Abstract
The co-occurrence of multiple psychoneurological symptoms, including pain, sleep disturbance, fatigue, depression, anxiety, and cognitive disturbance among adult cancer survivors led us to question which common biological mechanisms are shared among these conditions. Variances in tryptophan (Trp) levels and downstream metabolites of the kynurenine (Kyn) metabolic pathway are known to affect immune response and psychoneurological symptoms. The objective of this systematic review was to help us (a) better understand the role of the Kyn pathway in psychoneurological symptoms among adult cancer survivors and (b) identify common significant biomarkers across psychoneurological symptoms as a guide for future research. Some evidence has shown that decreased Trp levels and increased Kyn, Trp/Kyn ratio, and kynurenic acid/Trp ratio in parallel with immune activation are correlated with some psychoneurological symptoms among people undergoing cancer treatment, although discrepancies exist between studies. Kyn pathway activation could also be associated with psychoneurological symptoms among adult cancer survivors, but further research is needed to confirm its exact etiological role with respect to psychoneurological symptoms.
Keywords: kynurenine, tryptophan, metabolite, psychoneurological, symptom, cancer, survivor
Psychoneurological symptoms including pain, fatigue, depression, anxiety, cognitive disturbance, and sleep disturbance are common and distressing symptoms experienced by adult cancer survivors (Doong et al., 2015; Kim et al., 2008; Langford et al., 2016). People who receive a cancer diagnosis are referred to as cancer survivors from the time of diagnosis until the end of life. It is estimated that there will be 21.7 million cancer survivors in the United States by 2020 (Bluethmann et al., 2016). Up to 68% of cancer survivors report psychoneurological symptoms during cancer treatment (Starkweather et al., 2017). Some psychoneurological symptoms can persist even 5–10 years after completion of cancer treatment (Bower et al., 2006; Mejdahl et al., 2013). These psychoneurological symptoms have a detrimental impact on survivors’ functional status and quality of life (Denieffe et al., 2014; Garreau et al., 2006).
The co-occurrence of multiple psychoneurological symptoms with the onset of cancer has led researchers to interrogate the common mechanisms that may underlie such symptom clusters. Historically, authors have considered the model of cytokine-induced sickness behavior to be the biological mechanism that results in psychoneurological symptoms (Cleeland et al., 2003). Specifically, researchers have gathered a large amount of evidence supporting a link between increased levels of inflammatory cytokines and the onset of fatigue and depression among people living with cancer (Kwekkeboom et al., 2018; Starkweather et al., 2013).
The overarching hypothesis of this research area is that inflammation and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, circadian rhythms, and the serotonin system are putative biological mechanisms underlying psychoneurological symptoms (Kim, Barsevick, Fang, & Miaskowski, 2012). More recently, research has demonstrated that inflammation-induced activation of the kynurenine (Kyn) metabolic pathway of tryptophan (Trp) degradation plays a critical role in depression and fatigue among people living with cancer (Kim et al., 2015; Sforzini et al., 2019). This finding raises the possibility that the Kyn pathway plays an important role in cancer-related psychoneurological symptoms and warrants further investigation.
The activation of the indoleamine 2,3-dioxygenase 1 (IDO) and tryptophan 2,3-dioxygenase (TDO) pathways are relevant to Kyn metabolism (Figure 1). Trp is an essential amino acid that can only be acquired through diet. Humans utilize Trp for multiple vital functions, including structural and functional processes of protein biosynthesis and immunoregulation (Ball et al., 2014). Over 90% of available Trp is metabolized by the liver along the Kyn pathway (Badawy & Dougherty, 2016).
Figure 1.
Conceptual diagram of effects of inflammatory and hypothalamic-pituitary-adrenal (HPA)-axis activation on tryptophan and kynurenine pathways. Cancer and cancer treatment can activate inflammation and the HPA axis, which results in increased levels of inflammatory cytokines and cortisol. Stimulated by inflammatory cytokines and cortisol, the rate-limiting enzymes IDO and TDO are induced and catabolize tryptophan to kynurenine. CRP = C-reactive protein; IDO = indoleamine 2,3-dioxygenase 1; IFN-ϒ = interferon gamma; IL = interleukin; KAT = kynurenine aminotransferase; KMO = kynurenine monooxygenase; TDO = tryptophan 2,3-dioxygenase; TNF = tumor necrosis factor.
