Effects of Interferon-Alpha on Rhesus Monkeys: A Nonhuman Primate Model of Cytokine-Induced Depression

Felger, Jennifer C.; Alagbe, Oyetunde; Hu, Fang; Mook, Deborah; Freeman, Amanda; Sánchez, Mar M.; Kalin, Ned H.; Ratti, Emiliangelo; Nemeroff, Charles B.; Miller, Andrew H.

doi:10.1016/j.biopsych.2007.05.026

Cited by 189 publications

(149 citation statements)

References 54 publications

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“…Decreased dopamine release was also demonstrated in IFN-α-treated rhesus monkeys that, like humans, exhibit a depressive-like huddling behavior after chronic IFN-α exposure (Felger et al, 2007(Felger et al, , 2013b. Indeed, after 4 weeks of IFN-α administration at doses similar to those given to humans for cancer treatment, rhesus monkeys exhibited decreased CSF dopamine metabolites (Felger et al, 2007). Moreover, using in vivo microdialysis of basal ganglia nuclei, these laboratory animals demonstrated decreased extracellular dopamine release following administration (by reverse microdialysis) of potassium, which leads to a voltage-dependent dopamine release, as well as amphetamine, which stimulates dopamine release and blocks dopamine reuptake (Felger et al, 2013b).…”

Section: Inflammation Effects On Neurotransmitter Metabolismmentioning

confidence: 85%

“…For example, using PET, administration of radiolabeled L-DOPA to humans treated with IFN-α was found to lead to increased L-DOPA uptake and decreased L-DOPA release consistent with dopamine depletion (Capuron et al, 2012). Decreased dopamine release was also demonstrated in IFN-α-treated rhesus monkeys that, like humans, exhibit a depressive-like huddling behavior after chronic IFN-α exposure (Felger et al, 2007(Felger et al, , 2013b. Indeed, after 4 weeks of IFN-α administration at doses similar to those given to humans for cancer treatment, rhesus monkeys exhibited decreased CSF dopamine metabolites (Felger et al, 2007).…”

Section: Inflammation Effects On Neurotransmitter Metabolismmentioning

confidence: 99%

See 1 more Smart Citation

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

Miller

Haroon

Felger

2016

Neuropsychopharmacol

119

124

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A wealth of data has been amassed that details a complex, yet accessible, series of pathways by which the immune system, notably inflammation, can influence the brain and behavior. These data have opened the window to a diverse array of novel targets whose potential efficacy is tied to specific neurotransmitters and neurocircuits as well as specific behaviors. What is clear is that the impact of inflammation on the brain cuts across psychiatric disorders and engages dopaminergic and glutamatergic pathways that regulate motivation and motor activity as well as the sensitivity to threat. Given the ability to identify patient populations with increased inflammation, the precision of interventions can be further tuned, in conjunction with the ability to establish target engagement in the brain through the use of multiple neuroimaging strategies. After a brief overview of the mechanisms by which inflammation affects the brain and behavior, this review examines the extant literature on the efficacy of anti-inflammatory treatments, while forging guidelines for future intelligent clinical trial design. An examination of the most promising therapeutic strategies is also provided, along with some of the most exciting clinical trials that are currently being planned or underway.

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Section: Inflammation Effects On Neurotransmitter Metabolismmentioning

confidence: 85%

Section: Inflammation Effects On Neurotransmitter Metabolismmentioning

confidence: 99%

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

Miller

Haroon

Felger

2016

Neuropsychopharmacol

119

124

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“…A more recent study consistently showed that rhesus monkeys administered with IFN-α exhibit depressivelike huddling behavior and lower cerebrospinal fluid concentrations of a dopamine metabolite [84] . IFN-α a d m i n i s t r a t i o n h a s b e e n r e l a t e d t o d e p l e t i o n o f tetrahydrobiopterin, a cofactor for tyrosine hydroxylase (the rate-limiting enzyme in the synthesis of dopamine), so dopamine could be depleted in this way [85] .…”

Section: Dopaminementioning

confidence: 96%

Inflammation: a mechanism of depression?

Han

2014

Neurosci. Bull.

