Three important findings of the present study are as follows: First, repeated subanesthetic doses of ketamine had significantly superior antidepressant effects in TRD patients with comorbid pain compared with patients without pain. Second, before ketamine treatment, TRD patients with comorbid pain had an elevated inflammatory response compared with patients without pain and healthy controls. Third, ketamine exerted greater effects on modulating inflammation in TRD patients with pain than in patients without pain.
Subanesthetic ketamine can improve pain and depression comorbidities
The present study showed that 50% of TRD patients had comorbid pain, consistent with previous reports that the comorbidity rate of chronic pain and depression was approximately 40 to 60% [3, 4]. Our findings that TRD patients with or without pain showed similar severity of depressive symptoms suggested that painful symptoms were independent of the degree of depression, which was inconsistent with previous results that patients with MDD comorbid with chronic pain suffered from more severe depression [30, 31]. Note that the present study sample was treatment-resistant with a mixture of medicines as compared to other reports of MDD [30, 31]. Different objects the study chooses may result in a different conclusion that was at odds with the previous result.
Pain adversely affects the treatment response and prognosis of depression and vice versa. Patients with comorbid pain and depression were reported to experience a worse response to analgesic therapy than those without depressive symptoms . Patients who had more severe pain symptoms prior to selective serotonin reuptake inhibitor treatment experienced poorer responses . For TRD patients with pain in our study, the response rate to six infusions of ketamine was 72.7%, and the remission rate was 51.5%, which were significantly higher than patients without pain. Moreover, patients with comorbid pain also showed a significantly shorter time to achieve treatment response and remission. The better antidepressant outcomes in TRD patients comorbid with pain indicated that ketamine works on the brain through mechanisms different from the mechanisms of common antidepressants. Interestingly, the pain group also showed mild pain during ketamine treatment, even after ketamine treatment. A systematic review reported that headache is the most common acute side effect after ketamine treatment, especially in patients given intravenous ketamine . In the present study, pain symptoms were reported during 76 (19.2%) infusions from among the 396 total infusions of ketamine. Although most of them reported that the pain resolved shortly after dose administration, their VAS score, sensory index, affective index, and PPI still reflected pain symptoms because these assessments covered a 24-h post-infusion period.
Ketamine showed analgesic effects in patients suffering from acute and chronic pain, as well as rapidly robust antidepressant effects in patients with TRD. Several clinical studies have supported that subanesthetic doses of ketamine may be ideal for the treatment of pain and depression comorbidities. Subanesthetic ketamine can reduce depressive symptoms in chronic pain patients, even in patients with refractory neuropathic pain syndromes [23, 24]. Daily oral ketamine for 6 weeks also effectively improved depressive symptoms in patients with chronic pain with mild-to-moderate depression . Furthermore, in animal studies, ketamine has been reported to relieve pain-induced depression, which is independent of its antinociceptive effect. The foregoing results proved ketamine’s antidepressant and analgesic effects and gave rise to an interesting finding that TRD patients with pain achieved greater antidepressant outcomes than those without pain and took a shorter time to reach those outcomes.
Ketamine’s effect on modulating inflammation
A wealth of evidence supports the hypothesis that excessive activation of inflammation contributes to the pathophysiology of the comorbidity of pain and depression. Microglial activation in the hippocampus and thalamus was found in patients suffering from chronic fatigue syndrome who exhibited pain and depression using positron emission tomography scans , and microglial activation and increased inflammatory cytokine expression were found in pain- and mood-related brain regions in rodent models of depression-pain comorbidity [13, 35]. Activation of the inflammatory response was also found in patients with comorbid depression and pain. For example, higher plasma IL-6 levels were found in patients with chronic back pain and comorbid depression and in patients with burning mouth syndrome and depressive symptoms than in healthy controls [9, 10]. The present study revealed that, compared with healthy controls, TRD patients with or without pain both had elevated levels of both pro-inflammatory (e.g., IL-17α, IL-2, and IL-6) and anti-inflammatory (e.g., IL-10, IL-13) cytokines, as well as other cytokines (e.g., GM-CSF, fractalkine, MIP-3α, and MIP-1β), while anti-inflammatory IL-4 levels decreased in both the pain and without pain groups. These changes may be associated with the interaction between the immune-inflammatory response system (IRS) and the compensatory immune-regulatory reflex system (CIRS). In MDD, the IRS overreacts, as reflected by the increased levels of pro-inflammatory cytokines, which consequently induce the CIRS. The CIRS, associated with the elevation of T helper type 2 and T regulatory activities, results in increased anti-inflammatory cytokine levels, which in turn protect against the excessive IRS and restore a balanced state of the immune system [36, 37]. Therefore, the simultaneous activation of IRS and CIRS leads to the elevation of both pro-inflammatory and anti-inflammatory cytokines in patients with MDD, which was supported by several studies [38, 39]. However, anti-inflammatory IL-4 levels did not elevate in TRD patients, and IL-7 levels were observed to be lowly expressed in the non-pain group as compared to the healthy controls in the present study, suggesting a more complicated mechanism is involved in TRD.
