004; Husky et al. 2008; Marcus et al. 2005, 2008).

Epimyth and future challenges

Only scant research investigating neuroimmunological phenomena has directly assessed the role of sex in depression. Most of the available data refer to research conducted on either male or female subjects or in mixed samples of both sexes, in which the ratio of males to females suffered significant variations. Future research is imperative to clarify the complex associations between the immune system and the brain in depression. Therefore, the puzzling question posed herein: ‘whether sex matters in view of immune alterations in MD', still cannot be answered since the impact of sex in neuropsychiatric disorders is only poorly understood.

Despite the unequivocal need to determine whether/which of the reported immune alterations are of clinical importance, one cannot overlook the absolute necessity to explore human and animal biology, in both health and disease. It is possible that oestrogens’ actions on the immune system and the brain from ‘womb to tomb’ may have a significant impact on the pathophysiology, as well as in the course and outcome of MD. Hopefully, ‘sex-oriented’ neuroimmune preclinical experimentation, in parallel with clinical research, may expose sex-related biological, mechanistic or even pharmacotherapeutic insights into affective disorders.

Acknowledgements

The authors thank the reviewers for their inspiring comments on the manuscript.

Statement of Interest

None.

References

Adam
TC
Epel
ES
(
2007
).
Stress, eating and the reward system
.
Physiology and Behavior
 
91
,
449
458
.
[PubMed]
Ahmed
SA
Talal
N
(
1990
).
Sex hormones and the immune system – Part 2. Animal data
.
Baillieres Clinical Rheumatology
 
4
,
13
31
.
Akhondzadeh
S
Jafari
S
Raisi
F
Nasehi
AA
et al
(
2009
).
Clinical trial of adjunctive celecoxib treatment in patients with major depression: a double blind and placebo controlled trial
.
Depression and Anxiety
 
26
,
607
611
.
[PubMed]
Angele
MK
Schwacha
MG
Ayala
A
Chaudry
IH
(
2000
).
Effect of gender and sex hormones on immune responses following shock
.
Shock
 
14
,
81
90
.
[PubMed]
Ansar Ahmed
S
Penhale
WJ
Talal
N
(
1985
).
Sex hormones, immune responses, and autoimmune diseases. mechanisms of sex hormone action
.
American Journal of Pathology
 
121
,
531
551
.
[PubMed]
Antonijevic
IA
(
2006
).
Depressive disorders – is it time to endorse different pathophysiologies?
Psychoneuroendocrinology
 
31
,
1
15
.
[PubMed]
APA
(
2000
).
Diagnostic and Statistical Manual of Mental Disorders
 ,
4th edn.
Text Revision.
Washington DC
:
American Psychiatric Association
.
Arevalo
MA
Santos-Galindo
M
Bellini
MJ
Azcoitia
I
et al
(
2009
).
Actions of estrogens on glial cells: implications for neuroprotection
.
Biochimica et Biophysica Acta
 . Published online: 8 October 2009. doi:10.1016/j.bbagen.2009.10.002.
[PubMed]
Avitsur
R
Cohen
E
Yirmiya
R
(
1997
).
Effects of interleukin-1 on sexual attractivity in a model of sickness behavior
.
Physiology and Behavior
 
63
,
25
30
.
[PubMed]
Avitsur
R
Donchin
O
Barak
O
Cohen
E
et al
(
1995
).
Behavioral effects of interleukin-1 beta: modulation by gender, estrus cycle, and progesterone
.
Brain, Behavior, and Immunity
 
9
,
234
241
.
[PubMed]
Avitsur
R
Yirmiya
R
(
1999
).
The immunobiology of sexual behavior: gender differences in the suppression of sexual activity during illness
.
Pharmacology, Biochemistry and Behavior
 
64
,
787
796
.
Azpiroz
A
Fano
E
Garmendia
L
Arregi
A
et al
(
1999
).
Effects of chronic mild stress (CMS) and imipramine administration, on spleen mononuclear cell proliferative response, serum corticosterone level and brain norepinephrine content in male mice
.
Psychoneuroendocrinology
 
24
,
345
361
.
[PubMed]
Bastard
JP
Maachi
M
Lagathu
C
Kim
MJ
et al
(
2006
).
Recent advances in the relationship between obesity, inflammation, and insulin resistance
.
European Cytokine Network
 
17
,
4
12
.
[PubMed]
Bekris
S
Antoniou
K
Daskas
S
Papadopoulou-Daifoti
Z
(
2005
).
Behavioural and neurochemical effects induced by chronic mild stress applied to two different rat strains
.
Behavioral Brain Research
 
161
,
45
59
.
Bismar
H
Diel
I
Ziegler
R
Pfeilschifter
J
(
1995
).
Increased cytokine secretion by human bone marrow cells after menopause or discontinuation of estrogen replacement
.
Journal of Clinical Endocrinology and Metabolism
 
80
,
3351
3355
.
[PubMed]
Bonaccorso
S
Marino
V
Biondi
M
Grimaldi
F
et al
(
2002
).
Depression induced by treatment with interferon-alpha in patients affected by hepatitis C virus
.
Journal of Affective Disorders
 
72
,
237
241
.
[PubMed]
Bouman
A
Schipper
M
Heineman
MJ
Faas
MM
(
2004
).
Gender difference in the non-specific and specific immune response in humans
.
American Journal of Reproductive Immunology
 
52
,
19
26
.
[PubMed]
Breslau
N
Schultz
L
Peterson
E
(
1995
).
Sex differences in depression: a role for preexisting anxiety
.
Psychiatry Research
 
