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Prophylactic Treatment of Depression Induced by Interferon-

Received August 13, 1999; revised September 29, 1999; accepted December 29, 1999. From the Department of Psychiatry, Portland VA Medical Center, Portland, Oregon; the Department of Psychiatry, University of Maryland Medical Center & Psychiatry Service, Baltimore VA Medical Center, Baltimore, MD; and the Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. Address reprint requests to Dr. Hauser, Director, Joint VA/University Mood Disorders Programs, Baltimore VA Medical Center, 10 North Greene Street, Baltimore, MD 21201.

Key Words: Depression • Interferon-alpha • SSRI

Interferons (alpha, beta, and gamma) are a family of proteins that produce a regression or control over disease processes in more than a dozen cancers. In particular, interferon-alpha (IFN-) has been shown to be an effective therapy for chronic myelogenous leukemia (CML) as well as inhibiting malignant cell growth in multiple myeloma.^1–3 More recently, IFN- in combination with ribavirin has been an efficacious initial treatment for chronic hepatitis C, a disease that is estimated to affect between 3 and 4 million Americans.⁴

However, the benefits of IFN- can be overshadowed by its neurotoxicity, including fatigue, apathy, confusion, and impaired concentration.^5–7 In particular, the occurrence of depression as a common side effect of IFN- therapy has only recently begun to be fully appreciated. Although the specific incidence of IFN-–induced depression is not known, preliminary results from a prospective neuropsychological study of patients with CML before and during IFN- therapy found significant increases in depression subscales of the Minnesota Multiphasic Personality Inventory in 70% of patients during treatment.⁸ The pathophysiologic mechanism that causes the neuropsychiatric side effects, particularly depression, is unclear although various hypotheses have been suggested including a perturbation of serotonergic neurotransmitters.^8,9

Case reports suggest that various pharmaceutical agents including selective serotonin reuptake inhibitors (SSRIs), tricyclics, and opioid antagonists effectively ameliorate the central nervous system (CNS) side effects of IFN- treatment.^8,10–12 However, there have been no controlled studies of antidepressant treatment in patients with IFN-–induced depression. Despite the paucity of published reports, antidepressants are commonly used to treat IFN-–induced depression, and activating antidepressants are believed to be advantageous. To date, no studies have examined the efficacy of antidepressants as prophylactic therapy against depression induced by IFN-.

This case report shows the benefits of prophylactic treatment of depression with an SSRI in a 67-year-old man with melanoma. IFN- therapy was initiated and subsequently discontinued twice—secondary to development of severe depression and anxiety. Fluoxetine (20 mg/day) was started 2 weeks before restarting IFN- therapy for the third time. This prevented depression from developing and allowed him to remain on IFN- therapy.

Case Report

Mr. R. is a 67-year-old man with a diagnosis of malignant melanoma with no evidence of metastatic disease. He was started on a 1-year prophylactic program of IFN- therapy. Before the initiation of IFN- therapy, Mr. R. signed informed consent to participate in an ongoing University of Maryland School of Medicine Institutional Review Board-approved clinical research protocol that examines the CNS side effects of IFN- therapy. Before treatment, he was administered a Structured Clinical Interview for DSM-IV Axis Disorders Patient Edition (SCID-I/P) and the Beck Depression Inventory (BDI) to assess past and present episodes and symptoms of depression. The SCID revealed that Mr. R. had one past major depressive episode at age 55. The episode lasted about 3 months and resolved spontaneously. His baseline BDI score was 1. Throughout the course of IFN- therapy, symptoms of depression were measured on a weekly basis using the BDI (see Figure 1).

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FIGURE 1. A graphic representation of repeated Beck Depression Inventory (BDI) scores over a period of 26 weeks in a patient with interferon alpha-induced depression

For the first 4 weeks of treatment, Mr. R. was given 28 million units/m2 subcutaneously for 5 out of 7 days. At the start of the treatment, his only complaints were shakes and hot flashes, and he had a fever of 101–102, all of which subsided within the first 2 weeks of therapy. During Week 2, Mr. R. had a BDI score of 2. During Week 3, Mr. R. complained of fatigue, sleeping 9 hours compared with his usual 6 hours per night, increased inability to concentrate, and being able to work only half days. His score on the BDI was 3. At the end of Week 4, Mr. R. had a dramatic increase in symptoms of depression and anxiety; he reported feeling hopeless, and he was sleeping 11 hours a day. IFN- was discontinued over that weekend on the advice of his oncologist.

Two days later Mr. R. was admitted to the University of Maryland Hospital for depression and anxiety. He reported feeling alone, lost, panicked, and confused. His score on the BDI was 20. He was given lorazepam and discharged 5 days later on a dose of 1.0 mg po twice a day. During Week 7 there was improvement in his anxiety and depression, and lorazepam was discontinued. Mr. R. returned to work on a regular basis. His score on the BDI was 3. During Week 8, he had no new complaints and his score on the BDI was a 3. At his insistence IFN- was restarted at a dose of 8 million units/m2 subcutaneously 3 times a week. During Week 9, Mr. R.'s BDI score was 3. He continued to deny symptoms of depression or anxiety during Weeks 10 and 11, and his score for both weeks on the BDI was 2. By the end of Week 12 (4 weeks after IFN- therapy was restarted) Mr. R. started to develop symptoms of depression and anxiety, and his score on the BDI was 8.

