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© 2003 American Society for Clinical Oncology Differential Effects of Paroxetine on Fatigue and Depression: A Randomized, Double-Blind Trial From the University of Rochester Cancer Center Community Clinical Oncology Program
From the James P. Wilmot Cancer Center and the Department of Biostatistics, University of Rochester Medical Center, Rochester, NY; the Department of Physiology, St. George’s Hospital Medical School, London, United Kingdom; and the member sites of the University of Rochester Cancer Center Community Clinical Oncology Program Research Base. Address reprint requests to Gary R. Morrow, PhD, University of Rochester Cancer Center, 601 Elmwood Ave, Box 704, Rochester, NY 14642; e-mail: gary_morrow{at}urmc.rochester.edu.
Purpose: Fatigue and depression typically occur together in cancer patients, suggesting a common etiology, perhaps based on serotonin. This randomized clinical trial tested whether paroxetine, a selective serotonin reuptake inhibitor antidepressant known to modulate brain serotonin, would reduce fatigue in cancer patients and whether any reduction was related to depression. Patients and Methods: Cancer patients undergoing chemotherapy for the first time were assessed for fatigue. Of 704 patients who reported fatigue at their second chemotherapy cycle, 549 patients were randomly assigned to receive either 20 mg of oral paroxetine hydrochloride daily or placebo for 8 weeks. The assessments of fatigue and depression were performed at cycles 3 and 4 of chemotherapy. Results: A total of 244 patients treated with paroxetine and 235 patients treated with placebo provided assessable data. No difference was detected in fatigue between patient groups. At the end of the study, there was a difference between groups in the mean level of depression (Center for Epidemiologic Studies Depression scores, 12.0 v 14.8, respectively; P < .01). Conclusion: Paroxetine had no influence on fatigue in patients receiving chemotherapy. A possible explanation is that cancer-related fatigue does not involve a reduction in brain 5-HT levels.
CANCER-RELATED FATIGUE is a subjective experience with a clearly detrimental effect on a cancer patient’s quality of life and ability to sustain usual and desired personal, professional, and social relationships.1,2 Fatigue is among the most commonly reported side effects of cancer treatment and occurs in more than 80% of patients treated for cancer.3,4 Patients with cancer often describe their fatigue as pervasive, unusual, excessive, involving the whole body, disproportionate or unrelated to activity or exertion, and usually not relieved by rest or sleep.5 In contrast, fatigue induced by sleep disturbance6 or exertion7 is typically alleviated by rest. Although researchers have speculated about the nature and causes of cancer-related fatigue, there has been little systematic research on its etiology or treatment. Cancer patients frequently report that their fatigue begins with treatment, continues during the course of chemotherapy or radiation treatment, and then declines somewhat but remains at a higher-than-baseline rate after treatment has ended.8–10 Fatigue may persist for several years, even in patients with no apparent disease.11 Symptoms of depression are also common in cancer patients undergoing chemotherapy and have been reported by 40% to 82% of patients in various studies.11–13 Fatigue and depression frequently coexist in the same patient, and many studies have found a significant positive correlation between depression and treatment-induced fatigue.8,14,15 The consistent finding of a close association between depression and fatigue has led to the suggestion that there may be a common mechanism for their development.16 However, no study published to date has shown a causal relationship between depression and fatigue, and to our knowledge, no studies have examined the effect of an antidepressant on cancer-related fatigue.3,17 To test the hypothesis that administering the antidepressant medication paroxetine hydrochloride (Paxil, GlaxoSmithKline, Research Triangle Park, NC) during chemotherapy treatment would lead to a reduction in patient fatigue, we conducted a randomized, double-blind, placebo-controlled clinical trial including cancer patients studied during four successive chemotherapy treatments in community medical oncology practices. Paroxetine was selected because of the body of evidence implicating changes in brain 5-hydroxytryptamine (5-HT) in the pathogenesis of both depression18,19 and fatigue.20 (See review by Andrews and Morrow17.) Secondary aims included investigating whether the effectiveness of paroxetine on fatigue was related to the presence or absence of depression and describing the occurrence and severity of fatigue throughout the course of patients’ participation in the study.