58
,
1
12
.
[PubMed]
Brown
KJ
Grunberg
NE
(
1995
).
Effects of housing on male and female rats: crowding stresses males but calms females
.
Physiology and Behavior
 
58
,
1085
1089
.
[PubMed]
Cannon
JG
(
1998
).
Adaptive interactions between cytokines and the hypothalamic-pituitary-gonadal axis
.
Annals of the New York Academy of Sciences
 
856
,
234
242
.
[PubMed]
Capuron
L
Gumnick
JF
Musselman
DL
Lawson
DH
et al
(
2002
).
Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions
.
Neuropsychopharmacology
 
26
,
643
652
.
[PubMed]
Capuron
L
Miller
AH
(
2004
).
Cytokines and psychopathology: lessons from interferon-alpha
.
Biological Psychiatry
 
56
,
819
824
.
[PubMed]
Capuron
L
Miller
A
Irwin
M
(
2006
). Psychoneuroimmunology of depressive disorder: mechanisms and clinical implications. In:
Ader
R
(Ed.),
Psychoneuroimmunology
 ,
4th edn
(pp.
281
318
).
San Diego
:
Academic Press
.
Chen
JR
Yan
YT
Wang
TJ
Chen
LJ
Wang
YJ
Tseng
GF
(
2009
).
Gonadal hormones modulate the dendritic spine densities of primary cortical pyramidal neurons in adult female rat
.
Cerebral Cortex
 
19
,
2719
2727
.
[PubMed]
Clerici
M
Arosio
B
Mundo
E
Cattaneo
E
et al
(
2009
).
Cytokine polymorphisms in the pathophysiology of mood disorders
.
CNS Spectrum
 
14
,
419
25
.
Cooke
BM
Woolley
CS
(
2005
).
Gonadal hormone modulation of dendrites in the mammalian cNS
.
Journal of Neurobiology
 
64
,
34
46
.
[PubMed]
Cosgrove
KP
Mazure
CM
Staley
JK
(
2007
).
Evolving knowledge of sex differences in brain structure, function, and chemistry
.
Biological Psychiatry
 
62
,
847
855
.
[PubMed]
Cuijpers
P
Smit
F
(
2002
).
Excess mortality in depression: a meta-analysis of community studies
.
Journal of Affective Disorders
 
72
,
227
236
.
[PubMed]
Dalla
C
Antoniou
K
Drossopoulou
G
Xagoraris
M
et al
(
2005
).
Chronic mild stress impact: are females more vulnerable?
Neuroscience
 
135
,
703
714
.
[PubMed]
Dalla
C
Antoniou
K
Kokras
N
Drossopoulou
G
et al
(
2008
a).
Sex differences in the effects of two stress paradigms on dopaminergic neurotransmission
.
Physiology and Behavior
 
93
,
595
605
.
[PubMed]
Dalla
C
Edgecomb
C
Whetstone
AS
Shors
TJ
(
2008
b).
Females do not express learned helplessness like males do
.
Neuropsychopharmacology
 
33
,
1559
1569
.
[PubMed]
Dalla
C
Pitychoutis
PM
Kokras
N
Papadopoulou-Daifoti
Z
(
2010
).
Sex differences in animal models of depression and antidepressant response
.
Basic & Clinical Pharmacology & Toxicology
 
106
,
226
233
.
[PubMed]
Dalla
C
Whetstone
AS
Hodes
GE
Shors
TJ
(
2009
).
Stressful experience has opposite effects on dendritic spines in the hippocampus of cycling vs. masculinized females
.
Neuroscience Letters
 
449
,
52
56
.
[PubMed]
Dantzer
R
(
2001
).
Cytokine-induced sickness behavior: mechanisms and implications
.
Annals of the New York Academy of Sciences
 
933
,
222
234
.
[PubMed]
Dantzer
R
O'Connor
JC
Freund
GG
Johnson
RW
et al
(
2008
).
From inflammation to sickness and depression: when the immune system subjugates the brain
.
Nature Reviews Neuroscience
 
9
,
46
56
.
[PubMed]
Darnall
B
Zwickey
H
Aickin
M
(
2008
).
Interleukin-6 response to in-vivo pain catastrophizing: comparison by gender
.
Journal of Women's Health
 
17
,
1248
.
Darnall
BD
Suarez
EC
(
2009
).
Sex and gender in psychoneuroimmunology research: past, present and future
.
Brain, Behavior, and Immunity
 
23
,
595
604
.
[PubMed]
De Leon-Nava
MA
Nava
K
Soldevila
G
Lopez-Griego
L
et al
(
2009
).
Immune sexual dimorphism: effect of gonadal steroids on the expression of cytokines, sex steroid receptors, and lymphocyte proliferation
.
Journal of Steroid Biochemistry and Molecular Biology
 
113
,
57
64
.
[PubMed]
Dimayuga
FO
Reed
JL
Carnero
GA
Wang
C
et al
(
2005
).
Estrogen and brain inflammation: effects on microglial expression of MHC, costimulatory molecules and cytokines
.
Journal of Neuroimmunology
 
161
,
123
136
.
[PubMed]
Drossopoulou
G
Antoniou
K
Kitraki
E
Papathanasiou
G
et al
(
2004
).
Sex differences in behavioral, neurochemical and neuroendocrine effects induced by the forced swim test in rats
.
Neuroscience
 
