Biol Blood Marrow Transplant xxx (2014) 1e5

American Society for BloodASBMTand Marrow Transplantation

Risk Factors for Depression in PatientsUndergoing Hematopoietic CellTransplantation

Samantha B. Artherholt 1,2, Fangxin Hong 3,4,Donna L. Berry 5,6, Jesse R. Fann 1,2,7,8,*

1Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine,Seattle, Washington2 Seattle Cancer Care Alliance, Seattle, Washington3Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston,Massachusetts4Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts5Department of Nursing and Patient Care Sevices, Dana-Farber Cancer Institute, Boston, Massachusetts6Department of Medicine, Harvard Medical School, Boston, Massachusetts7 School of Public Health and Community Medicine, University of Washington, Seattle, Washington8 Fred Hutchinson Cancer Research Center, Seattle, Washington

Article history:

Received 27 November 2013Accepted 10 March 2014

Key Words:Hematopoietic stem celltransplantationDepressionHematopoietic celltransplantationBone marrow transplantationQuality of life

Financial disclosure: See Acknowle* Correspondence and reprint

University of Washington, Box 3598195-6560.

E-mail address: fann@uw.edu (

1083-8791/$ e see front matter �http://dx.doi.org/10.1016/j.bbmt.20

a b s t r a c tDespite the prevalence and known adverse impacts of depression after hematopoietic cell transplantation(HCT), little is known about the trajectory of depression occurring after HCT, or which pretransplantation riskfactors might help predict new or worsening post-HCT depression. This secondary analysis evaluated therelationships between pre-HCT patient-reported outcomes and demographic characteristics and post-HCTdepression. A total of 228 adult HCT patients were evaluated pre-HCT (T1) and again at 6 to 7 weeks post-HCT (T2), using touch-screen computers in the transplantation clinic during participation in a larger trial.Measures evaluated included the Symptom Distress Scale, the EORTC QLQ-C30 for quality of life, a single-itempain intensity question, and the Patient Health Questionnaire 9 for measurement of depression. At T1, rates ofdepression were quite low, with only 6% of participants reporting moderate or higher depression. At T2,however, the prevalence of moderate or higher depression was 31%. We observed a strong linear relationshipin PHQ-9 scores between T1 and T2 (P < .0001). Depression score at T1 was a significant predictor ofdepression score at T2 (P ¼ .03), as was poorer emotional function at T1 (P < .01). Our results indicate thatpost-HCT depression is common, even in patients with a low pre-HCT depression score. Frequent screeningfor symptoms of depression at critical time points, including 6 to 7 weeks post-HCT, are needed in thispopulation, followed by referrals to supportive care as appropriate.

� 2014 American Society for Blood and Marrow Transplantation.

INTRODUCTIONSuccess rates for hematopoietic cell transplantation (HCT)

have continued to improve as the procedure has beenincreasingly refined [1,2]. Despite this significant progress,HCT remains an extraordinarily stressful procedure physi-cally, mentally, and emotionally [3,4]. One significant, andpotentially limiting, symptom associated with HCT isdepression. Depression is one of the most common psychi-atric conditions occurring during and after cancer treatment.The estimated prevalence of depression across cancerpatients ranges from 3% to >50%, depending on the timingandmethod used to measure the symptoms [5]. Studies haveindicated that depression is prevalent in patients undergoingHCT, with an estimated one-quarter to one-third of HCTrecipients experiencing depression during the first 100days post-transplantation or during recovery from trans-plantation [3,6-9].

Depression has many potential negative psychosocial andphysical consequences in HCT recipients. It can interfere

dgments on page 4.requests: Jesse R. Fann, MD, MPH,6560, 1959 NE Pacific St, Seattle, WA

J.R. Fann).

2014 American Society for Blood and Marrow14.03.010

significantly with quality of life; physical, social, and recre-ational activities; and overall health, and can be comorbidwith other significant concerns, such as post-traumatic stressdisorder and suicidal ideation in HCT survivors [3,10,11].Depression also can interfere with cancer treatment adher-ence and is associated with negative health behaviors, suchas tobacco and alcohol use [12,13]. Depression is well knownto be associated with increased mortality in the generalpopulation [14-16], as well as in cancer patients [17].Depression may be an independent risk factor for survivalafter HCT over and above its status as a potential indicator ofpoorer health status [7,18].

