1. ¹King's College London, Section and Laboratory of Stress, Psychiatry and Immunology, Institute of Psychiatry, London, UK
2. ²MRC SGDP Centre, Institute of Psychiatry, King's College London, London, UK
3. ³Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
4. ⁴Division of Psychological Medicine and Psychiatry, Institute of Psychiatry, King's College London, Weston Education Centre, London, UK
5. ⁵Section of Neurobiology of Mood Disorders, Division of Psychological Medicine and Psychiatry, Institute of Psychiatry, King's College London, London, UK
6. ⁶Department of Hepatology, St James's Hospital, Dublin, Ireland
7. ⁷Department of Psychiatry, Cork University Hospital, Cork, Ireland

Correspondence: Dr CM Pariante, King's College London, Section and Laboratory of Stress, Psychiatry and Immunology, Institute of Psychiatry, Division of Psychological Medicine and Psychiatry, Centre for the Cellular Basis of Behaviour, The James Black Centre, 125 Coldharbour Lane, London SE5 9NU, UK. E-mail: c.pariante@iop.kcl.ac.uk

Received 29 March 2007; Revised 12 February 2008; Accepted 11 March 2008; Published online 6 May 2008.

Abstract

Depression and fatigue are frequent side effects of interferon- (IFN-) treatment, and there is compelling evidence that the inflammatory response system (including interleukin-6, IL-6) and the serotonergic system is important in the pathophysiology of such symptoms. Functional polymorphisms in the promoter region of the IL-6 gene (rs1800795) and serotonin transporter gene (5-HTTLPR) have been identified as regulating these systems. The present study aimed to determine if these polymorphisms were associated with the development of depression and fatigue during IFN- and ribavirin treatment. Ninety-eight Caucasian patients receiving pegylated IFN- and ribavirin treatment for chronic hepatitis C virus at King's College Hospital, London, and Emory University Hospital, Atlanta, participated in this prospective cohort study. Symptoms of depression and fatigue were measured before treatment and at weeks 4, 8, 12 and 24 during treatment. The 'low IL-6' synthesizing genotype (CC) was associated with significantly fewer symptoms of depression (effect size=0.7 at week 24; F=9.4, d.f.=436, P=0.002). The 'high transcription' serotonin transporter (5-HTT) genotype (LL) was also associated with significantly fewer symptoms of depression, but with a much smaller effect (effect size=0.2 at week 24; F=4.5, d.f.=436, P=0.03). Neither polymorphisms were associated with symptoms of fatigue (IL-6: F=1.2, d.f.=430, P=0.2; 5-HTT: F=0.5, d.f.=430, P=0.5). The smaller effects of the 5-HTT polymorphism on depression may be explained by an interaction between the genes (F=5.0, d.f.=434, P=0.02): the 'protective' effect of the 5-HTTLPR polymorphism was evident only in the presence of the 'low IL-6' genotype (F=5.4, d.f.=64, P=0.02), not in the presence of the 'high IL-6' genotype (F=2.2, d.f.=369, P=0.1). The association between the IL-6 polymorphism and reduced risk of depressive symptoms confirms the role of the inflammatory response system in the pathophysiology of IFN--induced depression; in contrast, the effect of the 5-HTT gene was small and perhaps dependent on the status of the inflammatory response.