126
,
849
857
.
[PubMed]
Edgar
VA
Cremaschi
GA
Sterin-Borda
L
Genaro
AM
(
2002
).
Altered expression of autonomic neurotransmitter receptors and proliferative responses in lymphocytes from a chronic mild stress model of depression: effects of fluoxetine
.
Brain, Behavior, and Immunity
 
16
,
333
350
.
[PubMed]
Edgar
VA
Silberman
DM
Cremaschi
GA
Zieher
LM
et al
(
2003
).
Altered lymphocyte catecholamine reactivity in mice subjected to chronic mild stress
.
Biochemical Pharmacology
 
65
,
15
23
.
[PubMed]
Edwards
KM
Burns
VE
Reynolds
T
Carroll
D
et al
(
2006
).
Acute stress exposure prior to influenza vaccination enhances antibody response in women
.
Brain, Behavior, and Immunity
 
20
,
159
168
.
[PubMed]
Eisenberger
NI
Inagaki
TK
Rameson
LT
Mashal
NM
et al
(
2009
).
An fMRI study of cytokine-induced depressed mood and social pain: the role of sex differences
.
Neuroimage
 
47
,
881
890
.
[PubMed]
Elenkov
IJ
(
2008
).
Neurohormonal-cytokine interactions: implications for inflammation, common human diseases and well-being
.
Neurochemistry International
 
52
,
40
51
.
[PubMed]
Engeland
CG
Kavaliers
M
Ossenkopp
KP
(
2003
).
Sex differences in the effects of muramyl dipeptide and lipopolysaccharide on locomotor activity and the development of behavioral tolerance in rats
.
Pharmacology, Biochemistry, and Behavior
 
74
,
433
447
.
[PubMed]
Engeland
CG
Kavaliers
M
Ossenkopp
KP
(
2006
).
Influence of the estrous cycle on tolerance development to LPS-induced sickness behaviors in rats
.
Psychoneuroendocrinology
 
31
,
510
525
.
[PubMed]
Estrada-Camarena
E
Fernandez-Guasti
A
Lopez-Rubalcava
C
(
2006
a).
Participation of the 5-HT1A receptor in the antidepressant-like effect of estrogens in the forced swimming test
.
Neuropsychopharmacology
 
31
,
247
255
.
[PubMed]
Estrada-Camarena
E
Lopez-Rubalcava
C
Fernandez-Guasti
A
(
2006
b).
Facilitating antidepressant-like actions of estrogens are mediated by 5-HT1A and estrogen receptors in the rat forced swimming test
.
Psychoneuroendocrinology
 
31
,
905
914
.
[PubMed]
Evans
DL
Folds
JD
Petitto
JM
Golden
RN
et al
(
1992
).
Circulating natural killer cell phenotypes in men and women with major depression. relation to cytotoxic activity and severity of depression
.
Archives of General Psychiatry
 
49
,
388
395
.
[PubMed]
Evans
DL
Ten Have
TR
Douglas
SD
Gettes
DR
et al
(
2002
).
Association of depression with viral load, CD8 T lymphocytes, and natural killer cells in women with hIV infection
.
American Journal of Psychiatry
 
159
,
1752
1759
.
[PubMed]
Fish
EN
(
2008
).
The X-files in immunity: sex-based differences predispose immune responses
.
Nature Reviews Immunology
 
8
,
737
744
.
[PubMed]
Folstad
I
Karter
J
(
1992
).
Parasites, bright males, and the immunocompetence handicap
.
American Naturalist
 
139
,
603
622
.
Fontana
RJ
Schwartz
SM
Gebremariam
A
Lok
AS
et al
(
2002
).
Emotional distress during interferon-alpha-2B and ribavirin treatment of chronic hepatitis C
.
Psychosomatics
 
43
,
378
385
.
[PubMed]
Fox
HS
Bond
BL
Parslow
TG
(
1991
).
Estrogen regulates the iFN-gamma promoter
.
Journal of Immunology
 
146
,
4362
4367
.
Frederic
F
Oliver
C
Wollman
E
Delhaye-Bouchaud
N
et al
(
1993
).
IL-1 and lPS induce a sexually dimorphic response of the hypothalamo-pituitary-adrenal axis in several mouse strains
.
European Cytokine Network
 
4
,
321
329
.
[PubMed]
Gaillard
RC
Spinedi
E
(
1998
).
Sex- and stress-steroids interactions and the immune system: evidence for a neuroendocrine-immunological sexual dimorphism
.
Domestic Animal Endocrinology
 
15
,
345
352
.
[PubMed]
Giltay
EJ
Fonk
JC
von Blomberg
BM
Drexhage
HA
et al
(
2000
).
In vivo effects of sex steroids on lymphocyte responsiveness and immunoglobulin levels in humans
.
Journal of Clinical Endocrinology and Metabolism
 
85
,
1648
1657
.
[PubMed]
Gohier
B
Goeb
JL
Rannou-Dubas
K
Fouchard
I
et al
(
2003
).
Hepatitis C, alpha interferon, anxiety and depression disorders: a prospective study of 71 patients
.
World Journal of Biological Psychiatry
 
4
,
115
118
.
[PubMed]
Goldstein
JM
Jerram
M
Abbs
B
Whitfield-Gabrieli
S
et al
(
2010
).
Sex differences in stress response circuitry activation dependent on female hormonal cycle
.
Journal of Neuroscience
 
30
,
431
438
.
[PubMed]
Gonsky
R
Deem
RL
Bream
JH
Young
HA
et al
(
2006
).
An IFNG SNP with an estrogen-like response element selectively enhances promoter expression in peripheral but not lamina propria T cells
.
Genes & Immunity
 
