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. Author manuscript; available in PMC: 2022 Dec 1.
Published in final edited form as: Aging Ment Health. 2020 Dec 7;25(12):2272–2278. doi: 10.1080/13607863.2020.1855626

A longitudinal analysis of the relationships between depression, fatigue, and pain in patients with heart failure

Julia L Sheffler 1, Sarah J Schmiege 2, Joleen Sussman 3, David B Bekelman 4
PMCID: PMC8796211  NIHMSID: NIHMS1766848  PMID: 33287562

Depression and chronic pain frequently co-occur, and both conditions are associated with lower quality of life and greater healthcare usage across the lifespan (Bair, Robinson, Katon, & Kroenke, 2003; Bernfort, Gerdle, Rahmqvist, Husberg, & Levin, 2015; Wu et al., 2015). These comorbid symptoms are especially common in older patients with heart failure (Conley, Feder, & Redeker, 2015). A review of the literature demonstrated the mean prevalence of pain symptoms for people with depression to be 65% and similar rates of comorbidity for symptoms of depression among pain patients (Bair et al., 2003; Li, 2015). This high comorbidity often complicates treatment of both disorders leading to poorer outcomes for patients (Emptage, Sturm, & Robinson, 2005; Tunks, Crook, & Weir, 2008). Conley and colleagues suggest that interventions targeted at depression, fatigue, and pain, specifically, may improve daily functioning in individuals with heart failure (Conley et al., 2015); however, cross-sectional studies of this type do not provide clarity on which symptoms may yield the most benefit as targets of intervention. The current study longitudinally examined the relationships between depression, fatigue, and pain in individuals with heart failure in order to clarify mechanisms that may inform treatment.

Competing Models of Depression and Pain

The relationship between pain and depression is complex, with many conflicting findings on the direction of the relationship. Some researchers have demonstrated that chronic pain increases the likelihood of developing depression through multiple pathways (see Barthas et al., 2015; Fishbain, Cutler, Rosomoff, & Rosomoff, 1997); however, there is also substantial research that depression is an antecedent risk factor for the onset and worsening of pain symptoms (Phyomaung et al., 2014; Pinheiro et al., 2015). Further, there is evidence that the presence of depression worsens the experience of pain in chronic conditions (Fifield, Tennen, Reisine, & McQuillan, 1998) and may predict pain-related disability (Lerman, Rudich, Brill, Shalev, & Shahar, 2015). In a review, Bair and colleagues (2003) summarize that pain is a common and unrecognized symptom of depression, while acknowledging that chronic pain may increase depressive symptoms and complicate the treatment of depression. Longitudinal designs have also found support for this hypothesis (Kroenke et al., 2011). For example, Geerlings and colleagues demonstrated a reciprocal relationship between pain and depression across a three-year span (Geerlings, Twisk, Beekman, Deeg, & van Tilburg, 2002). Li (2015) states that, “both conditions often co-occur, share some similar symptoms, and exacerbate one another” (p. 9). Given the ambiguity in the literature, the current study sought to assess the potentially bidirectional relationship between depression and pain using a longitudinal design.

The Role of Fatigue

Both depression and pain are associated with increased fatigue, which may be a common symptom or a potential pathway between pain and depression. For example, one study demonstrated that patients with higher levels of depression symptoms reported more fatigue, functional disability, and higher levels of pain than individuals with lower levels of depression (Fifield et al., 1998). Another study found that pain was associated with subsequent depression through its influence on fatigue (Hawker et al., 2011). Fatigue has also been found to act as an independent predictor of pain (Boggero, Rojas-Ramirez, & Carlson, 2017). Biologically, fatigue is often found to cluster with both depression and pain, which may be due to pro-inflammatory processes shared by both disorders (Bower et al., 2000; Jaremka et al., 2013; Ji et al., 2017; Motl & McAuley, 2009; Thornton, Andersen, & Blakely, 2010). Psychosocially, as a symptom of depression, fatigue carries the potential to negatively influence activities that might be beneficial to individuals with pain symptoms. Similarly, fatigue due to frequent or chronic pain may reduce important social and physical activities thereby increasing risk for depression. Thus, fatigue’s potential to act as a psychosocial pathway between depression and pain warrants further investigation. Understanding the role of fatigue may provide additional insight into the types of interventions most likely to benefit patients with depression and pain.