Currently, the literature recognizes two enzymes as catalyzing Trp to Kyn conversion: TDO and IDO. A recently discovered gene referred to as indoleamine 2,3-dioxygenase 2 (IDO2) has been implicated in Trp metabolism under nonphysiological conditions in vitro, but has yet to show a profound impact on Trp or Kyn levels in vivo. TDO is highly and constitutively expressed in the liver, but it is also present in the brain and induced or upregulated by endogenous and exogenous glucocorticoid(-like) molecules including cortisol and dexamethasone (Schröcksnadel et al., 2006). Under healthy physiological conditions, a majority of Trp is metabolized by TDO via the hepatic Kyn energy-producing pathway. However, under conditions of physiological or psychological stress, IDO is induced by pro-inflammatory cytokines arising from systemic inflammation and oxidative stress (Dantzer, 2016; Karu et al., 2016). Pro-inflammatory cytokines (interferon-γ) can stimulate increases in neopterin, an important biomarker of cellular immune system activation and inflammation (Heistermann & Higham, 2015; Kilicarslan et al., 2019). Pro-inflammatory cytokines including interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), and C-reactive protein (CRP) are often used as biomarkers to assess systematic inflammation, which can activate and/or induce/enhance IDO expression levels (Cho et al., 2017). IDO plays an important immunomodulatory role in autoimmunity, cancer, infectious disease, and tolerance during pregnancy (Van der Leek et al., 2017). Stimulated by inflammatory cytokines and cortisol, the rate-limiting enzymes IDO and TDO are induced and catabolize Trp to Kyn.
Trp metabolism affects psychoneurological symptoms in two ways: (a) under conditions of physiologic/psychological stress, IDO and TDO activity increases, which degrades Trp into Kyn, resulting in deprivation of Trp hydroxylase (a precursor of 5-hydroxytryptamine [5-HT] and serotonin); and (b) the neurotoxic metabolites 3-hydroxykynurenine (3-HK) and quinolinic acid (QA) and the neuroprotective metabolite kynurenic acid (KYNA) are synthesized (Karu et al., 2016). Kyn is catabolized through two distinct pathways: (a) synthesis of neurotoxic metabolites including 3-HK and QA by the enzyme kynurenine monooxygenase (KMO); and (b) catabolism into the neuroprotective metabolite KYNA (Ogyu et al., 2018). Kyn pathway metabolites (i.e., KYNA, 3-HK, and QA) have been found to have relationships with Alzheimer’s disease (Zwilling et al., 2011), major depressive disorder (Savitz et al., 2015), fatigue (Kim et al., 2015), and sleep problems (Cho et al., 2017). Recently, authors have questioned the hypothesis that Trp depletion and metabolism leads to immune response and depression, and research has focused more attention on the activity of Kyn metabolism (Dantzer, 2016).
With the increasing emphasis on symptom cluster research (Miaskowski et al., 2017), it is important to identify common biomarkers that may help to explain the underlying mechanisms common to the components of the psychoneurological symptom cluster among cancer survivors. However, few studies have identified common metabolomics biomarkers in the Kyn pathway that may be associated with psychoneurological symptoms among adult cancer survivors. The purposes of this systematic review were to (a) synthesize existing literature in order to better understand the role of the kynurenine pathway in psychoneurological symptoms among cancer survivors and (b) identify common significant biomarkers across psychoneurological symptoms as a guide for future research.
Methods
We performed a literature search to identify metabolites of the Kyn pathway associated with common psychoneurological symptoms among cancer survivors. We used the terms “kynurenine” and “cancer (or neoplasms or carcinoma)” along with “pain (or musculoskeletal pain),” “fatigue,” “sleep disturbance,” “depression,” “anxiety,” or “cognitive disturbance” to search for relevant articles in the PubMed, CINAHL, PsycINFO, and Web of Science databases (Figure 2). Two members of the study team (HL and TL) developed the inclusion and exclusion criteria for this review as well as the data abstraction criteria.
Figure 2.
Study selection process.
