Elevated Levels of Plasma Phenylalanine in Schizophrenia: A Guanosine Triphosphate Cyclohydrolase-1 Metabolic Pathway Abnormality?

Okusaga, Olaoluwa; Muravitskaja, Olesja; Fuchs, Dietmar; Ashraf, Ayesha; Hinman, Sarah; Giegling, Ina; Hartmann, Annette M.; Konte, Bettina; Friedl, Marion; Schiffman, Jason; Hong, Elliot; Reeves, Gloria; Groër, Maureen; Dantzer, Robert; Rujescu, Dan; Postolache, Teodor T.

doi:10.1371/journal.pone.0085945

Cited by 24 publications

(16 citation statements)

References 34 publications

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“…We have previously reported that Phe levels and Phe:Tyr ratio were elevated in the same cohort of patients with schizophrenia when compared with controls (40). To our knowledge, there have been no studies investigating links between blood levels of molecular precursors of dopamine and serotonin in relationship to smoking in patients with schizophrenia.…”

Section: Introductionmentioning

confidence: 84%

Blood Levels of Monoamine Precursors and Smoking in Patients with Schizophrenia

Mathai

Kanwar

Okusaga

et al. 2016

Front. Public Health

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Smoking is highly prevalent in patients with schizophrenia and exerts a negative impact on cardiovascular mortality in these patients. Smoking has complex interactions with monoamine metabolism through the ability of cigarette smoke to suppress Type 1 T helper cell (Th1) type immunity, the immunophenotype that is implicated in phenylalanine hydroxylase (PAH) dysfunction and tryptophan (Trp) breakdown to kynurenine (Kyn) via indoleamine 2,3-dioxygenase. Nicotine also induces tyrosine hydroxylase (TH) gene expression, leading to increased synthesis of catecholamines. Furthermore, there is evidence for PAH dysfunction in schizophrenia. This study aimed to compare the plasma levels of selected monoamine precursors and their metabolites in smokers vs. non-smokers in a large sample of patients with schizophrenia. We measured plasma phenylalanine (Phe), tyrosine (Tyr), Trp, and Kyn levels using high-performance liquid chromatography and calculated Phe:Tyr and Kyn:Trp ratios in 920 patients with schizophrenia. Analysis of variance and linear regression analyses were used to compare these endpoints between three groups of patients with schizophrenia: (1) current smokers, (2) past smokers, and (3) non-smokers. There were significant differences among the three groups with regards to Tyr levels [F(2,789) = 3.77, p = 0.02], with current smokers having lower Tyr levels when compared with non-smokers (p = 0.02). Kyn levels and Kyn:Trp ratio were different among the three groups [F(2,738) = 3.17, p = 0.04, F(2,738) = 3.61, p = 0.03] with current smokers having lower Kyn levels (p = 0.04) and higher Kyn:Trp ratio (p = 0.02) when compared with past smokers. These findings need to be replicated with protocols that include healthy controls to further elucidate the neurobiological underpinnings of altered Tyr and Kyn levels in smokers. Results do suggest potential molecular links between schizophrenia and smoking that may represent biomarkers and treatment targets for reducing an important modifiable cause of general morbidity and mortality in patients with schizophrenia.

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Section: Introductionmentioning

confidence: 84%

Blood Levels of Monoamine Precursors and Smoking in Patients with Schizophrenia

Mathai

Kanwar

Okusaga

et al. 2016

Front. Public Health

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“…Using high performance liquid chromatography (HPLC), plasma phenylalanine and tyrosine levels were measured using 3-nitro-L-tyrosine as an internal standard as described elsewhere [84, 89]. …”

Section: Methodsmentioning

confidence: 99%

Reciprocal moderation by Toxoplasma gondii seropositivity and blood phenylalanine – tyrosine ratio of their associations with trait aggression

et al. 2016

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AbstractWe previously reported that trait aggression, proposed as an endophenotype for suicidal behavior, is positively associated with Toxoplasma gondii (T. gondii) seropositivity in females, but not in males. Additionally, older males seropositive for T. gondii had lower scores on measures of trait aggression, including self-aggression. Trait aggression may be influenced by dopaminergic signaling, which is known to be moderated by gender and age, and potentially enhanced in T. gondii positives through the intrinsic production of dopamine by the microorganism. Therefore, we investigated associations between trait aggression and interactions between T. gondii enzyme-linked immunoabsorbant assay (ELISA) IgG titer-determined seropositivity and high-performance liquid chromatography- (HPLC-) measured blood levels of dopamine precursors phenylalanine (Phe), tyrosine (Tyr), and their ratio in a sample of 1000 psychiatrically healthy participants. Aggressive traits were assessed using the questionnaire for measuring factors of aggression (FAF), the German version of the Buss-Durkee hostility questionnaire. We found that 1) the decrease in trait aggression scores in T. gondii-positive older males was only present in individuals with a low Phe:Tyr ratio, and 2) that there was a positive correlation between Phe:Tyr ratio and total aggression and selected subscales of aggression in T. gondii-positive males, but not in T. gondii-negative males. These findings point toward a gender-specific reciprocal moderation by Phe:Tyr ratio and T. gondii seropositivity of their associations with aggression scores, and lead to experimental interventions geared to manipulating levels of dopamine precursors in selected T. gondii positive individuals with increased propensity for aggression.

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“…BH4 is involved in the production of various neurotransmitters including serotonin, dopamine, epinephrine, and norepinephrine and is vital in nitric oxide (NO) production (Richardson et al, 2007;Werner et al, 2011). Deficiency in BH4 has been associated to SCZ (Richardson et al, 2005, Okusaga et al, 2014, Milstien and Katusic, 1999. In the likely context of astrocyte activation during early neurodevelopmental, post-transcriptionally regulatory mutations along PCBD2 could have an important role in BH4 synthesis and regeneration pathway, causing damaging disturbances in the mentioned processes.…”

Section: Accepted Manuscriptmentioning

confidence: 99%