Cytokines, “Depression Due to A General Medical Condition,” and Antidepressant Drugs

Raz, Yael; Weidenfeld, Joseph; Pollak, Yehuda; Morag, Michal; Morag, A; Avitsur, Ronit; Barak, Ohr; Reichenberg, Avraham; Cohen, Eran; Shavit, Yehuda; Ovadia, Haim

doi:10.1007/978-0-585-37970-8_16

Cited by 180 publications

(127 citation statements)

References 209 publications

(213 reference statements)

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Section: Discussionmentioning

confidence: 99%

“…24, NO. 5 have recently argued that LPS (and probably other immune challenges) produces a depressive-like episode in animals, which is similar to the syndrome of "depression due to a general medical condition" in humans (Yirmiya 1996(Yirmiya , 1997Yirmiya et al 1999).In support of this hypothesis, we have previously demonstrated that chronic, but not acute, treatment with imipramine attenuated LPS-induced reduction in food consumption, body weight, social exploration, open field activity, and saccharin preference (Yirmiya 1996). A similar attenuation of LPS-induced sickness behavior has been recently reported following chronic administration of the TCA desipramine, but not the SSRI paroxetine or the selective norepinephrine reuptake inhibitor venlafaxine (Shen et al 1999).…”

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confidence: 99%

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

Yirmiya

Pollak

Barak

et al. 2001

Neuropsychopharmacology

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: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Yirmiya

Pollak

Barak

et al. 2001

Neuropsychopharmacology

203

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“…The strongest association has been speculation of a role for cytokines in depression, Both schizophrenia [191] and depression [192] have often been associated with immune abnormalities, but the clinical data have been inconclusive and often conflicting [193]. The link to depression was proposed based on the apparent similarities between sickness behavior and depression [194][195][196][197].…”

Section: Implications Of Cytokine-induced Effects On Neuro-transmissimentioning

confidence: 99%

“…However, an elevation of CSF IL-1 has been reported in a limited study [207], but this has not yet been confirmed. Nevertheless, it has been argued that sickness behavior in animals may be a model for depression [195][196][197]. It has also been argued that because COX inhibitors can attenuate IL-1-induced sickness behaviors, that they should be tested for the treatment depression.…”

Section: Implications Of Cytokine-induced Effects On Neuro-transmissimentioning

confidence: 99%

“…Although, depression is frequently associated with decreased activity, anorexia, and loss of libido, it can also be associated with hyperactivity and over-eating. Proponents of the cytokine theory have pointed out that both depression and IL-1 administration can be associated with abnormalities in sleep [195][196][197]. However, IL-1 increases the duration of slow-wave sleep [208], whereas by far the most common sleep abnormality in depressed patients is insomnia.…”

Section: Implications Of Cytokine-induced Effects On Neuro-transmissimentioning

confidence: 99%

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Effects of cytokines and infections on brain neurochemistry

Dunn

2006

Clinical Neuroscience Research

285

169

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Administration of cytokines to animals can elicit many effects on the brain, particularly neuroendocrine and behavioral effects. Cytokine administration also alters neurotransmission, which may underlie these effects. The most well studied effect is the activation of the hypothalamopituitary-adrenocortical (HPA) axis, especially that by interleukin-1 (IL-1). Peripheral and central administration of IL-1 also induces norepinephrine (NE) release in the brain, most markedly in the hypothalamus. Small changes in brain dopamine (DA) are occasionally observed, but these effects are not regionally selective. IL-1 also increases brain concentrations of tryptophan, and the metabolism of serotonin (5-HT) throughout the brain in a regionally nonselective manner. Increases of tryptophan and 5-HT, but not NE, are also elicited by IL-6, which also activates the HPA axis, although it is much less potent in these respects than IL-1. IL-2 has modest effects on DA, NE and 5-HT. Like IL-6, tumor necrosis factor-α (TNFα) activates the HPA axis, but affects NE and tryptophan only at high doses. The interferons (IFN's) induce fever and HPA axis activation in man, but such effects are weak or absent in rodents. The reported effects of IFN's on brain catecholamines and serotonin have been very varied. However, interferon-γ, and to a lesser extent, interferon-α, have profound effects on the catabolism of tryptophan, effectively reducing its concentration in plasma, and may thus limit brain 5-HT synthesis.Administration of endotoxin (LPS) elicits responses similar to those of IL-1. Bacterial and viral infections induce HPA activation, and also increase brain NE and 5-HT metabolism and brain tryptophan. Typically, there is also behavioral depression. These effects are strikingly similar to those of IL-1, suggesting that IL-1 secretion, which accompanies many infections, may mediate these responses. Studies with IL-1 antagonists, support this possibility, although in most cases the antagonism is incomplete, suggesting the existence of multiple mechanisms. Because LPS is known to stimulate the secretion of IL-1, IL-6 and TNFα, it seems likely that these cytokines mediate at least some of the responses, but studies with antagonists indicate that there are multiple mechanisms. The neurochemical responses to cytokines are likely to underlie the endocrine and behavioral responses. The NE response to IL-1 appears to be instrumental in the HPA activation, but other mechanisms exist. Neither the noradrenergic nor the serotonergic systems appear to be involved in the major behavioral responses. The significance of the serotonin response is unknown.

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