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Safety of the Treatment of Interferon-Alpha-Induced Depression

TO THE EDITOR: It is well accepted that interferon-alpha (IFN-) causes depressive symptoms in patients who receive it for the treatment of chronic hepatitis C, multiple sclerosis, melanoma, and other malignancies.¹ Depression is reported to be the most common severe side effect and the most common reason for IFN- dose modification or discontinuation.² In carefully controlled studies, the frequency of IFN--induced depression meeting criteria for a major depressive episode is as high as 33%.³ However, it is important to distinguish symptoms of depression that may be subsyndromal from criterion-based major depression before antidepressant treatment is initiated.

In their article, Dieperink et al.⁴ recommend using the Beck Depression Inventory to determine the need for antidepressant treatment before and during IFN- therapy. While the use of depression rating scales for regular screening and monitoring of patients before and during IFN- is encouraged,⁵ the authors recommended, based on their prospective study of 42 subjects, using cutoff scores such that a score of 15 or more would strongly suggest that antidepressant treatment be initiated. Dieperink et al.⁴ confirmed our findings that patients with elevated baseline scores on the Beck Depression Inventory have a greater risk for the development of IFN--induced depression,³ however, they used these data to suggest that patients with baseline Beck Depression Inventory scores above 6 may benefit from prophylactic antidepressant treatment, even though Beck Depression Inventory scores less than 10 suggest that patients are asymptomatic. They also recommended that prophylactic antidepressant treatment should be considered for all patients with baseline Beck Depression Inventory scores above 10.

There is potential risk in this approach in that Dieperink et al. recommended antidepressant use for an indication not yet approved by the Food and Drug Administration. The possibility of adverse events should be carefully considered. Specifically, there is the potential for increased retinal hemorrhaging and cotton wool spots. Incidences of retinopathy in patients receiving IFN- have ranged from 18% to 86% and are found more frequently in older patients and in patients with hypertension and/or diabetes mellitus.⁶ In a report by Hejny et al.,⁷ the authors described seven patients who developed retinopathy secondary to IFN- therapy. Of importance, six of these patients were also receiving antidepressant treatment with paroxetine, a selective serotonin reuptake inhibitor (SSRI). Similarly, the occurrence of retinal hemorrhage in a study of paroxetine prophylaxis for IFN--treated patients with melanoma was three of 20, and for one of these patients, the hemorrhages were reportedly irreversible.⁸

Another concern is the likelihood that SSRIs increase the risk of gastrointestinal bleeding.^9,10 Patients with hepatitis C and compromised liver function are at a greater risk for gastrointestinal bleeding. This risk is compounded by IFN- therapy and the common concomitant use of nonsteroidal anti-inflammatory drugs such as aspirin.

The mechanisms associated with IFN--induced retinopathy and abnormal bleeding with SSRI treatment are poorly understood. However, it is known that paroxetine and other SSRIs can bind to platelet serotonin uptake sites and subsequently alter cellular function.¹¹ In particular, SSRIs can decrease intraplatelet serotonin content, inhibit platelet function, and block pulmonary endothelial metabolism of serotonin, which may result in bleeding complications.^12,13 The risk of increasing the incidence of retinopathy by giving SSRIs to patients receiving IFN- therapy are unknown. Although there are certainly benefits of SSRI treatment for IFN--induced depression, we should not have a blanket policy of prescribing SSRIs to such patients until research is conducted that describes the risks and benefits of SSRI use in patients receiving IFN- therapy. Only then can clinicians explain the risks and benefits to their patients and patients can make informed decisions about SSRI treatment.

We know of no published controlled studies that have investigated prophylactic antidepressant treatment of patients with hepatitis C. We are currently involved in two double-blind, placebo-controlled studies to assess the effects of prophylactic antidepressant treatment on depressive symptoms associated with IFN- therapy in patients with chronic hepatitis C. Results from similar studies and ours will help to define the efficacy and safety of prophylactic antidepressant treatment as well as premature antidepressant treatment in patients who have some symptoms of depression but do not meet the criteria for IFN--induced major depression.

REFERENCES

1. Malek-Ahmadi P: Mood disorders associated with interferon treatment: theoretical and practical considerations. Ann Pharmacother 2001; 35:489–495[Abstract]
2. Kraus MR, Schäfer A, Csef H, Scheurlen M, Faller H: Emotional state, coping styles, and somatic variables in patients with chronic hepatitis C. Psychosomatics 2000; 41:377–384[Abstract/Free Full Text]
3. Hauser P, Khosla J, Aurora H, Laurin J, Kling MA, Hill J, Gulati M, Thornton AJ, Schultz RL, Valentine AD, Meyers CA, Howell CD: A prospective study of the incidence and open-label treatment of interferon-induced major depressive disorder in patients with hepatitis C. Mol Psychiatry 2002; 7:942–947[CrossRef][Medline]
4. Dieperink E, Ho SB, Thuras P, Willenbring ML: A prospective study of neuropsychiatric symptoms associated with interferon--2b and ribavirin therapy for patients with chronic hepatitis C. Psychosomatics 2003; 44:104–112[Abstract/Free Full Text]
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8. Musselman D, Lawson D, Gumnick J, Manatunga AK, Penna S, Goodkin RS, Greiner K, Nemeroff CB, Miller AH: Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med 2001; 344:961–966[Abstract/Free Full Text]
9. de Abajo FJ, Rodriguez LA, Montero D: Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study. Br Med J 1999; 319:1106–1109[Abstract/Free Full Text]
10. van Walraven C, Mamdani MM, Wells PS, Williams JI: Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study. Br Med J 2001; 323:655–658[Abstract/Free Full Text]
11. Helmeste DM, Tang SW, Reist C, Vu R: Serotonin uptake inhibitors modulate intracellular Ca2+ mobilization in platelets. Eur J Pharmacol 1995; 288:373–377[CrossRef][Medline]
12. Skop BP, Brown TM: Potential vascular and bleeding complications of treatment with selective serotonin reuptake inhibitors. Psychosomatics 1996; 37:12–16[Abstract/Free Full Text]
13. Hergovich N, Aigner M, Eichler HG, Entlicher J, Drucker C, Jilma B: Paroxetine decreases platelet serotonin storage and platelet function in human beings. Clin Pharmacol Ther 2000; 68:435–442[CrossRef][Medline]

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