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Psychosomatic Medicine 70:192-196 (2008)
© 2008 American Psychosomatic Society

ORIGINAL ARTICLES

Depression and Anxiety in Adults With Sickle Cell Disease: The PiSCES Project

James L. Levenson, MD, Donna K. McClish, PhD, Bassam A. Dahman, BS, Viktor E. Bovbjerg, PhD, MPH, Vanessa de A. Citero, MD, Lynne T. Penberthy, MD, MPH, Imoigele P. Aisiku, MD, MSCR, John D. Roberts, MD, Susan D. Roseff, MD and Wally R. Smith, MD

From the Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia (J.L.L., D.K.M., B.A.D., L.T.P., I.P.A., J.D.R., S.D.R., W.R.S.); Department of Psychology University of Virginia, Charlottesville, Virginia (V.E.B.); and the Department of Psychiatry Universidade Federal de Sao Paulo, Sao Paulo, Brazil (V.A.C.).

Address correspondence and reprint requests to James L. Levenson, MD, Department of Psychiatry, Virginia Commonwealth University, Box 980268, Richmond, VA 23298. E-mail: jlevenson{at}mcvh-vcu.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Objective: Depression and anxiety are common in sickle cell disease (SCD) but relatively little is known about their impact on SCD adults. This study measured prevalence of depression and anxiety in SCD adults, and their effects on crisis and noncrisis pain, quality-of-life, opioid usage, and healthcare utilization.

Methods: The Pain in Sickle Cell Epidemiology Study is a prospective cohort study in 308 SCD adults. Baseline variables included demographics, genotype, laboratory data, health-related quality-of-life, depression, and anxiety. Subjects completed daily diaries for up to 6 months, reporting sickle cell pain intensity, distress, interference, whether they were in a sickle cell crisis, as well as health care and opioid utilization.

Results: Two hundred thirty-two subjects who completed at least 1 month of diaries were studied; 27.6% were depressed and 6.5% had any anxiety disorder. Depressed subjects had pain on significantly more days than nondepressed subjects (mean pain days 71.1% versus 49.6%, p < .001). When in pain on noncrisis days, depressed subjects had higher mean pain, distress from pain, and interference from pain. Both depressed and anxious subjects had poorer functioning on all eight SF-36 subscales, even after controlling for demographics, hemoglobin type, and pain. The anxious subjects had more pain, distress from pain, and interference from pain, both on noncrisis pain days and on crisis days, and used opioids more often.

Conclusions: Depression and anxiety predicted more daily pain and poorer physical and mental quality-of-life in adults with SCD, and accounted for more of the variance in all domains of quality-of-life than hemoglobin type.

Key Words: depression • anxiety • pain • sickle cell disease

Abbreviations: SCD = sickle cell disease; PiSCES = Pain in Sickle Cell Epidemiology Study; ED = emergency department; PHQ = patient health questionnaire; MOS SF-36 = Medical Outcome Study 36 item Short Form-36; MMSE = mini mental status examination.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Sickle cell disease (SCD) is an autosomal recessive genetic disorder of hemoglobin structure whose primary symptomatic manifestation is pain, particularly acute episodes of ischemic pain, referred to as "crises", thought to be due to vaso-occlusion by deformed red blood cells. Opioids remain the mainstay of treatment for SCD crises. Crises may begin within the first year of life, and generally continue throughout life. Although in 1970 the estimated median survival for subjects with SCD was just 20 years, today many with SCD are living well into adulthood (1).

Consequently, much less is known about psychosocial factors in adults with SCD than in many other chronic medical disorders, with most studies to date addressing prevalence of depression. Depression and other psychiatric disorders are indeed common in SCD (2,3). Rates of depression are similar to those found in other serious chronic medical disorders, ranging from 18% to 44% (4–7), and are increased over rates in the general population even when one controls for illness-related physical symptoms (8). In a Nigerian study, subjects with SCD had a prevalence rate of depression greater than the rate of those with cancer or malaria (but less than those with HIV/AIDS) (9).

