Functional imaging of the interaction between interferon-alpha and serotonin in the brain

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

University of Pittsburgh

Department of Psychology
Funded in September, 2012: $200000 for 3 years


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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.



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Major depression is very common, disabling, and often difficult to fully treat to remission.  In many cases, inflammation has been implicated in depression’s etiology.  As one instance of this, administration of interferon-alpha (IFN-alpha) to non-depressed patients results in about 25% developing depression within 8-12 weeks of weekly IFN-alpha therapy.  This situation proffers the unique opportunity to prospectively examine (i) what is changing in the brains of subjects as they develop depression and (ii) determining sources of pre-existing vulnerability and resilience.  It is currently known that IFN-alpha may influence the serotonin (5-HT) system at multiple levels: (i) increasing enzymatic activity to shunt tryptophan away from 5-HT synthesis, (ii) affecting 5-HT release at synapses, (iii) increasing reuptake of 5-HT at synapses, and (iv) altering expression of post-synaptic 5-HT receptors. We’ve determined that genetic influences on 5-HT reuptake sites influences vulnerability to depression during IFN-alpha therapy.  We are therefore now interested in determining the functional consequences of this interaction between inflammation and 5-HT in the emotional circuitry of the brain.  It is possible that serotonin’s ability to modulate emotional neuro-circuitry is either (A) a pre-existing vulnerability to depression and/or (B) is influenced by IFN-alpha in such a way as to trigger a depressive episode.  5-HT modulation of brain function can be measured using intravenous injections of the 5-HT reuptake inhibitor citalopram, which acutely increases synaptic 5-HT, and which can thereby modulate fMRI BOLD (and/or arterial spin labeling) signals in response to emotionally salient stimuli.  We propose to employ this pharmaco-imaging technique before IFN-alpha therapy is started and then again about 3 weeks into therapy.  We will examine whether 5-HT modulation of activity in limbic and corticolimbic areas (e.g., amgydala, orbito-frontal cortex, ventrolateral prefrontal cortex, anterior cingulate, hippocampus, insula) prior to IFN-alpha therapy (and again during IFN-alpha therapy) is associated with subsequent depression development (diagnosed using both structured interviews and measured using questionnaires prospectively during treatment with IFN-alpha).


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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.