Schur, EA, Afari, N, Furbert, H, Olarte, M, Goldberg, J, Sullivan, PF, & Buchwald, D.
Feeling Bad in More Ways than One: Comorbidity Patterns of Medically Unexplained and Psychiatric Conditions.
Journal of General Internal Medicine. Volume 22, Number 6 / June, 2007.
Abstract
KEY WORDS primary care - fibromyalgia - chronic fatigue syndrome - back pain - depression
Clinicians have long observed that some patients are burdened with a large number of medical complaints, and the challenge of caring for these patients has been acknowledged.1 A subset of these patients has "medically unexplained" or "functional" conditions like chronic fatigue syndrome, irritable bowel syndrome, and fibromyalgia. Common psychiatric disorders such as major depression and anxiety are also frequently comorbid with these unexplained conditions but do not appear to fully explain them.2 It has been proposed that the spectrum of unexplained conditions may reflect one underlying syndrome.3
We therefore examined the associations among 9 conditions usually considered medically unexplained or psychiatric—chronic fatigue syndrome, low back pain, irritable bowel syndrome, chronic tension headache, fibromyalgia, temporomandibular joint disorder, major depression, panic attacks, and posttraumatic stress disorder—using a community-based twin registry. The goals of this study were to (a) describe the associations among these conditions, (b) use latent class analysis (LCA) to investigate complex interrelationships between these conditions, and (c) describe the demographic and clinical characteristics of individuals falling within each class identified by LCA.
All twins were participants in the University of Washington Twin Registry (UWTR), a community-based registry of twin pairs derived from applications for drivers' licenses in Washington State. The University of Washington receives lists of applicants who are twins, and each member of the pair is invited to join the UWTR and complete a health survey. Based on age and sex data for nonrespondents, registry participants are slightly younger and more likely to be female than the pool of potential twins. All UWTR procedures and the data collection involved in this study were approved by the University of Washington Institutional Review Board. Informed consent was obtained from all twins.
Nine conditions usually considered medically unexplained or psychiatric were chosen a priori for analyses. The presence of each condition was coded by the response to the question "Has your doctor ever told you that you have (specific condition)?" We chose this self-report method because diagnostic criteria for the conditions were not agreed upon or validated measures were unavailable or too lengthy for survey administration.
Demographic characteristics were self-reported. We dichotomized race, marital status, education, and general health status and calculated body mass index (BMI; weight/height2). Twins were asked about childhood similarity. Such questions classify zygosity with an accuracy of approximately 95% of that achieved with biological indicators.4
Initial analyses were conducted with SAS v9.1 (SAS Institute Inc., 2004). Odds ratios (OR) and 95% confidence intervals were calculated as measures of association among all of the conditions. For all analyses, data from each individual twin were considered separately. We used generalized estimating equations to account for the nonindependence of twins and clustering of twins within a pair. For these initial analyses, age and sex were chosen as a priori covariates in the adjusted model. Pairwise comparisons were performed only on adjusted ORs.
The sample included 1,042 monozygotic pairs, 828 dizygotic pairs, and 121 pairs of undetermined zygosity for a total of 3,982 individual twins. Of these, 3,937 had nonmissing data for all conditions and were included in the LCA. The mean age was 32.4 years (SD = 14.7); 86% were white and 61% were female.