National accreditation bodies, including the NationalComprehensive Cancer Network [19] and the Commission onCancer [20], have mandated that distress screening becompleted during treatment. For patients with clinical evi-dence of moderate or severe distress, the oncology teammust “assess the psychological, behavioral, and social prob-lems.that may interfere with their ability to participatefully in their health care and manage their illness and itsconsequences” [20]. Patients must then be referred forappropriate supportive care and creation of a follow-up plan.Thus, for HCT clinicians, early identification of depression is acritical element of comprehensive HCT care, along withappropriate referrals and interventions to address symp-toms. Understanding the risk factors and clinical course of

Transplantation.

S.B. Artherholt et al. / Biol Blood Marrow Transplant xxx (2014) 1e52

depressive symptoms after HCT will help informwith whomand at what time points screening should occur [11].

The time course of depressive symptoms may varysignificantly among HCT recipients. In some, depression mayoccur before HCT and persist (or even worsen) throughoutthe course of treatment, whereas in others, depression maynot appear until weeks or months after HCT, remaininga long-term concern for patients undergoing HCT. In onestudy of HCT survivors at 1 to 3 years post-transplantation,15% reported moderate to severe depressive symptoms,with recipients of allogeneic HCT (versus recipients ofautologous HCT) and those with poorer functional statusreporting higher levels of depression [10]. Another long-termstudy of recovery post-HCT found that 19% of patientscontinued to experience depressive symptoms at 5 yearspost-HCT [6].

Despite the prevalence and known adverse impacts ofdepression after HCT, little is known about the trajectory ofdepression immediately after HCT, orwhich pretransplantationrisk factors might help predict new or worsening depressionpost-HCT. We conducted the present analysis to evaluate therelationships betweenpre-HCT patient-reported outcomes anddemographic characteristics and post-HCT depression. Vari-ables of interest included symptom distress, quality of life,demographic data, and social roles (eg, vocational status,relationship status). The purpose of the analysis is to aid cli-nicians in identifying patients who might be at high risk fordepression in the early post-HCT period, facilitating earlydetection and thus more effective intervention for thosepatients.

PATIENTS AND METHODSSample

Research participants in the larger Electronic Self-Report Asses-smenteCancer (ESRA-C) study [21], from which these data werecollected, were recruited from the Seattle Cancer Care Alliance (SCCA), aconsortium of the University of Washington Medical Center, FredHutchinson Cancer Research Center, and Seattle Children’s Hospital. TheSCCA cared for 3609 new patients in 2006, when these data werecollected, the majority of whom (85%) were from Washington state.Eligibility criteria for the analytic sample included the following: newpatients being evaluated for HCT, at least 18 years of age, able tocommunicate in English, and able to understand the study informationand provide informed consent. Participants were included irrespective ofthe presence of diagnosis or treatment of psychiatric conditions, as longas they met the criteria for HCT. Between April 2005 and November 2006,a total of 228 eligible HCT patients were enrolled in the study.

ProceduresThe methods and procedures of the ESRA-C study have been described

in detail elsewhere [21]. In brief, baseline assessments (T1) were adminis-tered via touch-screen computer at a clinic visit before the start of HCTconditioning. At the first ambulatory visit post-HCT (at 6 to 7 weeks),patients were surveyed a second time (T2) using the samemethodology. Thetechnical aspects and navigability of the ESRA-C program have beendescribed previously [22-24]. The ESRA-C has beenwell received by patients[21,25]. During the T1 session, patients were presented with an introductoryscreen, followed by demographic questions. They were then presented with4 validated questionnaires during both the T1 and T2 survey sessions:

� SymptomDistress Scale (SDS) [26]. The 13-item SDS assesses the levelof symptom distress for 11 symptoms, including nausea, appetite,insomnia, pain, fatigue, concentration, and others. Each item is scoredon a scale of 1 to 5 with descriptive options. The SDS score is the sumof all item scores.