7
,
342
351
.
Grant
BF
Hasin
DS
Chou
SP
Stinson
FS
et al
(
2004
).
Nicotine dependence and psychiatric disorders in the United States
.
Archives of General Psychiatry
 
61
,
1107
1115
.
[PubMed]
Grewal
IS
Heilig
M
Miller
A
Sercarz
EE
(
1997
).
Environmental regulation of T-cell function in mice: group housing of males affects accessory cell function
.
Immunology
 
90
,
165
168
.
[PubMed]
Grigoriadis
S
Robinson
GE
(
2007
).
Gender issues in depression
.
Annals of Clinical Psychiatry
 
19
,
247
255
.
[PubMed]
Grossman
CJ
(
1984
).
Regulation of the immune system by sex steroids
.
Endocrine Reviews
 
5
,
435
455
.
[PubMed]
Grossman
CJ
Roselle
GA
Mendenhall
CL
(
1991
).
Sex steroid regulation of autoimmunity
.
Journal of Steroid Biochemistry and Molecular Biology
 
40
,
649
659
.
[PubMed]
Halbreich
U
Kahn
LS
(
2001
).
Role of estrogen in the aetiology and treatment of mood disorders
.
CNS Drugs
 
15
,
797
817
.
[PubMed]
Haller
J
Fuchs
E
Halasz
J
Makara
GB
(
1999
).
Defeat is a major stressor in males while social instability is stressful mainly in females: towards the development of a social stress model in female rats
.
Brain Research Bulletin
 
50
,
33
39
.
[PubMed]
Harmey
JH
Bucana
CD
Lu
W
Byrne
AM
et al
(
2002
).
Lipopolysaccharide-induced metastatic growth is associated with increased angiogenesis, vascular permeability and tumor cell invasion
.
International Journal of Cancer
 
101
,
415
422
.
Hasler
G
Drevets
WC
Manji
HK
Charney
DS
(
2004
).
Discovering endophenotypes for major depression
.
Neuropsychopharmacology
 
2
,
1765
1781
.
Herbert
TB
Cohen
S
(
1993
).
Depression and immunity: a meta-analytic review
.
Psychology Bulletin
 
113
,
472
486
.
Heyward
VH
Stolarczyk
LM
(
1996
). Body composition and levels of body fatness. In:
Heyward
VH
Stolarczyk
LM
(Eds),
Applied Body Composition Assessment
  (pp.
135
142
).
Champaign, IL: Human Kinetics Publishers
.
Holden
C
(
2005
).
Sex and the suffering brain
.
Science
 
308
,
1574
.
[PubMed]
Howren
MB
Lamkin
DM
Suls
J
(
2009
).
Associations of depression with c-reactive protein, IL-1, and IL-6: a meta-analysis
.
Psychosomatic Medicine
 
71
,
171
186
.
[PubMed]
Husky
MM
Mazure
CM
Paliwal
P
McKee
SA
(
2008
).
Gender differences in the comorbidity of smoking behavior and major depression
.
Drug and Alcohol Dependence
 
93
,
176
179
.
[PubMed]
Irwin
M
(
1999
).
Immune correlates of depression
.
Advances in Experimental Medicine and Biology
 
461
,
1
24
.
[PubMed]
Irwin
M
Costlow
C
Williams
H
Artin
KH
et al
(
1998
).
Cellular immunity to varicella-zoster virus in patients with major depression
.
Journal of Infectious Diseases
 
178
(
Suppl. 1
),
S104
108
.
[PubMed]
Irwin
MR
Wang
M
Ribeiro
D
Cho
HJ
et al
(
2008
).
Sleep loss activates cellular inflammatory signaling
.
Biological Psychiatry
 
64
,
538
540
.
[PubMed]
Iwasaki-Sekino
A
Mano-Otagiri
A
Ohata
H
Yamauchi
N
et al
(
2009
).
Gender differences in corticotropin and corticosterone secretion and corticotropin-releasing factor mRNA expression in the paraventricular nucleus of the hypothalamus and the central nucleus of the amygdala in response to footshock stress or psychological stress in rats
.
Psychoneuroendocrinology
 
34
,
226
237
.
[PubMed]
Jansson
M
Gatz
M
Berg
S
Johansson
B
et al
(
2004
).
Gender differences in heritability of depressive symptoms in the elderly
.
Psychological Medicine
 
34
,
471
479
.
[PubMed]
[PubMed]
Kamper
EF
Chatzigeorgiou
A
Tsimpoukidi
O
Kamper
M
et al
(
2009
).
Sex differences in oxidant/antioxidant balance under a chronic mild stress regime
.
Physiology and Behavior
 
98
,
215
222
.
[PubMed]
Kendler
KS
Gatz
M
Gardner
CO
Pedersen
NL
(
2006
).
A swedish national twin study of lifetime major depression
.
American Journal of Psychiatry
 
163
,
109
114
.
[PubMed]
Kessler
RC
(
2003
).
Epidemiology of women and depression
.
Journal of Affective Disorders
 
74
,
5
13
.
[PubMed]
Kessler
RC
Berglund
P
Demler
O
Jin
R
et al
(
2003
).
The epidemiology of major depressive disorder: results from the national comorbidity survey replication (NCS-R)
.
Journal of the American Medical Association
 
289
,
3095
3105
.
[PubMed]
Kessler
RC
Sonnega
A
Bromet
E
Hughes
M
et al
(
1995
).
Posttraumatic stress disorder in the national comorbidity survey
.
Archives of General Psychiatry
 