We included full-length articles in the present review if the study (a) presented data on the relationship between any of our symptoms of interest (pain, fatigue, sleep disturbance, depression, anxiety, or cognitive disturbance) and the metabolites of interest (Kyn-related metabolites), (b) focused on adult cancer survivors, (c) measured metabolite levels in serum or plasma, and (d) was conducted anywhere in the world but published in English. Because this is the first review of multiple psychoneurological symptoms among cancer survivors, we included any relevant articles published before April 2020 and did not limit the date range. We excluded animal studies, reviews, and editorials. The reasons for excluding animal studies were that it is difficult to assess psychological symptoms in animals, human studies have considered previous findings from animal studies, and there may be differences in the relationships between symptoms and metabolites in humans and other animals.
We developed a data abstraction tool to capture detailed data from the included studies, including author, year, study purpose, study design, sample characteristics, metabolites, symptom measurement, key findings, limitations, and strengths. Two reviewers independently abstracted the above data points from the final articles, and the study team compiled the results. We resolved disagreements through discussion to reach consensus. We then summarized common significant metabolites associated with psychoneurological symptoms. Two reviewers independently assessed the quality of the observational studies using the Newcastle–Ottawa scale (Luchini et al., 2017). They initially assessed three categories using this scale, including selection of the study population, comparability, and description of the outcome and then added sample size as an additional category. We defined high-quality studies as those with an overall score above 10, while intermediate-quality studies scored from 5 to 9 and low-quality studies from 0 to 4.
Results
The initial database search yielded 791 journal articles published through April 2020 that addressed Kyn metabolites and psychoneurological symptoms, with 509 duplicates. After an initial preliminary review, we excluded 272 studies for not meeting the inclusion criteria. Finally, we reviewed 10 studies in detail and included them in this systematic review and quality synthesis (see Figure 2).
Characteristics of Clinical Studies and Quality of Evidence
Table 1 summarizes study characteristics and findings. Across the 10 articles, sample sizes ranged from 17 to 244. Studies addressed a large variety of cancer types: breast cancers, lung cancers, pancreatic adenocarcinomas, metastatic renal cell carcinomas, melanomas, lymphomas, gastrointestinal tumors, hematological malignancies, and gynecological neoplasms. Assessments took place prior to surgery, during interferon-alpha (IFN-α) therapy, during chemotherapy, and after completing major treatments. Researchers quantified all metabolites from peripheral blood. The majority of the studies included a measure of depression (n = 7), but studies also looked at fatigue (n = 5), anxiety (n = 5), pain (n = 1), and cognitive disturbance (n = 1). We rated three of the studies (Fosså et al., 2020; Hüfner et al., 2015; Kurz et al., 2012) as high quality and the remaining seven as intermediate quality (Bannink et al., 2007; Botwinick et al., 2014; Capuron et al., 2003; Lyon et al., 2018; Pertl et al., 2013; Schroecksnadel et al., 2007; Van Gool et al., 2008). Details of the quality assessment of the included studies are presented in Table 2.
Table 1.
Summary of Included Studies of Kynurenine Metabolites and Psychoneurological Symptoms.