Furthermore, plasma levels of GM-CSF and IL-6 in TRD patients with pain were higher than those in patients without pain, reflecting that these patients are much more likely to suffer an elevated inflammatory response. A preclinical study also reported increased levels of the inflammatory cytokines IL-6, IL-1β, TNF-α, IL-4, and IL-10 in spared nerve ligation rats with a depression-like phenotype but not rats without a depression-like phenotype . Thus, an excessive inflammatory response may contribute to individual differences in the risks for the comorbidity of pain and depression.
Then, we further analyzed whether alterations in inflammatory cytokines were related to individual differences in ketamine’s effects on comorbid TRD and pain. Results of the linear mixed model showed no significant group main effects on any of cytokines, while most of the 19 inflammatory cytokine levels decreased after six infusions of ketamine in TRD patients as reflected by their significant time main effects, consistent with our previous findings in depressed patients without controlling pain . These alterations were observed in TRD patients with pain, including 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, while only TNF-α levels decreased after ketamine infusions in patients without pain. We speculate that there is a relationship between the modulation of inflammatory response and ketamine’s superior antidepressant effects in TRD patients with pain. Moreover, given that the TRD patients with pain exhibited higher plasma IL-6 and GM-CSF levels than the patients without pain before ketamine intervention, it is likely that patients who have elevated inflammatory responses may more easily benefit from ketamine. Similarly, higher IL-6 levels were reported as a potential predictor of ketamine’s antidepressant efficacy in a clinical study . In an animal study, spared nerved ligation rats with a depression-like phenotype showed lower serum levels of IL-1β and IL-6 than non-responders at baseline . Results from rats subjected to inescapable electric shock suggested that peripheral IL-6 may contribute to resilience versus susceptibility to inescapable stress . In addition, it was important to note that most cytokines showed significant reduction at 2 weeks after six ketamine infusions compared with baseline, not at day 13, indicating a possible existence of a delayed response in peripheral inflammatory cytokines like that in the brain after ketamine infusions in TRD patients with pain. Previous studies demonstrated that the response of inflammatory cytokines was out-of-sync with depressive symptoms after antidepressant treatment [37, 43]. Moreover, the IRS and CIRS pathways were active even in the remission stage of a mood disorder, which suggested that the original steady state may not be restored immediately after an acute episode .
Notably, anti-inflammatory IL-10 and IL-4 levels also decreased 2 weeks after the final ketamine infusion, which were significantly elevated in the pain group before ketamine treatment compared with healthy controls. These changes in IL-10 and IL-4 levels after ketamine treatment may be a result of the weakening of the CIRS response caused by decreased IRS activity. Similarly, our previous study found a significant decreased in a broad range of cytokines, also including anti-inflammatory IL-10 and IL-4 after 4 weeks of antidepressant treatment in patients with first-episode drug-naive MDD . A recent meta-analysis including 32 studies also revealed a significant decrease in both pro-inflammatory (e.g., IL-6) and anti-inflammatory (e.g., IL-4, IL-10) cytokine levels after antidepressant treatment .
Interestingly, correlations between changes in IL-6 levels and both antidepressant and analgesic effects were found in TRD patients with pain at day 13; however, further analysis showed that ketamine’s analgesic effect mediated the association between decreases of IL-6 levels and its antidepressant effect. Previous studies have also suggested that ketamine can decrease the expression of inflammatory cytokines in MDD patients, but the results regarding the relationship between the changes in cytokine levels and antidepressant efficacy have been inconsistent [46, 47]. Chen et al. found that the decrease in levels of TNF-α after a single dose of ketamine in patients with MDD was correlated with antidepressant efficacy , while no association was found in Park’s clinical study . In combination with the present results, the modulation of inflammation, especially the decrease of IL-6 levels, may play a more direct role in ketamine’s analgesic effect than its antidepressant effect. However, the precise mechanisms underlying the relationship between elevated inflammatory responses and susceptibility to the comorbidity of pain and depression are currently unknown. Further preclinical studies are warranted to determine the precise anti-inflammatory mechanism of ketamine in combined models of TRD and pain.
This study was associated with several limitations. First, the small patient sample size meant that it is impossible to perform subgroup analyses by the exact area of pain. Second, seven participants lacked inflammatory cytokine data at 2 weeks after ketamine treatment. The third limitation was that inflammatory cytokines were measured only in the peripheral blood, which does not directly reflect the inflammatory response in the brain. Finally, the absence of cytokine data in healthy volunteers at days 13 and 26 meant that we could not know how the inflammatory signatures of patients compare to healthy volunteer values at these points.