|
| Chronic fatigue syndrome | Low back pain | Irritable bowel syndrome | Chronic tension headache | Fibromyalgia | TMJ syndrome | Major depression | Panic attacks | Posttraumatic stress disorder |
|---|---|---|---|---|---|---|---|---|---|
| Chronic fatigue syndrome | – | 4.8 (4.4–5.5) | 4.2 (2.1–8.2) | 11.5 (8.1–16.6) | 38.6 (36.1–41.2) | 4.8 (4.0–5.8) | 10.6 (6.4–17.7) | 6.0 (4.7–7.5) | 9.4 (9.3–9.5) |
| Low back pain | 4.2 (4.1–4.3) | – | 3.0 (2.5–3.5) | 2.8 (2.0–4.0) | 7.5 (6.8–8.2) | 2.4 (2.2–2.7) | 3.3 (3.1–3.5) | 2.8 (2.6–3.0) | 3.4 (3.0–3.9) |
| Irritable bowel syndrome | 3.2 (1.6–6.1) | 2.1 (1.6–2.8) | – | 2.6 (1.6–4.3) | 2.6 (1.1–5.8) | 1.5 (0.8–2.8) | 1.7 (1.1–2.6) | 1.6 (0.6–4.2) | 2.3 (1.3–4.3) |
| Chronic tension headache | 10.7 (8.0–14.1) | 2.7 (2.0–3.6) | 2.6 (1.7–3.9) | – | 6.6 (6.6–6.7) | 3.8 (3.4–4.2) | 5.1 (4.5–5.8) | 4.4 (3.8–5.0) | 5.3 (4.6–6.1) |
| Fibromyalgia | 29.1 (26.9–31.5) | 5.2 (4.4–5.9) | 1.7 (0.8–3.9) | 5.0 (4.3–5.7) | – | 10.4 (5.4–20.1) | 6.1 (5.3–6.9) | 4.2 (3.5–5.0) | 9.0 (7.6–10.8) |
| TMJ syndrome | 3.8 (3.4–4.2) | 2.1 (1.8–2.3) | 1.2 (0.6–2.3) | 3.1 (2.6–3.7) | 7.0 (3.7–13.4) | – | 4.1 (4.1–4.2) | 3.4 (2.4–4.8) | 6.6 (6.2–7.1) |
| Major depression | 9.4 (5.2–16.8) | 3.2 (2.9–3.5) | 1.6 (1.0–2.4) | 4.5 (4.2–4.9) | 4.6 (3.8–5.7) | 3.4 (3.2–3.5) | – | 14.0 (13.1–14.9) | 20.3 (19.1–21.5) |
| Panic attacks | 5.1 (4.2–6.2) | 2.5 (2.4–2.6) | 1.4 (0.5–4.2) | 3.9 (3.6–4.1) | 3.1 (2.7–3.6) | 2.7 (1.8–4.2) | 12.7 (11.2–14.4) | – | 16.6 (12.2–22.6) |
| Posttraumatic stress disorder | 7.2 (6.9–8.0) | 2.8 (2.4–3.3) | 1.6 (0.7–3.5) | 4.7 (4.5–4.9) | 6.5 (5.6–7.6) | 5.4 (4.8–5.9) | 18.8 (17.0–20.8) | 14.9 (10.8–20.5) | – |
| Item | Overall sample (N = 3,937) | Class I (2%) multiplex | Class II (8%) depression and anxiety | Class III (17%) depression | Class IV (73%) unaffected | P value* |
|---|---|---|---|---|---|---|
| Variables in latent class analysis | ||||||
| Female sex % | 61 | 89↑ | 77↑ | 86↑ | 53 | – |
| Low back pain % | 27 | 91↑ | 47↑ | 47↑ | 19 | – |
| Major depression % | 20 | 85↑ | 97↑ | 53↑ | 2 | – |
| Panic attacks % | 12 | 55↑ | 92↑ | 9 | 3 | – |
| Chronic tension headache % | 8 | 49↑ | 20 | 30↑ | 1 | – |
| Irritable bowel syndrome % | 6 | 63↑ | 16 | 18 | 0 | – |
| TMJ syndrome % | 5 | 45↑ | 10 | 18 | 1 | – |
| Posttraumatic stress disorder % | 4 | 45↑ | 31↑ | 0 | 0 | – |
| Chronic fatigue syndrome % | 2 | 61↑ | 4 | 6 | 0 | – |
| Fibromyalgia % | 2 | 61↑ | 0 | 4 | 0 | – |
| Demographic and clinical characteristics | ||||||
| Married or living with partner % | 40 | 51 | 42 | 50 | 37 | <0.001 |
| College education or more % | 57 | 63 | 56 | 62 | 56 | <0.010 |
| Health fair or poor % | 6 | 40 | 17 | 11 | 3 | <0.001 |
| Age in years, mean (SD) | 32.3 (14.7) | 35.7 (14.9) | 42.4 (12.8) | 34.9 (14.6) | 31.1 (14.6) | <0.001 |
| Psychiatric visits in past 3 months, mean (SD) and median | 0.30 (1.9) | 0.81 (2.1) | 1.4 (3.8) | 0.51 (2.2) | 0.11 (1.4) | <0.001 |
| 0 | 0 | 0 | 0 | 0 | ||
| Medical visits in past 3 months, mean (SD) and median | 1.3 (3.0) | 2.9 (4.9) | 2.6 (6.9) | 1.7 (2.6) | 1.0 (2.2) | <0.001 |
| 1 | 1 | 1 | 1 | 0 | ||
| Alternative practitioner visits in past 3 months, mean (SD) and median | 0.68 (3.7) | 2.3 (5.5) | 1.6 (7.6) | 0.81 (2.7) | 0.5 (3.1) | <0.001 |
| 0 | 0 | 0 | 0 | 0 | ||
| Total health visits in past 3 months, mean (SD) and median | 2.4 (5.5) | 6.0 (8.2) | 5.6 (11.2) | 3.1 (4.6) | 1.6 (4.5) | <0.001 |
| 1 | 3 | 2 | 1 | 1 | ||
| Body mass index, mean kg/m2 (SD) | 24.7 (5.1) | 27.5 (6.9) | 25.6 (6.4) | 25.4 (5.7) | 24.4 (4.7) | <0.001 |
| Episodes of vigorous exercise per week, mean (SD) | 1.4 (2.7) | 0.77 (1.6) | 1.1 (2.0) | 1.0 (2.0) | 1.6 (2.9) | 0.115 |
| Episodes of moderate exercise per week, mean (SD) | 2.6 (4.1) | 2.2 (3.8) | 2.9 (7.1) | 2.2 (2.6) | 2.7 (3.9) | <0.001 |
Class I (2% of sample) had markedly high proportions of individuals who reported all of the 9 syndromes. Class II (8% of sample) participants had high proportions of multiple mental health conditions including major depression, panic attacks, and posttraumatic stress disorder, and low back pain. Class III (17% of sample) participants reported high proportions of depression, low back pain, and headache. Class IV (73% of sample) had the lowest proportion of females and low probabilities for all 9 conditions. There was poor agreement between class assignments for twin pairs (Cohen's kappa = 0.1).
