Cytokines and depression: fortuitous or causative association?

Dantzer, Robert; Wollman, Emmanuelle E.; Vitkoviç, Ljubiša; Yirmiya, Raz

doi:10.1038/sj.mp.4000572

Cited by 157 publications

(74 citation statements)

References 38 publications

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“…These findings replicate the results of many previous studies, which demonstrated that activation of the immune system by LPS, as well as other immune challenges, induces a reduction in appetite and body weight, suppres- sion of locomotor, exploratory, and social activity, fatigue and malaise, impairment in cognitive abilities, reduced libido and sexual behavior, and anhedonia (Anisman and Merali 1999;Dantzer et al 1999;Maier and Watkins 1998;Yirmiya 1996;Yirmiya et al 1994Yirmiya et al , 1999. Our results also demonstrate that LPS produced a marked depletion of CRH-41 ME content, which reflects its release into the portal vessels (Chappell et al 1986), with a concomitant elevation in plasma corticosterone levels.…”

Section: Discussionsupporting

confidence: 90%

Effects of Antidepressant Drugs on the Behavioral and Physiological Responses to Lipopolysaccharide (LPS) in Rodents

Yirmiya

Pollak

Barak

et al. 2001

Neuropsychopharmacology

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203

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Antidepressants produce various immunomodulatory effects, as well as an attenuation of the behavioral responses to immune challenges, such as lipopolysaccharide (LPS). To explore further the effects of antidepressants on neuroimmune interactions, rats were treated daily with either fluoxetine (Prozac) or saline for 5 weeks, and various behavioral, neuroendocrine, and immune functions were measured following administration of either LPS or saline. Chronic fluoxetine treatment significantly attenuated the anorexia and body weight loss, as well as the depletion of CRH-41 from the median eminence and the elevation in serum corticosterone levels induced by LPS. Chronic treatment with imipramine also attenuated LPS-induced adrenocortical activation. In rats and in mice, which normally display a biphasic body temperature response to LPS (initial hypothermia followed by hyperthermia), chronic treatment with fluoxetine completely abolished the hypothermic response and facilitated and strengthened the hyperthermic response. The effects of antidepressants on the responsiveness to LPS are probably not mediated by their effects on peripheral proinflammatory cytokine production, because LPS-induced expression of TNFSeveral lines of evidence indicate that antidepressants produce various immunomodulatory effects. In depressed patients, the effects of antidepressants are variable and seem to be related to the immune status of the patients at the initiation of the treatment. When depression was associated with immune activation, antidepressants reduced immune function and cytokine secretion. For example, the increased plasma levels of IL-6 during acute depression were normalized by 8-week treatment with fluoxetine (Sluzewska et al. 1995), the increased monocyte counts in depressed patients were reduced following 6-weeks treatment with tricyclic antidepressants (TCAs) (Seidel et al. 1996), and the increased numbers of leukocytes and neutrophils were also reduced by antidepressant treatment (Maes et al. 24 , NO . 5 1997). On the other hand, when immune functions were found to be normal, antidepressants had no immunological effects; for example, chronic moclobemide treatment had no effect on monocytes functions, TNF ␣ production or IFN ␥ levels (Landmann et al. 1997). Moreover, in a study of depressed patients who exhibited immune suppression before treatment, the TCA clomipramine increased the production of IL-1 ␤ , IL-2, and IL-3 (Weizman et al. 1994).In experimental animals, TCAs as well as selective serotonin reuptake inhibitors (SSRIs) produce mainly immune suppression and anti-inflammatory effects. For example, antidepressant treatment in vivo inhibited the increased acute phase response in olfactory bulbectomized rats, a useful animal model of depression (Song and Leonard 1994), reduced the production of interleukin-1 (IL-1) and IL-2 in a chronic mild stress model of depression (Kubera et al. 1996), inhibited immune activation in rats with experimental allergic neuritis (Zhu et al. 1994), and produced anti-inflammatory ...

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Section: Discussionsupporting

confidence: 90%

Effects of Antidepressant Drugs on the Behavioral and Physiological Responses to Lipopolysaccharide (LPS) in Rodents

Yirmiya

Pollak

Barak

et al. 2001

Neuropsychopharmacology

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203

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“…Depression also appears to have an immune substrate, which has been discussed extensively elsewhere. 50,51 Of interest, an association between depression and atopy has been recently reported in the Northern Finland 1966 Birth Cohort. 52,53 It is noteworthy that CRHR1 has a key role in inflammation, 54,55 and that CRHR1 antagonists, which have been used to treat depression, 34,35 also suppress peripheral inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…[56][57][58] Antidepressants are known to modulate inflammatory responses after chronic administration, in a time course that is reminiscent of the time frame of antidepressant effects and they also confer protection against cytokine-induced depressive-like biological and behavioral changes. 50,51,[59][60][61] Moreover, concentrations of circulating immune mediators have been found to be elevated in depression. 62,63 Future studies should examine whether there is an interaction between the therapeutic effects of CRHR1 on inflammation and depression or if these are independent of each other.…”

