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Depression and interferon-alpha therapy

Beaumont Hospital, PO Box 1297, Beaumont Road, Dublin 9, Republic of Ireland

EDITED BY LOUISE HOWARD

In their case report, McAllister-Williams et al (2000) hypothesise that recurrence of major depression following treatment with interferon-alpha (IFN) is related to its capacity to impair serotonin synthesis by inducing enzymes that degrade tryptophan and they cite in vitro evidence in support of this. We suggest that there are other in vivo biological effects of this treatment, which may explain the association of IFN with depression.

First, it is possible that the pathogenesis of depressive symptoms following treatment with IFN is related to disturbance of the hypothalamic-pituitary-adrenal (HPA) axis. Overactivity of the HPA axis occurs commonly in people with major depressive disorder (Dinan, 1994), the rates of overactivity increasing with growing severity of depression. There is evidence to suggest that the effects of antidepressants on mood may be brought about by re-equilibration of the HPA axis (Barden et al, 1995). Exogenous IFN therapy has been found to increase plasma adrenocorticotrophic hormone (ACTH) and serum cortisol in humans (Shimizu et al, 1995). The mechanism, however, does not appear to be a direct one as exogenous IFN is a polypeptide that does not cross the blood-brain barrier and direct application of IFN to cultured pituitary cells does not release ACTH. Indirect effects of exogenous IFN on the HPA axis may occur through activation of endogenous cytokines, specifically interleukin-6 (IL-6) which is known to stimulate release of corticotrophin-releasing factor from rat hypothalamus in vitro. Furthermore, increase in serum IL-6 following in vivo IFN is positively correlated with the IFN-induced changes in serum cortisol (Shimizu et al, 1995).

Second, the possible effects of IFN on tryptophan availability to which the authors refer may be a secondary effect of immune system activation. Major depression is associated with an activation of the immune-inflammatory response system, with cell-mediated increases in serum levels of pro-inflammatory cytokines including IL-6. Reduced availability of tryptophan in depression may be a result of this inflammatory response activation (Song et al, 1997). Exogenous IFN also activates pro-inflammatory cytokines.

Paradigms about the aetiology of major depressive disorder are expanding beyond a narrow monoamine-centred concept. Clearly, stress, either medical or psychological, is important in the aetiology of depression. The major stress axis, the HPA, which is overactive in major depression, is potently activated by both exogenous and endogenous cytokines.

We suggest, therefore, that these biological pathways are important in the pathophysiology of depression during treatment with IFN.

REFERENCES

Barden, N., Reul, J. M. & Holsboer, F. (1995) Do antidepressants stabilise mood in depression through actions on the hypothalamic-pituitary-adrenal system? Trends in Neuroscience, 18, 6-17.[CrossRef][Medline]

Dinan, T. G. (1994) Glucocorticoids and the genesis of depressive illness. A psychobiological model. British Journal of Psychiatry, 164, 365-371.[Abstract/Free Full Text]

McAllister-Williams, R. H., Young, A. H. & Menkes, D. B. (2000) Antidepressant response reversed by interferon (letter). British Journal of Psychiatry, 176, 93.[Free Full Text]

Shimizu, H., Ohtani, K., Sato, N., et al (1995) Increase in serum interleukin-6, plasma ACTH and serum cortisol levels after systemic interferon- administration. Endocrine Journal, 42, 551-556.[Medline]

Song, C., Lin, A., Bonaccorso, S., et al (1998) The inflammatory response system and the availability of plasma tryptophan in patients with primary sleep disorders and major depression. Journal of Affective Disorders, 49, 211-219.[CrossRef][Medline]

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