Cognitive impairment and pain in depression: The mediating role of the kynurenine pathway

Abstract

BACKGROUND

The tryptophan-kynurenine (TRP-KYN) pathway may be implicated in the pathophysiology of cognitive impairment and pain severity in major depressive disorder (MDD); however, few studies have explored the intricacies of their interaction.

AIM

To investigate the relationship between the TRP-KYN pathway and cognitive function in MDD patients with and without painful physical symptoms (PPS).

METHODS

Seventy patients with MDD were recruited, including 33 and 37 with and without PSS, respectively. The Hamilton Depression Scale, the Hamilton Anxiety Scale, and the Short-form of McGill pain questionnaire (SFMPQ) were used to assess clinical symptoms. Cognitive function was assessed by the MATRICS Consensus Cognitive Battery (MCCB) score. TRP-KYN pathway metabolites’ serum levels were measured using high-performance liquid chromatography-tandem mass spectrometry.

RESULTS

The with PPS group exhibited significantly higher TRP-KYN ratios than did the without PPS group; in the former, the SFMPQ scores positively and negatively correlated with the TRP-KYN ratio and total MCCB score, respectively. Regression analysis indicated that body mass index and SFMPQ scores were significantly associated with the TRP-KYN ratio, predicting 30% of the variance.

CONCLUSION

The TRP-KYN ratio is a potential biomarker for identifying patients with depression accompanied by pain symptoms, and targeting it may represent a novel therapeutic strategy for managing pain in these individuals. Further elucidation of the biological mechanisms underlying cognitive impairment in MDD patients with PPS is warranted.

Key Words: Cognition; Pain; Depression; Kynurenine; Tryptophan

Core Tip: This study explores the relationship between the tryptophan-kynurenine (TRP-KYN) pathway and cognitive function in major depressive disorder (MDD) patients with and without painful physical symptoms. By analyzing serum metabolites and clinical assessments, we found that KYN level and TRP/KYN ratio were associated with pain severity but not with cognitive performance. These findings highlight the potential dissociation between pain-related and cognitive mechanisms in MDD and underscore the need for further studies on the biopsychosocial underpinnings of depression-related cognitive dysfunction.

INTRODUCTION

Major depressive disorder (MDD) is a heterogeneous disease. Notably, painful physical symptoms (PPS) are common in this condition. A systematic review and meta-analysis of observational studies found that the overall pain prevalence in these patients was 55.2%[1]. Depressive symptoms exert differential effects on cognitive impairment, and their influence on functional disability may exceed that of overall depression severity[2]. Deficits in attention, memory and learning, executive function, and psychomotor processing are particularly debilitating in patients with MDD[3-5], both during depression episodes and remission[6,7]. Additionally, several studies have demonstrated that the poorer the cognitive function, the more severe the depressive symptoms[8-12]. PPS and cognitive dysfunction correlate with poor MDD outcomes, including more severe depression, lower quality of life, and poor treatment response. Therefore, research should focus on the intricacies of these relationships and identify potential therapeutic targets for individuals with depression and sub-symptoms.

The tryptophan-kynurenine (TRP-KYN) pathway is a metabolic pathway that involves the degradation of the amino acid TRP, producing several metabolites, including kynurenic acid (KA) and quinolinic acid (QA), which may exert neuroactive effects. Importantly, it has been implicated in various neuropsychiatric disorders, including depression[13,14]. Several previous studies reported the dysregulation of the KYN pathway in depression and provided insights into the potential role of these metabolites as biomarkers[15]. Some research suggests that activation of the KYN pathway is associated with inflammatory processes; moreover, inflammation has been implicated in pain perception[16-18]. Furthermore, elevated KYN metabolite levels, particularly QA, have been linked to neuroinflammation, potentially contributing to pain sensitivity[19]. KA, another pathway metabolite, is a glutamate receptor antagonist. Notably, dysregulation in glutamate neurotransmission has been implicated in both depression and cognitive dysfunction[20], and changes in the KYN pathway may affect the balance between neuroprotective and neurotoxic metabolites and influence neurotransmitter systems. Cognitive impairments are common in depression, and alterations in neurotransmitter systems, including glutamate, have been implicated in these cognitive deficits. Therefore, dysregulation of the KYN pathway may contribute to cognitive dysfunction through its impact on glutamate receptors and neuroinflammatory processes.

