Neural Correlates of Cytokine-Induced Depression:

Focus on Pre-Synaptic Striatal Dopamine Function

Lucile Capuron, Ph.D.

Emory University, Atlanta, GA

Grant Program:

David Mahoney Neuroimaging Program

Funded in:

September 2003, for 4 years

Funding Amount:

$100,000

Abstract

Neural Correlates of Cytokine-Induced Depression: Focus on Pre-Synaptic Striatal Dopamine Function

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.

Hypothesis

Hypothesis:
Recent theories have proposed that proinflammatory cytokines, released during inflammation, may participate in the development of depression and other behavioral alterations in the medically ill. The pathways involved have yet to be elucidated. The fundamental hypothesis to be tested in this proposal is that cytokines alter striatal dopamine function, which in turn underlies the development of specific neuropsychiatric symptoms, including most notably anhedonia, psychomotor slowing, fatigue/anergia, and affective flattening. As a model system, we will study patients with chronic hepatitis C undergoing treatment with the cytokine, interferon (IFN)-α. IFN-α is a potent inducer of proinflammatory cytokines, including interleukin (IL)-6, and causes symptoms of depression in 30-50% of patients. Thus, IFN-α-induced depression provides a unique opportunity to further understand the neural substrates of cytokine-induced mood disorders.

Goals:
To determine the effects of the cytokine IFN-α on pre-synaptic striatal dopamine function in patients with chronic hepatitis C using PET with [18F]fluorodopa ([18F]DOPA), and to assess the relationship between IFN-α-induced neuropsychiatric/neurovegetative symptoms and dopamine function as measured by PET. These aims are designed to elucidate the neural correlates of cytokine-induced depression in medically ill patients. By characterizing the neurochemical pathways involved, the present work will help identify relevant targets for the diagnosis and treatment of depression in the medically ill.

Methods:
Twelve patients with chronic hepatitis C eligible to receive treatment with PEG-IFN-α plus ribavirin will be enrolled in the study. At baseline (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. 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. 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.

Findings:
Lay Results:
This project evaluated the mechanisms by which medical illnesses are associated with high rates of depression and fatigue. Using brain imaging, the study identified alterations in the metabolism of dopamine, a key neurotransmitter in the regulation of multiple behaviors including mood, motivation/reward, motor activity, sleep, and cognition. The results indicate that dopamine is a key target for future studies on the diagnosis and treatment of behavioral problems, including depression and fatigue, in medically ill patients.

Scientific Results:
This project investigated the impact of the innate immune cytokine, interferon (IFN)-α, on basal ganglia dopamine metabolism as a method to understand pathophysiologic pathways by which medical illnesses are associated with high rates of behavioral co-morbidities, such as depression and fatigue. Using positron emission tomography and 6-[18F]-fluoro-L-dopa (FDOPA), we found markedly increased rates of FDOPA uptake in the caudate and putamen secondary to IFN-α administration using a pre-post design. The results indicate increased synthetic activity in presynaptic dopamine neurons, possibly secondary to reduced inhibitory feedback through activation of dopamine autoreceptors. Given the hypodopaminergic phenotype seen in IFN-α-treated patients, these data suggest that one mechanism by which innate immune cytokines may contribute to symptoms of depression and fatigue is through depletion of dopamine in relevant basal ganglia nuclei.

Selected Publications

Capuron L., Raison C., Musselman D.L., Lawson D.H., Nemeroff C.B., and Miller A.H. Association of exaggerated HPA axis response to the initial injection of interferon-α with development of depression during interferon-α therapy. Am J Psychiatry. 2003 Jul;160(7):1342-5 .

Capuron L., Gumnick J.F., Musselman D.L., Lawson D.H., Reemsnyder A., Nemeroff C.B., and Miller A.H. Neurobehavioral effects of interferon-α in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology. 2002 May;26(5):643-52 .

Capuron L., Pagnoni G., Lawson D.H., Demetrashvili M., Woolwine B., Kilts C.D., Bremner J.D., Nemeroff C.B., and Miller A.H. (2002). Altered fronto-pallidal activity during high-dose interferon-α treatment as determined by positron emission tomography. Washington, DC: Soc Neurosci, Abstr. 498.5

Capuron L., Neurauter G., Lawson D.H., Musselman D.L., Nemeroff C.B., Fuchs D., and Miller A.H. Interferon-α-induced changes in tryptophan metabolism: Relationships to depression and paroxetine treatment. Biol Psychiatry. 2003 Nov 1;54(9):906-14.

Capuron L. and Ravaud A. Prediction of the depressive effects of interferon alfa therapy by the patient’s initial affective state. N Engl J Med. 1999 Apr 29;340(17):1370 .