In their case report, McAllister-Williams et al (Reference McAllister-Williams, Young and Menkes2000) hypothesise that recurrence of major depression following treatment with interferon-alpha (IFNα) 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 IFNα with depression.

First, it is possible that the pathogenesis of depressive symptoms following treatment with IFNα is related to disturbance of the hypothalamic-pituitary-adrenal (HPA) axis. Overactivity of the HPA axis occurs commonly in people with major depressive disorder (Reference DinanDinan, 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 (Reference Barden, Reul and HolsboerBarden et al, 1995). Exogenous IFNα therapy has been found to increase plasma adrenocorticotrophic hormone (ACTH) and serum cortisol in humans (Reference Shimizu, Ohtani and SatoShimizu et al, 1995). The mechanism, however, does not appear to be a direct one as exogenous IFNα is a polypeptide that does not cross the blood-brain barrier and direct application of IFNα to cultured pituitary cells does not release ACTH. Indirect effects of exogenous IFNα 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 IFNα is positively correlated with the IFNα-induced changes in serum cortisol (Reference Shimizu, Ohtani and SatoShimizu et al, 1995).

Second, the possible effects of IFNα 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 IFNα 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 IFNα.