52
,
1048
1060
.
[PubMed]
Khairova
RA
Machado-Vieira
R
Du
J
Manji
HK
(
2009
).
A potential role for pro-inflammatory cytokines in regulating synaptic plasticity in major depressive disorder
.
International Journal of Neuropsychopharmacology
 
12
,
561
578
.
[PubMed]
[PubMed]
Kim
Y-K
Na
K-S
Shin
K-H
Jung
H-Y
et al
(
2007
).
Cytokine imbalance in the pathophysiology of major depressive disorder
.
Progress in Neuro-Psychopharmacology and Biological Psychiatry
 
31
,
1044
1053
.
[PubMed]
Kioukia-Fougia
N
Antoniou
K
Bekris
S
Liapi
C
et al
(
2002
).
The effects of stress exposure on the hypothalamic-pituitary-adrenal axis, thymus, thyroid hormones and glucose levels
.
Progress in Neuropsychopharmacology and Biological Psychiatry
 
26
,
823
830
.
Kornstein
SG
(
1997
).
Gender differences in depression: implications for treatment
.
Journal of Clinical Psychiatry
 
58
(
Suppl. 15
),
12
18
.
[PubMed]
Kornstein
SG
Schatzberg
AF
Thase
ME
Yonkers
KA
et al
(
2000
).
Gender differences in treatment response to sertraline vs. imipramine in chronic depression
.
American Journal of Psychiatry
 
157
,
1445
1452
.
[PubMed]
Koskinas
J
Merkouraki
P
Manesis
E
Hadziyannis
S
(
2002
).
Assessment of depression in patients with chronic hepatitis: effect of interferon treatment
.
Digestive Diseases
 
20
,
284
288
.
[PubMed]
Kraus
MR
Schafer
A
Faller
H
Csef
H
et al
(
2003
).
Psychiatric symptoms in patients with chronic hepatitis C receiving interferon alfa-2b therapy
.
Journal of Clinical Psychiatry
 
64
,
708
714
.
[PubMed]
Krzych
U
Strausser
HR
Bressler
JP
Goldstein
AL
(
1981
).
Effects of sex hormones on some t and b cell functions, evidenced by differential immune expression between male and female mice and cyclic pattern of immune responsiveness during the estrous cycle in female mice
.
American Journal of Reproductive Immunology
 
1
,
73
77
.
[PubMed]
Kubera
M
Basta-Kaim
A
Holan
V
Simbirtsev
A
et al
(
1998
).
Effect of mild chronic stress, as a model of depression, on the immunoreactivity of C57BL/6 mice
.
International Journal of Immunopharmacology
 
20
,
781
789
.
[PubMed]
Kubera
M
Maes
M
Holan
V
Basta-Kaim
A
et al
(
2001
).
Prolonged desipramine treatment increases the production of interleukin-10, an anti-inflammatory cytokine, in C57BL/6 mice subjected to the chronic mild stress model of depression
.
Journal of Affective Disorders
 
63
,
171
178
.
[PubMed]
Lanquillon
S
Krieg
JC
Bening-Abu-Shach
U
Vedder
H
(
2000
).
Cytokine production and treatment response in major depressive disorder
.
Neuropsychopharmacology
 
22
,
370
379
.
[PubMed]
Laroux
FS
(
2004
).
Mechanisms of inflammation: the good, the bad and the ugly
.
Frontiers in Bioscience
 
9
,
3156
3162
.
[PubMed]
Lengi
AJ
Phillips
RA
Karpuzoglu
E
Ahmed
SA
(
2007
).
Estrogen selectively regulates chemokines in murine splenocytes
.
Journal of Leukocyte Biology
 
81
,
1065
1074
.
[PubMed]
Leposavic
G
Pilipovic
I
Radojevic
K
Pesic
V
et al
(
2008
).
Catecholamines as immunomodulators: a role for adrenoceptor-mediated mechanisms in fine tuning of T-cell development
.
Autonomic Neuroscience
 
144
,
1
12
.
[PubMed]
Leserman
J
(
2003
).
HIV disease progression: depression, stress, and possible mechanisms
.
Biological Psychiatry
 
54
,
295
306
.
[PubMed]
Leserman
J
(
2008
).
Role of depression, stress, and trauma in HIV disease progression
.
Psychosomatic Medicine
 
70
,
539
545
.
[PubMed]
Luppino
FS
de Wit
LM
Bouvy
PF
Stijnen
T
et al
(
2010
).
Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies
.
Archives of General Psychiatry
 
67
,
220
229
.
[PubMed]
Maes
M
(
1994
).
Cytokines in major depression
.
Biological Psychiatry
 
36
,
498
499
.
[PubMed]
Marcus
SM
Kerber
KB
Rush
AJ
Wisniewski
SR
et al
(
2008
).
Sex differences in depression symptoms in treatment-seeking adults: confirmatory analyses from the sequenced treatment alternatives to relieve depression study
.
Comprehensive Psychiatry
 
49
,
238
246
.
[PubMed]
Marcus
SM
Young
EA
Kerber
KB
Kornstein
S
et al
(
2005
).
Gender differences in depression: findings from the STAR*D study
.
Journal of Affective Disorders
 
87
,
141
150
.
[PubMed]
Marriott
I
Bost
KL
Huet-Hudson
YM
(
2006
).
Sexual dimorphism in expression of receptors for bacterial lipopolysaccharides in murine macrophages: a possible mechanism for gender-based differences in endotoxic shock susceptibility
.
Journal of Reproductive Immunology
 