| Author, Year, Location | Study Purpose | Study Design | Sample Characteristics | Metabolites | Symptoms (Instruments) | Limitations | Strengths | Key Findings |
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| Fosså et al. (2020), Norway | Evaluate possible changes in metabolites in cancer survivors with chronic fatigue; focused on amino acids, pathways related to inflammation, immune activation, and vitamin B6 | Cross-sectional |
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| Lyon et al. (2018), Mid-Atlantic region, US | Identify metabolites associated with changes in levels of psychoneurological symptoms after chemotherapy | Longitudinal (pre chemotherapy, 1–2 weeks post chemotherapy) |
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| Hüfner et al. (2015), Innsbruck, Austria | Investigate the complex pathophysiology behind the interaction of breast cancer and psychological distress | Cross-sectional |
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| Botwinick et al. (2014), New York, US | Test the role of the kynurenine pathway in depression and tumor-induced immunosuppression | Cross-sectional |
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| Pertl et al. (2013), Dublin, Ireland | Investigate the associations between fatigue and inflammatory cytokines and Trp metabolism in breast cancer patients | Longitudinal (pre chemotherapy, post cancer treatment, several months post treatment) |
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| Kurz et al. (2012), Innsbruck, Austria | Characterize the relationships between concentrations of immune-activation markers and QoL and fatigue | Cross-sectional |
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| Van Gool et al. (2008), Rotterdam, Netherlands | Investigate the balance between neurotoxic and neuroprotective metabolites of Kyn in a subgroup of patients with metastatic renal cell carcinoma | Longitudinal (pre standard IFN-α, and at 4 weeks, 8 weeks, and 6 months on standard IFN-α) |
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| Bannink et al. (2007), Rotterdam, Netherlands | Investigate whether alterations in Trp metabolism occur during IFN-α treatment in oncology patients and whether these changes are associated with emerging psychiatric symptoms | Longitudinal (pre standard IFN-α, and at 4 weeks, 8 weeks, and 6 months on standard IFN-α) |
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| Schroecksnadel et al. (2007), Innsbruck, Austria | Explore the relationships of QoL and fatigue with Trp metabolic changes and immune activation status among patients with various types of malignancy | Cross-sectional |
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| Capuron et al. (2003), Atlanta, GA, US | Examine the relationships among TRP metabolism, immune cell activation, and development and treatment of depressive symptoms during IFN-α therapy | RCT (placebo or paroxetine) |
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Notes. 3-HAA = 3-hydroxyanthranilic acid; 3-HK = 3-hydroxykynurenine; 5-HIAA = 5-hydroxyindoleacetic acid; ANX+/− = patients with/without anxiety; BAI = Beck Anxiety Inventory; BAS = Brief Anxiety Scale; BCA+/− = patients with/without breast cancer; BDI = Beck Depression Inventory; BFI = Brief Fatigue Inventory; BMI = body mass index; BPI = Brief Pain Inventory; CRP = C-reactive protein; DPR+/− = patients with/without a diagnosis of depression; ESR = erythrocyte sedimentation rate; FACT-F = Functional Assessment of Cancer Therapy–Fatigue scale; HADS = Hospital Anxiety and Depression Scale; HAM-D = Hamilton Depression Rating Scale; HAS = Hamilton Anxiety Scale; IDO = indoleamine 2,3-dioxygenase 1; IFN = interferon; IL = interleukin; Kyn = kynurenine; KYNA = kynurenic acid; LNAA = large neutral amino acids; MADRS = Montgomery–Åsberg Depression Rating Scale; NA = nicotinic acid; NAM = nicotinamide; NRS = Neurotoxicity Rating Scale; PAr index = pyridoxic acid/(pyridoxal + pyridoxal 5’-phosphate); Pic = picolinic acid; QA = quinolinic acid; QoL = quality of life; RCT = randomized controlled trial; SCL-90 = Symptom Check List–90; STAI = Spielberger et al. State–Trait Anxiety Inventory; TDO = tryptophan 2,3-dioxygenase; TNF = tumor necrosis factor; Trp = tryptophan; XA = xanthurenic acid.
Table 2.
Quality Assessment of Reviews Studies.
| Authors, Year | Selection of Study Population | Comparability of Results | Exposure or Outcome | Sample Size | Overall Score |
|---|---|---|---|---|---|
| Fosså et al. (2020) | 4 | 1 | 3 | 2 | 10 |
| Lyon et al. (2018) | 3 | 0 | 3 | 1 | 7 |
| Hüfner et al. (2015) | 3 | 2 | 3 | 2 | 10 |
| Botwinick et al. (2014) | 4 | 1 | 3 | 1 | 9 |
| Pertl et al. (2013) | 4 | 1 | 2 | 2 | 9 |
| Kurz et al. (2012) | 4 | 2 | 3 | 1 | 10 |
| Van Gool et al. (2008) | 4 | 1 | 2 | 1 | 8 |
| Bannink et al. (2007) | 4 | 1 | 3 | 1 | 9 |
| Schroecksnadel et al. (2007) | 4 | 1 | 2 | 2 | 9 |
| Capuron et al. (2003) | 3 | 2 | 3 | 1 | 9 |
Note. Scores for each quality-assessment category were defined as follows. Selection of study population: assessed based on representativeness of the sample, selection of non-exposed cohort, ascertainment of exposure, and demonstration that outcome was not present at start of study. Comparability of results: 0 = no adjustment for confounding factors or the use of psychotropic medications, 1 = adjustment for either the main confounding factors or the use of psychotropic medications, 2 = adjustment for both the main confounding factors and use of psychotropic medications. Exposure or outcome: For prospective cohort studies, outcome was assessed based on assessment of outcome, follow-up period adequate to capture outcomes, adequacy of follow-up of cohorts; for cross-sectional studies, exposure was assessed based on inclusion of a precise definition of outcome, assessment of outcome, and use of appropriate statistical tests. Sample size: 1 = 25–50, 2 = more than 50. Overall score: 0–4 = low quality, 5–9 = intermediate quality, 10–11 = high quality.
