The present results indicate that a polymorphism in the promoter region of IDO1 gene (rs9657182) predicts the development of moderate or severe depressive symptoms during IFN-α therapy in Caucasian subjects undergoing treatment for chronic hepatitis C. This finding, which remained significant after adjustment for multiple comparisons, was not found in a significantly smaller sample of African Americans, who exhibited an almost 50% lower frequency of the risk allele (C) and few CC homozygotes (n=9). Taken together, the data are consistent with the notion that IDO activity may play an important role in the pathophysiology of IFN-α-induced depression as well as depression induced by other forms of immune stimulation.
IDO is expressed in multiple immune cells throughout the body including monocytes, macrophages, microglia and dendritic cells and can be induced by a multiple cytokines such as IFN-α, IFN-γ and TNF-α. As noted previously, IDO activation leads to the breakdown of TRP into KYN, thereby reducing the availability of TRP, which not only is involved in the regulation of T cells,49
but also is the primary precursor of serotonin, a prominent neurotransmitter in the neurobiology of mood disorders.50–51
Activation of IDO plays a critical role in depressive-like symptoms in laboratory animals following exposure to inflammatory stimuli such as lipopolysaccharide (LPS) and bacille Calmette-Guérin (BCG), an attenuated form of Mycobacterium bovis.52–53
Treatment of mice with LPS or BCG induces IDO mRNA in the brain, and administration of the specific IDO inhibitor, 1-methyltryptophan, blocks both LPS- and BCG-induced increases in immobility during the forced swim and tail suspension tests.52–53
In addition, mice genetically deficient in IDO are resistant to depressive-like behaviors following BCG inoculation, despite induction of proinflammatory cytokines.53
Evidence of IDO activation (decreases in peripheral blood TRP and increases in peripheral blood KYN) also have been associated with depressive symptoms in humans including patients undergoing IFN-α treatment34–36,54–55
as well as patients with cancer and patients infected with HIV.56–57
Of note, peripheral administration of KYN alone can induce depressive-like behavior in laboratory animals.52,58
Blood borne KYN, which is a primary source for central nervous system (CNS) kynurenines, is taken up into the brain through the large amino acid transporter, where it is further metabolized in microglia and astrocytes to QUIN and KA, respectively.33
QUIN is an excitotoxic neuromodulator which promotes glutamate release through direct stimulation of N-methyl-D-aspartate receptors, while also inducing oxidative stress including lipid peroxidation.33,60–63
Increased CNS QUIN has been associated with several neurodegenerative disorders such as Alzheimer’s Disease, amyotrophic lateral sclerosis, and Huntington’s Disease, as well as the dementia complex associated with HIV infection.64–68
In contrast to QUIN, KA has been shown to antagonize glutamate release and block excitatory neurotransmission.33
Of relevance to depression, when injected into the striatum of rats, KA significantly reduces extracellular dopamine, a key neurotransmitter involved in motivation and reward circuitry.69
Recent data indicate that following IFN-α administration, increases in peripheral blood KYN are associated with significant increases in CSF KYN.70
Moreover, increased CSF KYN was accompanied by significant increases in both CSF KA and QUIN. Both CSF KYN and QUIN were significantly correlated with IFN-α-induced depression.70
Taken together with the association of variants in IDO1
with IFN-α-induced depression, these data provide strong reason to believe that IDO is an important pathway by which cytokines influence behavior.
Strengths and weaknesses of the study warrant consideration. A large sample of patients free of psychotropic medications and without significant depressive symptoms at baseline was exposed to standardized doses of a chronic immune stimulus, thereby allowing significant control of the gene-environment interaction that was the focus of the study. Moreover, assessment of depressive symptom severity was conducted via an automated, centralized data collection system, limiting variability across sites. In addition, baseline factors that may have influenced the development of moderate to severe depressive symptoms were assessed and included as covariates in statistical analyses where appropriate. Further, a significant number of patients exhibited moderate or severe depressive symptoms (CES-D >20) at treatment week 12 (n=124), and the primary study outcome variable (development of moderate or severe depressive symptoms) represents a clinically relevant endpoint that warrants IFN-α dosage reduction or discontinuation according to established treatment guidelines. Finally, the risk allele at rs9657182 locus (C) is common in Caucasians (66%) with 19% of Caucasian subjects being CC homozygotes.
Regarding weaknesses, the study had significantly reduced power to detect the association between rs9657182 (IDO1
) variants and IFN-α-induced depression in African Americans. In addition, it is unclear to what extent variants of rs9657182 may alter the function of IDO1
. Blood samples were not obtained for the purpose of measuring tryptophan or the IDO metabolite kynurenine. Moreover, the alleles of rs9657182 have not been shown to alter any transcription factor binding sites. Nevertheless, the rs9657182 resides in a linkage disequilibrium block encompassing the 20 kilobases upstream of IDO1
, which includes at least 6 additional polymorphisms (). Thus, rs9657182 may promote a change in gene function on its own (independent of effects on transcription factor binding), or through association with one of the other polymorphisms tagged by rs9657182, several of which appear to alter consensus binding sites of factors involved in the transcription of a variety of genes (e.g. GATA1, GATA3 and ETS1). Of note, the second IDO polymorphism (rs7820268) that was found to be associated with IFN-alpha-induced depressive symptoms is in weak linkage disequilibrium with rs9657182 (r2
=0.26)(). These data provide further evidence of an impact of polymorphisms within this region of the IDO1
gene on IFN-alpha-induced depressive symptoms, warranting detailed functional assays to elucidate the potential importance of this region. Of note, the current study did not replicate previous findings regarding a SNP in the promoter region of the IL-6 gene (rs1800795) which predicted IFN-alpha-induced depressive symptoms.21
Discrepancies may relate to differences in study endpoints which were development of moderate to severe depression in the current study and change of depressive symptoms from baseline in the previous study. Finally, it should be mentioned that there were no standardized clinician-administered assessments to establish a diagnosis of major depression, the severity of depressive symptoms, or a past history of either substance abuse or psychiatric disorder. Nevertheless, despite these limitations, past history of psychiatric disorder as well as baseline depressive symptoms were significant predictors of depression during IFN-α therapy as has been reported previously.15
In summary, the association of a polymorphism in the promoter region of the IDO1 gene with significant depressive symptoms during chronic exposure to IFN-α provides further support for the role of IDO in cytokine-induced behavioral pathology. Moreover, the results suggest that IDO and its downstream products including KYN, KA and QUIN represent novel biomarkers and/or treatment targets for management of behavioral changes secondary to IFN-α and/or chronic immune stimulation.