Changes in Plasma Tetrahydrobiopterin Levels of Depressives in Depressive and Remission Phases: Reconfirmed by Measurement with an Internal Standard

Mizutani, M; Ohta, Tatsuro; Nakazawa, Ken; Nagatsu, Toshiharu

doi:10.1159/000119064

Cited by 22 publications

(15 citation statements)

References 6 publications

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“…Central BH2 concentrations were significantly elevated during IFN-alpha administration, and the percent of total biopterins comprised of BH4 was significantly reduced, indicating potential inflammatory-cytokine-induced stimulation of GTP-cyclohydrolase I activity and BH4 synthesis that is rapidly oxidized to BH2 (Cunnington and Channon 2010). Interestingly, previous studies have reported similar findings of increased total biopterins and decreased ratio of BH4 to total biopterins in the plasma of patients with major depression (Hashimoto et al 1994; Hashimoto et al 1990). In the present study, a significant correlation between decreased CSF BH4 and increased CSF IL-6 concentrations, and a trend for a positive association between decreased CSF BH4 and HVA concentrations, was observed in spite of a small sample size.…”

Section: Discussionsupporting

confidence: 73%

Tyrosine metabolism during interferon-alpha administration: Association with fatigue and CSF dopamine concentrations

Felger

Marvar

et al. 2013

Brain, Behavior, and Immunity

154

106

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Chronic exposure to interferon (IFN)-alpha, an innate immune cytokine, produces high rates of behavioral disturbances, including depression and fatigue. These effects may be mediated by the actions of IFN-alpha on dopamine (DA) metabolism in the basal ganglia. Diminished conversion of phenylalanine (Phen) to tyrosine (Tyr), the primary amino acid precursor of DA, has been associated with inflammation, and may reflect decreased activity of the enzyme phenylalanine-hydroxylase (PAH). This study investigated the peripheral Phen/Tyr ratio in relation to cerebrospinal fluid (CSF) concentrations of DA and its metabolites in subjects treated with IFN-alpha plus ribavirin for hepatitis C and controls awaiting IFN-alpha therapy. Plasma Phen/Tyr ratios were significantly increased in IFN-alpha-treated subjects (n=25) compared to controls (n=9), and were negatively correlated with CSF DA (r=−0.59, df=15, p<0.05) and its metabolite, homovanillic acid (r=−0.67, df=15, p<0.01), and positively correlated with fatigue (r=0.44, df=23, p<0.05) in IFN-alpha-treated patients but not controls. Given the role of tetrahydrobiopterin (BH4) in the PAH conversion of Phen to Tyr, CSF concentrations of BH4 and its inactive oxidized form, dihydrobiopterin (BH2), were examined along with CSF interleukin (IL)-6 in a subset of patients. BH2 concentrations were significantly increased in IFN-alpha-treated patients (n=12) compared to controls (n=7), and decreased CSF BH4 concentrations correlated with increased CSF IL-6 (r=−0.57, df=12, p<0.05). These results indicate that IFN-alpha is associated with decreased peripheral conversion of Phen to Tyr, which in turn is associated with reduced DA in the brain as well as fatigue. These alterations may be related to oxidation of BH4 secondary to IFN-alpha-induced activation of a CNS inflammatory response.

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Section: Discussionsupporting

confidence: 73%

Tyrosine metabolism during interferon-alpha administration: Association with fatigue and CSF dopamine concentrations

Felger

Marvar

et al. 2013

Brain, Behavior, and Immunity

154

106

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“…One of these enzymes is GTP-cyclohydrolase 1 (GTP-CH1) (Felger and Miller, 2012;Haroon et al, 2012), which produces neopterin at the expense of tetrahydrobiopterin, or BH4, a co-factor essential for dopamine and serotonin biosyntheses (Capuron et al, 2011c;Murr et al, 2002;Oxenkrug et al, 2011). Consistent with the hypothesis that inflammation-induced alterations in the GTP-CH1 pathway contributes to the development of neuropsychiatric symptoms, reduced BH4 levels are reported in patients with psychiatric disorders (Hashimoto et al, 1994;Hoekstra et al, 2001). Similarly, increased blood neopterin concentrations correlate with a higher number of depressive episodes in patients with major depression (Celik et al, 2010).…”

