Genetic and Biochemical Markers of Interferon-Induced Depression.

• Objective of project: Interferon-a (IFN)-induced depression is a common complication of its use in treating patients for hepatitis C (HCV), with reports of up to 44% of patients experiencing these depressive side effects. The central hypothesis of the proposed research is that polymorphisms in specific serotonergic genes are associated with a propensity to develop IFN-induced depression. Further, IFN-induced decreases in tryptophan and serotonin levels are putatively related to the emergence of depressive symptoms during IFN therapy. The objective of this proposal is to identify predictors of IFN-induced depression such that depressive side effects can be better managed and treated thus permitting patients to complete a full course of IFN therapy.
• Research plan: We plan to test our hypothesis and accomplish the objectives of this application by pursuing the following two specific objectives:

• to evaluate the role of genetic loci that may contribute to the vulnerability to IFN using association analyses. Vulnerability is operationalized as the maximal Beck Depression Inventory-II (BDI-II) score, co-varying for pre-treatment BDI-II scores, and
• to identify the effects and time course of antiviral therapy on potential biomarkers of IFN-induced depression, including tryptophan, 5-HT, and cortisol levels. Changes in biochemical levels will be compared to depressive symptomology and genetic vulnerability.
• Methodology: Patients will be asked to participate in a prospective study in which they will be monitored during the course of IFN therapy for symptoms of depression and for biochemical changes measured in their blood. 120 HCV patients initiating IFN therapy will be recruited (3/month for 40 months) from the Portland VA and the Long Beach VA Medical Centers. Following baseline assessments, subjects will be followed every 2 weeks for a period of 4 months. The development of major depression, depressive symptoms, and related IFN-induced side effects will be monitored using rating scales. For genetic and biochemical measures, blood samples will be collected prior to and during IFN therapy. Patients will be tested for certain genetic polymorphisms.

Analyses. Using linear regression, genotype will be the independent variable, and co-varying for baseline BDI-II score, the maximal BDI-II score will be examined as a dependent variable. An ANOVA for repeated measures will be performed to determine the effects of IFN therapy on tryptophan, 5-HT, and cortisol levels. In addition, the relationship between interferon induced MDD and certain polymorphisms will be examined.

• Findings, results or conclusions reached to date: In preliminary studies we found that 33% of HCV patients on IFN therapy developed major depressive disorder during the course of treatment. In addition, preliminary pilot results suggest that the 5-HT transporter polymorphism short allele and the "C" allele for the tryptophan hydroxylase polymorphism may increase vulnerability to IFN-induced depression.
• Clinical relevance: There are currently no known, reliable predictors of IFN-induced depression. The chronic disease of HCV infection collectively affects approximately 4 million Americans and 200 million people worldwide. IFN is the only clinically approved medication whose long-term use can reduce the risk of a fatal outcome and even be curative in some individuals. However, side effects associated with IFN therapy represent a major obstacle to adequate treatment for patients with HCV, often resulting in the discontinuation IFN therapy.

Inclusion criteria

• Serum positive for hepatitis C
• Age 18 or older
• Not pregnant and using adequate contraception
• Hepatologist-determined patient is a candidate for interferon therapy
• Written/signed informed consent specific for this protocol has been obtained prior to entry

Exclusion criteria

• Diagnosis of active: depression, psychotic symptoms, or bipolar disorder (or history of bipolar disorder) during the previous 3 months
• On antidepressant medications for any reason
• Currently abusing any substances such as alcohol or intravenous drugs, or having abused in the past 6 months.