� The European Organization for Research and Treatment of Cancer(EORTC) Quality of Life Questionnaire (QLQ)-C30, version 3 [27].The EORTC QLQ-C30 is a questionnaire developed to assess the qualityof life of cancer patients, including those undergoing HCT [28].The QLQ-C30 incorporates 9 multi-item scales, including 5 functionalscales (physical, role, cognitive, emotional and social), 3 symptomscales (fatigue, pain, nausea and vomiting), and a global health and

quality of life scale. Each subscale is a multi-item index that yields ascore of 0 to 100, with higher scores indicating better function for thefunctional scales (eg, emotional function) andmore symptoms for thesymptom scales (eg, fatigue). Emotional function questions coversuch symptoms as irritability, worry, tension, and depression.

� A single-item numerical pain intensity scale of 0 to 10, with0 indicating no pain and 10 indicating the worst pain imaginable.

� The 9-item Patient Health Questionnaire (PHQ-9) depression scale[29]. The PHQ-9 has been validated for in-person self-report orinterviewer administration, as well as for administration over thetelephone [30-33]. Standard PHQ-9 depression scores were cate-gorized as follows: none (�4), mild (5 to 9), moderate (10 to 14),moderately severe (15 to 19), and severe (�20). A score of 10 hasbeen identified as the optimal cutoff for identifying probable majordepressive disorder (sensitivity, 0.88; specificity, 0.88) in primarycare patients [29]. For analysis, we classified patients into 2 groups,“no/mild” depression (PHQ-9 total score <10) and “moderate orhigher” depression (PHQ-9 total score �10). To minimize patientburden, we used the presence of at least 1 cardinal symptom ofdepression on at least half of the days in the previous 2 weeks,either anhedonia or depressed mood, as a trigger for completingthe remaining 7 items of the PHQ-9. Initial screening in thismanner, known as the PHQ-2, has been validated in medical pop-ulations [34-36]. Participants who did not trigger the full PHQ-9were classified as having “no/mild” depression. To provide addi-tional data for distressed subjects, the full PHQ-9 was also triggeredin the case of specific responses on the QLQ-C30 (score of �50 on apossible 100 for the Emotional Function or Cognitive Functionsubscale) or SDS (score of �3 on the response range of 1 to 5 for thefear/worry, concentration, or sleep disturbance items).

AnalysisBaseline patient socioeconomic factors and quality of life measures

were compared between dropouts and those completing the study usingthe t-test for continuous variables (age) or the Fisher exact/chi-square testfor categorical variables. A generalized McNemar test was used to check forpotential pattern changes in depression between T1 and T2. Logisticregressionwas used to predict moderate or higher depression at T2, with alist of preselected baseline variables, including minority (or not), income,education, working status, computer use, partnered (or not), transplanttype, and baseline measures on the QLQ-C30, SDS, pain intensity scale, andthe PHQ-9. The factors were first checked individually, adjusting for T1depression status, and then factors with a P value <.20 were included inthe multivariable model. Backward model selection was used for variableselection, and all variables with a P value <.10 were retained in the finalmodel. Odds ratios and 2-sided P values were calculated. Analyses wereperformed with SAS version 9.2 (SAS Institute, Cary, NC) and R version2.15.0 (R Institute for Statistical Computing, Vienna, Austria).

RESULTSA total of 228 HCT recipients were enrolled in the study.

Thirty-six of the participants did not complete the assess-ment at both time points, with attrition due mainly to deathor illness; thus, the final analytic sample comprised 192participants. There were no significant differences in de-mographic characteristics between study completers andnoncompleters, although there were trends toward older age(P ¼ .06) and lower likelihood of working at T1 (P ¼ .07) innoncompleters compared with completers. However, non-completers did have significantly lower global quality of lifescores (subscale of the QLQ-C30) at T1 compared withcompleters (P ¼ .04).

Demographic and clinical characteristics of the 192study participants are shown in Table 1. The sample was59% male, and the majority were married, had 2 or moreyears of college education, and used computers at homeand/or work. Participants were predominately Caucasianand non-Hispanic/Latino (91%). The majority of partici-pants (59%) were working, on medical leave, or in school.