Section: Neuropsychiatric Effects Of Inflammation: Evidence and Mechamentioning

confidence: 87%

Role of Adiposity-Driven Inflammation in Depressive Morbidity

Capuron

Lasselin

Castanon

2016

Neuropsychopharmacol

138

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Depression and metabolic disorders, including overweight and obesity, appear tightly interrelated. The prevalence of these conditions is concurrently growing worldwide, and both depression and overweight/obesity represent substantial risk factors for multiple medical complications. Moreover, there is now multiple evidence for a bidirectional relationship between depression and increased adiposity, with overweight/obesity being associated with an increased prevalence of depression, and in turn, depression augmenting the risk of weight gain and obesity. Although the reasons for this intricate link between depression and increased adiposity remain unclear, converging clinical and preclinical evidence points to a critical role for inflammatory processes and related alterations of brain functions. In support of this notion, increased adiposity leads to a chronic low-grade activation of inflammatory processes, which have been shown elsewhere to have a potent role in the pathophysiology of depression. It is therefore highly possible that adiposity-driven inflammation contributes to the development of depressive disorders and their growing prevalence worldwide. This review will present recent evidence in support of this hypothesis and will discuss the underlying mechanisms and potential therapeutic targets. Altogether, findings presented here should help to better understand the mechanisms linking adiposity to depression and facilitate the identification of new preventive and/or therapeutic strategies.

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“…Other studies have shown a relationship between BH 4 activity and antidepressants. [6][7][8][9][10] Several pharmacogenomic studies investigating mood-regulating drugs have shown altered expression in several components of the BH 4 pathway. [11][12][13] Together, this evidence supports a link between the BH 4 pathway and mood control, as well as in antidepressant function.…”

Section: Introductionmentioning

confidence: 99%

A polymorphism of the GTP-cyclohydrolase I feedback regulator gene alters transcriptional activity and may affect response to SSRI antidepressants

et al. 2010

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Tetrahydrobiopterin (BH 4 ) is an essential cofactor for synthesis of many neurotransmitters including serotonin. In serotonergic neurons, BH 4 is tightly regulated by GTP-cyclohydrolase I feedback regulator (GFRP). Given the pivotal role of the serotonergic system in mood disorders and selective serotonin reuptake inhibitors (SSRIs) antidepressant function, we tested the hypothesis that GFRP gene (GCHFR) variants would modify response to antidepressants in subjects with major depression. Two single nucleotide polymorphisms (rs7164342 and rs7163862) in the GCHFR promoter were identified and occurred as two haplotypes (GA or TT). A multiple regression analysis revealed that homozygous individuals for the TT haplotype were less likely to respond to the SSRI fluoxetine than to the tricyclic antidepressant nortriptyline (P ¼ 0.037). Moreover, the TT haplotype showed a reduced transcription rate in luciferase reporter gene assays, which may impact on BH 4 -mediated neurotransmitter production, thus suggesting a biological process through which GCHFR promoter variants might influence antidepressant response.

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Changes in Plasma Tetrahydrobiopterin Levels of Depressives in Depressive and Remission Phases: Reconfirmed by Measurement with an Internal Standard

Cited by 22 publications

References 6 publications

Tyrosine metabolism during interferon-alpha administration: Association with fatigue and CSF dopamine concentrations

Tyrosine metabolism during interferon-alpha administration: Association with fatigue and CSF dopamine concentrations

Role of Adiposity-Driven Inflammation in Depressive Morbidity

A polymorphism of the GTP-cyclohydrolase I feedback regulator gene alters transcriptional activity and may affect response to SSRI antidepressants

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