Pain, Depression, and Heart Failure

Examination of these relationships is especially important in the context of serious age-related illnesses such as heart failure. Depression and pain are both common and frequently comorbid symptoms in patients with heart failure and are associated with diminished quality of life and greater functional impairment (Conley et al., 2015). Depression, in particular, may be an especially important factor in this population. For example, there is strong epidemiological evidence that depression increases the risk of cardiovascular morbidity and mortality through its influence on both biological (e.g., inflammation) and lifestyle factors (e.g., physical inactivity; Penninx, 2017). For patients with heart failure specifically, depression is associated with a higher symptom burden, including lack of energy and non-cardiac pain (Haedtke et al., 2019). This literature suggests that depression in heart failure patients may be an initial causative factor in worsening fatigue and physical activity, as well as the perception of pain in this population. However, given the bidirectional relationships observed between pain and depression in previous literature, it is important to closely examine the directionality of these relationships in heart failure patients as a potentially distinct sample. Further, fatigue is a prevalent symptom of heart failure that is also known to be associated with worse pain symptomatology (Boggero et al., 2017). Thus, it is possible that depression may worsen both fatigue and pain symptoms directly, while also indirectly influencing pain through fatigue. We assessed these direct and mediating pathways longitudinally in a clinical sample of patients with heart failure.

Hypotheses

We conducted a secondary data analysis of longitudinal assessments of depression, pain, and fatigue in individuals with heart failure. Based on the existing literature, we hypothesized the following:

  • H1: Baseline depression will be associated with new onset of pain symptoms.

  • H2: Baseline pain will be associated with new onset of depression symptoms.

  • H3: Fatigue will be associated with a) subsequent pain symptoms, and b) fatigue may explain the relationship between depression and pain.

Methods

This study used data from a NIH-funded randomized controlled trial that compared a Collaborative Care to Alleviate Symptoms and Adjust to Illness (CASA) intervention to usual care in three (urban safety net, Veterans Affairs (VA), and academic-affiliated) health systems. The methods and primary trial outcomes have been previously reported (Bekelman et al., 2016, Bekelman et al., 2018).

Population

Patients with chronic heart failure were identified through study sites’ electronic health records. During the study screening process, patients who were symptomatic and reported reduced heart failure-specific health status were targeted for enrollment. Patients with active substance abuse, dementia, schizophrenia, or bipolar affective disorder were excluded.

Measures

Demographics (baseline).

Participants reported their age, sex, and education level (1=Less than high school graduate, 2=High school graduate or GED, 3=Some college, 4=College graduate, 5=Any post-graduate work). These variables were included in all models as covariates.

Depression (baseline, 6-months, and 12-months).

The Patient Health Questionnaire(PHQ-9; Kroenke, Spitzer, & Williams, 2001) was used to assess depressive symptoms in the sample. This self-report scale has been well-validated in clinical settings and is designed to assess the core symptoms of Major Depressive Disorder. Depressive symptoms were analyzed as a continuous variable, summing the numbers corresponding with symptom severity.

Fatigue (6 months).

The Patient-Reported Outcomes Measure Information System Short Form 8a was used to measure fatigue (range, 0–40; higher score indicates more fatigue; Cella et al., 2010). The 6-month assessment of fatigue was chosen to establish temporal precedence in fatigue’s role as a mediator, as this served as the middle point between baseline and follow-up.

Pain (baseline and 12 months).

The PEG (Krebs et al., 2009), which consists of three items derived from the Brief Pain Inventory were used to measure pain intensity (P), interference with enjoyment of life (E), and interference with general activity (G). Items were rated 1–10 and summed, then averaged, resulting in a range of 0–10, with higher scores indicating higher pain and interference with life.