Association Between Metabolites and Psychoneurological Symptoms
Discrepancies exist between the studies regarding the correlation between psychoneurological symptoms and Kyn pathway metabolites. Evidence from eight studies showed that decreased Trp levels and increased values for Kyn, Trp/Kyn and KYNA/Trp ratios in parallel with immune activation with increased CRP and neopterin are correlated with certain psychoneurological symptoms among cancer survivors (Botwinick et al., 2014; Capuron et al., 2003; Fosså et al., 2020; Hüfner et al., 2015; Kurz et al., 2012; Lyon et al., 2018; Pertl et al., 2013; Schroecksnadel et al., 2007).
Among the five studies addressing fatigue and cancer, three found a significant correlation between Kyn pathway metabolites and fatigue (Fosså et al., 2020; Kurz et al., 2012; Schroecksnadel et al., 2007). Decreased Trp levels and increased Kyn/Trp ratios, CRP levels, and neopterin levels were correlated with more-severe fatigue. Two other studies did not find a correlation (Lyon et al., 2018; Pertl et al., 2013).
Among the seven studies addressing depression and anxiety, four found a significant correlation between Kyn pathway metabolites and depression or anxiety (Botwinick et al., 2014; Capuron et al., 2003; Hüfner et al., 2015; Pertl et al., 2013). Decreased Trp levels and KYNA/Trp ratios and increased Kyn/Trp ratios and neopterin levels were correlated with more-severe depression or anxiety. The remaining three studies did not find a significant correlation (Bannink et al., 2007; Lyon et al., 2018; Van Gool et al., 2008).
Finally, two studies found significant correlations between Kyn pathway metabolites and cognitive disturbance (Capuron et al., 2003) or pain (Lyon et al., 2018). Decreased Trp levels were associated with more-severe pain and cognitive disturbance.
Discussion
This systematic review is the first to explore Kyn metabolites and multiple psychoneurological symptoms among adult cancer survivors. The Kyn pathway may play a role in the development of psychoneurological symptoms among cancer survivors, but there are inconsistent findings regarding the exact relationships between metabolites and symptoms. Differences in cancer type and stage, cancer treatment, antidepressant drugs, age, gender, and study design might have played a role in these discrepancies. This review includes studies that measured metabolites and symptoms during different cancer treatments. Thus, we discuss the results separately by cancer-treatment status.
Prior to Tumor Surgery
Only one study found a negative correlation between the KYNA/Trp ratio and severity of depression and anxiety (Botwinick et al., 2014). In the study, which evaluated 17 cancer survivors with pancreatic adenocarcinoma prior to surgery, Researchers reported that tumor burden was positively correlated to Kyn level. These results indicate that pancreatic cancer may influence depression and anxiety through the Kyn pathway and that tumor burden can influence Kyn activity. Prior to surgery and cancer treatment, IDO activity and Trp catabolism play a critical role in tumor progression and immunobiology. Emerging evidence shows that IDO activity and Trp metabolism may suppress tumor immune surveillance and support tumor escape from the immune system (Hornyák et al., 2018). Moreover, Kyn can bind the aryl hydrocarbon receptor and suppress CD8+ T cells and natural killer cells, which creates an immune-suppressive environment and enhances tumor immune escape (Heng et al., 2016). Given the critical role of IDO and Kyn catabolism in the proliferation of tumors, more studies are needed to investigate the relationship between Kyn metabolites and psychoneurological symptoms prior to surgery, especially studies that can control for the stage of cancer.
