The Editor’s choice May 2024

Antonina Mikocka-Walus, JPR’s Deputy Editor

Jess Fiedorowicz, JPR’s Editor-in-Chief

“Depression as a Mediator Between Chronic Pain and Cardiovascular Disease“

Our latest Editor’s Choice “Mediating effect of depressive symptoms on the relationship of chronic pain and cardiovascular disease among Chinese population:  Evidence from the CHARLS” by Erya Miao, Qun Wu and Yi Cai of Wuhan China utilized longitudinal data to disentangle the relationship between chronic pain, depressive symptoms, and cardiovascular disease (CVD).¹  To do so, the authors analyzed >6,500 participants in the China Health and Retirement Longitudinal Study (CHARLS), a nationally represented longitudinal survey of Chinese adults age 45 and above.

The CHARLS cohort, which has been featured in other recent papers in the journal,^2-7 provides a valuable data resource to address this study’s aim to explore the correlation between chronic pain and CVD risk and examine whether depressive symptoms mediate this association.  The authors excluded from the sample those without information on pain, depressive symptoms, or CVD and those who already head CVD in 2011, the year of the baseline survey. They also excluded those missing covariates, with height and weight the most commonly missing.  This resulted in a final sample of 6,552 participants, from whom 3.4% developed CVD at the end of a two-year observation period.  Chronic pain was associated with a doubling of risk for CVD (RR 2.00, 95% CI 1.33-3.00), adjusting for age, gender, educational background, drinking, smoking, physical, activity, BMI, and hypertension.  Notably, the analysis adjusted for some CVD risk factors and not others, largely on statistical grounds when comparing those with and without CVD.  We generally encourage investigators to consider both clinical and statistical considerations in determining what variables to adjust for.^8,9  When including depressive symptoms, based on the 10-item Center for Epidemiologic Studies Depression Scale CES-D-10 score ≥10) in the model, the RR decreased to 1.67 (95% CI 1.16-2.41), leading the authors to estimate through the distribution of product method that 33% of the effect of pain on CVD was mediated through depressive symptoms. The authors conceptualized this relationship as higher levels of chronic pain leading to worse depressive symptoms, which, in turn, may lead to an increased risk of CVD.

In both the introduction and the discussion, the authors cite a Mendelian randomization study from a European sample suggesting that mental disorders (as well as smoking initiation, physical activity and BMI) serve as mediators between multi-site chronic pain and CVD.¹⁰ The study utilized data from a genome-wide association study that included 387 649 individuals from the UK Biobank and other relevant genome-wide association studies.

Their results extend this finding and they go on to discuss a putative mechanism related to chronic pain activating the sympathetic nervous system and drawing on the recent review which argued that maladaptive changes within a common neural network (involving both the sympathetic nervous system and pain perception) contribute to sympathetic overactivation and cardiovascular disease in the setting of chronic pain¹¹.  Recent research also highlights a potential role for this mechanism in mood-related CVD,¹² suggesting that perhaps both chronic pain and depression may activate this mechanism with perhaps any chronic pain-mediated depressive symptoms amplifying the signal.

The discussion by Miao and colleagues is a great example how population based observational studies can be used to test hypothesis from other study design.  These large observational studies can both test and inform hypotheses from other study designs to elucidate mechanisms.  While many discussions focus on the results of similar studies using comparable study designs, the integration of findings across study designs is particularly compelling.  We encourage others to design statistical analyses plans from large representative observations studies to test hypotheses that arise in other study designs and vice versa.  If you are inspired to do so based on this editorial, please send it our way and note this in the cover letter of your submission.  We always appreciate seeing personalized cover letters or cover letters that place the study in some context for us to understand.  The topic of how pain and depression can influence CVD has long been of interest to the journal^13,14 and we hope to see future submissions on this very topic.

