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Quality of life (QOL) issues are particularly important for cancer patients. Fatigue, which is generally difficult to treat (1–3), seriously interferes with QOL by substantially diminishing patient ability to carry out meaningful daily activities (4). There is considerable diagnostic confusion over cancer-related fatigue (CRF) in the literature (5). Depending on the sample of patients and the type of measure used, prevalence estimates of fatigue during cancer treatment range from 25% to 99%. Between 17% and 30% of long-term survivors report problems with fatigue for several years after they complete treatment (6). Atkinson and colleagues published a set of guidelines designed to assist in the identification and treatment of CRF (4). Cella and colleagues proposed a set of diagnostic criteria for “Cancer-Related Fatigue Syndrome” that specifically consider CRF as distinct from major depression or somatoform disorders, but do not address the relation with adjustment disorder (7). Interventions for the treatment of CRF are at an early stage of development and have followed those for the treatment of fatigue in noncancer populations. These have included both nonpharmacologic approaches (8) and pharmacologic agents, including psychostimulant drugs, especially methylphenidate (9–13). Hydrocortisone has been used in noncancer fatigue but not investigated in CRF populations (14). Several anti- depressants, including fluoxetine (15–17), paroxetine (18,19), and mirtazepine (20,21), have shown effectiveness in treating depression in cancer patients. Fluoxetine (15,17) and paroxetine (19) have shown some promise in treating fatigue. The use of bupropion has been suggested but not reported (22–24). Bupropion is an atypical antidepressant drug, chemically unrelated to tricyclic and tetracyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and other known antidepressant agents. Psychopharmacologically, it shares a wide range of actions with psychostimulants. The mode of action is believed to involve primarily dopaminergic and noradrenergic rather than serotonergic mechanisms (24–26). The safety of bupropion in humans has been extensively studied (27–29). Bupropion has been used successfully in the treatment of attention-deficit hyperactivity disorder in adults (30–32) and children (33–37) and to increase the functional status of patients with depression (38). It has also been used to treat chronic fatigue syndrome (39,40), antidepressant-induced fatigue (41), and fatigue associated with multiple sclerosis (42). These lines of evidence suggest that bupropion is a stimulating drug with a unique mode of action making it suitable for the treatment of CRF. The effectiveness of bupropion in alleviating CRF has not been previously described and is the focus of this report MethodsPatient Characteristics Table 1 shows the demographic information, the psychiatric and oncological diagnoses, and the current medications for each patient. After assessment and discussion of the risks (for example, occurrence of seizures) and potential benefits of bupropion treatment, all subjects gave informed consent for treatment and for publication of this report. If the psychiatric disorder exclusion criterion were disregarded, all subjects met Cella’s criteria for CRF.
Treatment Program ResultsThe degree of fatigue was rated in 6 subjects as very much improved, in 2 subjects as much improved, and in 5 subjects as minimally improved (Table 2). One patient showed no change, and a single patient reported feeling much worse (with respect to fatigue symptoms) following bupropion treatment. In total, 13 of 15 subjects reported improvement, with 8 rated as much improved or better. In all patients, the improvement occurred within 2 to 4 weeks.
DiscussionThe case-series approach chosen for this study provided an opportunity to examine the effect of bupropion on the fatigue of a small number of cancer patients. The response in terms of decreased fatigue was often dramatic and prompt. For example, patient 1 presented for psychiatric evaluation following chemotherapy, complaining of persistent severe fatigue, increased anxiety, and irritability. Bupropion SR was started at 150 mg daily. When seen 15 days later, he reported significantly increased energy levels with a mild but tolerable increase in anxiety and insomnia that was managed by taking the medication as early in the day as possible. He was able to return to work full-time. In other instances the response was slower. Patient 10, a 37-year-old man with oligodendroglioma, presented complaining of fatigue, poor concentration, and irritability. Bupropion SR was started at 100 mg daily. After a month of treatment, he reported improved attention and mood. Some hyperreflexia was also observed. Following 2 months of treatment, he reported excellent energy, improved concentration, and no problems with hyperreflexia Three subjects discontinued bupropion treatment because of side effects. A good example is patient 11, who reported feeling worse after bupropion treatment, with an increase