During Chemotherapy
Established evidence shows that a pro-inflammatory cytokine network can be activated in response to tissue damage during chemotherapy and lead to cancer-related psychoneurological symptoms (Bower & Lamkin, 2013; Kwekkeboom et al., 2018). Few studies have investigated the effect of chemotherapy on the Kyn pathway, and the results are inconclusive. Lyon et al. (2018) found increased Kyn levels and Kyn/Trp ratios after chemotherapy among 19 individuals with breast cancer. Decreased Trp levels were associated only with pain but not with other psychoneurological symptoms. However, Pertl et al. (2013) reported increased Trp levels and no significant changes in Kyn levels during chemotherapy among individuals with breast cancer. Kyn levels predicted significant changes in depression but not fatigue during chemotherapy. Additionally, Kurz et al. (2012) found significant correlations between the Kyn/Trp ratio with immune activation and fatigue among individuals with lung cancer. These differences in findings among studies may be due to different cancer types and chemotherapeutic agents. Nonetheless, some evidence does suggest that chemotherapy may influence depression, pain, and fatigue directly or indirectly through a Kyn pathway. More longitudinal studies are needed to follow individuals with different cancer tumor sites through chemotherapy to confirm the effect of chemotherapy on Kyn pathways and the association with psychoneurological symptoms.
During IFN-α Therapy
IFN-α therapy has been widely used for people with hepatitis C (HCV) infection, metastatic renal cell carcinoma, and melanoma, with reported neuropsychiatric side effects (Franscina Pinto & Andrade, 2016; Van Gool et al., 2008). All the relevant studies in the present review showed significant changes in Trp and Kyn pathway metabolites during IFN-α therapy, such as decreased Trp levels, increased Kyn levels, increased neopterin levels, and increased Kyn/Trp ratios (Bannink et al., 2007; Capuron et al., 2003; Van Gool et al., 2008).
The influence of IFN-α therapy on the Kyn pathway is clear; nevertheless, findings are still inconclusive regarding whether changes in neuropsychiatric symptoms are related to Kyn pathway activation induced by IFN-α. Capuron et al. (2003) examined the relationships between Trp metabolism and depressive symptoms in a randomized controlled trial of 26 people with malignant melanoma during IFN-α therapy (15 participants received the placebo, and 11 participants received paroxetine). They found decreased Trp levels among participants who were antidepressant-free and had worse depressive, anxious, and cognitive symptoms, but Trp levels were not correlated with neurovegetative symptoms (e.g., fatigue, anorexia) or somatic symptoms (e.g., pain, gastrointestinal distress). Compared with the nondepressed participants, the participants who developed major depression had significantly greater increases in Kyn levels and neopterin levels and decreases in Trp levels.
In contrast, Bannink et al. (2007) conducted a longitudinal study of 43 cancer survivors with metastatic renal cell carcinoma or melanoma during IFN-α therapy and found no correlations between Kyn pathway metabolites and depression or anxiety. Similarly, Van Gool et al. (2008) found no evidence to support the idea that the balance of metabolites of the Kyn pathway underlies the neuropsychiatric side effects of IFN-α in their study among 24 survivors with metastatic renal cell carcinoma. Even though established evidence shows that the activation of the Kyn pathway plays a critical role in depressive symptoms among people with HCV receiving IFN-α therapy (Murakami et al., 2016), its exact role in adult cancer survivors is uncertain. Large studies are needed in study populations of cancer survivors undergoing IFN-α therapy that are homogenous by tumor type and large enough to allow subgroup analysis of those concurrently taking antidepressants.
