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. 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. Sixty-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. TRD 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. This 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. ChiCTR , ChiCTR-OOC-17012239. Registered on 26 May 2017

中文翻译：

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血浆炎性细胞因子和伴随疼痛的难治性抑郁症：氯胺酮改善

难治性抑郁症（TRD）和疼痛在临床上经常并存。氯胺酮具有镇痛和抗抑郁作用，但很少有研究评估在合并疼痛的 TRD 患者中反复使用氯胺酮对抗抑郁结果的个体差异。我们的目的是确定氯胺酮对有或无疼痛的 TRD 患者的抗抑郁作用的差异，然后检查炎性细胞因子是否可能有助于氯胺酮的作用。66 名 TRD 患者接受了六次氯胺酮输注。使用 Luminex 测定在基线和输注后（第 13 天和第 26 天）评估 19 种炎性细胞因子的血浆水平。还检查了 60 名健康对照 (HC) 的血浆炎性细胞因子。伴有疼痛的 TRD 患者抗抑郁反应率较高（χ2 = 4.062，P = 0. 044) 和缓解率 (χ2 = 4.062, P = 0.044) 比没有疼痛的患者。在氯胺酮治疗前，疼痛组的 GM-CSF 和 IL-6 水平高于非疼痛组和 HC 组。在疼痛组中，第 13 天的 TNF-α 和 IL-6 水平以及 GM-CSF、fractalkine、IFN-γ、IL-10、MIP-3α、IL-12P70、IL-17α、IL-1β、IL- 2、第26天IL-4、IL-23、IL-5、IL-6、IL-7、MIP-1β、TNF-α低于基线；在非疼痛组中，第 13 天和第 26 天的 TNF-α 水平低于基线水平。在疼痛组中，IL-6 的变化与第 13 天疼痛强度（β = 0.333，P = 0.001）和抑郁症状（β = 0.478，P = 0.005）的改善有关。路径分析显示直接（β = 2.995，P = 0.028）和间接（β = 0.867，P = 0。042) IL-6 变化对抑郁症状改善的影响均具有统计学意义。这项研究表明，升高的炎症反应在有或没有疼痛的 TRD 患者的个体差异中起关键作用。氯胺酮对伴有疼痛的 TRD 患者表现出很好的抗抑郁和镇痛作用，这可能与其调节炎症的作用有关。ChiCTR，ChiCTR-OOC-17012239。2017 年 5 月 26 日注册