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In recent decades, major depression has become more prevalent and research has shown that immune activation and cytokine production may be involved. This review is mainly focused on the contribution of infl ammation to depression. We fi rst briefl y introduce the infl ammatory biomarkers of depression, then discuss the sources of cytokines in the brain, and fi nally describe the neuroimmunological mechanisms underlying the association between infl ammation and depression.Keywords: depression; infl ammation; cytokines; hypothalamic-pituitary-adrenal axis; 5-HT; neuroplasticity ·Review· IntroductionThe prevalence of major depression has increased dramatically over the past few decades [1] , and women are nearly twice as likely as men to develop depressive disorder [2] . Depression is classified as a brain disorder, but its symptomatology includes some behaviors that also occur during chronic infl ammatory stress [3] . Research has shown that immune activation and the production of cytokines may be involved in depression [4] , so this relationship has received much attention. In fact, three causal pathways have been proposed: depression to inflammation, inflammation to depression, and a bidirectional relationship [5] . In this review, we focus on the impact of inflammation on depression and the underlying mechanisms. Cytokines are small cell-signaling proteins that mediate and regulate immune responses and inflammation, and can be divided into two categories:the pro-inflammatory cytokines interleukin (IL)-1 β, IL-6, IL-8, and tumor necrosis factor (TNF)-α, and the anti-inflammatory cytokines IL-1Rα, IL-4, IL-10, and transforming growth factor (TGF)-β1. Generally, t he proinfl ammatory cytokines promote systemic infl ammation and are essential for the initiation of an infl ammatory response to disease [6] , while the anti-inflammatory cytokines antagonize these actions to reduce inflammation and promote healing [6,7] . Moreover, some cytokines play dual roles [8] . In the central nervous system (CNS), the cellular source, function, and mechanisms of action of cytokines differ from those in the periphery. In the following, we briefl y introduce the current research on infl ammatory biomarkers of depression. Infl ammatory Biomarkers of DepressionSo far, there are neither universally accepted or defi nitive biomarkers of depression [9] , nor effective methods to assess the severity, endophenotypes, or response to treatment [10] .However, sufficient evidence has suggested changes in the circulating levels of cytokines in depressed patients, which can be reversed by antidepressant treatments [11,12] .So, many studies have aimed to clarify the neurobiological changes in depression and to establish inflammatory biomarkers. The peripheral levels of IL-6, TNF-α, and IL-1β are increased in patients with depression [13][14][15][16][17] , and antidepressant treatments reverse this effect [18][19][20] . These consistent results demonstrate that IL-6, TNF-α, and IL-1β are putative biomarkers for depression. However, due to the he...

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“…Inflammatory cytokines can decrease BDNF signaling (Cortese et al, 2011;Tong et al, 2008), as can lipopolysaccharide injections (Guan and Fang, 2006). Therefore, in addition to IFN-a's effects on serotonin , dopamine (Felger et al, 2007), glutamate (Raison et al, 2010b), and the hypothalamic-pituitary-adrenal axis (Raison et al, 2010a), a decrease in BDNF may ultimately be the reason for the development of depression during IFN-a treatment. Related to this, social isolation decreases central BDNF, an effect which is likely mediated by the inflammatory cytokine IL1b (Barrientos et al, 2003;Ben Menachem-Zidon et al, 2008;Koo and Duman, 2008).…”

Section: Introductionmentioning

confidence: 99%

Brain-Derived Neurotrophic Factor Serum Levels and Genotype: Association with Depression during Interferon-α Treatment

Lotrich

Albusaysi

Ferrell

2012

Neuropsychopharmacol

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Depression has been associated with inflammation, and inflammation may both influence and interact with growth factors such as brainderived neurotrophic factor (BDNF). Both the functional Val66Met BDNF polymorphism (rs6265) and BDNF levels have been associated with depression. It is thus plausible that decreased BDNF could mediate and/or moderate cytokine-induced depression. We therefore prospectively employed the Beck Depression Inventory-II (BDI-II), the Hospital Anxiety and Depression Scale (HADS), and the Montgomery-Asberg Depression Rating Scale (MADRS) in 124 initially euthymic patients during treatment with interferon-alpha (IFN-a), assessing serum BDNF and rs6265. Using mixed-effect repeated measures, lower pretreatment BDNF was associated with higher depression symptoms during IFN-a treatment (F 144,17.2 ¼ 6.8; Po0.0001). However, although the Met allele was associated with lower BDNF levels (F 1,83.0 ¼ 5.0; P ¼ 0.03), it was only associated with increased MADRS scores (F 4,8.9 ¼ 20.3; Po0.001), and not the BDI-II or HADS. An exploratory comparison of individual BDI-II items indicated that the Met allele was associated with suicidal ideation, sadness, and worthlessness, but not neurovegetative symptoms. Conversely, the serotonin transporter promoter polymorphism (5-HTTLPR) short allele was associated with neurovegetative symptoms such as insomnia, poor appetite and fatigue, but not sadness, worthlessness, or suicidal ideation. IFN-a therapy further lowered BDNF serum levels (F 4,37.7 ¼ 5.0; P ¼ 0.003), but this decrease occurred regardless of depression development. The findings thus do not support the hypothesis that decreasing BDNF is the primary pathway by which IFN-a worsens depression. Nonetheless, the results support the hypothesis that BDNF levels influence resiliency against developing inflammatory cytokine-associated depression, and specifically to a subset of symptoms distinct from those influenced by 5-HTTLPR. Neuropsychopharmacology (2013) 38, 985-995;

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Effects of Interferon-Alpha on Rhesus Monkeys: A Nonhuman Primate Model of Cytokine-Induced Depression

Abstract: IFN-alpha evoked behavioral, neuroendocrine, and immune responses in rhesus monkeys that are similar to humans. Moreover, alterations in hypothalamic-pituitary-adrenal axis responses and dopamine metabolism may contribute to IFN-alpha-induced depressive-like huddling behavior.

Cited by 189 publications

References 54 publications

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

Inflammation: a mechanism of depression?

Brain-Derived Neurotrophic Factor Serum Levels and Genotype: Association with Depression during Interferon-α Treatment

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