Patients Study participants were patients at 18 oncology private-practice groups in the United States that were grantees of the National Cancer Institute’s Community Clinical Oncology Program (CCOP). The trial reported here was developed and managed by the University of Rochester Cancer Center CCOP Research Base. Patients were enrolled between June 23, 1997, and April 19, 1999. Adult patients at least 18 years old with a diagnosis of any type of cancer were potentially eligible if they were scheduled to begin the first of at least four cycles of chemotherapy without concurrent radiation therapy or interferon treatment. Patients taking psychotropic medications, monoamine oxidase inhibitors, tryptophan or warfarin for therapeutic anticoagulation; those with a history of mania or seizures; and those who reported having been hospitalized for any psychiatric condition were ineligible. Lorazepam, given once immediately before chemotherapy infusion to reduce anxiety, was allowed, as was low-dose warfarin given for maintenance of venous access devices. The Institutional Review Board of the University of Rochester and that of each participating site approved the protocol in accordance with an assurance filed with and approved by the United States Department of Health and Human Services. Written informed consent was obtained from each study participant.
Design and Procedures
Study medication (a 30-day supply of blinded paroxetine 20 mg or an identical appearing placebo) was sent immediately to each eligible patient by mail with instructions to begin taking one tablet daily by mouth in the morning no later than day 10 of cycle 2. A follow-up phone call by the study nurse before day 10 confirmed receipt of study medication and materials and provided an opportunity for any additional questions to be answered. Patients received a second 30-day supply of study medication at their third chemotherapy cycle. They completed the same packet of assessment forms after chemotherapy treatments 3 and 4 (outcome assessments) and received a telephoned reminder to complete the forms and return them by mail between days 5 and 7 of both cycles. Patients stopped taking study medication (paroxetine or placebo) after day 7 of chemotherapy cycle 4. Figure 1
Assessments Assessments completed at cycle 2 were used as baseline data, and assessments from treatment cycles 3 and 4 were used as outcome data. Change in fatigue between baseline and the seventh day after cycle 4 was the primary study outcome. Three measures were used to assess fatigue: the total score of the Fatigue Symptom Checklist (FSCL),22 the MAF,23 and the Monopolar Profile of Mood States (POMS) Short Form Fatigue/Inertia (F/I) subscale.24 The FSCL22,25 is a 30-item Likert-type scale in which the presence and intensity of each item is indicated on a 5-point scale wherein 1 is "absence of" and 5 is "a great deal." Both the number and intensity of symptoms can be calculated for the scale as a whole; subscale scores can also be calculated. Reliabilities for the total FSCL score range from 0.92 to 0.94. The MAF23 has 16 questions, 14 of which are semantic rating scales anchored by 1 for "not at all" and 10 for "a great deal." Four dimensions of fatigue (severity, distress, interference with activities of daily living, and timing) can be assessed. An internal consistency of 0.93 has been shown in 133 medically ill subjects, and convergent and divergent validity have also been demonstrated.26,27 The Fatigue/Inertia (F/I) subscale of the Monopolar POMS Short Form consists of five items. Reliability ranging from 0.86 to 0.95 has been reported in six population samples.24
Depression was assessed using the total score of the Center for Epidemiological Studies Depression (CES-D) scale 28 and the Depression-Dejection (DD) subscale score of the POMS.24 The CES-D scale was initially developed for use in the general population, and a score of 16 or greater was used to indicate the presence of significant depressive symptoms.28 In this sample of medically ill patients, we used a more conservative cutoff score of 19, as suggested by Turk and Okifuji,29 who reported a sensitivity of 0.82, a specificity of 0.62, a positive predictive value of 0.68, and a negative predictive value of 0.78 for this cut point in diagnosing depression in medically ill patients. The CES-D scale has also shown good internal consistency (
Analysis
The Data analysis was limited to patients who provided complete data. Outcome measures at the final assessment (after chemotherapy cycle 4) were missing for 23 of the patients randomly assigned to paroxetine and 20 of the patients randomly assigned to placebo, and the corresponding value at the third assessment (cycle 3) was used in its place.