71
,
12
27
.
[PubMed]
McCombe
PA
Greer
JM
Mackay
IR
(
2009
).
Sexual dimorphism in autoimmune disease
.
Current Molecular Medicine
 
9
,
1058
1079
.
[PubMed]
McCoy
SJ
Beal
JM
Saunders
B
Hill
EN
et al
(
2008
).
Risk factors for postpartum depression: a retrospective investigation
.
Journal of Reproductive Medicine
 
53
,
166
170
.
[PubMed]
McNally
L
Bhagwagar
Z
Hannestad
J
(
2008
).
Inflammation, glutamate, and glia in depression: a literature review
.
CNS Spectrum
 
13
,
501
510
.
Mendlewicz
J
Kriwin
P
Oswald
P
Souery
D
et al
(
2006
).
Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study
.
International Clinical Psychopharmacology
 
21
,
227
231
.
[PubMed]
Merali
Z
Brennan
K
Brau
P
Anisman
H
(
2003
).
Dissociating anorexia and anhedonia elicited by interleukin-1beta: antidepressant and gender effects on responding for ‘free chow’ and ‘earned’ sucrose intake
.
Psychopharmacology (Berlin)
 
165
,
413
418
.
Mesquita
AR
Correia-Neves
M
Roque
S
Castro
AG
et al
(
2008
).
IL-10 modulates depressive-like behavior
.
Journal of Psychiatric Research
 
43
,
89
97
.
[PubMed]
Migeon
BR
(
2007
).
Why females are mosaics, X-chromosome inactivation, and sex differences in disease
.
Gender Medicine
 
4
,
97
105
.
[PubMed]
Miller
AH
(
2010
).
Depression and immunity: a role for T cells?
Brain, Behavior, and Immunity
 
24
,
1
8
.
[PubMed]
Miller
AH
Maletic
V
Raison
CL
(
2009
).
Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression
.
Biological Psychiatry
 
65
,
732
741
.
[PubMed]
Mohamed-Ali
V
Pinkney
JH
Coppack
SW
(
1998
).
Adipose tissue as an endocrine and paracrine organ
.
International Journal of Obesity and Related Metabolic Disorders
 
22
,
1145
1158
.
[PubMed]
MohanKumar
SM
MohanKumar
PS
Quadri
SK
(
1999
).
Lipopolysaccharide-induced changes in monoamines in specific areas of the brain: blockade by interleukin-1 receptor antagonist
.
Brain Research
 
824
,
232
237
.
[PubMed]
Morale
MC
Gallo
F
Tirolo
C
Testa
N
et al
(
2001
).
Neuroendocrine-immune (NEI) circuitry from neuron-glial interactions to function: focus on gender and HPA-HPG interactions on early programming of the NEI system
.
Immunology & Cell Biology
 
79
,
400
417
.
Mossner
R
Mikova
O
Koutsilieri
E
Saoud
M
et al
(
2007
).
Consensus paper of the wFSBP task force on biological markers: biological markers in depression
.
World Journal of Biological Psychiatry
 
8
,
141
174
.
[PubMed]
Muller
N
Schwarz
MJ
Dehning
S
Douhe
A
et al
(
2006
).
The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine
.
Molecular Psychiatry
 
11
,
680
684
.
[PubMed]
Musselman
DL
Lawson
DH
Gumnick
JF
Manatunga
AK
et al
(
2001
).
Paroxetine for the prevention of depression induced by high-dose interferon alfa
.
New England Journal of Medicine
 
344
,
961
966
.
[PubMed]
Myint
AM
Leonard
BE
Steinbusch
HW
Kim
YK
(
2005
).
Th1, Th2, and Th3 cytokine alterations in major depression
.
Journal of Affective Disorders
 
88
,
167
173
.
[PubMed]
Nalbandian
G
Kovats
S
(
2005
).
Understanding sex biases in immunity: effects of estrogen on the differentiation and function of antigen-presenting cells
.
Immunology Research
 
31
,
91
106
.
Naor
R
Domankevich
V
Shemer
S
Sominsky
L
et al
(
2009
).
Metastatic-promoting effects of lPS: sexual dimorphism and mediation by catecholamines and prostaglandins
.
Brain, Behavior, and Immunity
 
23
,
611
621
.
[PubMed]
Nemeroff
CB
Bremner
JD
Foa
EB
Mayberg
HS
et al
(
2006
).
Posttraumatic stress disorder: a state-of-the-science review
.
Journal of Psychiatric Research
 
40
,
1
21
.
[PubMed]
Nestler
EJ
Barrot
M
DiLeone
RJ
Eisch
AJ
et al
(
2002
).
Neurobiology of depression
.
Neuron
 
34
,
13
25
.
[PubMed]
Nunn
CL
Lindenfors
P
Pursall
ER
Rolff
J
(
2009
).
On sexual dimorphism in immune function
.
Philosophical Transactions of the Royal Society of London, Series B: Biological Sciences
 
364
,
61
69
.
Olsen
NJ
Kovacs
WJ
(
1996
).
Gonadal steroids and immunity
.
Endocrine Reviews
 
17
,
369
384
.
[PubMed]
Oxman
MN
Levin
MJ
Johnson
GR
Schmader
KE
et al
(
2005
).
A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults
.
New England Journal of Medicine
 
352
,
2271
2284
.
[PubMed]
Palanza
P
(
2001
).
Animal models of anxiety and depression: how are females different?
Neuroscience & Biobehavioral Reviews
 