There are many potential contributing causes to depressive symptomatology in SCD, including the chronicity of the illness, the unpredictability of crises, chronic pain, and the overwhelming nature of medical complications including anemia, fatigue, growth retardation, leg ulcers, renal failure, strokes, and substantially reduced life expectancy (8). SCD begins in childhood and may result in social derision, disability, and financial stress (10), as well as stigmatization for pseudoaddiction to opioid analgesics (11). Chronically, prescribed opioids may contribute a component of substance-induced mood disorder (3). Ehigie found that adults with SCD had lower self-esteem than those with HIV/AIDS or cancer had (9).

However, there are few adult SCD studies of the association of depression and anxiety with pain, pain response such as opioid use and health care utilization, and quality of life. Because pain is the hallmark of this disorder, understanding its relationship to depression may lead to better pain treatment interventions and outcomes. Thus, in this report, we examine the prevalence of depression and anxiety in a cohort of adults with SCD, and their association with crisis and noncrisis pain, pain-related distress and interference with their lives, quality of life, opioid usage, and health care utilization.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
The Pain in Sickle Cell Epidemiology Study (PiSCES) is a longitudinal, epidemiologic study of pain in SCD, with particular emphasis on potentially mutable etiologic, nonbiological variables. It is also a methodological study of the relationship between pain, crises, and health care utilization in SCD. The methods of PiSCES have been described in detail elsewhere (12).

We enrolled 308 subjects between July 2002 and August 2004 and collected baseline information, laboratory data and daily pain diary data for up to 6 months. Two hundred thirty-two subjects met the inclusion criteria of filling at out at least 1 month of diaries. Subjects were enrolled in both medical center and community settings, with most from the Richmond and Tidewater areas. Subjects aged 16 years and older were eligible for enrollment. The Institutional Review Board of Virginia Commonwealth University approved the study. After informed consent was obtained, subjects were screened with the mini mental status examination (MMSE) (13) to assure capacity to provide reliable data (none were excluded on this basis).

Diary Data
Filled out daily for up to 6 months, the diary asked subjects to report about the previous 24 hours: the worst sickle cell pain intensity ("how badly I hurt"), the worst distress ("how upset I felt because of pain"), and the worst interference ("How much the pain kept me from work, school, housework, family/friends"), each on a scale from zero (none) to nine(worst); whether or not they were in a sickle cell crisis, and whether they had gone for a scheduled or unscheduled physician visit, Emergency Department (ED) visit or were hospitalized due to sickle cell pain. Subjects also indicated the medications taken for sickle cell pain, and the amount of relief provided by pain medications. We calculated various summary measures from the diary for this study. Mean daily pain was calculated as the sum of the pain intensity for all diary days, divided by the total number of diary days. The mean was separately calculated on days the subject reported being in a crisis, and on days when a crisis was not reported. Similar measures were calculated for distress and interference. A pain day was defined as a day with pain greater than zero. The percent of days with utilization was calculated, with utilization defined as unscheduled clinic visits, ED visits or hospitalizations for SCD. This was also calculated separately for days with unscheduled clinic visits, ED visits, and days with hospitalizations. A sickle cell crisis episode was defined as consecutive days in which the patient marked "crisis" on the diary. Missing diary days immediately preceded and followed by a crisis were considered part of the same crisis. Pain episodes and utilization episodes were constructed similarly.

Baseline Data
Health related quality of life was assessed at baseline using the Medical Outcome Study 36 item Short Form (MOS SF-36) (14), a well-known and accepted generic measure of health related to functional status and well being. There are eight SF-36 subscales measured on a scale from 0 to 100 (with 0 being the worst and 100 the best score). The SF-36 has good reliability and validity in subjects with chronic pain (15). We have reported overall SF-36 results elsewhere (16).

Sickle cell genotype (Sβ+ thalassemia, Sβ° thalassemia, SC, and SS) is a known predictor of disease severity, health care utilization, and mortality (1). For this study, genotype was obtained either directly from the blood specimen obtained from the patient at enrollment or from the patient’s medical record. Because there were few subjects with Sβ+ thalassemia and Sβ° thalassemia, for purposes of analyses, two groups were defined. The more severe genotype grouping included SS and Sβ° thalassemia, and the less severe group included SC and Sβ+ thalassemia.