A total of 902 patients at the 18 CCOP sites met initial medical eligibility requirements. Of these, 704 patients (78%) completed baseline (cycle 2) questionnaires and 198 patients (22%) did not continue on study because they were no longer medically eligible, did not complete baseline questionnaires, or, in the case of 43 of these patients, refused random assignment to treatment. Despite having received a thorough explanation about being assigned to take active drug or placebo if they experienced fatigue after cycle 2 and signing a consent form detailing study responsibilities, these 43 patients did not wish to take additional medication and withdrew from the study. Two patients reported fatigue when telephoned after cycle 2 and were randomly assigned to treatment, in accordance with study procedures, but subsequently did not report fatigue on the forms they completed. They are included in the analyses.
Of the 704 patients who completed baseline questionnaires, fatigue was reported by 549 patients (78%), and they were randomly assigned to receive either drug (n = 277) or placebo (n = 272); 155 patients (22%) did not report fatigue at cycle 2 and were observed without any intervention. Of these 549 randomly assigned patients, 479 patients (87%; 244 in the paroxetine group and 235 in the placebo group) completed outcome questionnaires after cycle 3, cycle 4, or both cycles, and were assessable. The remaining 70 patients (13%) did not provide outcome data at either cycle 3 or 4 and are not included in the analysis. Two patients were discontinued from the study because of adverse events (skin rash and pulmonary embolus) possibly related to the study medication (Fig 2
There were no significant differences between the paroxetine and placebo groups in mean baseline measures of fatigue (MAF question 1; paroxetine group mean, 5.6; placebo mean, 5.7; P = .310) or depression (CES-D scale total score, 14.8 v 15.8; P = .77) using Student’s t test. Similarly, there were no differences in baseline levels of fatigue or depression by whether patients provided outcome data (ie, were assessable or not) for all patients or by assigned intervention. Half the patients in the paroxetine group had a baseline fatigue score greater than 5 (range, 1 to 10) compared with 49% of the patients in the control group. Using a total CES-D scale score of 19 or greater to indicate depression, 32% of patients in each group had significant symptoms of depression at baseline.
Table 1
All measures of depression and fatigue were strongly correlated at both baseline and study outcome (P < .01 for all). The median correlation coefficient between the CES-D and the POMS DD subscale across the three measurement points was 0.81 (Pearson). The median correlation among the MAF question 1, the FSCL, and the POMS-F/I subscale over the three measurement points was 0.69 (Pearson). The median correlation between the depression and fatigue measures over the three time points was 0.61. Paroxetine had neither beneficial nor detrimental effects on fatigue. There were no significant differences at cycle 4 between the paroxetine and placebo groups in the mean score of MAF question 1 (5.5 v 5.4; P = .76), mean number of fatigue symptoms (FSCL score, 52.3 v 53.8; P = .40), or mean scores of the POMS-F/I (7.7 v 8.4, P = .18) or vigor (3.8 v 3.7, P = .83) subscales. ANCOVA with MAF question 1 at cycle 4 as the dependent variable, controlling for baseline level of fatigue, confirmed the lack of effect of paroxetine on fatigue. At the conclusion of study participation (day 7, cycle 4), the paroxetine group had a significantly lower mean level of depression than the group receiving placebo, as indicated by the total CES-D score (12.0 v 14.8; P = .003), as well as the DD subscale of the POMS (2.0 v 3.1; P < .001). The mean decrease in CES-D score from baseline to cycle 4 was 18.9% in the paroxetine group and 6.3% in the control group. An effect of paroxetine on depression was found as early as the third cycle of chemotherapy (CES-D score, 12.6 paroxetine v 14.9 placebo; P = .014; POMS-DD score, 2.2 paroxetine v 3.1 placebo; P = .004). By cycle 4, only 21% of patients in the paroxetine group had CES-D scores greater than 19 compared with 29% of patients in the placebo group (P = .051). ANCOVA with CES-D score at cycle 4 as the dependent variable, controlling for baseline depression scores, confirmed that the dose of paroxetine provided was more effective than placebo in reducing depression (P = .001). Treatment with paroxetine also favorably affected patients’ general mood. At cycle 4, the mean total POMS score for the intervention group was 11.4, compared with 15.2 for the placebo group (P = .013). A lower score indicates less mood disturbance.