Changes in PHQ-9 depression categories from T1 to T2 arepresented in Table 2. At T1, rates of depressionwere low, withonly 11 participants (6%) reporting moderate or higher

Table 3Univariate Logistic Regression Predicting Moderate or Higher Depression(PHQ-9 Score �10) at T2, Adjusting for Depression Status at Baseline

T1 Predictor b Odds Ratio P Value

Male sex �0.12 0.89 .73Minority race/ethnicity* �0.97 0.38 .18Working at T1y 0.54 1.72 .12College education or more 0.58 1.78 .18Married or partnered 0.53 1.69 .19Annual income �$55,000 0.17 1.18 .63Computer userz 0.01 1.01 .98Global quality of life, EORTC QLQ-C30 �0.01 0.99 .15Physical function, EORTC QLQ-C30 �0.01 0.99 .43Role function, EORTC QLQ-C30) 0 1 .56Emotional function, EORTC QLQ-C30 �0.04 0.96 <.01Cognitive function, EORTC QLQ-C30 0 1 .66Social function, EORTC QLQ-C30 0 1 .45Fatigue, SDS 0.01 1.01 .15Nausea/vomiting, SDS 0 1 .96Pain, SDS 0 1 .94Total symptom distress, SDS 0.08 1.08 .02Allogenieic transplant 0.33 1.39 .33Impact on sexual activities and interest 0.11 1.12 .32Fever/chills �0.06 0.94 .89

PHQ-9 indicates 9-item Patient Health Questionnaire; T1, pre-HCT; EORTCEuropean Organization for Research and Treatment of Cancer; SDS, Symp-ton Distress Scale.Depression status at T1 is significantly associated with that at T2 (P< .0001).Significant predictors are in bold type.

* Defined as non-Caucasian race and/or Hispanic/Latino ethnicity, byself-report.

y Defined as working full-time, part-time, on full or partial medical leave,or student. “Not working” is defined as being unemployed or retired at T1.

z Uses a computer at least sometimes at home or work.

Table 1Baseline Demographic Data and Clinical Characteristics (n ¼ 192)

Variable Value

Age, yr, median (range) 51 (19-75)Male sex, n (%) 114 (59)Minority race/ethnicity, n (%)* 17 (9)Married or partnered, n (%) 139 (72)College education or more, n (%) 147 (77)Annual income �$55,000, n (%) 103 (54)Working at T1, n (%)y 114 (59)Computer user, n (%)z 177 (92)Cancer diagnosis, n (%)Leukemias 92 (48)Lymphomas 59 (31)Myelomas 38 (20)Other 3 (2)

Transplant type, n (%)Autologous 76 (40)Allogeneic 116 (60)

* Defined as non-Caucasian race and/or Hispanic/Latino ethnicity, byself-report.

y Defined as working full-time, part-time, on full or partial medical leave,or student. “Not working” is defined as being unemployed or fully retired.

z Uses a computer sometimes or often at home or work.

S.B. Artherholt et al. / Biol Blood Marrow Transplant xxx (2014) 1e5 3

depression. This number increased to 60 (31%) at T2, how-ever. This difference in the percentage of participants expe-riencing moderate or higher depression between T2 and T1was significant (P < .001, generalized McNemar test).

We found a strong linear relationship in PHQ-9 categoryscores between T1 and T2 (P < .0001). Results of univariateanalyses are shown in Table 3. Adjusting for T1 depressionstatus, depression at T2 was associated with pooreremotional function (P < .01) and greater symptom distress(P ¼ .02) at T1. Transplant type (autologous versus alloge-neic) was not a significant predictor of elevated depressionat T2. The prevalence of moderate or higher depression was7% (8 of 116) at T1 and 34% (40 of 116) at T2 in the allo-geneic HCT recipients, and 4% (3 of 76) at T1 and 26% (20 of76) at T2 in the autologous HCT recipients. These differ-ences were not statistically significant (P ¼ .53 at T1, P ¼ .27at T2).

