Thirty-nine percent of euthymic subjects developed MDD, consistent with a growing literature [3
], although this literature is complicated by retrospective, non-standardized diagnoses, and/or the present of active baseline mood disorder or antidepressants [23
]. Notably, this study was specifically designed to prospectively assess IFN-α's effects while avoiding confounding biases from active neuropsychiatric illness and/or co-prescribed psychoactive medications.
Three orthogonal sets of symptoms were worsened following IFN-α: depression (BDI and HADS), hostility and anxiety (subscales within the SCL-90), and general symptoms on other SCL-90 subscales. This is consistent with a prior observation that IFN-induced depression-specific symptoms are distinct from general somatic and fatigue symptoms [8
]. IFN-induced “MDD” may, in fact, potentially reflect a combination of three different phenomena (depression-specific, anxiety/hostility, and general psychiatric/somatic complaints).
The only factor predicting BDI at month one was the baseline BDI, which was consistent with multiple prior reports [23
], and which highlights the importance of controlling for baseline BDI in our assessments. Personality styles have been proposed to increase vulnerability to depression, although there have been many methodological problems [49
]; for example, depression or subsyndromal depression can contaminate measures of personality such as neuroticism. In our prospective study, the development of a categorical DSM-IV MDE was predicted by a combination of high neuroticism and low agreeableness, when controlling for baseline BDI. The low pre-treatment agreeableness appeared to be related to the development of increased hostility on IFN-α. This supports the hypothesis that personality can independently influence vulnerability, even to a biologic trigger such as IFN-α.
Surprisingly, a past history of MDE did not predict vulnerability to IFN-induced depression. This may reflect several possibilities: difficulties with accurately diagnosing past MDE retrospectively using the SCID, different “types” of MDE have different vulnerabilities, this could have been the first time for some subjects to encounter a truly depressogenic stimulus, we excluded patients with active MDD, and/or vulnerability may change over the life-span.
Important caveats include: (i) Many HCV patients already have co-morbid psychiatric disorders [50
]. This study was designed to assess IFN-α's influence on euthymic subjects, limiting clinical generalizability to this specific group. (ii) Depression symptoms would likely worsen in the absence of intervention. This was effectively censored by psychiatric treatment, necessary for ethical reasons and necessitating our focus on one month for quantitative data. (iii) A placebo control was not used. However, we estimate that less than 1% developed MDD unrelated to the IFN-α treatment -- given that the incidence of MDD in medical illness is about 2% per year [53
]. (iv) We did not control for the dose and brand of ribavirin or pegylated IFN-α2. Whether different brands (e.g. PEG-IFN-α2b vs PEG-IFN-α2a vs. non-pegylated) and/or doses can differentially influence these psychiatric side effects will require future controlled trials.
In summary, this study supports the conclusion that even pegylated IFN-α can induce major depression, and it can do so in patients without a history of major depression. Moreover, IFN-α can trigger a distinct condition of worsening hostility. Prophylactic therapy has been considered for euthymic patients to prevent IFN-α-induced depression [20
], but this may not be risk free [20
]. The results from this study suggest that vulnerability may be clinically predictable, and therefore prophylaxis could be appropriately targeted. This may have implications both for understanding vulnerability to MDD as well as for appropriately targeting prophylactic antidepressant therapy.