Functional Imaging of the Interaction Between Interferon-Alpha and Serotonin in the Brain

Francis E. Lotrich, M.D., Ph.D.

University of Pittsburgh, Pittsburgh, PA, Department of Psychology

Grant Program:

David Mahoney Neuroimaging Program

Funded in:

September 2012, for 3 years

Funding Amount:


Lay Summary

Imaging may reveal how major depressive disorder develops and identify those at risk

Investigators will use BOLD fMRI and “arterial spin labeling” to explore how neural transmission of serotonin is altered in people who develop major depressive disorder in the presence of inflammation, and to identify factors that may determine pre-existing vulnerability or resilience to developing this disorder.

Major depressive disorder (MDD) involves abnormalities in serotonin transmission in brain networks involved in emotion. MDD is also associated with elevated brain levels of inflammatory molecules called cytokines that enter the brain in response to infections, and other factors. Direct evidence that MDD is linked to inflammation comes from the finding that about 25 percent of non-depressed people with hepatitis C virus develop MDD while being treated with interferon, which mounts an inflammatory attack against the virus. Inflammation interacts with serotonin at multiple stages, including when brain cells release serotonin for use by their neighbors and then take some it back up. The investigators had previously found that genetic factors can lead to a change in the molecule that takes serotonin back up, thereby affecting the amount of serotonin seen by neighboring cells. They hypothesize, therefore, that people’s pre-existing level of serotonin reuptake may predict whether or not they will be vulnerable or resilient to developing MDD during inflammation; and, that imaging can identify and therefore predict patients at risk of developing MDD during interferon treatment.

Using both BOLD fMRI and fMRI with arterial spin labeling contrast, the investigators can detect differences in brain function in people with different genotypes, and also the effects on regional brain function of chronically administered interferon treatment .Investigators will image brain regions involved in emotion in 40 non-depressed people with hepatitis C while they view pictures of emotion-laden faces and neutral shapes. Imaging will be undertaken before and again once during a several month-long course of weekly interferon treatment. Patients also will be clinically evaluated for evidence of MDD, and provided treatment if they develop it. Investigators will compare imaging results of serotonin functioning in those who do and do not develop MDD, and also will compare each patient’s images taken before and after interferon treatment to determine: 1) whether base-line (pre-treatment) imaging shows alterations in serotonin functioning that predict those at risk for developing MDD; and 2) how serotonin functioning differs among those who develop MDD compared to those who remain depression-free.

Significance: Findings may help to determine processes involved in developing MDD, identify targets for drugs that prevent or treat MDD in association with inflammation, and provide the first step for developing a biomarker for predicting those at risk.

Investigator Biographies

Francis E. Lotrich, M.D., Ph.D.

Dr. Francis Lotrich is a board-certified psychiatrist, currently assistant professor at the University of Pittsburgh Medical Center (UPMC) and Western Psychiatric Institute and Clinic (WPIC). He received his undergraduate training in biology at Reed College in Portland, OR.  Following this, he obtained both an M.D. at the Oregon Health Sciences University as well as a Ph.D. in Behavioral Neuroscience.  His subsequent training in psychiatry was at WPIC in Pittsburgh, PA.  His research interests have focused on depression, and specifically why some people develop this disorder and others don’t.  He is likewise interested in why treatments work in some people and not others.  This has led to a more specific focus on how and why inflammation triggers depression in some people and not others. One major approach being used is to examine the effects of interferon-alpha in both humans and mice.  In humans about 25% develop depression following injections with interferon, though most do not. A number of techniques are being employed to compare those on interferon therapy: PET scans, fMRI scans, polysomnography, genetics, etc. The goal is the development of more targeted and specific interventions to either treat or prevent depression.