The results of multivariate analyses are shown in Table 4.In multivariate analysis, T1 depression score remained asignificant predictor of depression scores at T2 (P ¼ .03), asdid poorer emotional function at T1 (P < .01); however,elevated symptom distress was no longer significant (P ¼.18)in predicting elevated depression at T2. T1 working statustrended toward significance (P ¼ .07), such that those whowere working at T1 (even if on medical leave during theirtreatment) had higher rates of depression at T2. All possible2-way interactions in the multivariate model were tested,and none were found to be significant.

Table 2Change in PHQ-9 Depression Scores from T1 to T2

T2 Total

No/mild Moderate or higher

T1No/mild 131 (68.2%) 50 (26.1%) 181 (94.3%)Moderate or higher 1 (0.5%) 10 (5.2%) 11 (5.7%)

Total 132 (68.7%) 60 (31.3%) 192 (100%)

PHQ-9 indicates 9-item Patient Health Questionnaire; T1, pre-HCT.The number of participants (with percentage of total number) meetingcriteria for no/mild and moderate or higher depression categories, based onPHQ-9 scores, is listed at each time point. Categories: no/mild depression,PHQ-9 score <10; moderate or higher depression, PHQ-9 score �10.

DISCUSSIONThis exploratory investigation adds to the growing body

of literature indicating that depression is common after HCT,and provides information to help identify patients at risk forpost-HCT depression. Although few patients (6%) met thecriteria for moderate or higher depression before HCT, nearlyone-third (31%) met the criteria for moderate or higherdepression when assessed at 6 to 7 weeks post-HCT. Manyparticipants who had elevated depression scores at T2 werenot depressed at T1, indicating that even if a patient seems tobe doing well emotionally before HCT, he or she may be atsignificant risk for post-HCT depression.

At our center, as at many others, all HCT recipients receivea comprehensive social work evaluation before undergoingtransplantation. Several factors put patients at elevated riskfor post-HCT depression, and these factors should help cli-nicians identify patients whomerit closer monitoring as theyproceed through the transplantation process. Not surpris-ingly, depression scores at T1 were strongly associated with

Table 4Multivariate Logistic Regression Predicting Moderate or Higher Depression(PHQ-9 Score �10) at T2, Adjusting for Depression Status at Baseline

T1 Predictor b Odds Ratio P Value

Moderate or higher depression(PHQ-9 score ‡10)

2.44 11.49 .03

Working at T1* 0.65 1.92 .07Emotional function, EORTC QLQ-C30 �0.034 0.96 <.01

PHQ-9 indicates 9-item Patient Health Questionnaire; T1, pre-HCT;EORTC, European Organization for Research and Treatment of Cancer.Bold text indicates significant predictors; predictors trending towardsignificance are in italics.

* Defined as working full-time, working part-time, on full or partialmedical leave, or student. “Not working” is defined as being unemployed orfully retired at T1.

S.B. Artherholt et al. / Biol Blood Marrow Transplant xxx (2014) 1e54

those at T2. Thus, patients who enter the HCT process withsymptoms of depression should be monitored closely forworsening symptoms post-HCT. Another risk factor forelevated depression at T2 was lower self-reported emotionalfunction, a subscale of the EORTC QLQ-C30, at T1. This effectwas significant even after controlling for depression scores atT1, indicating the need for clinicians to attend not only tosymptoms of depression per se, but also to other broadindicators of emotional distress before HCT, such as anxiety,tension, and irritability. Others also have identified pre-transplantation distress (usually defined as anxiety ordepression) as the strongest predictor of post-HCT anxiety ordepression [6,37].

The overall pretransplantation symptom burden wasanother predictor of post-transplantation difficulties withdepression. Elevated SDS scores were predictive of highdepression post-HCT in our univariate analysis (controllingfor baseline depression), underscoring the importance ofhelping patients cope with their myriad symptoms beforeundergoing HCT and of rescreening patients with highbaseline symptom burden for depression at 1 to 2 monthspost-HCT. The impact of symptom distress at T1 was notsignificant when analyzed in a multivariate model, however,possibly indicating that emotional distress (whichmay resultin part from symptom burden) is a stronger factor predictingfuture depression.

