Plasma inflammatory cytokines and treatment-resistant depression with comorbid pain: improvement by ketamine

Yanling Zhou,Xiaofeng Lan,Chengyu Wang,Yuping Ning,Hanqiu Li,Ziyuan Chao

doi:10.1186/s12974-021-02245-5

Abstract

BackgroundTreatment-resistant depression (TRD) and pain frequently coexist clinically. Ketamine has analgesic and antidepressant effects, but few studies have evaluated individual differences in antidepressant outcomes to repeated ketamine in TRD patients with comorbid pain. Our aims were to determine the difference in ketamine’s antidepressant effects in TRD patients with or without pain and then to examine whether inflammatory cytokines might contribute to ketamine’s effect.MethodsSixty-six patients with TRD received six infusions of ketamine. Plasma levels of 19 inflammatory cytokines were assessed at baseline and post-infusion (day 13 and day 26) using the Luminex assay. Plasma inflammatory cytokines of sixty healthy controls (HCs) were also examined.ResultsTRD patients with pain had a higher antidepressant response rate (χ2 = 4.062, P = 0.044) and remission rate (χ2 = 4.062, P = 0.044) than patients without pain. Before ketamine treatment, GM-CSF and IL-6 levels were higher in the pain group than in the non-pain and HC groups. In the pain group, levels of TNF-α and IL-6 at day 13 and GM-CSF, fractalkine, IFN-γ, IL-10, MIP-3α, IL-12P70, IL-17α, IL-1β, IL-2, IL-4, IL-23, IL-5, IL-6, IL-7, MIP-1β, and TNF-α at day 26 were lower than those at baseline; in the non-pain group, TNF-α levels at day 13 and day 26 were lower than those at baseline. In the pain group, the changes of IL-6 were associated with improvement in pain intensity (β = 0.333, P = 0.001) and depressive symptoms (β = 0.478, P = 0.005) at day 13. Path analysis showed the direct (β = 2.995, P = 0.028) and indirect (β = 0.867, P = 0.042) effects of changes of IL-6 on improvement in depressive symptoms both were statistically significant.ConclusionThis study suggested that an elevated inflammatory response plays a critical role in individual differences in TRD patients with or without pain. Ketamine showed great antidepressant and analgesic effects in TRD patients with pain, which may be related to its effects on modulating inflammation.Trial registrationChiCTR, ChiCTR-OOC-17012239. Registered on 26 May 2017

Highlights

Treatment-resistant depression (TRD) and pain frequently coexist clinically
Increased pro-inflammatory cytokine expression in the brain, especially tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β in the hippocampus, amygdala, anterior cingulate, and frontal cortex, contributes to the development of depression pain comorbidity, which has been repeatedly shown in rodent models of neuropathic and inflammatory pain that exhibit depressive-like behavior and, in rodent models of depression that display altered nociceptive responses [11,12,13]
Efficacy of ketamine treatment Montgomery-Asberg depression rating scale (MADRS) scores at baseline did not differ between the pain and non-pain groups

Summary

Introduction

Treatment-resistant depression (TRD) and pain frequently coexist clinically. Ketamine has analgesic and antidepressant effects, but few studies have evaluated individual differences in antidepressant outcomes to repeated ketamine in TRD patients with comorbid pain. TNF-α is another general inflammatory mediator reported to be increased in patients with depression and comorbid with pain, and augmented peripheral levels of TNF-α were associated with reduced pain thresholds in a correlative analysis [14]. Elevated peripheral C-reactive protein levels and depression symptoms were observed in patients with fibromyalgia or sciatica, while higher Creactive protein levels correlated with greater depressive symptoms [15, 16]. Taken together, these data suggest that a persistent inflammatory response may underlie comorbid depression and pain or at least partly contribute to the development of this comorbidity

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