Increasing evidence suggests that abnormalities in KYN metabolites might contribute to cognitive deficits’ and pain perception’s pathogenesis[21-25]. Importantly, the KYN pathway may be a shared mechanism influencing both pain perception and cognitive function in depression; thus, its dysregulation leads to an imbalance in the production of metabolites, potentially contributing to the complex interplay between pain and cognitive symptoms in individuals with depression. Crucially, research in this area is ongoing, and the precise mechanisms linking KYN metabolites, pain, and cognition in depression are not fully elucidated. In a recent study, we presented evidence that KYN pathway is vital in the pathophysiology of PPS in depression[26].

Here, we hypothesized that MDD patients with PPS would exhibit more severe cognitive impairment, with these deficits correlating with alterations in TRP-KYN pathway metabolites. Therefore, this study aimed to investigate the relationship between the TRP-KYN pathway and cognitive function in MDD patients with and without PPS.

MATERIALS AND METHODS

Participants

This cross-sectional study was conducted at Beijing Huilongguan Hospital, from September 2019 to February 2021. Inclusion criteria comprised age between 18 years and 55 years and MDD diagnosis. Exclusion criteria included patients with cardio-cerebrovascular, central nervous system diseases, organic brain dysfunction, substance dependence or abuse, and other psychological problems. All patients met the International Classification of diseases, 10^th edition, and the diagnostic criteria for depression; moreover, they were diagnosed by two experienced psychiatrists. Seventy patients with MDD were recruited, with 33 and 37 classified into the with PPS (score ≥ 4) and without PPS (score = 0) groups, respectively, based on the visual analog scale (VAS)[27,28].

The sample size was calculated using G*Power 3.1 for an independent two-sample t-test. Based on prior studies reporting KYN metabolic differences between the with PPS and without PPS groups (effect size d = 0.94)[26], a minimum of 22 participants per group was required (α = 0.05, two-tailed; β = 0.10, power = 90%).

This study was conducted in accordance with the Declaration of Helsinki and received ethical approval from the Institutional Review Board of Beijing Huilongguan Hospital (Beijing Huilongguan Ethics Committee, No. 2019-43). All participants provided written informed consent after receiving a detailed explanation of the study objectives and procedures, potential risks and benefits, confidentiality protection, voluntary participation, and withdrawal rights.

Clinical assessment

All participants completed the sociodemographic information and clinical assessment. Sociodemographic information, including age, sex, body weight, height, and education level, was recorded for all individuals using a standard form. The psychological states of all patients were assessed through the Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), and Short-form of McGill pain questionnaire (SFMPQ). Pain intensity was measured on the morning of the second day following enrollment using a 10 cm VAS. Participants were instructed to rate their average pain intensity over the past week, with 0 cm and 10 cm indicating “no pain” and “worst pain imaginable”, respectively.

Cognitive tests

Cognitive function was measured by the MATRICS Consensus Cognitive Battery (MCCB)[29], which includes 10 standardized tests measuring functions in seven cognitive domains as follows: (1) Processing speed (Trail Making Test Part A, BACS Symbol Coding Test, Category Fluency Test); (2) Attention/vigilance (Continuous Performance Test-Identical Pairs); (3) Working memory (Letter-Number Span, Wechsler Memory Scale Spatial Span); (4) Verbal learning (Hopkins Verbal Learning Test); (5) Visual learning (Brief Visuospatial Memory Test); (6) Reasoning and problem solving (Neuropsychological Assessment Battery Mazes); and (7) Social cognition (Mayer–Salovey–Caruso Emotional Intelligence Test Managing Emotions Branch). The MCCB provides a score for each cognitive domain as well as a composite score derived from the seven domain scores. Here, the Chinese version of the MCCB was employed in all subjects[30].

TRP metabolites analysis

Overnight fasting blood samples were collected and centrifuged at 3000 r/minute for 10 minute. The serum was removed and stored in polypropylene aliquot tubes at −80 °C until analysis. Serum levels of TRP metabolites (TRP, KYN, KA, 3-hydroxykynurenine, and serotonin) were quantified using high-performance liquid chromatography-tandem mass spectrometry following an established procedure[31].

