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Bupropion Sustained Release Treatment Reduces
Fatigue in Cancer Patients

Jodi L Cullum, MSc (Health Psych)1, Agnieszka E Wojciechowski, BSc2, Guy Pelletier, PhD3,
J Steven A Simpson, PhD, MD4

Objective: To demonstrate that bupropion sustained release (SR) can reduce the symptoms
of fatigue experienced by cancer patients.
Method: We studied an open-label case series of outpatients with fatigue referred for psy-
chiatric assessment from a tertiary care cancer centre. Inclusion criteria were the presence
of fatigue or depression with marked fatigue. Clinical status was assessed using the Global
Clinical Improvement scale.
Results: Fifteen subjects with various cancer sites and psychiatric diagnoses were treated
with bupropion SR (modal dose 150 mg) for up to 2 years. Most (13 of 15) saw improve-
ment. Thirteen patients had minor, expectable side effects, and 10 patients were able to
continue with bupropion for an extended time. All subjects who improved showed im-
provement within 2 to 4 weeks.
Conclusions: This is the first report that shows bupropion SR can reduce fatigue in cancer
patients. Controlled studies with more homogeneous samples would be necessary to estab-
lish the efficacy of this intervention. Further studies should address whether this effect of
bupropion is separate from its action as an antidepressant.
Information on funding and support and author affiliations appears at the end of the article.
Clinical Implications
· This is preliminary evidence that bupropion sustained release can reduce fatigue in cancer · Fatigue is a common, difficult-to-treat adjustment reaction for cancer patients following stan- Limitations
· This is an uncontrolled case series.
· Confirmation of our results is needed through randomized, placebo-controlled studies.
· A formal assessment of the magnitude of depressive symptoms was not conducted.
· Generalizability of these findings is limited by the highly select patient population.
Key Words: bupropion, fatigue, treatment, cancer, clinical case series
Qualityoflife(QOL)issuesareparticularlyimportantfor prevalenceestimatesoffatigueduringcancertreatmentrange cancer patients. Fatigue, which is generally difficult to from 25% to 99%. Between 17% and 30% of long-term survi- treat (1–3), seriously interferes with QOL by substantially vors report problems with fatigue for several years after they diminishing patient ability to carry out meaningful daily activ- ities (4). There is considerable diagnostic confusion over can- Atkinson and colleagues published a set of guidelines cer-related fatigue (CRF) in the literature (5). Depending on designed to assist in the identification and treatment of CRF the sample of patients and the type of measure used, (4). Cella and colleagues proposed a set of diagnostic criteria Can J Psychiatry, Vol 49, No 2, February 2004 W The Canadian Journal of Psychiatry—Brief Communication
for “Cancer-Related Fatigue Syndrome” that specifically con- were enrolled in the study. Their thyroid status was reviewed, sider CRF as distinct from major depression or somatoform and where necessary, thyroid-stimulating hormone levels disorders, but do not address the relation with adjustment were measured prior to treatment with bupropion. Prior anti- depressant therapies were discontinued in all but a singleinstance (patient 2), and all other medications and over- Interventions for the treatment of CRF are at an early stage of the-counter preparations were held constant for the duration development and have followed those for the treatment of fatigue in noncancer populations. These have included bothnonpharmacologic approaches (8) and pharmacologic agents, Table 1 shows the demographic information, the psychiatric including psychostimulant drugs, especially methylphenidate and oncological diagnoses, and the current medications for (9–13). Hydrocortisone has been used in noncancer fatigue each patient. After assessment and discussion of the risks (for but not investigated in CRF populations (14). Several anti- example, occurrence of seizures) and potential benefits of depressants, including fluoxetine (15–17), paroxetine bupropion treatment, all subjects gave informed consent for (18,19), and mirtazepine (20,21), have shown effectiveness in treatment and for publication of this report. If the psychiatric treating depression in cancer patients. Fluoxetine (15,17) and disorder exclusion criterion were disregarded, all subjects met paroxetine (19) have shown some promise in treating fatigue.
The use of bupropion has been suggested but not reported In all patients, bupropion was started at 100 or 150 mg daily, Bupropion is an atypical antidepressant drug, chemically and the dosage was adjusted according to the patient’s unrelated to tricyclic and tetracyclic antidepressants, selective response. Following treatment, subjects were rated for sever- serotonin reuptake inhibitors (SSRIs), and other known anti- ity of illness and improvement of fatigue on the Clinical depressant agents. Psychopharmacologically, it shares a wide Global Improvement (CGI) scale (43) by a clinician not range of actions with psychostimulants. The mode of action is directly involved in these pharmacologic trials. Table 2 shows b e l i e v e d t o i n v o l v e p r i ma r i l y d o p a mi n e r g i c a n d the initial severity of illness, the final dosage of bupropion, the noradrenergic rather than serotonergic mechanisms (24–26).
side effects, and the CGI improvement score. Most subjects The safety of bupropion in humans has been extensively (13 of 15) reported some of the most common bupropion side effects, such as increased anxiety, dry mouth, nausea, insom- Bupropion has been used successfully in the treatment of nia, tremor, and tinnitus. These were rated as mostly mild to attention-deficit hyperactivity disorder in adults (30–32) and children (33–37) and to increase the functional status ofpatients with depression (38). It has also been used to treat chronic fatigue syndrome (39,40), antidepressant-induced The degree of fatigue was rated in 6 subjects as very much fatigue (41), and fatigue associated with multiple sclerosis improved, in 2 subjects as much improved, and in 5 subjects as (42). These lines of evidence suggest that bupropion is a stim- minimally improved (Table 2). One patient showed no ulating drug with a unique mode of action making it suitable change, and a single patient reported feeling much worse for the treatment of CRF. The effectiveness of bupropion in (with respect to fatigue symptoms) following bupropion treat- alleviating CRF has not been previously described and is the ment. In total, 13 of 15 subjects reported improvement, with 8 rated as much improved or better. In all patients, the improve-ment occurred within 2 to 4 weeks.
Discussion