in nausea, depression, and some blurring of vision. Bupropion was discontinued for lack of sustained response in 2 other subjects. Thus, 10 subjects were able to benefit from bupropion SR for up to 2 years. In examining the aggregate responses, there appeared to be no clear benefit in terms of fatigue symptoms for higher doses (200 to 300 mg) of bupropion over lower doses (100 to 150 mg). The major safety issue attributed to bupropion is the increased incidence of seizures (44). Although the frequency of seizures as a result of medication has been shown to increase in 1 out of 1000 people, this side effect is serious and must be monitored closely. In our case series, 1 patient with a history of grand mal seizures was on antiepileptic medication while taking bupropion and did not report an increase in the frequency of seizures. Another had a history of partial seizures, which were also controlled by medication. Upon initiating a trial of bupropion, the frequency of partial seizures reportedly increased but did not concern the patient, as it remained within the range of previous experience. The patient chose not to increase antiepileptic medication to avoid the side effect of sedation as previously experienced The manufacturers of bupropion SR list seizure disorders as a contraindication for bupropion treatment and list factors that increase the likelihood of seizures as cause for extreme caution. This includes subjects with a central nervous system tumor. Unfortunately, there is no information on the risks to subjects who are on adequate dosages of antiepileptic medication, since all such subjects have been systematically excluded from studies sponsored by drug companies. Alternative drug therapies for fatigue, such as methylphenidate, amphetamines, and corticosteroids, all lower the seizure threshold. In addition, some antidepressants are associated with an increased rate of seizures that is comparable to, or higher than, that for bupropion SR—for example, venlafaxine (0.26%, product monograph) or fluoxetine (0.2%, product monograph). ConclusionBupropion treatment appears to offer an alternative to currently available treatments for fatigue in select cancer subjects. Generally, bupropion is well tolerated. It has a low potential for abuse, and it is not a controlled substance. Future placebo-controlled studies with this medication are warranted, especially where subjects are evaluated with standardized fatigue inventories and symptoms of major depression are formally assessed by blinded raters. Studies in combination with nonpharmacologic approaches would be particularly useful. Funding and SupportThis study was funded by a summer studentship grant to Agnieszka E Wojciechowski from the Centre for Advancement of Health, Calgary Health Region. AcknowledgementsThe authors thank Dr Michael Trew and Dr Maureen Angen for helpful comments during the development of the manuscript References1. Valentine AD, Meyers CA. Cognitive and mood disturbance as causes and symptoms of fatigue in cancer subjects. Cancer 2001;92(Suppl 6):1694–8. 2. Schwartz AL, Nail LM, Chen S, Meek P, Barsevick AM, King ME, and others. Fatigue patterns observed in subjects receiving chemotherapy and radiotherapy. Cancer Invest 2000;18(1):11–9. 3. NIH state-of-the-science conference statement on symptom management in cancer: pain, depression and fatigue; 2002. http://consensus.nih.gov. Accessed November 14, 2002 4. Mock V, Atkinson A, Barsevick A, Cella D, Cimprich B, Cleeland C, and others. NCCN practice guidelines for cancer-related fatigue. Oncology (Huntingt) 2000;14(11A):151–61 5. Cleeland CS. Cancer-related symptoms. Semin Radiat Oncol 2000;10:175–90. 6. Servaes P, Verhagen C, Bleijenberg G. Fatigue in cancer patients during and after treatment: prevalence, correlates and interventions. Eur J Cancer 2002;38(1):27–43 7. Cella D, Davis K, Breitbart W, Curt G. Cancer-related fatigue: prevalence of proposed diagnostic criteria in a United States sample of cancer survivors. J Clin Oncol 2001;19:3385–91. 8. Winningham ML. Strategies for managing cancer-related fatigue syndrome: a rehabilitation approach. Cancer 2001;92(Suppl 4):988–97. 9. Masand P, Chaudhary P. Methylphenidate treatment of poststroke depression in a patient with global aphasia. Ann Clin Psychiatry 1994;6:271–4. 10. Masand P, Pickett P, Murray GB. Psychostimulants for secondary depression in medical illness. Psychosomatics 1991;32:203–8 11. Olin J, Masand P. Psychostimulants for depression in hospitalized cancer subjects. Psychosomatics 1996;37:57–62 12. Thabet AA, Vostanis P. Social adversities and anxiety disorders in the Gaza Strip. Arch Dis Childhood 1998;78:439–42. 13. Meyers CA, Weitzner MA, Valentine AD, Levin VA. Methylphenidate therapy improves cognition, mood and function of brain tumor subjects. J Clin Oncol 1998;16:2522–7. 14. Cleare AJ, Heap E, Malhi GS, Wessely S, O’Keane V, Miell J. Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial. Lancet 1999;353:455–8 15. Holland JC, Romano SR, Heiligenstein JH, Tepner RG, Wilson MG. A controlled trial of fluoxetine and desipramine in depressed women with advanced cancer. Psychooncology 1998;7:291–300. 