Statistical Analyses

Preliminary analysis of demographics and sample characteristics were performed. Criterion and predictor variables were analyzed to ensure their conformation to the basic assumptions of a regression analysis. Missing data was addressed using the full-information maximum-likelihood approach in Mplus (version 7.11)(version 7.11; Muthén & Muthén, 2012), which is a recommended approach to account for data that are missing at random in path analytic models (Wu et al., 2015). The sample was collapsed across conditions, and study arm was included as a covariate in all analyses. The full-information maximum-likelihood approach generates an estimated covariance matrix of missing data points. Preliminary analyses and descriptive statistics were completed using SPSS 25, while all path analytic and mediation models were estimated using Mplus.

We first examined the direct effects of baseline depression on new onset pain symptoms 12-months later, and baseline pain on new onset depression symptoms at 12-months. Next, we used bootstrapped mediation in Mplus to examine the bidirectional models of pain and depression, with fatigue (6-months) as a mediator. For both outcomes (depression and pain measured at 12-months), baseline covariates included age, sex, education level, arm of study, and baseline levels of the outcome variable (i.e., pain or depression). Fatigue at 6-months was assessed as a potential mediator between baseline depression and new onset pain symptoms and of baseline pain on new onset depression. The path analytic framework allows both indirect paths to be analyzed simultaneously in order to account for the covariance between outcomes. Of note, given that the PHQ-9 includes an item assessing fatigue, we analyzed models including and excluding this item. We also assessed models including history of depression diagnosis as a covariate. There were no significant differences in the mediation findings between these models; thus, we included all PHQ-9 items in the reported results to maintain construct validity and excluded history of depression diagnosis to reduce multicollinearity.

Results

See Table 1 for full descriptive characteristics of the sample. Briefly, the majority of the population was Caucasian (71.8%) and male (78.5%) and there was diversity in education and income. See Table 2 for correlations between variables in the path analysis/mediation models.

Table 1.

Demographic characteristics of the full sample.

Collapsed Across Intervention Arm
N M (SD) Percent
Age 317 65.38(11.22) -
Sex (male) 249 - 78.5
Race (Caucasian) 227 - 71.8
Income:
 Less than or equal to $20,000 131 - 43.4
 $20,001–$40,000 75 - 24.8
 $40,001–$60,000 56 - 18.5
 More than $60,000 40 - 13.3
Education:
 Less than high school diploma 19 - 6.0
 High school graduate or GED 77 - 24.4
 Some College 122 - 38.6
 College graduate 56 - 17.7
 Post-graduate education 42 - 13.3
PHQ-9 baseline 310 9.90 (5.88) -
PHQ-9 6-month 240 8.33 (5.67) -
PHQ-9 12-month 222 7.89 (5.81) -
Fatigue (baseline) - -
Fatigue (6-month) 245 16.60 (8.56) -
Fatigue (12-month) - -
Pain (baseline) 316 4.78 (2.86) -
Pain (6-month) - -
Pain (12-month) 223 4.28 (2.80) -
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Note. Pain (range=0–10); PHQ-9 (depression; range=0–27); Fatigue (range=8–40).

Table 2.

Cotrrelations of variables in regression analyses.

1. Age 2. Sex 3. Education 4. PHQ (baseline) 5. PHQ (12-month) 6. Fatigue (6-month) 7. Pain (baseline) 8. Pain (12-month)
1 1 −.160** .158** −.348** −.253** −.190** −.246** −.221**
2 1 −.087 .068 .072 .074 .110 .097
3 1 −.160** −.130 −.074 −.284** −.132
4 1 .715** .476** .448** .401**
5 1 .513** .340** .437**
6 1 .282** .412**
7 1 .676**
8 1
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Note:

**

p<.001

sex (1=male, 2=female); education (1=Less than high school graduate, 2=High school graduate or GED, 3=Some college, 4=College graduate, 5=Any post-graduate work); PHQ=Patient Health Questionnaire 9.

Depression-Pain Relationship (Hypotheses 1 & 2)

To assess our first hypothesis, the direct effects between depression and pain were examined, excluding fatigue from the model. Baseline depressive symptoms were significantly associated with new onset of pain symptoms (b=.062, SE=.029, p=.036) when baseline pain was included in the model. Inconsistent with our second hypothesis, however, baseline pain was not associated with new onset of depressive symptoms (b=.054, SE=.108 p=.614) after accounting for baseline depressive symptoms.

