The Promise and Limitations of Anti-Inflammatory Agents for the Treatment of Major Depressive Disorder

Raison, Charles L.

doi:10.1007/7854_2016_26

Cited by 26 publications

(16 citation statements)

References 53 publications

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“…However, when analyzing baseline hs-CRP values to predict response to infliximab, a plasma hs-CRP concentration greater than 5mg/L was found to be the point at which infliximab-treated patients exhibited a greater decrease in HAM-D score than placebo patients ( Raison et al, 2013 ). The effect size of participants with hs-CRP levels higher than 5mg/L was 0.41, which is in line with the efficacy of antidepressants against placebo in most studies ( Raison, 2016 ).…”

Section: The Anti-inflammatory Effect Of Antidepressantssupporting

confidence: 76%

Anti-inflammatory treatment for major depressive disorder: implications for patients with an elevated immune profile and non-responders to standard antidepressant therapy

et al. 2017

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Major depressive disorder (MDD) is a prevalent and disabling psychiatric disease with rates of non-responsiveness to antidepressants ranging from 30–50%. Historically, the monoamine depletion hypothesis has dominated the view on the pathophysiology of depression. However, the lack of responsiveness to antidepressants and treatment resistance suggests that additional mechanisms might play a role. Evidence has shown that a subgroup of depressive patients may have an underlying immune deregulation that could explain the lack of therapeutic benefit from antidepressants. Stimuli like inflammation and infection can trigger the activation of microglia to release pro-inflammatory cytokines, acting on two main pathways: (1) activation of the hypothalamic–pituitary adrenal axis, generating an imbalance in the serotonergic and noradrenergic circuits; (2) increased activity of the enzyme indoleamine-2,3-dioxygenase, resulting in depletion of serotonin levels and the production of quinolinic acid. If this hypothesis is proven true, the subgroup of MDD patients with increased levels of pro-inflammatory cytokines, mainly IL-6, TNF-α and IL-1β, might benefit from an anti-inflammatory intervention. Here, we discuss the pre-clinical and clinical studies that have provided support for treatment with non-steroidal anti-inflammatory drugs in depressed patients with inflammatory comorbidities or an elevated immune profile, as well as evidences for anti-inflammatory properties of standard antidepressants.

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Section: The Anti-inflammatory Effect Of Antidepressantssupporting

confidence: 76%

Anti-inflammatory treatment for major depressive disorder: implications for patients with an elevated immune profile and non-responders to standard antidepressant therapy

et al. 2017

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“…In identifying the precise Research Domain Criteria driven by inflammation it has been recognized that inflammatory processes represent pivotal factors in the psychopathology of symptom dimensions shared by different psychiatric conditions ( 200 ). In testing the therapeutic potential of antiinflammatory agents in depressed patients ( 236 ), the TNF-α blocker infliximab has been found to improve symptoms only in patients with high inflammatory markers, while patients with low levels of peripheral inflammation experience rather negative effects ( 237 ). A similar response pattern has been reported for the treatment with omega-3 fatty acids ( 238 ).…”

Section: Cytokine Hypothesis Of Depressionmentioning

confidence: 99%

Visceral Inflammation and Immune Activation Stress the Brain

et al. 2017

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Stress refers to a dynamic process in which the homeostasis of an organism is challenged, the outcome depending on the type, severity, and duration of stressors involved, the stress responses triggered, and the stress resilience of the organism. Importantly, the relationship between stress and the immune system is bidirectional, as not only stressors have an impact on immune function, but alterations in immune function themselves can elicit stress responses. Such bidirectional interactions have been prominently identified to occur in the gastrointestinal tract in which there is a close cross-talk between the gut microbiota and the local immune system, governed by the permeability of the intestinal mucosa. External stressors disturb the homeostasis between microbiota and gut, these disturbances being signaled to the brain via multiple communication pathways constituting the gut–brain axis, ultimately eliciting stress responses and perturbations of brain function. In view of these relationships, the present article sets out to highlight some of the interactions between peripheral immune activation, especially in the visceral system, and brain function, behavior, and stress coping. These issues are exemplified by the way through which the intestinal microbiota as well as microbe-associated molecular patterns including lipopolysaccharide communicate with the immune system and brain, and the mechanisms whereby overt inflammation in the GI tract impacts on emotional-affective behavior, pain sensitivity, and stress coping. The interactions between the peripheral immune system and the brain take place along the gut–brain axis, the major communication pathways of which comprise microbial metabolites, gut hormones, immune mediators, and sensory neurons. Through these signaling systems, several transmitter and neuropeptide systems within the brain are altered under conditions of peripheral immune stress, enabling adaptive processes related to stress coping and resilience to take place. These aspects of the impact of immune stress on molecular and behavioral processes in the brain have a bearing on several disturbances of mental health and highlight novel opportunities of therapeutic intervention.

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“…In patients with chronic elevation of inflammatory markers, anti-inflammatory drugs have potential anti-depressant efficacy (Raison, 2017). Thus, patients with elevated Kyn production should benefit from therapeutics that modulate the Kynurenine Pathway .…”

Section: Introductionmentioning

confidence: 99%

Desipramine decreases expression of human and murine indoleamine-2,3-dioxygenases

Brooks

Janda

Lawson

et al. 2017

Brain, Behavior, and Immunity

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Abundant evidence connects depression symptomology with immune system activation, stress and subsequently elevated levels of kynurenine. Anti-depressants, such as the tricyclic norepinephrine/serotonin reuptake inhibitor desipramine (Desip), were developed under the premise that increasing extracellular neurotransmitter level was the sole mechanism by which they alleviate depressive symptomologies. However, evidence suggests that anti-depressants have additional actions that contribute to their therapeutic potential. The Kynurenine Pathway produces tryptophan metabolites that modulate neurotransmitter activity. This recognition identified another putative pathway for anti-depressant targeting. Considering a recognized role of the Kynurenine Pathway in depression, we investigated the potential for Desip to alter expression of rate-limiting enzymes of this pathway: indoleamine-2,3-dioxygenases (Ido1 and Ido2). Mice were administered lipopolysaccharide (LPS) or synthetic glucocorticoid dexamethasone (Dex) with Desip to determine if Desip alters indoleamine-dioxygenase (DO) expression in vivo following a modeled immune and stress response. This work was followed by treating murine and human peripheral blood mononuclear cells (PBMCs) with interferon-gamma (IFNγ) and Desip. In vivo: Desip blocked LPS-induced Ido1 expression in hippocampi, astrocytes, microglia and PBMCs and Ido2 expression by PBMCs. Ex vivo: Desip decreased IFNγ-induced Ido1 and Ido2 expression in murine PBMCs. This effect was directly translatable to the human system as Desip decreased IDO1 and IDO2 expression by human PBMCs. These data demonstrate for the first time that an anti-depressant alters expression of Ido1 and Ido2, identifying a possible new mechanism behind anti-depressant activity. Furthermore, we propose the assessment of PBMCs for anti-depressant responsiveness using IDO expression as a biomarker.

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The Promise and Limitations of Anti-Inflammatory Agents for the Treatment of Major Depressive Disorder

Cited by 26 publications

References 53 publications

Anti-inflammatory treatment for major depressive disorder: implications for patients with an elevated immune profile and non-responders to standard antidepressant therapy

Anti-inflammatory treatment for major depressive disorder: implications for patients with an elevated immune profile and non-responders to standard antidepressant therapy

Visceral Inflammation and Immune Activation Stress the Brain

Desipramine decreases expression of human and murine indoleamine-2,3-dioxygenases

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