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 to improve the recognition and treatment of depression in cancer patients: a demonstration project. J Pain Symptom Manage 2002;24:318–27. 17. Fisch MJ, Loehrer PJ, Kristeller J, Passik S, Jung SH, Shen J, and others. Fluoxetine versus placebo in advanced cancer outpatients: a double-blinded trial of the Hoosier oncology group. J Clin Oncol 2003;21:1937–43. 18. Pezzella G, Moslinger-Gehmayr R, Contu A. Treatment of depression in patients with breast cancer: a comparison between paroxetine and amitriptyline. Breast Cancer Res Treat 2001;70(1):1–10. 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 cancer. J Pain Symptom Manage 2002;23:337–45. 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 other distressing symptoms. J Pain Symptom Manage 2002;23:442–7. 21. Van Gool AR, Bannink M, Stronks DL, Vos MS. Mirtazapine in cancer patients. J Pain Symptom Manage 2003;25(1):7–8. 22. Stahl SM. The psychopharmacology of energy and fatigue. J Clin Psychiatry 2002;63(1):7–8. 23. Schwartz L, Lander M, Chochinov HM. Current management of depression in cancer patients. Oncology (Huntingt) 2002;16:1102–15. 24. Burks TF. New agents for the treatment of cancer-related fatigue. Cancer 2001;92(Suppl 6):1714–8. 25. Vassout A, Bruinink A, Krauss J, Waldmeier P, Bischoff S. Regulation of dopamine receptors by bupropion: comparison with antidepressants and CNS stimulants. J Recept Res 1993;13:341–54. 26. Hoffman DC. The use of place conditioning in studying the neuropharmacology of drug reinforcement, Brain Res Bull 1989;23:373–87. 27. Tucker WE. Preclinical toxicology of bupropion: an overview. J Clin Psychiatry 1983;44(5):60–2. 28. Settle EC, Stahl SM, Batey SR, Johnston JA, Ascher JA. Safety profile of sustained-release bupropion in depression: results of three clinical trials. Clin Ther 1999;21:454–63. 29. Kirksey DF, Harto-Truax N. Private practice evaluation of the safety and efficacy of bupropion in depressed outpatients. J Clin Psychiatry 1983;44:143–7 30. Wender PH, Reimherr FW. Bupropion treatment of attention-deficit hyper- activity disorder in adults. Am J Psychiatry 1990;147:1018–20. 31. Wilens TE, Biederman J, Spencer TJ, Prince J. Pharmacotherapy of adult attention deficit/hyperactivity disorder: a review. J Clin Psychopharmacol 1995;15:270–9. 32. Cantwell DP. ADHD through the life span: the role of bupropion in treatment. J Clin Psychiatry 1998;59(4):92–4. 33. Barrickman LL, Perry PJ, Allen AJ, and others. Bupropion versus methylphenidate in the treatment of attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 1995;34:649–57. 34. Cyr M, Brown CS. Current drug therapy recommendations for the treatment of attention deficit hyperactivity disorder. Drugs 1998;56:215–23. 35. Findling RL, Dogin JW. Psychopharmacology of ADHD: children and adolescents. J Clin Psychiatry 1998;59(Suppl 7):42–9. 36. Wender PH. Pharmacotherapy of attention-deficit/hyperactivity disorder in adults. J Clin Psychiatry 1998;59(7):76–9. 37. Popper CW. Pharmacologic alternatives to psychostimulants for the treatment of attention-deficit/hyperactivity disorder. Child Adolesc Psychiatr Clin N Am 2000;9:605–46. 38. Mauskopf JA, Simeon GP, Miles MA, Westlund RE, Davison JRT. Functional status in depressed subjects: the relationship to disease severity and disease resolution. J Clin Psychiatry 1996;57:588–92. 39. Goodnick PJ. Bupropion in chronic fatigue syndrome. Am J Psychiatry 1990;147:1091. 40. Goodnick PJ, Sandoval R, Brickman A, Klimas NG. Bupropion treatment of luoxetine-resistant chronic fatigue syndrome. Biol Psychiatry 1992;32:834–8. 41. Green TR. Bupropion for SSRI-induced Fatigue. J Clin Psychiatry 1997;58:174 42. Duffy JD, Campbell J. Bupropion for the treatment of fatigue associated with multiple sclerosis. Psychosomatics 1994;35:170–1. 43. Clinical Global Impression (CGI). In: Guy W, editor. ECDEU assessment for psychopharmacology. Rev ed. Rockville (MD): National Institute of Mental Health; 1976. p 217–22 44. Kumar R. Important safety information regarding bupropion. Mississauga: GlaxoSmithKline; July 3; 2001. Www.hc-sc.gc.ca/hpb-dgps/therapeut/zfiles/ english/advisory/industry/zyban_e.pdf. Accessed September 24, 2002. Author(s)Manuscript received October 2002, revised, and accepted November 2003. 1. Research Assistant, Department of Psychosocial Resources, Tom Baker Cancer Centre, Calgary, Alberta. 2.Medical Student, Medical Class of 2004, University of Calgary, Calgary, Alberta 3. Clinical Psychologist, Department of Psychosocial Resources, Tom Baker Cancer Centre; Department of Oncology, University of Calgary, Calgary, Alberta. 4. Psychiatrist, Consultation Liaison Division, Department of Psychiatry, Foothills Hospital; Associate Professor, Departments of Psychiatry and Oncology, University of Calgary, Calgary, Alberta Address for correspondence: Dr JSA Simpson, Foothills Hospital, Department of Psychiatry, 1403–29 Street NW, Calgary, AB T2N 2T9 email: steve.simpson@calgaryhealthregion.ca
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