The Role of Fatigue (Hypothesis 3)

Next, we examined the direct effects within the full mediation model (Figure 1). Baseline depressive symptoms were associated with fatigue at 6-months (b=.693, SE=.091, p<.001), while baseline pain was not associated with later fatigue (b=.232, SE=.210, p=.269). Consistent with Hypothesis 3a, fatigue was also associated with new onset of pain symptoms (b=.065, SE=.022, p=.003), as well as new onset of depressive symptoms (b=.148, SE=.039, p<.001). Thus, the direct effects demonstrate that only baseline depression is associated with fatigue, but fatigue is associated with both new onset of pain and depressive symptoms.

Figure 1.

Figure 1.

Open in a new tab

Only significant pathways are shown, including unstandardized betas (standard error).

Fatigue as a Mediator.

To complete our assessment of Hypothesis 3b, we examined a mediation model using baseline depression to predict pain symptoms at 12-months and assessed whether 6-month fatigue symptoms accounted for this relationship. In this model, the indirect effect of depression on new onset of pain symptoms through fatigue was significant (b=.045, SE=.017, p=.008). Thus, fatigue at 6-months mediated the relationship between baseline depression and new onset of pain symptoms after 12-months.

Though there was not a direct effect of pain on later depressive symptoms, as a final step, we assessed whether there was an indirect effect of pain on later depressive symptoms through fatigue (Hypothesis 3b). The indirect effect was non-significant (b=.034, SE=.034, p=.318). Thus, when baseline pain is accounted for across models, pain does not appear to predict depressive symptoms in any of our models.

Discussion

This longitudinal study found that depression was associated with new onset of pain symptoms, while pain did not predict new onset of depressive symptoms or fatigue. Further, using a model of the indirect effect, we found that the relationship between depression and the development of later pain symptoms was accounted for by fatigue symptoms. These findings have implications for understanding the directionality of the depression-pain relationship, as well as for the potential treatment of depression and pain in in the context of heart failure.

Pain, Depression, and Fatigue

Based on prior research demonstrating conflicting results regarding the direction of effect between depression and pain (Fishbain et al., 1997; Phyomaung et al., 2014; Pinheiro et al., 2015), we hypothesized the potential for bidirectionality in these relationships. However, the bidirectionality of the relationship between depression and pain was not demonstrated in the current sample. Instead, we found that once baseline levels of depression and pain were included in the models, only depression was associated with the development of later pain symptoms; pain was not associated with the development of later depression.

This finding is consistent with review studies conducted in the context of other chronic conditions (Phyomaung et al., 2014; Pinheiro et al., 2015), but were inconsistent with an older, large review paper (see Fishbain et al., 1997). One possibility is that many of the articles comprising the older review consisted of cross-sectional comparisons between those with and without chronic pain in more general populations (Fishbain et al., 1997), while our study was able to assess these relationships longitudinally in a specific population – patients with heart failure. Prior work conducted specifically among patients with heart failure observed cross-sectional associations among pain, depression, and fatigue (Conley et al., 2015; C. Haedtke, Smith, VanBuren, Klein, & Turvey, 2017), and a prospective cohort study among those with advanced heart failure observed differences in chest pain and fatigue among those with depression (Sullivan, Levy, Russo, & Spertus, 2004). Further, depression is especially common among individuals with heart failure and associated with multiple adverse outcomes in this population, although it is often underdiagnosed and undertreated (Celano, Villegas, Albanese, Gaggin, & Huffman, 2018). Thus, the link and direction of the relationship between depression and pain may be especially important in this population.

Fatigue has been well-recognized as related to both depression and pain (Conley et al., 2015; Fifield et al., 1998; Hawker et al., 2011). In our analyses, fatigue predicted both later pain and later depression, and fully accounted for the relationship between depression and later pain symptoms. These analyses demonstrate that fatigue is an important mechanism through which depression influences pain. Depression is commonly associated with feelings of exhaustion (i.e., fatigue) that reduce motivation and physical activity. It is possible that this fatigue resulting from depression may then further inhibit physical activities and exercise that may be beneficial in mitigating pain symptoms. In fact, fatigue is known to contribute to reduced physical activity in older individuals (Egerton Chstin, Stensvold, & Helbostad, 2015). This concept is key in psychological models of chronic pain, which emphasize the importance of reducing pain behaviors, such as avoidance of physical activity(McCracken & Morley, 2014). Fatigue, especially fatigue related to depression, may exacerbate pain behaviors and undermine cognitive motivation as well. Though this explanation could not be explicitly tested in the current dataset, this represents a potential testable mechanism for future research.