When the effect of paroxetine on fatigue was estimated separately for the depressed and nondepressed subgroups, no significant effect of paroxetine on fatigue was found for either subgroup of patients. Additional subgroup analyses showed no difference in the effect of the intervention by sex, age (median split), indication for treatment (adjuvant treatment v treatment for metastatic disease), or by whether patients were more or less fatigued at baseline. Baseline levels of fatigue predicted fatigue levels at cycle 4 for all assessable patients together, as well as for patients assigned to each group. The mean MAF question 1 score at cycle 4 was 4.6 for patients with baseline score
We conducted a post hoc analysis to determine the level of statistical power of the study to detect a difference in fatigue between the two treatment groups as assessed by question 1 of the MAF when measured at cycle 4. Our analysis, using values from the control group (mean, 5.4; standard deviation, 2.5) showed 93% power to detect a difference in mean scores between the treatment group (n = 244) and control group (n = 235) of 0.80, representing a 15% decrease in fatigue.
Paroxetine at a dose of 20 mg once daily had no effect on fatigue associated with chemotherapy in this randomized, placebo-controlled clinical trial involving 479 patients with cancer. In contrast, paroxetine significantly reduced symptoms of depression within 3 weeks after its initiation. The overall decrease in depression, as assessed by the CES-D, was 12.6% greater in the paroxetine group than in the control group, providing evidence that the dose selected had biologic activity on central serotinergic pathways involved in depression and mood. Although depression and fatigue were strongly correlated in our sample, only depression was affected by the intervention. Given that this study did not stipulate evidence of depression as an eligibility criterion and enrolled patients were not seeking treatment for depression, the clinical relevance of our finding that paroxetine reduced depression cannot be ascertained. Unfortunately, we did not include a qualityof-life instrument and therefore are unable to relate this statistically significant decrease in depression to a clinically meaningful change in quality of life. Our outcome measures, however, did include the POMS, and paroxetine was found to have a beneficial effect on patients’ overall psychological mood. Consistent with previous studies,3,4 fatigue was common. Seventy-eight percent of patients reported fatigue by cycle 2, with half of all patients rating their fatigue as grade 5 or greater on a 10-point scale. Thirty-two percent were experiencing what are considered clinically significant symptoms of depression by cycle 2 (indicated by a CES-D score of 19 or greater). Seventy-two (13%) of the 549 randomly assigned patients did not complete the study (ie, they did not provide any outcome data). This dropout rate was less than pretrial statistical power estimates and lower than that found in other studies evaluating the efficacy of paroxetine for patients with depression and other diagnoses such as social anxiety disorder, obsessive compulsive disorder, and panic disorder.21,31 Eligibility requirements were optimized for accrual of the widest variety of patients and diagnoses possible. The sample included both men and women ranging in age group from young adulthood to elderly, with a variety of malignant diseases. A large proportion were women with breast cancer—a group that currently constitutes the largest category of patients undergoing cyclic chemotherapy. Because our study population was typical of cancer patients undergoing cyclic chemotherapy, results should be generalizable to that population. We believe that the dosage and length of time patients took paroxetine was adequate to test its potential to reduce fatigue. The dose used, 20 mg once daily, is the generally recommended initial dose and was effective in relieving depression in randomized clinical trials conducted to determine the drug’s efficacy,21,31 which showed a significant drug effect within 6 weeks after the start of medication administration. Our study showed that symptoms of depression were reduced in the intervention group during two chemotherapy cycles, demonstrating that an adequate clinical dose was used. In this sample, each treatment cycle was generally 4 to 6 weeks long, so the typical patient took medication for at least 8 weeks before final assessment. Although we cannot exclude the possibility that a higher dose of the selective serotonin reuptake inhibitor (SSRI) might have a beneficial effect on fatigue, we believe this possibility to be remote, in