Three important findings of the present study are as follows: First, the depressed patients with comorbid pain had an elevated inflammatory response compared with the depressed patients without pain and healthy controls. Second, repeated subanesthetic doses of ketamine had significantly superior antidepressant effects in the depressed patients with comorbid pain compared with the patients without pain. Third, ketamine exerted greater downregulation effects in the depressed patients with pain than in the patients without pain. This study is the first to examine the role of plasma inflammatory cytokines in clinical individual differences in depression comorbid with pain. In addition, this is the first study to explore clinical individual differences in ketamine’s antidepressant effects in individuals with comorbid depression and pain, as well as the role of plasma inflammatory cytokines in ketamine’s antidepressant response in those patients.
The present study showed that 46.2% of patients with MDD had comorbid pain, consistent with previous reports that the comorbidity rate of chronic pain and depression is approximately 40–60% [3, 4]. Our findings that depressed 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].
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 [32], 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, 33]. Activation of the inflammatory response was also found in comorbid depression and pain patients. 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]. In addition, higher serum IL-6 levels in patients suffering from burning mouth syndrome and depressive symptoms exhibited more pain [9]. In the present study, in addition to IL-6, other inflammatory cytokines, including GM-CSF, fractalkine, IL-10, MIP-3α, IL-13, IL-17α, IL-1β, IL-2, IL-6 and MIP-1β, were elevated in depressed patients with pain, while the levels of IL-4 decreased. Furthermore, plasma levels of GMCSF, IL-1β and IL-6 in depressed patients with pain were higher than those in patients without pain. An excessive inflammatory response may contribute to individual differences in risks for the comorbidity of pain and depression. A preclinical study 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 [34]. Polymorphisms related to the inflammatory response may be moderators of depressive reactions to stress. IL-1β genetic variation and attendant increased IL-1β expression were found to be associated with high risks for stress-induced depression in a large cohort of youths [34]. Thus, it is likely that genetic variants that enhance immune reactivity might create vulnerability to pain and depression comorbidity. Further studies examining differences in immune gene expression between depressed patients with or without pain are needed to confirm this speculation.
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 [35]. Patients who had more severe pain symptoms prior to selective serotonin reuptake inhibitor treatment experienced poorer responses [30]. For depressed patients with pain in our study, the rate of response to six infusions of ketamine was 73.1%, and the remission rate was 48.1%, which were significantly higher than those without pain. Moreover, patients with comorbid pain also showed a significantly shorter time to achieve treatment response and remission. The better antidepressant outcomes in depressed 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 [36]. In the present study, pain symptoms were reported during 84 (17.9%) infusions from among the 468 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 postinfusion period.
Ketamine showed analgesic effects in patients suffering from acute and chronic pain, as well as rapidly robust antidepressant effects in patients with MDD. 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 [26]. Furthermore, in animal studies, ketamine has been reported to relieve pain-induced depression, which is independent of its antinociceptive effect. The present study is the first to examine the efficacy of repeated ketamine in depressed patients with pain. The results again proved ketamine’s antidepressant and analgesic effects and gave rise to an interesting finding that depressed patients with pain achieved greater antidepressant outcomes than those without pain and took a shorter time to reach those outcomes.
Then, we further analyzed whether alterations in inflammatory cytokines were related to individual differences in ketamine’s effects on comorbid depression and pain. We observed that most of the 19 inflammatory cytokine levels decreased from the mean change values after six infusions of ketamine treatment, consistent with our previous findings in an overlapping sample [27]. By comparing changes in inflammatory cytokine levels after ketamine treatment, a greater decrease in IL-6 levels at 24 h after six infusions and greater decreases in IL-10, MIP-3α, IL-1β, IL-5 and IL-6 levels at two weeks after six infusions were observed in patients with pain than in patients without pain. We speculate that there is a relationship between downregulation of the inflammatory response and ketamine’s superior antidepressant effects in patients with pain. Moreover, given that the depressed patients with pain exhibited higher plasma IL-1β, IL-6 and GM-CSF levels than the patients without pain before the ketamine intervention, it is likely that patients who have elevated inflammatory responses may more easily benefit from ketamine. In previous clinical studies, higher levels of IL-6 and IL-1β were reported as potential predictors of ketamine’s antidepressant efficacy [37]. In an animal study, spared nerved ligation rats with a depression-like phenotype showed lower serum levels of IL-1β and IL-6 than nonresponders at baseline [34]. In addition, the results from rats subjected to inescapable electric shock suggested that peripheral IL-6 may contribute to resilience versus susceptibility to inescapable stress [38]. Thus, IL-6 was the only inflammatory cytokine that displayed a greater decrease immediately after ketamine treatment in the patients with pain than in the patients without pain.
Interestingly, correlations between changes in IL-6 levels and both antidepressant and analgesic effects were found in the depressed patients with pain at day 13; however, further analysis showed that ketamine’s analgesic effect mediated the association between decreases in 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 changes in cytokine levels and antidepressant efficacy have been inconsistent. 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 [39], while no association was found in Park’s clinical study [40]. In combination with the present results, the downregulated inflammation, especially the decrease in 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 depression and pain.
This study was associated with several limitations. First, the patient sample was relatively small. The small sample size made it impossible to perform subgroup analyses by the 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 peripheral blood, which does not directly reflect the inflammatory response in the brain.
Our study suggested that an elevated inflammatory response plays a critical role in the individual differences among depressed patients with or without pain. Ketamine showed great antidepressant and analgesic effects in depressed patients with pain, which may be related to its anti-inflammatory effect. Further preclinical studies to address the precise anti-inflammatory mechanism of ketamine and future therapies based on such a mechanistic understanding can be developed to better serve those with a depression and pain comorbidity.