REFERENCES:

1. Miao E, Wu Q, Cai Y. Mediating effect of depressive symptoms on the relationship of chronic pain and cardiovascular diseases among Chinese population: Evidence from the CHARLS. J Psychosom Res 2024;180:111639. (In eng). DOI: 10.1016/j.jpsychores.2024.111639.
2. Guo R, Yang L, Pan Y, Shen J, Zhao F. Association between threat-related adverse childhood experiences and chronic lung diseases in a middle and older aged population: A cross-sectional and longitudinal study in China. J Psychosom Res 2024;182:111692. (In eng). DOI: 10.1016/j.jpsychores.2024.111692.
3. Ni J, Yan Y, Du W, Tian Y, Fan L. Depressive symptoms, alone or together with physical comorbidity, are predictive of healthcare use and spending in older adults. J Psychosom Res 2023;174:111482. (In eng). DOI: 10.1016/j.jpsychores.2023.111482.
4. Ren X, Jiang M, Han L, Zheng X. Depressive symptoms and sleep duration in relation to chronic kidney disease: Evidence from the China health and retirement longitudinal study. J Psychosom Res 2023;174:111494. (In eng). DOI: 10.1016/j.jpsychores.2023.111494.
5. He D, Fan Y, Qiao Y, Liu S, Zheng X, Zhu J. Depressive symptom trajectories and new-onset arthritis in a middle-aged and elderly Chinese population. J Psychosom Res 2023;172:111422. (In eng). DOI: 10.1016/j.jpsychores.2023.111422.
6. An L, Ma L, Xu N, Yu B. Life satisfaction, depressive symptoms, and blood pressure in the middle-aged and older Chinese population. J Psychosom Res 2023;170:111367. (In eng). DOI: 10.1016/j.jpsychores.2023.111367.
7. Zheng X, Jiang M, Ren X, Han L, Shen S. Distinct depressive symptom trajectories are associated with incident diabetes among Chinese middle-aged and older adults: The China Health and Retirement Longitudinal Study. J Psychosom Res 2023;164:111082. (In eng). DOI: 10.1016/j.jpsychores.2022.111082.
8. Hernán MA, Hernández-Díaz S, Werler MM, Mitchell AA. Causal knowledge as a prerequisite for confounding evaluation: an application to birth defects epidemiology. Am J Epidemiol 2002;155(2):176-84. (In eng). DOI: 10.1093/aje/155.2.176.
9. Lee PH. Should we adjust for a confounder if empirical and theoretical criteria yield contradictory results? A simulation study. Sci Rep 2014;4:6085. (In eng). DOI: 10.1038/srep06085.
10. Lin L, Lin J, Qiu J, et al. Genetic liability to multi-site chronic pain increases the risk of cardiovascular disease. Br J Anaesth 2023;131(2):373-384. (In eng). DOI: 10.1016/j.bja.2023.04.020.
11. Reynolds CA, Minic Z. Chronic Pain-Associated Cardiovascular Disease: The Role of Sympathetic Nerve Activity. Int J Mol Sci 2023;24(6) (In eng). DOI: 10.3390/ijms24065378.
12. Ortiz A, Bradler K, Moorti P, et al. Increased sympathetic tone is associated with illness burden in bipolar disorder. J Affect Disord 2022;297:471-476. (In eng). DOI: 10.1016/j.jad.2021.10.089.
13. Tolmunen T, Lehto SM, Laukkanen J, Ronkainen K, Julkunen J, Kauhanen J. Somatic concerns, depressive traits, atherosclerosis and the incidence of cardiovascular disease in ageing Finnish men. J Psychosom Res 2015;79(3):207-13. (In eng). DOI: 10.1016/j.jpsychores.2015.05.006.
14. de Heer EW, Palacios JE, Adèr HJ, van Marwijk HWJ, Tylee A, van der Feltz-Cornelis CM. Chest pain, depression and anxiety in coronary heart disease: Consequence or cause? A prospective clinical study in primary care. J Psychosom Res 2020;129:109891. (In eng). DOI: 10.1016/j.jpsychores.2019.109891.