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Background  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.    Methods  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.    Results  TRD patients with pain had a higher antidepressant response rate ( χ  2  = 4.062,  P  = 0.044) and remission rate ( χ  2  = 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.    Conclusion  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.    Trial registration   ChiCTR , ChiCTR-OOC-17012239. Registered on 26 May 2017    Supplementary Information  The online version contains supplementary material available at 10.1186/s12974-021-02245-5.

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