Medically ill patients experience depression 5-10 times more often than the general population. In addition, depression in the medically ill is associated with reduced treatment adherence, reduced quality of life, and, most importantly, increased morbidity and mortality. Although the etiology of depression in the medically ill remains to be elucidated, there has been an increasing interest in the potential contribution of proinflammatory cytokines. Recent theories have proposed that proinflammatory cytokines, which are released during inflammatory processes that accompany a wide range of illnesses, induce neurobiological and behavioral changes that overlap with those seen in depression.
The long-term objectives of the proposed work are to further elucidate the neural correlates of this cytokine-induced depressive syndrome and to establish its relevance to mood disorders in the medically ill. As a model system to study cytokine-induced depression, we will examine patients with chronic hepatitis C undergoing treatment with the cytokine interferon (IFN)-α. IFN-α is a potent inducer of proinflammatory cytokines, especially interleukin (IL)-6, and causes depressive symptoms in 30-50% of patients, depending on the dose. In addition to its impact on the patient's quality of life and compliance to treatment, the occurrence of depressive symptoms during IFN-α therapy may also compromise treatment efficacy. The mechanisms by which IFN-α induces neuropsychiatric symptoms. as well as the management strategies of these effects. remain to be elucidated. Recent data obtained by our group support the hypothesis of fronto-striatal dysfunction, possibly mediated by dopamine down-regulation, during IFN-α treatment.
The objectives of the present study are 1) to assess changes in pre-synaptic striatal dopamine function during IFN-α therapy using PET with [18F]fluorodopa ([18F]DOPA) and 2) to determine the relationship between IFN-α-induced neuropsychiatric/neurovegetative symptoms and dopamine function as measured by PET. Twelve patients with chronic hepatitis C (HCV) eligible to receive treatment with PEG-IFN-α plus ribavirin will be enrolled in the study. At baseline (i.e., before initiating IFN-α therapy) and after 12 weeks of IFN-α therapy, patients will undergo a PET scan using [18F]DOPA followed by neuropsychiatric assessments. In addition, a magnetic resonance imaging (MRI) will be acquired at baseline in order to improve brain image resolution for the study of specific brain regions of interest. [18F]DOPA (5.5 mCi) will be injected through a catheter inserted into a vein. Brain scanning will start immediately after the injection of the tracer. Data for nine time frames of 10 minutes each will be collected using a Siemens ECAT 921 tomograph. For data analysis, regions of interest will be will drawn on the aligned MRI slices in which the caudate and putamen are readily visible, and the regions will be copied onto the PET images. Occipital cortex regions of interest, in which [18F]DOPA uptake is assumed to be negligible, will be used as reference regions. Regional [18F]DOPA uptake rates (Ki values) will be computed from the regional time-activity curves obtained between 30 and 90 minutes by using the Patlak graphical analysis method. Changes in dopamine activity in these regions of interest between baseline and 12 weeks of IFN-α will be assessed and correlated with specific neuropsychiatric symptoms, including psychomotor slowing, anhedonia and affective flattening.
By identifying the fundamental neurochemical alterations associated with IFN-α, this study will help define relevant therapeutic targets for the treatment of IFN-α-induced behavioral symptoms. By extension, such targets also should be relevant to treating depression in the medically ill.