Overall, these findings have significant implications for individuals with heart failure, who may be especially vulnerable to the negative effects of pain. For example, pain is consistently related to poorer quality of life (Niv & Kreitler, 2001) and higher usage of pain medications such as opioids. For individuals with heart failure, pain medications may further impact heart functioning (Gislason, et al., 2009); while lower quality of life may be further exacerbated by other heart failure symptoms (While & Kiek, 2009). Given the already growing shift in health care to identify alternative treatments to opioids, our findings suggest that interventions targeting depression and fatigue may provide an indirect pathway to reduce pain in patients with heart failure. Recent reviews suggest that cognitive behavior therapy and selective serotonin reuptake inhibitors are safe and may improve mental health outcomes for individuals with heart failure (Celano et al., 2018).

Limitations

There are some limitations of the study. First, the sample was mostly white males and therefore may not generalize to primarily female or more diverse populations. It is notable, however, that white males have the highest rates of heart failure, and thus the current sample is generally reflective of the heart failure population (Benjamin et al., 2019). Next, Depressive symptoms measured using the PHQ-9 may be related to other mood disorders or no psychiatric diagnosis. Further, the general levels of depression and pain were relatively mild in this sample, and thus it is possible that these relationships may differ in populations with more severe symptoms. There was missing data at 6- and 12- months due to death and drop-out, similar to other studies of seriously ill patients (Rogers et al., 2017; Zimmermann et al., 2014). The primary analyses were collected in the context of an intervention and therefore did not reflect observational longitudinal data; however, the current analyses adjusted for intervention condition, and prior analyses showed the intervention did not impact pain symptoms at 12-months (Bekelman et al., 2018), lending support to the role of baseline depression in predicting later pain.

Future Directions

Future research directions include increasing our understanding the biological or psychological mechanisms underlying the indirect effects observed in this study. While it was not possible to determine why fatigue accounted for the relationship between depression and pain, future research should examine whether the sequelae of fatigue (e.g., activity reduction) explains such mechanisms. Comprehensive models should account for the biological, cognitive, and behavioral components of depression and fatigue. Inclusion of these factors may help isolate specific mechanisms linking depression, fatigue, and pain and increase the feasibility of a precision medicine approach in this population. Our results also provide support that interventions that focus specifically on depression (e.g., psychotherapy or SSRI medications) or fatigue (e.g., through behavioral activation) may reduce pain symptoms in individuals with heart failure, which is consistent with psychological models of pain for other conditions (McCracken & Morley, 2014). Future studies could examine whether these effects depend on severity of depression (adjustment disorder vs. major depressive disorder) or on other medical illnesses. Given the importance of reducing pain and pain medications for individuals with heart failure (e.g., non-steroidal anti-inflammatory medications and opioids), assessing psychological interventions targeting pain through depression and fatigue in this population may be a valuable direction for future research.

Conclusions

In sum, our findings provide a clearer understanding of the direction between depression and pain symptoms in the context of heart failure. Specifically, depression is a risk factor for later pain symptoms, and this relationship is largely accounted for by fatigue. These findings demonstrate that depression and fatigue may be key to reducing pain symptoms in this population. Because depression, fatigue, and pain are such common symptoms among individuals with heart failure, our findings may provide an important step towards improving the precision of interventions in this population.

Funding:

This work was supported by the National Institute of Nursing Research [NIH R01-013422]; NIH/NCATS Colorado CTSA [UL1 TR001082]; and the Department of Veterans Affairs, Rocky Mountain Regional VA Medical Center. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the National Institutes of Health, the Department of Veterans Affairs or the United States government.

Contributor Information

Julia L. Sheffler, Florida State University

Sarah J. Schmiege, University of Colorado

Joleen Sussman, Rocky Mountain Regional VAMC

David B. Bekelman, Rocky Mountain Regional VAMC

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