Statistical analysis

Data were analyzed using Statistical Package for the Social Sciences version 22.0 and are presented as mean ± SD. The Shapiro–Wilk test tested normality. Comparisons between two independent groups were compared via Pearson's χ² test (for categorical data), unpaired Student’s t-test (for normally distributed data), or a Mann–Whitney U-test (for non-normally distributed data). Additionally, covariance analysis compared the differences in MCCB score and TRP-KYN pathway metabolites, controlling for age, sex, body mass index (BMI), education level, and medications as covariates. Regression analysis explored the correlation between metabolites and clinical symptoms in all patients; sex, age, and BMI were used as covariates. A Bonferroni correction was applied to adjust for multiple comparisons. Statistical significance was defined as P < 0.05, and all P values were two-tailed.

RESULTS

Demographic and clinical characteristics

There were no significant differences in sex, age, BMI, education, age of onset, illness duration, and medications between the with PPS and without PPS groups. The with PPS group demonstrated higher HAMD (P = 0.04) and HAMA (P = 0.002) scores than did the without PPS group. Pain was confirmed in the PPS group, with a mean rating of 4.85 on the VAS, and a mean score of 18 on the SFMPQ (Table 1).

Table 1 Demographic and clinical characteristics in the with- and without painful physical symptoms groups, n (%).

Variable	With PPS group (n = 33)	Without PPS group (n = 37)	t/z/χ2 value	P value
Sex (female/male)	16/17	23/14	1.322	0.250
Age (years)	32.61 ± 13.15	32.35 ± 13.02	-0.312	0.755
Body mass index (kg/m2)	23.99 ± 2.97	23.41 ± 4.30	-1.553	0.120
Education (years)	13.67 ± 3.28	14.27 ± 3.07	-0.756	0.450
Age of onset	27.21 ± 12.23	28.35 ± 13.60	-0.053	0.958
Hamilton Depression Scale	23.56 ± 7.42	19.54 ± 6.02	-2.052	0.040
Hamilton Anxiety Scale	20.52 ± 9.37	14.30 ± 6.72	-3.156	0.002
Short-form of McGill pain questionnaire	18.00 ± 12.56	N/A
Visual analog scale	4.85 ± 1.79	N/A
Medication			0.165	0.983
Selective serotonin reuptake inhibitors	20 (60)	23 (62)
Serotonin norepinephrine reuptake inhibitors	9 (27)	9 (24)
Other antidepressants	6 (18)	8 (22)
Antipsychotics	3 (9)	3 (8)
Mood stabilizers	15 (45)	18 (49)

N/A: Not applicable; PPS: Painful physical symptoms.

Differences in cognition between the with PPS and without PPS groups

After controlling for age, sex, education level, and medications as covariates, the PPS group exhibited significantly poorer performance in attention/vigilance (P = 0.049), along with lower total MCCB scores (P = 0.047), compared to the without PPS group. Nonetheless, these differences disappeared following Bonferroni correction for multiple comparisons (Table 2).

Table 2 Differences in cognition between the with and without painful physical symptoms groups.

Variable	With PPS group (n = 33)	Without PPS group (n = 37)	F value	P value
Verbal learning	53.70 ± 7.79	53.70 ± 9.60	0.069	0.794
Reasoning and problem solving	49.88 ± 9.92	52.70 ± 9.81	1.707	0.196
Visual learning	46.97 ± 9.52	50.00 ± 10.31	1.383	0.244
Social cognition	44.61 ± 13.34	45.38 ± 12.08	0.076	0.784
Attention/vigilance	48.85 ± 10.34	52.92 ± 5.93	4.029	0.049
Speed of processing working memory	51.00 ± 9.32	55.46 ± 8.39	3.987	0.050
Total MATRICS consensus	52.52 ± 9.38	56.03 ± 7.58	2.350	0.130
Cognitive battery	48.33 ± 8.93	53.16 ± 6.45	4.107	0.047

PPS: Painful physical symptoms.