Depression and anxiety were measured using the Patient Health Questionnaire (PHQ). The PHQ is a widely utilized screening instrument based on subjects’ self-reported symptoms that was designed to facilitate the recognition and diagnosis of the most common mental disorders in primary care subjects (17). The PHQ has been found to have excellent reliability and validity across a variety of ambulatory medical populations in several different countries. Because the questionnaire relies on patient self-report, it does not generate definitive diagnoses, but is highly sensitive (18,19). There is good agreement between PHQ diagnoses and those of independent mental health professionals (17). For the purposes of this study, we combined the two depression diagnoses generated by the PHQ (major depressive syndrome, other depressive syndrome) into a single category of depression (as noted below, we also analyzed them separately and found very similar results). We similarly combined the two anxiety diagnoses (panic syndrome, other anxiety syndrome) into a single category of anxiety.

Statistical Methods
Chi-squared tests were used to compare categorical variables; t-tests were used for continuous variables and Wilcoxon rank sum test was used with ordinal variables to compare subjects included and excluded for analysis, and those with and without depression at baseline. Analysis of covariance was used to compare quality of life variables between depressed and nondepressed subjects when controlling for covariates such as genotype, pain, and variables that differed between groups at baseline. Mixed models were used to compare daily pain, distress, interference, and relief between depressed and nondepressed subjects. For binary variables representing pain days, crisis days, opiate use and health care utilization, generalized estimating equations (GEE) methods were used. The mixed model and GEE methods were used to control for the repeated measures within subject. When significant, models were refit, controlling for any demographic variables found to differ at baseline, to determine if the relationship remained significant. Analyses were repeated to compare subjects with and without anxiety. All analyses were performed using SAS Version 9.1 statistical software (SAS Institute, Cary NC).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 NOTES
 REFERENCES
 
A total of 232 subjects met the inclusion criteria of filling out at least 30 complete diaries and constitute the analysis sample. Subjects in the analysis sample were similar to those excluded for filling out an insufficient number of diaries on demographics (except for age), depression scores, whether they abused alcohol, and quality of life measures (SF-36). Subjects who did not complete sufficient diaries tended to be younger (30.2 versus 34.3, p < .01). Characteristics of the analysis sample are shown in Table 1. The mean age was 34 (16–64), 61.6% were women, and subjects were predominantly with low-income (62% earn <$20,000 annual income). None were excluded on the basis of MMSE score. For the sample as a whole, acute health care utilization for SCD pain occurred on 3.7% of diary days, whereas self-reported crises (with or without health care utilization) occurred on 14.7% of days.


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  		TABLE 1. Description of PiSCES Cohort (N = 232)

 

We found that 27.6% of subjects were designated as depressed on the PHQ (13.8% had major depression and 13.8% had other depression) and 6.5% had any anxiety disorder (3.0% had panic syndrome, 2.7% had other anxiety, and 0.9% had both). Fully 80% of those with an anxiety disorder also had depression. Depressed subjects were a little older (37.6 versus 33.0, p = .005) and more likely to be poor than those without depression (80.6% with depression versus 54.9% without depression earned <$20,000 annual income, p < .001), but did not differ on marital status, education, length of study participation, or hematologic measures (hematocrit, hemoglobin type, and white blood cell count). The percentage of depressed women was higher than the percentage of depressed men (31.5% versus 21.3%) but this fell short of significance (p = .09). The only difference in demographic or medical measures between anxious and nonanxious subjects was in income—those who were anxious were marginally somewhat poorer (p = .05).