that not even a trend toward efficacy was noted at the dose given. It is also unlikely that the absence of any detectable benefit regarding fatigue was due to the substitution of question 1 of the MAF for the complete MAF as an outcome measure, given that there were no significant differences in fatigue between the active and control groups when fatigue was evaluated using other instruments, including the F/I and Vigor subscales of the POMS, an instrument that has been validated in cancer patients, and the FSCL. Somnolence, asthenia, and fatigue have been reported as adverse effects by some patients treated with paroxetine. We believe it is unlikely that the drug contributed to patients’ fatigue, however, in that there were no significant differences in measured levels of fatigue between the two study groups at any time during the course of the study. If paroxetine were enhancing fatigue, patients in the intervention group would be expected to report more fatigue at cycles 3 and 4 than those in the control group. They did not. The finding of an improved global mood (total POMS score) for the paroxetine but not the placebo group indicates that this measure of mood may be independent of fatigue as the global mood measure changed, whereas fatigue did not. We hypothesized that fatigue and depression shared a final common neural pathway involving serotonin. If so, an antidepressant of the SSRI class likely could mitigate both the fatigue and depression associated with cancer treatment by increasing the availability of 5-HT in the synaptic space. Study results are not consistent with this hypothesis. Rather, the data show that depression and fatigue are differentially affected by an SSRI known to modulate brain 5-HT levels. If there is a final common pathway to the expression of both fatigue and depression, it is unlikely to involve central serotonin. Other pharmacologic agents (eg, psychostimulants)32,33 and perhaps non-pharmacologic interventions (eg, cognitive behavioral therapy, which has been effective in patients with chronic fatigue syndrome)34 may be worthy of further controlled study.
The authors indicated no potential conflicts of interest.
We thank the principal investigators of University of Rochester Cancer Center CCOP Research Base affiliates and their staff members who were involved in the study: Phillip J. Kuebler (Columbus CCOP), David K. King (Greater Phoenix CCOP), Brian Issell, (Hawaii MBCCOP), Raymond S. Lord (Kalamazoo CCOP), Tarit K. Banerjee (Marshfield Medical Research Foundation CCOP), Tom R. Fitch (Mayo Clinic Scottsdale CCOP), Patrick J. Flynn (Metro-Minnesota CCOP), Vincent P. Vinceiguerra (North Shore University Hospital CCOP), Richard J. Rosenbluth (Northern New Jersey CCOP), H. Irving Pierce (Northwest CCOP), James N. Atkins (Southeast Cancer Control Consortium), Jeffrey J. Kirshner (Syracuse Hematology-Oncology CCOP), Marcel E. Conrad (University of South Alabama MBCCOP), John Roberts (VCU MBCCOP), Paul Weiden (Virginia Mason CCOP) and Harry E. Hynes (Wichita CCOP). The study could not have been done without them. We also wish to acknowledge the outstanding work of Jacque L. Lindke, Project Manager of the University of Rochester Cancer Center CCOP Research Base who assured that all national and local regulatory requirements were met throughout the conduct of the protocol. We also thank Shonda Ranson for making sure that the data collected were of the highest quality, and Alexandra DiMatteo for her unflagging attention to detail. The following were contributors to this study: Gary Morrow, Principal Investigator of the URCC CCOP Research Base, developed the original idea for the study, had overall responsibility for ensuring the study’s approval by the National Cancer Institute, and generally oversaw its conduct and completion. Gary Morrow and Jane Hickok codeveloped the research protocol with significant input regarding its design and the feasibility for its conduct from URCC CCOP Research Base Affiliate Principal Investigators Patrick J. Flynn, Harry E. Hynes, Tarit K. Banerjee, Jeffrey J. Kirshner, and David K. King. Richard Raubertas developed the analytic approach and wrote the Statistical Section of the protocol. Jane Hickok was responsible for the literature review, answered study-related questions from individual CCOP clinical research coordinators, and carried out statistical analysis of data according to the plan outlined in the research protocol. Paul Andrews contributed his knowledge about the basic science of serotonin and its potential role in cancer-related fatigue. Gary Morrow and Jane Hickok cowrote the article with factual and editorial contributions from Joseph Roscoe and Paul Andrews.