Differences in TRP-KYN pathway metabolites between the with PPS and without PPS groups

After controlling for age, sex, BMI, and medication as covariates, the PPS group demonstrated significantly higher KYN levels (P = 0.013; it did not survive Bonferroni correction) and TRP-KYN ratio (P < 0.001; significance retained after Bonferroni correction) compared to the without PPS group (Table 3). Further analysis revealed that patients taking serotonin-norepinephrine inhibitors (n = 11) exhibited a significantly lower KA/QA ratio (P = 0.01) compared to those receiving selective serotonin reuptake inhibitors (n = 24).

Table 3 Differences in tryptophan-kynurenine pathway metabolites between the with and without painful physical symptoms groups.

Variable	With PPS group (n = 33)	Without PPS group (n = 37)	F value	P value
TRP	11.18 ± 2.17	11.51 ± 1.82	1.657	0.202
KYN	396.58 ± 92.55	333.62 ± 92.46	6.508	0.013
KA	2.52 ± 0.92	2.70 ± 2.12	1.063	0.306
QA	29.61 ± 13.12	27.25 ± 15.70	0.153	0.697
3-hydroxykynurenine	4.35 ± 1.75	4.13 ± 2.14	0.494	0.485
5-hydroxytryptamine	33.39 ± 40.01	22.71 ± 27.91	1.560	0.216
TRP-KYN	35.99 ± 7.82	29.00 ± 7.15	14.076	< 0.001
KA/QA	0.09 ± 0.04	0.10 ± 0.05	1.132	0.291

KA: Kynurenic acid; KYN: Kynurenine; PPS: Painful physical symptoms; QA: Quinolinic acid; TRP: Tryptophan.

Correlation between clinical symptoms and the TRP-KYN pathway metabolites

In the with PPS group, after adjusting for age, sex, BMI, education level, and medications, the SFMPQ score positively and negatively correlated with the TRP-KYN ratio (r = 0.555, P = 0.004, 95%CI: 0.134–0.784) and the total MCCB score (r = -0.392, P = 0.039, 95%CI: -0.677 to 0.098), respectively.

Regression analysis was performed with each KYN metabolite entered separately as the dependent variable, while pain, cognition, sex, age, BMI, and medications served as the independent variables, indicating that BMI (β = 0.281, t = 2.654, P = 0.01), sex (β = -0.326, t = -2.947, P = 0.004), and pain (β = -0.279, t = -2.639, P = 0.01) were significantly associated with KYN levels, predicting 34.8% of the variance (R² = 0.348, adjusted R² = 0.297). Furthermore, BMI (β = 0.275, t = 2.505, P = 0.015) and pain (β = -0.394, t = -3.597, P = 0.001) were significantly associated with the TRP-KYN ratio, predicting 30% of the variance (R² = 0.300, adjusted R² = 0.245).

The with PPS group demonstrated significantly higher TRP-KYN ratios than did the without PPS group. In the former, the SFMPQ scores positively and negatively correlated with the TRP-KYN ratio and the total MCCB score, respectively. Regression analysis found BMI and pain to be significantly associated with KYN metabolites.

DISCUSSION

The main findings of this study are as follows: (1) Pain severity positively correlated with an elevated serum TRP-KYN ratio and cognitive deficit in patients with PPS; and (2) Serum KYN levels and the TRP-KYN ratio were associated with pain perception rather than cognitive performance in patients with depression.

Significant reductions in attention/vigilance and total MCCB score were identified in the with PPS group. Notably, previous research found worse cognitive performance in patients suffering from chronic pain and depression than it did in healthy volunteers, specifically in the domains of selective attention, concentration, working memory, and processing speed abilities[32-34]. Depression may impair cognitive task performance, decreasing attention control, processing efficiency, initiation and problem solving, thereby affecting planning and impeding cognitive flexibility[35-37]. Furthermore, patients with chronic pain displayed slower reaction times than did matched controls in cognitive tests, particularly in tests related to psychomotor ability[38]. Additionally, higher depression and anxiety levels were found in the with PPS group, which is consistent with the findings of a previous study wherein subjects with anxiety traits exhibited increased predisposition to develop pain and poor vigilance performance[39]. Notably, depression was associated with the occurrence of making mistakes during a task measuring sustained attention[40]. The impact of anxiety and depression on task performance may represent an important psychological aspect of attention and vigilance deficits due to pain. Thus, the combined presence of depression and pain is likely to exert a worse effect on cognitive function.