Depressed SCD subjects did not differ on how often they were in crisis, but had pain on significantly more days than nondepressed subjects (Table 2). Depressed and nondepressed subjects did not differ in their mean pain, their mean associated distress, or their mean life interference, considering only days when they were in an SCD crisis, or considering only days when they sought urgent health care for SCD pain. However, considering only noncrisis days when they experienced pain (which constituted 40% of all days and 73% of all pain days for the whole sample), depressed and nondepressed subjects differed significantly. On these days, mean pain for depressed subjects was 16.2% higher, mean distress from pain was 32.2% higher, and mean interference with their lives was 38.6% higher. Depressed and nondepressed subjects did not differ in their opioid use at baseline, but depressed subjects used opioids more often and received less pain relief from them, although these differences lost significance after controlling for age and income.


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  		TABLE 2. Association Between Depression and Pain Variables (Means ± SD)

 

Depressed and nondepressed subjects did not differ on measures of urgent health care utilization, i.e., unscheduled clinic visits, emergency room use, or hospitalization for SCD (Table 3). The median of scheduled appointments for SCD for depressed subjects was about 50% greater than those not depressed, but this difference was no longer statistically significant after controlling for age and income (p = .09).


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  		TABLE 3. Association Between Depression and Health Care Utilization (Median Percent of Days, and Number of Subjects Who Utilized the Particular Resource)

 

Depressed subjects had significantly poorer functioning on all eight subscales of the SF-36 compared with nondepressed subjects (Table 4), with mean scores 24% to 54% lower. In regression models predicting the quality of life subscales, depression accounted for more of the variance in SF-36 scores than did hemoglobin type. Further, depression remained a significant predictor of SF-36 scores in these regressions, even after controlling for demographics, hemoglobin type, and pain measures. All of the earlier findings were similar regardless of which PHQ diagnosis of depression we used—any depressive syndrome, major depressive syndrome, or other depressive syndrome.


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  		TABLE 4. Association Between Depression and Quality of Life

 

Because 80% of the subjects with an anxiety disorder were also depressed, they mostly represented a subsample of anxious-depressed subjects. Thus results comparing subjects with anxiety disorder with those without generally followed the same pattern as depressed versus nondepressed. Exceptions were that on crisis days subjects who were anxious reported more pain (5.40 ± 1.78 versus 6.77 ± 1.65, p = .004), more distress (4.03 ± 2.17 versus 6.04 ± 2.51, p = .002), and more interference, (4.34 ± 2.23 versus 6.43 ± 2.54, p = .05). Anxious subjects used opioids more often at home (a significant difference with and without controlling for age and income). Anxious subjects also did not have significantly more scheduled doctor visits than subjects who were not anxious (Tables not shown).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
NOTES
 REFERENCES
 
We found a high (27.6%) prevalence of significant depression in adults with SCD, within the range reported by others (although direct comparison is precluded by the diversity of measures used). This rate is much higher than that reported in the general adult African-American population (20,21), but similar to that found in other chronic medical disorders like diabetes mellitus, coronary artery disease, or hepatitis C (22). Depressed SCD subjects did not differ from nondepressed subjects on how often they were in crisis or sought urgent medical care, but had pain on significantly more days. Further, on noncrisis days when they still had pain, depressed subjects’ pain, distress, and interference from pain were more intense than that of nondepressed subjects. This is consistent with the findings in studies across a wide range of painful illnesses (e.g., rheumatoid and osteoarthritis, chronic back pain, headache, diabetic neuropathy, coronary artery disease) that depression is associated with more pain, more distress, and more impairment (23,24). It must be noted however that the relationship between depression and pain is complex. Depression and pain symptoms commonly occur together, each is a risk factor for the other, and each affects clinical outcomes in the other domain (23). This study has identified associations between depression and pain variables in SCD, but it does not permit conclusions regarding to what extent depression in SCD causes more pain versus having more pain causes depression. From a clinical perspective, these possibilities both seem likely to be true. Further study with interventions directed at depression would provide answers to this unresolved issue and has the potential to positively affect quality of life for these chronically ill patients.

