A Randomized Controlled Trial of the Tumor Necrosis Factor-alpha Antagonist Infliximab in Treatment Resistant Depression: Role of Baseline Inflammatory Biomarkers

By Charles L Raison, R. Rutherford, B. Woolwine, C. Shuo, P. Schettler, Daniel F. Drake, E. Haroon, Andrew H. Miller. JAMA psychiatry, 2013

1,538 citations recorded by the source corpus.

Context Increased inflammatory biomarkers predict antidepressant non-response, and inflammatory cytokines can sabotage and circumvent mechanisms of action of conventional antidepressant therapy. Objective To determine whether inhibition of the inflammatory cytokine tumor necrosis factor (TNF)-alpha reduces depressive symptoms in patients with treatment resistant depression (TRD) and whether increased baseline plasma inflammatory biomarkers including high sensitivity c-reactive protein (hs-CRP), TNF-alpha and its soluble receptors predict treatment response. Design Double-blind, placebo-controlled, randomized clinical trial. Setting Outpatient infusion center, Emory University. Participants Sixty medically-stable outpatients with major depression on a consistent antidepressant regimen or medication-free (n=23) for ≥4 weeks and moderate treatment resistance as determined by the Massachusetts General Hospital Staging method. Interventions Three infusions of the TNF-alpha antagonist infliximab (5mg/kg)(n=30) or placebo (n=30) at baseline and weeks 2 and 6 of a 12-week trial. Main Outcome Measure 17-item Hamilton Depression Rating Scale (HAM-D-17). Results No overall difference in change of HAM-D-17 scores between treatment groups across time was found. However, there was a significant interaction between treatment, time and log baseline hs-CRP (p=0.01), with change in HAM-D-17 scores (Baseline to Week 12) favoring infliximab-treated patients at a baseline hs-CRP>5mg/L and placebo-treated patients at a baseline hs-CRP≤5mg/L. Exploratory analyses focusing on patients with a baseline hs-CRP>5mg/L revealed a treatment response (≥50% reduction in HAM-D-17 at any point during treatment) of 62% (8/13) in the infliximab group versus 33% (3/9) in placebo-treated patients (p=0.19). Baseline concentrations of TNF-alpha and its soluble receptors were significantly higher in infliximab-treated responders versus non-responders (p<0.05), and infliximab-treated responders exhibited significantly greater decreases in hs-CRP from Baseline to Week 12 compared to placebo-treated responders (p<0.01). Drop-outs and adverse events were limited and did not differ between groups. Conclusions This proof-of-concept study suggests that TNF-alpha antagonism does not have generalized efficacy in TRD, but may improve depressive symptoms in patients with high baseline inflammatory biomarkers. Trial Registration ClinicalTrials.gov Identifier: NCT00463580

Subfields: Behavioral Neuroscience, Biological Psychiatry, Pharmacology

View Paper: https://www.semanticscholar.org/paper/3cf28cef3a0f41912a0210ad78986a3d821a8cc0

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Citations in the corpus

Inflammation: depression fans the flames and feasts on the heat. (2015, background): “suggested by literature (17) Well-established risk stratification”
From Stress to Inflammation and Major Depressive Disorder: A Social Signal Transduction Theory of Depression (2014, methodology): “Participants were randomly assigned to receive either three infusions of the TNF- antagonist infliximab or placebo at baseline, Week 2, and Week 6 of a 12-week clinical trial (Raison et al., 2013).”
Understanding the somatic consequences of depression: biological mechanisms and the role of depression symptom profile (2013, background): “[153] found a TNF-α antagonist to reduce depressive symptoms in persons with high baseline inflammatory markers.”
Inflammatory markers in depression: A meta-analysis of mean differences and variability in 5,166 patients and 5,083 controls (2020, neutral): “Howes PII: S0889-1591(19)31191-2 DOI: https://doi.”
Cytokine Targets in the Brain: Impact on Neurotransmitters and Neurocircuits (2013, background): “More recently, the TNF inhibitor infliximab was given to patients with treatment resistant depression in a randomized placebo-controlled trial.[36] In this study, infliximab reduced depression and anxiety symptoms, but only in patients with increased inflammation as measured by CRP.”
Early-Life Adversity and Physical and Emotional Health across the Lifespan: A Neuro-Immune Network Hypothesis (2015, background): “Moreover, a recent clinical trial showed that a cytokine antagonist —infliximab—reduces depressive symptoms in treatment-resistant patients with elevated inflammatory markers (91).”
Inflammatory Cytokines in Depression: Neurobiological Mechanisms and Therapeutic Implications (2013, background): “As discussed above, a similar TNF-alpha antagonist, infliximab, was successful in a placebo-controlled trial in improving depressive symptoms in patients that were moderately resistant to antidepressant treatment, but only in those subjects that exhibited high baseline inflammatory biomarkers (Raiso”
Why Sleep Is Important for Health: A Psychoneuroimmunology Perspective (2014, background): “Finally, antagonism of endogenous inflammation shows promise in reducing depressive symptoms and possibly in the remission of depression in groups of depressed patients with high levels of inflammation (Raison et al. 2013, Tyring et al. 2006).”
Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress (2014, positive): “Similar strategies to block TNF-α with infliximab have shown promise in MDD patients with heightened inflammatory load (45).”
Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond (2017, background): “It may be the case that anti-inflammatory interventions are only efficacious in those individuals who show significantly elevated levels of inflammation, similar to what has been described in depression (Raison et al, 2013).”