Demographic and clinical characteristics of each class are presented in Table 2. The results suggest differences across groups, most notably between class I and class IV. Class I individuals most often reported fair or poor general health status and had the highest mean BMI, the highest total number of health care visits, and the lowest exercise frequencies.
We found consistent patterns of comorbidity between medically unexplained conditions in a community sample of twins. Two percent of our sample had high prevalences of all 9 conditions. Although depression and anxiety also commonly co-occurred with medically unexplained conditions, twins with predominantly mental health conditions appeared to be in distinct classes. Twins with a high burden of physical and mental illness were distinguished from healthy participants by their increased health care use, worse self-reported health status, higher BMI, and lower levels of physical exertion.
Our findings support proposals that a common pathway9 or a single disease process3 may underlie these clinically defined syndromes. The recent identification of candidate genes associated with chronic fatigue syndrome10 could eventually reveal not only the physiological underpinnings of chronic fatigue, but common pathways for multiple currently unexplained syndromes.
Frequencies of medically unexplained syndromes were not markedly increased in the twins with the greatest psychiatric comorbidity and utilization of psychiatric care (class II). In contrast, the primary physical complaint was localized: low back pain. Again, localized symptoms of low back pain and headache predominated over medically unexplained syndromes in sufferers of depression alone (class III). These results concur with literature on both psychiatric comorbidity11 and the association of mental health diagnoses with back pain12 and chronic tension headache.13 The comorbidity of mental illness and localized symptoms may reflect a limited ability to cope with common symptoms like headache or back pain in individuals with depression and anxiety. In sum, we found that twins with predominantly mental illness were distinct from those with the highest burden of medically unexplained syndromes, echoing prior findings.14 For clinicians, these data reiterate the importance of screening for psychiatric conditions when painful or medically unexplained conditions are present.
This study was cross-sectional, thus limiting any conclusions about causality for the observed associations. In addition, the clinical conditions were assessed by single-item self-report of a doctor's diagnosis, which can be subject to response bias. However, our overall prevalences are comparable to available published general population rates for chronic fatigue syndrome,15 low back pain,16 fibromyalgia,17 major depression,11 panic, 18 and posttraumatic stress disorder.19 Our use of self-report data may explain the lower-than-expected overall prevalence of irritable bowel syndrome, as research suggests that a large undiagnosed symptomatic population may exist.20
In summary, this study is unique in its use of a community-based sample of twins and diverse statistical approaches to examine patterns of comorbidity for 9 conditions seen in primary care. We defined a group with multiple medically unexplained syndromes who appeared to be distinct from individuals with primarily mental health diagnoses. Clinicians may find our results helpful for several reasons. First, they suggest individuals should be screened for comorbid disorders such as posttraumatic stress disorder when depression and anxiety are present and for major depression when low back pain and chronic headache are reported. Second, our findings also help clinicians understand that distressed patients are not merely accumulating diagnoses or somatic complaints, but have a constellation of conditions that frequently coexist, analogous to metabolic syndrome. Multiple medications for symptom management alone can be minimized, focusing instead on proven behavioral strategies such as graduated exercise or cognitive behavioral therapy. Finally, research seeking unified etiologies and treatment strategies is needed. Such ground-breaking work may eventually allow clinicians to feel confidence instead of consternation when treating patients with multiple unexplained, comorbid conditions.
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