25
,
219
233
.
Penninx
BW
Geerlings
SW
Deeg
DJ
van Eijk
JT
et al
(
1999
).
Minor and major depression and the risk of death in older persons
.
Archives of General Psychiatry
 
56
,
889
895
.
[PubMed]
Pernis
AB
(
2007
).
Estrogen and CD4+ T cells
.
Current Opinion in Rheumatology
 
19
,
414
420
.
[PubMed]
Pilipovic
I
Vidic-Dankovic
B
Perisic
M
Radojevic
K
et al
(
2008
).
Sexual dimorphism in the catecholamine-containing thymus microenvironment: a role for gonadal hormones
.
Journal of Neuroimmunology
 
195
,
7
20
.
[PubMed]
Pitychoutis
PM
Griva
E
Ioannou
K
Tsitsilonis
OE
et al
(
2009
a).
Chronic antidepressant treatment exerts sexually dimorphic immunomodulatory effects in an experimental model of major depression: do females lack an advantage?
International Journal of Neuropsychopharmacology
 
12
,
1157
1163
.
[PubMed]
[PubMed]
Pitychoutis
PM
Nakamura
K
Tsonis
PA
Papadopoulou-Daifoti
Z
(
2009
b).
Neurochemical and behavioral alterations in an inflammatory model of depression: sex differences exposed
.
Neuroscience
 
159
,
1216
1232
.
[PubMed]
Prange-Kiel
J
Fester
L
Zhou
L
Jarry
H
et al
(
2009
).
Estrus cyclicity of spinogenesis: underlying mechanisms
.
Journal of Neural Transmission
 
116
,
1417
1425
.
[PubMed]
Raison
CL
Demetrashvili
M
Capuron
L
Miller
AH
(
2005
).
Neuropsychiatric adverse effects of interferon-alpha: recognition and management
.
CNS Drugs
 
19
,
105
123
.
[PubMed]
Roberts
RE
Kaplan
GA
Camacho
TC
(
1990
).
Psychological distress and mortality: evidence from the Alameda County Study
.
Social Science & Medicine
 
31
,
527
536
.
Rohleder
N
Schommer
NC
Hellhammer
DH
Engel
R
et al
(
2001
).
Sex differences in glucocorticoid sensitivity of proinflammatory cytokine production after psychosocial stress
.
Psychosomatic Medicine
 
63
,
966
972
.
[PubMed]
Rudisch
B
Nemeroff
CB
(
2003
).
Epidemiology of comorbid coronary artery disease and depression
.
Biological Psychiatry
 
54
,
227
240
.
[PubMed]
Rush
AJ
(
2007
).
STAR*D: what have we learned?
American Journal of Psychiatry
 
164
,
201
204
.
[PubMed]
Saad
AH
Shoukrey
N
(
1988
).
Sexual dimorphism on the immune responses of the snake, psammophis sibilans
.
Immunobiology
 
177
,
404
419
.
[PubMed]
Sephton
SE
Dhabhar
FS
Keuroghlian
AS
Giese-Davis
J
et al
(
2009
).
Depression, cortisol, and suppressed cell-mediated immunity in metastatic breast cancer
.
Brain, Behavior, and Immunity
 
23
,
1148
1155
.
[PubMed]
Sierra
A
Gottfried-Blackmore
A
Milner
TA
McEwen
BS
et al
(
2008
).
Steroid hormone receptor expression and function in microglia
.
Glia
 
56
,
659
674
.
[PubMed]
Silberman
DM
Wald
M
Genaro
AM
(
2002
).
Effects of chronic mild stress on lymphocyte proliferative response. participation of serum thyroid hormones and corticosterone
.
International Immunopharmacology
 
2
,
487
497
.
[PubMed]
Smith
RS
(
1991
).
The macrophage theory of depression
.
Medical Hypotheses
 
35
,
298
306
.
[PubMed]
Soares
CN
Almeida
OP
Joffe
H
Cohen
LS
(
2001
).
Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial
.
Archives of General Psychiatry
 
58
,
529
534
.
[PubMed]
Solomon
MB
Herman
JP
(
2009
).
Sex differences in psychopathology: of gonads, adrenals and mental illness
.
Physiology and Behavior
 
97
,
250
258
.
[PubMed]
Somers
JM
Goldner
EM
Waraich
P
Hsu
L
(
2006
).
Prevalence and incidence studies of anxiety disorders: a systematic review of the literature
.
Canadian Journal of Psychiatry
 
51
,
100
113
.
Spinedi
E
Gaillard
RC
Chisari
A
(
2002
).
Sexual dimorphism of neuroendocrine-immune interactions
.
Frontiers of Hormone Research
 
29
,
91
107
.
[PubMed]
Spinedi
E
Salas
M
Chisari
A
Perone
M
et al
(
1994
).
Sex differences in the hypothalamo-pituitary-adrenal axis response to inflammatory and neuroendocrine stressors. evidence for a pituitary defect in the autoimmune disease-susceptible female Lewis rat
.
Neuroendocrinology
 
60
,
609
617
.
[PubMed]
Stefanski
V
Gruner
S
(
2006
).
Gender difference in basal and stress levels of peripheral blood leukocytes in laboratory rats
.
Brain, Behavior, and Immunity
 
20
,
369
377
.
[PubMed]
Stein
MB
Jang
KL
Taylor
S
Vernon
PA
et al
(
2002
).
Genetic and environmental influences on trauma exposure and posttraumatic stress disorder symptoms: a twin study
.
American Journal of Psychiatry
 