Following Major Treatment
Among cancer survivors who finish major treatment, researchers have consistently observed that immune-mediated Trp degradation and Kyn metabolism are related to cancer-related fatigue, depression, and anxiety. Among a group of 154 breast cancer survivors, Hüfner et al. (2015) found increased neopterin levels and phenylalanine/tyrosine ratios in survivors with depression as well as increased Kyn/Trp ratios and neopterin levels in those with state anxiety. Their findings were consistent with those of Schroecksnadel et al. (2007), who found increased Kyn/Trp ratios and immune activation to be associated with increased fatigue among 146 cancer survivors and also found lower Trp levels among those with progressive disease. Recently, Fosså et al. (2020) evaluated changes in metabolites and fatigue among 244 cancer survivors. They found significantly decreased Trp levels in fatigued survivors. Kyn/Trp ratios and neopterin levels were higher in fatigued than in nonfatigued survivors with borderline significance, and the difference was more prominent in men survivors than in women survivors, a finding consistent with other studies showing that the Trp breakdown differs between men and women (Reininghaus et al., 2019). Future studies are needed to control for the effects of gender and cancer stage and to track the changes in Kyn pathway metabolites and symptoms among cancer survivors who have completed major cancer treatment.
Common Biomarkers of Psychoneurological Symptoms
Relationships between Kyn pathway metabolites and psychoneurological symptoms among cancer survivors were insufficiently clear and inconsistent across studies, especially for pain, sleep, and cognitive disturbance. Although the exact relationships between Kyn pathway metabolites and psychoneurological symptoms are uncertain at this point, researchers can use the list of biomarkers (Table 3) that were significant across studies as a base to guide future studies.
Table 3.
Kynurenine and Related Metabolites (Biomarkers) Associated With Psychoneurological Symptoms.
| Metabolite | Pain | Fatigue | Depression | Anxiety | Cognitive Function |
|---|---|---|---|---|---|
| Trp | Xa | Xb,c | Xd | Xd | Xd |
| Kyn | Xd,h | ||||
| Kyn/Trp | Xb,c,g | Xf | |||
| KYNA/Trp | Xe | Xe | |||
| CRP | Xc,g,h | Xh | |||
| IL-6 | Xh | ||||
| Neopterin | Xc,g | Xd |
Note. Metabolites in this table were associated with at least two psychoneurological symptoms in adult cancer survivors. CRP = C-reactive protein; IL = interleukin; Kyn = kynurenine; KYNA = kynurenic acid; Trp = tryptophan.
a Lower levels of Trp were related to higher levels of pain (Lyon et al., 2018); bLower Trp levels with higher Kyn/Trp ratio and neopterin levels were correlated with higher levels of fatigue (Fosså et al., 2020); cLower levels of Trp with higher Kyn/Trp ratio and levels of neopterin and CRP were correlated with higher levels of fatigue (Schroecksnadel et al., 2007); dDecreases in Trp level correlated with increased depressive, anxious, and cognitive symptoms, while higher levels of Kyn and neopterin and lower levels of Trp were correlated with the presence of depression (Capuron et al., 2003); eNegative correlations between Kyna/Trp ratio and depression and anxiety (Botwinick et al., 2014); fHigher Kyn/Trp ratio was correlated with higher state anxiety scores (Hüfner et al., 2015); gHigher CRP and neopterin levels and Kyn/Trp ratio were correlated with higher levels of fatigue (Kurz et al., 2012); hHigher Kyn levels were correlated with higher depression levels, and IL-6 levels covaried with fatigue (Pertl et al., 2013).
Some studies indicated that lower Trp levels were correlated with worse pain, fatigue, depression, anxiety, or cognitive function (Capuron et al., 2003; Fosså et al., 2020; Lyon et al., 2018; Schroecksnadel et al., 2007), while other studies did not find a significant correlation between Trp levels and symptoms. Likewise, while authors have tended to hypothesize that Trp depletion leads to immune response and depression, others have recently challenged this hypothesis (Dantzer, 2016) because administration of Kyn alone can lead to depressive-like symptoms without Trp depletion.
As with the findings for Trp levels, some studies found that higher values for Kyn, the Kyn/Trp ratio, CRP, and neopterin were associated with increased fatigue, depression, or anxiety, while other studies did not find significant correlations. Researchers commonly use the Kyn/Trp ratio as a proxy for IDO activity levels (Raison et al., 2010), and increased IDO activity is associated with chronic immune activation, which is the putative mechanism for psychoneurological symptoms (Savitz et al., 2015). The Kyn/Trp ratio predicts overall survival among people with cancer (Wang et al., 2018; Zhai et al., 2015) and mortality rate among people with acquired immune deficiency syndrome (Wang et al., 2019). Studies with findings of significant correlations between the Kyn pathway and fatigue or depression (Fosså et al., 2020; Kurz et al., 2012; Schroecksnadel et al., 2007) tended to include more people with advanced disease and higher inflammatory activity than studies without significant findings (Lyon et al., 2018; Pertl et al., 2013). Therefore, it will be important to consider cancer stage and assess inflammatory and immune activity in future studies.