Because of his inability to tolerate his symptoms of depression and anxiety, Mr. R. took himself off of IFN- therapy during Week 13 and did not inform his treating physicians until the end of Week 13, at which point his BDI score was 16. Mr. R. remained off IFN- for 2 weeks, and by the end of Week 15, his BDI score was 3. He considered IFN- treatment life-saving, and he again insisted on restarting IFN-. Because he had two episodes of depression precipitated by IFN-, prophylactic treatment with an SSRI and its potential side effects were discussed with Mr. R. He agreed to this treatment and was started on fluoxetine (20 mg). At the end of Week 16, Mr. R. returned with no new complaints, except for problems sleeping at night. His BDI score was 4. He was prescribed trazodone (50 mg po at bedtime). At the end of Week 17, his BDI score was 3 and IFN- was restarted at 8 million units/m2 subcutaneously 3 times a week. IFN- was increased to 18 million units/m2 subcutaneously 3 times a week at Week 18, and at the end of Week 19, his BDI score was 2. His BDI score gradually increased to 6 by Week 22 but then subsequently decreased while on the initial doses of fluoxetine and trazodone. He has remained without symptoms of depression and anxiety through Week 26 and his IFN- was increased again to 20 million units/m2 subcutaneously 3 times a week. He has remained symptom free.

Discussion

This is a case report of a 67-year-old man with a history of major depression who received IFN- to prevent recurrence of melanoma and who was also monitored closely with weekly BDIs to assess evolving symptoms of depression (see Figure 1). His history and BDI scores suggested that IFN- therapy rapidly precipitated depression on two separate occasions necessitating discontinuation of IFN- therapy before an antidepressant medication could be prescribed. On both occasions, discontinuation of IFN- therapy resulted in the resolution of depression within 1 to 2 weeks. Although lorazepam was prescribed for anxiety during the first episode of IFN-–induced depression, it is unlikely that lorazepam was the primary reason for the amelioration of depressive symptomatology. We confirmed this hypothesis by the resolution of the second episode of depression after discontinuation of IFN- therapy alone and without subsequent use of a psychopharmacologic intervention.

Fluoxetine (20 mg/day) was initiated 2 weeks before restarting IFN- therapy for the third time. Scores on the BDI and patient self-report suggested that fluoxetine suppressed the development of depressive symptomatology. This prophylactic treatment remained effective after Mr. R.'s dose of IFN- was increased from 8 million units/m2 to 18 million units/m2, 3 times per week, and then again increased from 18 million units/m2 to 20 million units/m2, 3 times per week. This prophylactic treatment allowed Mr. R. to continue on IFN- therapy, a treatment that he considered life-saving.

Treatment of IFN-–induced depression with an SSRI has been previously reported.¹⁰ Currently, there are no published studies documenting the efficacy of treating patients with antidepressant medication before initiating IFN- therapy. Our study suggests that the prophylactic use of SSRIs—fluoxetine in particular—may prevent the development of IFN-–induced depression in individuals with a history of depression. In addition, the prophylactic use of the SSRIs may benefit individuals not susceptible to depression, may reduce the incidence of depression induced by IFN-, and thereby increase the number of patients with cancer and hepatitis diagnoses who could benefit from interferon therapy. However, future studies are needed to address these issues as well as the issue of the risks and benefits of the prophylactic use of SSRIs versus waiting to treat once symptoms manifest. Furthermore, the specificity of SSRI treatment of IFN-–induced depression is not known, and future controlled studies using different classes of antidepressants must be conducted in order to begin to elucidate the pathophysiologic mechanism IFN- –induced depression.

ACKNOWLEDGMENTS

The authors are grateful to the various physicians who have referred patients to our research studies and to Mr. R., without whose cooperation the work could not have been done. The first author also wishes to thank Cathy Hauser and our new addition, Katia Kaylyn Rose, for editorial and other support. Finally the authors wish to thank Pat Hunt from Integrated Therapeutics and Schering- Plough, Inc., for their support of our investigator-initiated research studies on the CNS side effects of interferon.

REFERENCES

1. Silver RT: Chronic myelogenous leukemia, in Cancer Medicine. Philadelphia, PA, Lea & Febiger, 1993, pp 1934–1942
2. Kirkwood JM, Strawderman MH, Ernstoff MS, et al: Interferon alpha II-B: adjuvant therapy of high risk resected cutaneous melanoma. Focal and cooperative oncology group trial EST 1684. J Clin Oncol 1996; 14:7–17[Abstract]
3. Witt PL, Linder DJ, et al: Pharmacology of interferons: induced proteins, cell activation, and antitumor activity, in Cancer Chemotherapy and Biotherapy: Principles and Practice. Philadelphia, PA, Lippincott-Raven, 1996, pp 585–607
4. McHutchinson JG, Gordon SC, Schiff ER, et al: Interferon alpha- 2b alone or in combination with ribavirin as the initial treatment for chronic hepatitis C. N Eng J Med 1998; 339:1485–1492
5. Adams F, Quesada JR, Gutterman JU: Neuropsychiatric manifestations of human leukocyte interferon therapy in patients with cancer. JAMA 1984; 252:938–941[Abstract/Free Full Text]
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7. Triozzi PL, Kinney P, Rhinehart JJ: Central nervous system toxicity of biological response modifiers. Ann NY Acad Sci 1990; 594:347– 354[Medline]
8. Valentine AD, Meyers CA, Kling MA, et al: Mood and cognitive side effects of interferon alpha therapy. Seminars in Oncology 1998; 25:39–47[Medline]
9. Lincinio J, Kling MA, Hauser P: Cytokines and brain function: relevance to interferon-alpha-induced mood and cognitive changes. Seminars in Oncology 1998; 25:30–38[Medline]
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