The case-series approach chosen for this study provided an Cancer patients consecutively referred for psychiatric assess- opportunity to examine the effect of bupropion on the fatigue of ment at the Tom Baker Cancer Centre in Calgary were consid- a small number of cancer patients. The response in terms of ered for bupropion treatment if they 1) had low energy as their decreased fatigue was often dramatic and prompt. For example, presenting complaint (n = 8), 2) had clinically impairing patient 1 presented for psychiatric evaluation following chemo- fatigue following prior treatment with an SSRI (n = 1), and 3) therapy, complaining of persistent severe fatigue, increased identified fatigue out of proportion to other depressive symp- anxiety, and irritability. Bupropion SR was started at 150 mg toms in the clinical interview (n = 6). Subjects were excluded daily. When seen 15 days later, he reported significantly if they were receiving erythropoietin treatment, were in need increased energy levels with a mild but tolerable increase in of a blood transfusion, had a history or symptoms of diabetes, anxiety and insomnia that was managed by taking the medica- or had an active rheumatologic condition. Fifteen patients tion as early in the day as possible. He was able to return to work W Can J Psychiatry, Vol 49, No 2, February 2004 Bupropion Sustained Release Treatment Reduces Fatigue in Cancer Patients
Table 1 Demographic and medication histories
dexamethasone,dilantin, diltiazem,leuprolide acetate,morphine, phenytoin,prednisone,rofecoxib clonazepam,lorazepam,prednisone,risperidone,vigabatrin maleate, omeprazole vitamins B and Cmagnesium,megestrol acetate Can J Psychiatry, Vol 49, No 2, February 2004 W The Canadian Journal of Psychiatry—Brief Communication
Table 2 Outcome (CGI score)
Dry mouth, mild agitation, irritability(at 150 mg) Mild nausea, blurred vision, confusion,depression Pruritis, headaches, tearfulness, sore eyes full-time. In other instances the response was slower. Patient increase antiepileptic medication to avoid the side effect of 10, a 37-year-old man with oligodendroglioma, presented com- plaining of fatigue, poor concentration, and irritability.
Bupropion SR was started at 100 mg daily. After a month of The manufacturers of bupropion SR list seizure disorders as a treatment, he reported improved attention and mood. Some contraindication for bupropion treatment and list factors that hyperreflexia was also observed. Following 2 months of treat- increase the likelihood of seizures as cause for extreme caution.
ment, he reported excellent energy, improved concentration, This includes subjects with a central nervous system tumor.
Unfortunately, there is no information on the risks to subjectswho are on adequate dosages of antiepileptic medication, since Three subjects discontinued bupropion treatment because of all such subjects have been systematically excluded from stud- side effects. A good example is patient 11, who reported feeling ies sponsored by drug companies. Alternative drug therapies worse after bupropion treatment, with an increase in nausea, for fatigue, such as methylphenidate, amphetamines, and depression, and some blurring of vision. Bupropion was dis- corticosteroids, all lower the seizure threshold. In addition, continued for lack of sustained response in 2 other subjects.
some antidepressants are associated with an increased rate of Thus, 10 subjects were able to benefit from bupropion SR for seizures that is comparable to, or higher than, that for up to 2 years. In examining the aggregate responses, there bupropion SR—for example, venlafaxine (0.26%, product appeared to be no clear benefit in terms of fatigue symptoms for monograph) or fluoxetine (0.2%, product monograph).
higher doses (200 to 300 mg) of bupropion over lower doses(100 to 150 mg). The major safety issue attributed to bupropionis the increased incidence of seizures (44). Although the fre- Conclusion
quency of seizures as a result of medication has been shown to Bupropion treatment appears to offer an alternative to cur- increase in 1 out of 1000 people, this side effect is serious and rently available treatments for fatigue in select cancer sub- must be monitored closely. In our case series, 1 patient with a jects. Generally, bupropion is well tolerated. It has a low history of grand mal seizures was on antiepileptic medication potential for abuse, and it is not a controlled substance. Future while taking bupropion and did not report an increase in the fre- placebo-controlled studies with this medication are war- quency of seizures. Another had a history of partial seizures, ranted, especially where subjects are evaluated with standard- which were also controlled by medication. Upon initiating a ized fatigue inventories and symptoms of major depression trial of bupropion, the frequency of partial seizures reportedly are formally assessed by blinded raters. Studies in combina- increased but did not concern the patient, as it remained within tion with nonpharmacologic approaches would be particu- the range of previous experience. The patient chose not to W Can J Psychiatry, Vol 49, No 2, February 2004 Bupropion Sustained Release Treatment Reduces Fatigue in Cancer Patients
22. Stahl SM. The psychopharmacology of energy and fatigue. J Clin Psychiatry Funding and Support
This study was funded by a summer studentship grant to 23. Schwartz L, Lander M, Chochinov HM. Current management of depression in Agnieszka E Wojciechowski from the Centre for Advancement of cancer patients. Oncology (Huntingt) 2002;16:1102–15.
24. Burks TF. New agents for the treatment of cancer-related fatigue. Cancer 25. Vassout A, Bruinink A, Krauss J, Waldmeier P, Bischoff S. Regulation of dopa- mine receptors by bupropion: comparison with antidepressants and CNS stimu- Acknowledgements
lants. J Recept Res 1993;13:341–54.
The authors thank Dr Michael Trew and Dr Maureen Angen for 26. Hoffman DC. The use of place conditioning in studying the neuropharmacology helpful comments during the development of the manuscript.
of drug reinforcement, Brain Res Bull 1989;23:373–87.
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Research Assistant, Department of Psychosocial Resources, Tom Baker Fluoxetine versus placebo in advanced cancer outpatients: a double-blinded trial of the Hoosier oncology group. J Clin Oncol 2003;21:1937–43.
Medical Student, Medical Class of 2004, University of Calgary, Calgary, 18. Pezzella G, Moslinger-Gehmayr R, Contu A. Treatment of depression in patients with breast cancer: a comparison between paroxetine and amitriptyline. Breast 3Clinical Psychologist, Department of Psychosocial Resources, Tom Baker Cancer Centre; Department of Oncology, University of Calgary, Calgary, 19. Weitzner MA, Moncello J, Jacobsen PB, Minton S. A pilot trial of paroxetine for the treatment of hot flashes and associated symptoms in women with breast can- 4Psychiatrist, Consultation Liaison Division, Department of Psychiatry, cer. J Pain Symptom Manage 2002;23:337–45.
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e-mail: steve.simpson@calgaryhealthregion.ca Can J Psychiatry, Vol 49, No 2, February 2004 W The Canadian Journal of Psychiatry—Brief Communication
Résumé : Le traitement au bupropion à libération prolongée réduit la fatigue
chez les patients cancéreux

