The plasma tetrahydrobiopterin levels in patients with affective disorders

Hashimoto, Ryo; Ozaki, Norio; Ohta, Tatsuro; Kasahara, Yoriko; Kaneda, Norio; Nagatsu, T

doi:10.1016/0006-3223(90)90487-m

Cited by 25 publications

(16 citation statements)

References 15 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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“…Pairwise comparisons made among diagnostic groups on adjusted log biopterin scores and using a Bonferroni adjustment for multiple comparisons demonstrate that schizophrenia and schizoaffective disorder differ from normal control (P < 0.05) and schizophrenia differs from bipolar disorder (P < 0.05) levels that were higher in bipolar disorder subjects, when compared to controls, although in that study only four patients were investigated [23]. However, as dietary phenylalanine has been shown to stimulate BH 4 synthesis, it is difficult to directly compare our study of fasting plasma biopterin levels, with other studies where subject's fasting status was not specified [23]. From our data, we can suggest that some of the more severe and debilitating symptoms observed in schizophrenic and schizoaffective disorder subjects, that are not commonly found in bipolar disorder subjects, may be related to a significant BH 4 synthesis defect.…”

Section: Discussionmentioning

confidence: 95%

“…Two investigations report biopterin data for bipolar disorder subjects. In one there were no differences in urinary biopterin levels between bipolar patients (n = 9) and normal controls (n = 8) [22], while the second reported higher plasma biopterin levels in bipolar II disorder patients (n = 4) than in normal controls (n = 8) [23]. To our knowledge no previous studies of biopterin levels have been conducted in patients with schizoaffective disorder, while in schizophrenia, two small studies reported no significant difference between biopterin levels of schizophrenic and normal control groups in either urine, n = 21 patients and 28 control subjects [22] or cerebrospinal fluid (CSF) measured in 11 schizophrenics and 24 controls [24], and one study of serum biopterin levels found a significant deficit in patients with schizophrenia (n = 17) versus normal controls (n = 114) [25].…”

Section: Introductionmentioning

confidence: 88%

Analysis of Plasma Biopterin Levels in Psychiatric Disorders Suggests a Common BH4 Deficit in Schizophrenia and Schizoaffective Disorder

et al. 2006

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Tetrahydrobiopterin (BH4) is an essential cofactor for amine neurotransmitter synthesis. BH4 also stimulates and modulates the glutamatergic system, and regulates the synthesis of nitric oxide by nitric oxide synthases. A connection between BH4 deficiencies and psychiatric disorders has been previously reported; major depression and obsessive-compulsive disorder have been found in subjects with a BH4 deficiency disorder and more recently we have observed a robust plasma deficit of biopterin (a measure of BH4), in a large group of schizophrenic patients compared to control subjects. To extend our previous finding in schizophrenia, we analyzed plasma biopterin levels from patients with schizoaffective and bipolar disorders. A significant difference in biopterin was seen among the diagnostic groups (P < 0.0001). Post hoc analyses indicated significant biopterin deficits relative to the normal control group for the schizoaffective group, who had biopterin levels comparable to the schizophrenic group. Bipolar disorder subjects had plasma biopterin levels that were higher that the schizoaffective disorder group and significantly higher than the schizophrenic group. The demonstrated significant biopterin deficit in both schizophrenia and schizoaffective disorder, may suggest an etiological role of a BH4 deficit in these two disorders, via dysregulation of neurotransmitter systems.

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“…Recently, we reported that total biopterin levels in the plasma of patients with affective disorders both in the depressive and hypomanic phases were elevated as com pared with those of normal controls, although BH4 levels of the patients were increased in the hypomanic phase and were decreased in the depressive phase in compari son with those of normal controls, and that the ratio of BH4 to the total biopterin in the plasma of the patients with affective disorders was significantly low as com pared with that of normal controls [Hashimoto et al, 1990] , In this report, the plasma levels of total biopterin and BH4 in patients with affective disorders or other psychiatric disorders, under no influence of psycho tropic drugs as long as possible, were measured in the symptomatic phase and were compared with those of normal controls.…”

mentioning

confidence: 91%

Plasma Tetrahydrobiopterin Levels in Patients with Psychiatric Disorders

Ozaki¹,

Ohta²,

Kasahara³

et al. 1990

Neuropsychobiology

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The plasma total biopterin and tetrahydrobiopterin (BH₄) levels of 24 psychiatric patients were measured in the symptomatic phase, under no influence of psychotropic drugs as long as possible, and were compared with those of normal controls. The significant increase in total biopterin levels was observed only in the plasma of the patients with affective disorders or panic disorder in the depressive mood. A significant decrease in BH4 levels was observed only in the plasma of the patients with depression, and an increase in BH₄ levels was observed only in the patients with hypomania. The changes of these biopterin levels in plasma could be a disease effect or a phase effect.

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The plasma tetrahydrobiopterin levels in patients with affective disorders

Cited by 25 publications

References 15 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

Analysis of Plasma Biopterin Levels in Psychiatric Disorders Suggests a Common BH4 Deficit in Schizophrenia and Schizoaffective Disorder

Plasma Tetrahydrobiopterin Levels in Patients with Psychiatric Disorders

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