An interesting, albeit nonsignificant, trend noted wasthat participants with a vocational status that impliedcontinuing responsibility for this role (including those whowere working full time or part time, on full- or part-timeleave, or in school) at T1 had higher depression at T2. Onepotential explanation for this trend is that being employedor in school carries with it a set of expectations and stressthat continues into HCT, even if the patient is on leave. It ispossible that the added stress of these vocational demandscontributes to depression after HCT. Indeed, a recent study ofa non-HCT cancer sample found that work-related stress iscommon during cancer treatment, even in patients onmedical leave [38]. Patients who are working or in school insome capacity during the HCT process may require addi-tional support and strategies for managing vocational de-mands and stress in the context of diminished medical andpsychosocial reserves. This issuemerits exploration in futurestudies.

Strengths of this study include the use of reliable andvalidated self-reporting instruments at 2 time points in awell-established HCT program. Thus, we were able to iden-tify several pretransplantation predictors associated withdepression at T2. Nonetheless, the relative weakness of theassociations that we found suggests that other predisposingand precipitating factors may contribute to depression post-HCT. The time course of depression symptoms from T1 to T2likely reflects the uniqueness of HCT compared with othercancer treatments. Given the eligibility criteria for trans-plantation, it is possible that HCT recipients report that theyare more optimistic and hopeful at baseline (ie, beforetransplantation) than other patients starting cancer treat-ment, who are often extremely distressed after receivingtheir diagnosis and before starting their initial treatments[8]. In addition, our T2 assessment was done at 6 to 7 weekspost-HCT, the time when most patients are discharged fromthe hospital and have had several weeks to recover fromdeconditioning and other lingering acute symptoms, therebyminimizing the direct effects of acute hospitalization ondepressive symptoms. In many cases, however, adverse

physical symptoms are still present at 6 to 7 weeks post-HCT,and these symptoms might have affected self-reports ofmood. Future studies should examine the course and longi-tudinal predictors of depression at additional post-HCT timepoints. In our analysis, transplant type (allogeneic versusautologous) was not predictive of post-HCT depression, butthis variable warrants more thorough evaluation in futurestudies, given that these 2 groups of HCT recipients can havesignificantly different post-transplantation medical courses.

An additional strength of this study is the electroniccollection of data via touch-screen computers. The majorityof our participants were familiar with computers. Previousstudies have shown that measurement of depression andsymptom distress with touch screen computers is feasibleand reliable [8]. Moreover, computer-administered symptomscreens are clinically useful, readily providing real-timescores and symptom information to clinicians, who canthen discuss it with patients in a timely manner [21]. Ourdata were collected only via computer, however, and ourfindings should be replicated in populations less well-acquainted with this modality.

The participants in this study were relatively well-educated and affluent, and predominantly Caucasian andnon-Hispanic/Latino. It is possible that samples of morediverse groups might have differing rates of, and risk factorsfor, post-HCT depression. Future studies should addressthese concerns. Finally, there are broad knowledge gaps interms of the effectiveness of brief interventions to addressdepression and enhance coping that can be implemented inthe HCT setting.

Organizations such as the American College of SurgeonsCommission on Cancer [20] mandate screening for distress(including depression, anxiety, and other psychosocial diffi-culties) at least once for all patients treated at participatingcancer centers. However, our findings suggest that screeningfor distress just once pretransplantation may be insufficient,and that 6 to 7 weeks post-HCT may be an importantassessment point. This study and others have demonstratedthat depression screening is feasible and accepted by bothpatients and medical providers in a busy HCT clinic setting[8,11]. Our findings underscore the importance of assessingemotional distress in HCT clinics at multiple time pointsduring the course of treatment. Periodic depressionscreening at pivotal points along the trajectory of treatmentand recovery provides opportunities for earlier referral andintervention for those patients who are either alreadyexperiencing depressive symptoms or at risk for developingdepression. Proactive efforts to manage depression in HCTrecipients may improve their overall recovery and post-transplantation quality of life.

ACKNOWLEDGMENTSThe authors thank Barbara Halpenny, project director, and

Rosemary Ford, transplant clinic nurse manager, for theirassistance with this project.

Financial disclosure: This workwas funded by the NationalInstitute of Nursing Research (Grant R01 NR008726).

Conflict of interest statement: There are no conflicts ofinterest to report.

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