Objectif : Démontrer que le bupropion à libération prolongée (LP) peut réduire les symptômes de fa-
tigue que présentent les patients cancéreux.
Méthode : Nous avons étudié une série de cas ouverts de patients externes présentant de la fatigue et
adressés à une évaluation psychiatrique d’un centre de soins tertiaires du cancer. Les critères
d’inclusion étaient la présence de fatigue ou de dépression avec fatigue marquée. L’état clinique était
évalué à l’aide de l’échelle d’amélioration clinique générale (GCIS).
Résultats : Quinze sujets ayant différents sièges du cancer et diagnostics psychiatriques ont été traités
au bupropion à LP (dose modale 150 mg) pendant jusqu’à 2 ans. La plupart (13 sur 15) ont constaté
une amélioration. Treize sujets sur 15 ont eu des effets secondaires mineurs prévisibles, et 10 ont été
en mesure de continuer le bupropion sur une période prolongée. Chez tous les sujets qui se sont
améliorés, cette amélioration s’est produite entre 2 et 4 semaines.
Conclusions : Ceci est la première étude qui révèle que le bupropion à LP peut réduire la fatigue chez
les patients cancéreux. Des études contrôlées avec des échantillons plus homogènes sont nécessaires
pour établir l’efficacité de cette intervention. Les futures études devraient déterminer si cet effet du
brupopion est distinct de son action comme antidépresseur.
W Can J Psychiatry, Vol 49, No 2, February 2004

Source: http://ww1.cpa-apc.org:8080/Publications/Archives/CJP/2004/february/simpson.pdf

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