Here, higher SFMPQ scores correlated with lower MCCB total scores in the with PPS group. Previous studies have demonstrated that cognitive function was negatively affected in chronic pain patients[41-43]; moreover, pain duration was inversely associated with cognitive performance[44,45]. Nevertheless, the interplay between pain and cognitive dysfunction remains complex and incompletely elucidated. A previous study reported that abnormal prefrontal cortex function was observed more often in individuals with chronic pain than in healthy controls; additionally, it was inversely related to pain intensity[46]. This may be explained by the shared anatomical pathways of the central nervous system, considering that gray matter volume changes in the frontal, cingulate, and insular cortex are commonly implicated in both pain-experience processing and cognitive processing[38]. Alternatively, pain catastrophizing may affect both the cognitive performance of individuals during the test and difficulties with shifting attention away from painful or threatening stimuli[47]. Overall, pain symptoms’ improvements may positively affect cognitive impairment, further enhancing MDD rehabilitation.

Here, serum KYN levels and the TRP-KYN ratio were associated with pain but not with cognition in patients with MDD. First, these positive findings corroborate those of earlier studies that found physical symptoms are influenced by the KYN pathway[48-50] and align with our previous work, suggesting that the KYN pathway may be crucial in pain pathophysiology in patients with MDD. TRP depletion and KYN accumulation appear to be important contributors to pain phenotypes and may explain the persistent reduction of serotonin levels associated with the exacerbation and persistence of chronic pain[51]. Second, the negative findings contrast the idea that KYNs may be a relevant biomarker for cognition in depression. In female subjects with MDD, the level of KYN is negatively correlated with learning function[21]; moreover, it is associated with worse overall cognition and attention at 12-month follow-up in infants with cerebral malaria[52]. Variations in population characteristics, such as inflammation state and age distribution, could account for the differences across studies. Several investigations have reported that proinflammatory cytokines decrease cognitive performance[53-55], while KYNs may simply be biomarkers withing the broader inflammatory response[56]. Additionally, evidence from other psychiatric disorders supports the role of KYNs metabolites in cognitive function[22,23,57,58]. Conversely, previous research did not account for pseudodementia; crucially, this is a reversible cognitive dysfunction caused by depression[59], distinguishing it from true neurodegenerative disease. Thus, our findings imply that the KYN pathway is implicated in the pathological mechanism of pain perception, rather than to the cognitive alterations found in depression. Potential mediating pathways, such as neuroinflammation, glutamatergic dysregulation, and oxidative stress, require further investigation[60,61].

Some limitations should be considered when interpreting these results. First, the peripheral levels of TRP-KYN pathway metabolites do not accurately reflect their concentration in the central nervous system, although substantial research found a high correlation between peripheral and cerebrospinal fluid KYN metabolites[62,63]. Second, the cross-sectional design of this study precluded causal inferences regarding temporal relationships between cognitive function and pain severity; therefore, longitudinal validation is warranted. Third, TRP metabolism is influenced by sunlight exposure and diurnal rhythms[64,65]. Future work should standardize sampling times and account for seasonal effects. Fourth, the single-site recruitment strategy and reliance on self-reported measures of pain intensity may limit generalizability, particularly across diverse cultural or environmental contexts. Finally, most findings did not survive rigorous multiple comparison correction, suggesting these preliminary associations require replication in larger, controlled cohorts. In future studies, we will employ integrated metabolomics and proteomics approaches in large-sample longitudinal studies to explore the associations between TRP-KYN pathway metabolites and cognitive function in MDD patients with PPS.

CONCLUSION

The TRP-KYN ratio and cognitive performance were associated with more severe PPS, whereas KYN levels and the TRP-KYN ratio significantly correlated with pain severity rather than cognitive deficits in depression. Therefore, the TRP-KYN ratio may be a potential biomarker for identifying patients with depression and pain symptoms; targeting it may represent a novel therapeutic strategy for managing pain in depression. Further elucidation of the biological mechanisms underlying cognitive impairment in MDD patients with PPS is warranted[66,67].

ACKNOWLEDGEMENTS

We sincerely thank all participants for their involvement in this study. We also gratefully acknowledge the contributions of our clinical and research staff for their assistance with data collection and analysis.