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-
· 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
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
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-
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-
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.
27. Tucker WE. Preclinical toxicology of bupropion: an overview. J Clin Psychiatry
28. Settle EC, Stahl SM, Batey SR, Johnston JA, Ascher JA. Safety profile of
sustained-release bupropion in depression: results of three clinical trials. ClinTher 1999;21:454–63.
1. Valentine AD, Meyers CA. Cognitive and mood disturbance as causes and symp-
29. Kirksey DF, Harto-Truax N. Private practice evaluation of the safety and effi-
toms of fatigue in cancer subjects. Cancer 2001;92(Suppl 6):1694 –8.
cacy of bupropion in depressed outpatients. J Clin Psychiatry 1983;44:143–7.
2. Schwartz AL, Nail LM, Chen S, Meek P, Barsevick AM, King ME, and others.
30. Wender PH, Reimherr FW. Bupropion treatment of attention-deficit hyper-
Fatigue patterns observed in subjects receiving chemotherapy and radiotherapy.
activity disorder in adults. Am J Psychiatry 1990;147:1018–20.
31. Wilens TE, Biederman J, Spencer TJ, Prince J. Pharmacotherapy of adult atten-
3. NIH state-of-the-science conference statement on symptom management in can-
tion deficit/hyperactivity disorder: a review. J Clin Psychopharmacol
cer: pain, depression and fatigue; 2002. http://consensus.nih.gov. Accessed
32. Cantwell DP. ADHD through the life span: the role of bupropion in treatment.
4. Mock V, Atkinson A, Barsevick A, Cella D, Cimprich B, Cleeland C, and others.
J Clin Psychiatry 1998;59(4):92–4.
NCCN practice guidelines for cancer-related fatigue. Oncology (Huntingt)
33. Barrickman LL, Perry PJ, Allen AJ, and others. Bupropion versus
methylphenidate in the treatment of attention-deficit hyperactivity disorder. J Am
5. Cleeland CS. Cancer-related symptoms. Semin Radiat Oncol 2000;10:175–90.
Acad Child Adolesc Psychiatry 1995;34:649–57.
6. Servaes P, Verhagen C, Bleijenberg G. Fatigue in cancer patients during and af-
34. Cyr M, Brown CS. Current drug therapy recommendations for the treatment of
ter treatment: prevalence, correlates and interventions. Eur J Cancer
attention deficit hyperactivity disorder. Drugs 1998;56:215–23.
35. Findling RL, Dogin JW. Psychopharmacology of ADHD: children and adoles-
7. Cella D, Davis K, Breitbart W, Curt G. Cancer-related fatigue: prevalence of
cents. J Clin Psychiatry 1998;59(Suppl 7):42–9.
proposed diagnostic criteria in a United States sample of cancer survivors. J Clin
36. Wender PH. Pharmacotherapy of attention-deficit/hyperactivity disorder in
adults. J Clin Psychiatry 1998;59(7):76–9.
8. Winningham ML. Strategies for managing cancer-related fatigue syndrome: a re-
37. Popper CW. Pharmacologic alternatives to psychostimulants for the treatment of
habilitation approach. Cancer 2001;92(Suppl 4):988 –97.
attention-deficit/hyperactivity disorder. Child Adolesc Psychiatr Clin N Am
9. Masand P, Chaudhary P. Methylphenidate treatment of poststroke depression in
a patient with global aphasia. Ann Clin Psychiatry 1994;6:271– 4.
38. Mauskopf JA, Simeon GP, Miles MA, Westlund RE, Davison JRT. Functional
10. Masand P, Pickett P, Murray GB. Psychostimulants for secondary depression in
status in depressed subjects: the relationship to disease severity and disease reso -
medical illness. Psychosomatics 1991;32:203–8.
lution. J Clin Psychiatry 1996;57:588–92.
11. Olin J, Masand P. Psychostimulants for depression in hospitalized cancer sub -
39. Goodnick PJ. Bupropion in chronic fatigue syndrome. Am J Psychiatry
jects. Psychosomatics 1996;37:57–62.
12. Weitzner MA, Meyers CA, Valentine AD. Methylphenidate in the treatment of
neurobehavioural slowing associated with cancer and cancer treatment.
40. Goodnick PJ, Sandoval R, Brickman A, Klimas NG. Bupropion treatment of
J Neuropsychiatry Clin Neurosci 1995;7:347–50.
luoxetine-resistant chronic fatigue syndrome. Biol Psychiatry 1992;32:834–8.
13. Meyers CA, Weitzner MA, Valentine AD, Levin VA. Methylphenidate therapy
41. Green TR. Bupropion for SSRI-induced Fatigue. J Clin Psychiatry 1997;58:174.
improves cognition, mood and function of brain tumor subjects. J Clin Oncol
42. Duffy JD, Campbell J. Bupropion for the treatment of fatigue associated with
multiple sclerosis. Psychosomatics 1994;35:170–1.
14. Cleare AJ, Heap E, Malhi GS, Wessely S, O’Keane V, Miell J. Low-dose hydro-
43. Clinical Global Impression (CGI). In: Guy W, editor. ECDEU assessment for
cortisone in chronic fatigue syndrome: a randomised crossover trial. Lancet
psychopharmacology. Rev ed. Rockville (MD): National Institute of Mental
15. Holland JC, Romano SR, Heiligenstein JH, Tepner RG, Wilson MG. A con-
44. Kumar R. Important safety information regarding bupropion. Mississauga:
trolled trial of fluoxetine and desipramine in depressed women with advanced
GlaxoSmithKline; July 3; 2001. Www.hc-sc.gc.ca/hpb-dgps/therapeut/zfiles/
cancer. Psychooncology 1998;7:291–300.
english/advisory/industry/zyban_e.pdf. Accessed September 24, 2002.
16. Passik SD, Kirsh KL, Theobald D, Donaghy K, Holtsclaw E, Edgerton S, and
others. Use of a depression screening tool and a fluoxetine-based algorithm toimprove the recognition and treatment of depression in cancer patients: a demon -
Manuscript received October 2002, revised, and accepted November 2003.
stration project. J Pain Symptom Manage 2002;24:318–27.
17. Fisch MJ, Loehrer PJ, Kristeller J, Passik S, Jung SH, Shen J, and others.
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.
Foothills Hospital; Associate Professor, Departments of Psychiatry and On-
20. Theobald D, Kirsch KL, Holtsclaw E, Donaghy K, Passik SD. An open-label,
crossover trial of mirtazapine (15 and 30 mg) in cancer patients with pain and
cology, University of Calgary, Calgary, Alberta.
other distressing symptoms. J Pain Symptom Manage 2002;23:442–7. Address for correspondence: Dr JSA Simpson, Foothills Hospital, Depart-
21. Van Gool AR, Bannink M, Stronks DL, Vos MS. Mirtazapine in cancer patients.
ment of Psychiatry, 1403–29 Street NW, Calgary, AB T2N 2T9
J Pain Symptom Manage 2003;25(1):7–8.
e-mail: [email protected]
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
CLOZARIL: Starting a Patient 1. Call the CLOZARIL National Registry (CNR) to obtain a rechallenge number and to confirm that you and your pharmacy are registered. 2 . Obtain a baseline WBC with ANC from patient. If within normal limits, WBC ≥ 3500/ mm3, ANC ≥ 2000/ mm3, prescribe CLOZARIL tablets. 3. Submit WBC and ANC information to the registered pharmacy. 4. Please be pre