159
,
1675
1681
.
[PubMed]
Steiner
M
Allgulander
C
Ravindran
A
Kosar
H
et al
(
2005
).
Gender differences in clinical presentation and response to sertraline treatment of generalized anxiety disorder
.
Human Psychopharmacology
 
20
,
3
13
.
[PubMed]
Stewart
DE
Ashraf
IJ
Munce
SE
(
2006
).
Women's mental health: a silent cause of mortality and morbidity
.
International Journal of Gynecology & Obstetrics
 
94
,
343
349
.
Stommel
M
Given
BA
Given
CW
(
2002
).
Depression and functional status as predictors of death among cancer patients
.
Cancer
 
94
,
2719
2727
.
[PubMed]
Suarez
EC
(
2008
).
Self-reported symptoms of sleep disturbance and inflammation, coagulation, insulin resistance and psychosocial distress: evidence for gender disparity
.
Brain, Behavior, and Immunity
 
22
,
960
968
.
[PubMed]
Suarez
EC
Krishnan
KR
(
2006
).
The relation of free plasma tryptophan to anger, hostility, and aggression in a nonpatient sample of adult men and women
.
Annals of Behavioral Medicine
 
31
,
254
260
.
[PubMed]
Sullivan
DA
Hann
LE
(
1989
).
Hormonal influence on the secretory immune system of the eye: endocrine impact on the lacrimal gland accumulation and secretion of IgA and IgG
.
Journal of Steroid Biochemistry
 
34
,
253
262
.
[PubMed]
Szuster-Ciesielska
A
Slotwinska
M
Stachura
A
Marmurowska-Michalowska
H
et al
(
2008
).
Accelerated apoptosis of blood leukocytes and oxidative stress in blood of patients with major depression
.
Progress in Neuropsychopharmacology and Biological Psychiatry
 
32
,
686
694
.
Tonelli
LH
Holmes
A
Postolache
TT
(
2008
).
Intranasal immune challenge induces sex-dependent depressive-like behavior and cytokine expression in the brain
.
Neuropsychopharmacology
 
33
,
1038
1048
.
[PubMed]
Tsigos
C
Chrousos
GP
(
2002
).
Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress
.
Journal of Psychosomatic Research
 
53
,
865
871
.
[PubMed]
Tyring
S
Gottlieb
A
Papp
K
Gordon
K
et al
(
2006
).
Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial
.
Lancet
 
367
,
29
35
.
[PubMed]
Uhl
K
Parekh
A
Kweder
S
(
2007
).
Females in clinical studies: where are we going?
Clinical Pharmacology & Therapeutics
 
81
,
600
602
.
Vigod
SN
Stewart
DE
(
2009
).
Emergent research in the cause of mental illness in women across the lifespan
.
Current Opinion in Psychiatry
 
22
,
396
400
.
[PubMed]
Weissman
MM
Pilowsky
DJ
Wickramaratne
PJ
Talati
A
et al
(
2006
).
Remissions in maternal depression and child psychopathology: a STAR*D-child report
.
Journal of the American Medical Association
 
295
,
1389
1398
.
[PubMed]
WHO
(
2005
).
Gender and women's mental health
  (http://www.who.int/mental_health/prevention/genderwomen/en/). Accessed 18 March 2010.
WHO
(
2009
).
Women's health
  (http://www.who.int/mediacentre/factsheets/fs334/en/index.html). Accessed 20 March 2010.
Willner
P
(
2005
).
Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS
.
Neuropsychobiology
 
52
,
90
110
.
[PubMed]
Wise
DD
Felker
A
Stahl
SM
(
2008
).
Tailoring treatment of depression for women across the reproductive lifecycle: the importance of pregnancy, vasomotor symptoms, and other estrogen-Related events in psychopharmacology
.
CNS Spectrums
 
13
,
647
662
.
[PubMed]
Woiciechowsky
C
Schoning
B
Lanksch
WR
Volk
HD
et al
(
1999
).
Mechanisms of brain-mediated systemic anti-inflammatory syndrome causing immunodepression
.
Journal of Molecular Medicine
 
77
,
769
780
.
[PubMed]
Wright
CE
Strike
PC
Brydon
L
Steptoe
A
(
2005
).
Acute inflammation and negative mood: mediation by cytokine activation
.
Brain, Behavior, and Immunity
 
19
,
345
350
.
[PubMed]
Yirmiya
R
(
1996
).
Endotoxin produces a depressive-like episode in rats
.
Brain Research
 
711
,
163
174
.
[PubMed]
Young
MA
Scheftner
WA
Fawcett
J
Klerman
GL
(
1990
).
Gender differences in the clinical features of unipolar major depressive disorder
.
Journal of Nervous and Mental Disease
 
178
,
200
203
.
[PubMed]
Zampeli
E
Pitychoutis
PM
Papadopoulou-Daifoti
Z
Tiligada
E
(
2009
).
Systemic challenge with lipopolysaccharide increases histamine levels in the conjunctiva and cartilage, but not hypothalamus of sprague dawley rats
.
Inflammation Research
 
58
(
Suppl. 1
),
49
50
.
[PubMed]
Zheng
D
Macera
CA
Croft
JB
Giles
WH
et al
(
1997
).
Major depression and all-cause mortality among white adults in the united states
.
Annals of Epidemiology
 
7
,
213
218
.
[PubMed]
Zorrilla
EP
Luborsky
L
McKay
JR
Rosenthal
R
et al
(
2001
).
The relationship of depression and stressors to immunological assays: a meta-analytic review
.
Brain, Behavior, and Immunity
 
15
,
199
226
.
[PubMed]