Section: Discussionmentioning

confidence: 99%

Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans

et al. 2004

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There are well-replicated, independent lines of evidence supporting a role for corticotropinreleasing hormone (CRH) in the pathophysiology of depression. CRH receptor 1 (CRHR1), which we first mapped in the brain in 1994, has been implicated in the treatment of depression and anxiety. We studied the association of CRHR1 genotypes with the phenotype of antidepressant treatment response in 80 depressed Mexican-Americans in Los Angeles who completed a prospective randomized, placebo lead-in, double-blind treatment of fluoxetine or desipramine, with active treatment for 8 weeks. Subjects were included into the study if they had a diagnosis of depression without other confounding medical or psychiatric diagnoses or treatments. All patients were followed weekly and assessed for changes in the Hamilton rating scales for anxiety (HAM-A) and depression (HAM-D). Inclusion criteria in the study included a HAM-D of 18 or higher. Because CRHR1 affects both depression and anxiety. Patients were classified into a high-anxiety (HA) group if their HAM-A score was 18 or higher and in a low-anxiety (LA) group if their HAM-A score was less than 18. Utilizing the haplotype-tag single-nucleotide polymorphisms rs1876828, rs242939 and rs242941, we tested for haplotypic association between CRHR1 and 8-week response to daily antidepressant treatment. In the HA group (n ¼ 54), homozygosity for the GAG haplotype was associated with a relative 70% greater reduction in HAM-A scores compared to heterozygous (63.174.5 vs 37.176.9%, respectively, P ¼ 0.002). For HAM-D, GAG haplotype homozygosity was associated with a 31% greater reduction in scores after treatment compared to heterozygous (67.374.3 vs 51.276.0%, respectively, P ¼ 0.03). In those with loweranxiety levels at screening, there were no associations between CRHR1 genotype and percent change in HAM-A or HAM-D. These findings of increased response to antidepressants in highly anxious patients homozygous for the GAG haplotype of CRHR1 need to be independently validated and replicated. Such work would support the hypotheses that response to antidepressant treatment is heterogeneous and that the CRHR1 gene and possibly other genes in stress-inflammatory pathways are involved in response to antidepressant treatment. These findings also suggest that variations in the CRHR1 gene may affect response to CRHR1 agonists or antagonists. All data are deposited in www.pharmgkb. Keywords: corticotropin-releasing hormone; corticotropin-releasing hormone receptor; MexicanAmerican; Hispanic; depression; anxiety Major depression is a common and complex disorder of gene-environment interactions. 1 The specific genetic substrates and precipitating environmental factors have not yet been elucidated. The disorder affects 10% of males and 20% of females and has a point prevalence of 3%. Its cost to the US economy exceeds 100 billion dollars per year. 2 Over 20 drugs are approved by the US Food and Drug Administration for treatment of depression, each one with efficacy of approximately 60%. Various subgroups ...

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“…This is not surprising because several key functions that have been related to the CNS actions of cytokines, such as sleep, food intake, body weight regulation, cognition, behavior, temperature and neuroendocrine transduction, 20 are known to be dysregulated in major depression. In the next article in this issue Dantzer and colleagues provide further discussion on the role of cytokines in depressive disorder, 90 and in a News & Views and accompanying Image in this issue, PlataSalamán and Turrin discuss in broader terms the role of CNS cytokines in neurological and psychiatric disorders. 91,92 …”

Section: Discussionmentioning

confidence: 99%

The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection

1999

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Depression represents a major public health problem. It is estimated that 13-20% of the population has some depressive symptoms at any given time and about 5% of the population is assumed to suffer from major depression. Known pathological processes include ischemia, neoplasia, necrosis, apoptosis, infection, and inflammation. Of those, inflammation is the most compatible with the waxing and waning course of depression, and could explain the biology of this disorder that has a fluctuating course with severe episodes that can be followed by partial or complete remission. Over the years a body of evidence has been accumulated suggesting that major depression is associated with dysfunction of inflammatory mediators. Major depression commonly co-occurs with ischemic heart disease and decreased bone mineral density. Depressive symptoms are known to have a negative impact on cardiovascular prognosis, increasing the mortality rate of coronary artery disease. Several lines of evidence indicate that brain cytokines, principally interleukin-1␤ (IL-1␤) and IL-1 receptor antagonist may have a role in the biology of major depression, and that they might additionally be involved in the pathophysiology and somatic consequences of depression as well as in the effects of antidepressant treatment. A particularly unique and novel aspect of the studies and views discussed here is their potential to lead to interventions which may reduce the morbidity and mortality risks for osteoporosis, cardiovascular disease, and behavioral symptoms in patients with major depression. We also discuss the emerging concept of peripheral and central cytokine compartments: their integration and differential regulation is a key element for the optimal functioning of the immune and nervous systems.

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Cytokines and depression: fortuitous or causative association?

Cited by 157 publications

References 38 publications

Effects of Antidepressant Drugs on the Behavioral and Physiological Responses to Lipopolysaccharide (LPS) in Rodents

Effects of Antidepressant Drugs on the Behavioral and Physiological Responses to Lipopolysaccharide (LPS) in Rodents

Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans

The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection

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