We found that in the PiSCES sample, depression was a more potent predictor of physical and mental health-related quality of life (as measured by the SF-36), than was genotype. This is notable since genotype is a known predictor of SCD disease severity (1). Similar results have been found in other chronic diseases. For example, in the Heart and Soul Study, depression in subjects with coronary artery disease (CAD) was associated with greater physical limitations, worse quality of life (QOL), and worse health, even after adjusting for measures of cardiac function, but left ventricular function and ischemia were not (25). Depression is a strong predictor of poorer quality of life and/or greater disability in chronic hepatitis C (26), diabetes mellitus (27), rheumatoid arthritis (28), and many other disorders (29). Systematic reviews including multiple chronic medical disorders have concluded that depression has at least as much impact, if not greater impact, on functional impairment and quality of life than objective physiologic measures (23,24).

In this cohort study, patients with high anxiety mostly represented a subsample of anxious-depressed subjects. Therefore, not surprisingly, anxiety resulted in as much or greater an impact on pain and quality of life as did depression. Compared with those with lower anxiety, the high-anxiety subjects had more days in pain, more days in crisis, and higher pain, distress, and interference both on crisis and noncrisis days. This is consistent with the finding that anxiety predicts more pain in a wide variety of other disorders, e.g., rheumatoid arthritis (30), coronary artery disease (31), diabetic neuropathy (32), and recurrent genital herpes (33). As noted earlier for depression, the results of this study demonstrate an association between anxiety and more pain, but its design does not permit conclusions about causality. As with depression, anxiety in our patients with SCD was associated with much poorer health-related quality of life, but no increase in urgent health care utilization.

In general medical populations, psychiatric comorbidity has been associated with increased health care utilization (34). Somewhat contrary to this finding, we did not find any increase in unscheduled clinic visits, ED visits, or hospitalizations associated with baseline depression or anxiety. The one exception was that depressed subjects had 50% more scheduled outpatient visits than nondepressed subjects, but this difference became nonsignificant after controlling for age and income. Since most of the utilization reported by our subjects was for SCD crises, the need for medical care during a crisis may overshadow any influence by depression or anxiety. Because we only measured utilization for SCD, we cannot determine whether psychiatrically distressed SCD patients used more health care for other reasons.

In patients with painful conditions, lower economic status has been associated with greater painful symptom burden (35), worse functional outcome (36), and difficulties in accessing care (37). Because subjects in our sample with depression were poorer than were those without depression, we considered the potential influence of economic status on the study variables. Controlling for income reduced the significance of some of the differences in pain variables, but not in quality of life. The relationship between depression, pain, and poverty is a complex one, with each having the potential of worsening the others (38). Our data do not permit conclusions regarding to what extent each of these is caused by the others.

Several other limitations of this study must be noted. Although the PHQ is considered reasonably valid as a diagnostic instrument in ambulatory medical subjects, it is based on self-report. Health care utilization and opioid use were also self-reported data. We considered the possibility of differential enrollment, diary completion, or dropout, but there was no evidence that those with more depression or anxiety were more likely to be excluded from the study, fail to fill out diaries, or drop out sooner.

In summary, depression and anxiety predicted more daily pain and poorer physical and mental quality of life in adults with SCD. Depression also accounted for more of the variance in health-related quality of life than hemoglobin type. Our findings have implications for both clinical care and for future research. Our data point out the importance of recognizing and treating anxiety and depression in adults with SCD, as in other chronic, painful illnesses. We have no data on recognition rates of depression and anxiety disorders in SCD, but they are likely under-recognized. Our findings suggest that clinicians who manage pain in SCD should routinely screen for depression and anxiety. Most of the days on which subjects reported pain were not sickle cell crisis days, and it was on those noncrisis pain days that depression seems to have significantly increased pain. This suggests that treatment interventions aimed at pain and/or depression in SCD should not focus primarily on the patients in SCD crisis who come to acute care settings.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
REFERENCES
 
The Pain in Sickle Cell Epidemiology Study was supported by NIH Grant 1R01HL064122-01.

Received for publication February 24, 2007; revision received September 23, 2007.

DOI:10.1097/PSY.0b013e31815ff5c5


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 

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Pain Management in Sickle Cell Disease: Palliative Care Begins at Birth?
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