Supported by National Cancer Institute grant U10CA 37420. GlaxoSmithKline provided study medication and an unrestricted educational grant to help support investigator meeting expenses.
1. Varricchio CG: Selecting a tool for measuring fatigue. Oncol Nurs Forum 12:122–127, 1985[Medline] 2. Broeckel JA, Jacobsen PB, Balducci L, et al: Quality of life after adjuvant chemotherapy for breast cancer. Breast Cancer Res Treat 62:141–150, 2000[CrossRef][Medline] 3. Stone P, Richards M, Hardy J: Fatigue in patients with cancer. Eur J Cancer 34:1670–1676, 1998[CrossRef][Medline]
4. Stone P, Richardson A, Ream E, et al: Cancer-related fatigue: Inevitable, unimportant, and untreatable? Results of a multi-centre patient survey: Cancer Fatigue Forum. Ann Oncol 11:971–975, 2000 5. Piper BF: Subjective fatigue in women receiving six cycles of adjuvant chemotherapy for breast cancer [dissertation]. San Francisco, CA: University of California; 1992 6. Horne J: Sleep deprivation, in Why We Sleep. New York, NY, Oxford University Press, 1989, pp 13–78 7. Miller RG, Giannini D, Milner-Brown HS, et al: Effects of fatiguing exercise on high-energy phosphates, force and EMG: Evidence for three phases of recovery. Muscle Nerve 10:810–821, 1987[CrossRef][Medline] 8. Blesch KS, Paice JA, Wickham R, et al: Correlates of fatigue in people with breast or lung cancer. Oncol Nurs Forum 18:81–87, 1991[Medline] 9. Jacobsen PB, Hann DM, Azzarello LM, et al: Fatigue in women receiving adjuvant chemotherapy for breast cancer: Characteristics, course and correlates. J Pain Symptom Manage 18:233–242, 1999[CrossRef][Medline]
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32. Breitbart W, Rosenfeld B, Kaim M, et al: A randomized, double-blind, placebo-controlled trial of psychostimulants for the treatment of fatigue in ambulatory patients with human immunodeficiency virus disease. Arch Intern Med 161:411–420, 2001 33. Morrow GR, Andrews PL, Hickok JT, et al: Fatigue associated with cancer and its treatment. Support Care Cancer 10:389–398, 2002[CrossRef][Medline] 34. Prins JB, Bleijenberg G, Bazelmans E, et al: Cognitive behavior therapy for chronic fatigue syndrome: A multicentre randomized controlled trial. Lancet 357:841–847, 2001[CrossRef][Medline] Submitted April 10, 2002; accepted October 1, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
> 0.85), test-retest reliability, and construct validity in comparison testing of women with breast cancer and healthy women.
2 and Student’s t tests were used as appropriate to determine the significance of differences in baseline and outcome measures between study groups. To assess the role of depression in the effectiveness of paroxetine for fatigue, patients were divided into "depressed" and "not depressed" subgroups on the basis of a cutoff score of 19 on the CES-D scale at their baseline assessment, and the effect of paroxetine on fatigue was estimated separately for the two subgroups, using analysis of covariance (ANCOVA) and controlling for baseline fatigue. Similarly, patients were divided by their MAF question 1 scores at the baseline assessment into subgroups with more or less fatigue (
5 v > 5 [range, 1 to 10]). 