Meanwhile, Hüfner et al. (2015) found a weak association between neopterin and the Kyn/Trp ratio. This evidence suggests that IDO activity induced by immune activation is not the only way to activate the Kyn pathway. Other factors, such as stress and glucocorticoid-activated TDO, may also influence the Kyn pathway and psychoneurological symptoms. Because people with cancer experience tremendous stress during cancer diagnosis and treatment, it would be informative to measure stress and cortisol levels while assessing metabolites in future studies.
Most studies in this review were focused on Trp and Kyn levels and did not measure downstream KYNA and QA. Only two studies measured KYNA and QA and examined the imbalance of neuroprotective and neurodegenerative effects of the Kyn pathway. Given the evidence that lower levels of KYNA and higher levels of QA are routinely observed in people with depression (Ogyu et al., 2018) and Alzheimer’s disease (Zwilling et al., 2011), future studies are needed to evaluate QA and KYNA levels along with Kyn, Trp, and neopterin levels among people with cancer.
Study Limitations
It is important to acknowledge several limitations we noted across these studies. First, most of the studies had small sample sizes, did not control for fasting status, and had variation in the time of day of blood collection. Even though it is hard to control fasting status, collecting blood at fixed times would reduce the influence of circadian rhythms. Second, some studies did not control for the influence of confounding factors, including age, sex, cancer stage, and pharmacologic agents. Notably, some antidepressants can modulate Trp and Kyn metabolism (Eskelund et al., 2017), and sex is associated with different types of changes in Kyn/Trp ratios and neopterin (Reininghaus et al., 2019). These sources of variability might have impacted our findings of associations between metabolites and psychoneurological symptoms. Therefore, future studies are needed that look at larger homogenous populations stratified by tumor type, cancer treatment, and possible immunological status while controlling for confounding factors (i.e., age, sex, cancer stage, pharmacologic agents). Longitudinal studies are also needed to assess metabolites and psychoneurological changes during and after chemotherapy, radiation therapy, immune therapy and after major treatments. Given the coexistence of multiple psychoneurological symptoms among people living with cancer, future research should evaluate the cluster of psychoneurological symptoms and their relationships with Kyn metabolites.
Conclusion
In this systematic review we summarized the Kyn pathway and identified common metabolites of the Kyn pathway associated with multiple psychoneurological symptoms among adult cancer survivors. Evidence from eight studies showed that decreased Trp levels and increased values for Kyn and the Trp/Kyn and KYNA/Trp ratios in parallel with immune activation with increased CRP and neopterin may be correlated with certain psychoneurological symptoms among cancer survivors, although discrepancies still exist between studies. Thus, while Kyn pathway activation could be associated with psychoneurological symptoms among cancer survivors, determining its exact etiological role in relation to these symptoms will require further research. Future researchers should include the metabolites we identified through this review in symptom studies to expand our understanding of the biological mechanisms underlying psychoneurological symptoms among adult cancer survivors. These metabolites may also serve as biomarkers for future individualized and/or targeted interventions aimed at reversing the negative symptoms associated with high levels of distress and/or maladaptive biobehavioral effects among adult cancer survivors.
Acknowledgment
The authors would like to thank Kyra Freestar for manuscript editing.
Footnotes
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Institute of Nursing Research of the National Institutes of Health (award number K24NR015340). MBL is supported by the National Institute of Nursing Research of the National Institutes of Health under award number K23NR018482. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
ORCID iDs: Hongjin Li 
https://orcid.org/0000-0002-5466-1192
Tingting Liu
https://orcid.org/0000-0002-7348-809X
Lacey W. Heinsberg
https://orcid.org/0000-0002-7690-5485
References
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