Development of a simultaneous LC-MS/MS analytical method for plasma: 16 antipsychotics approved in Japan and 4 drug metabolites.

The increased risk of adverse drug reactions due to the concomitant use of antipsychotics is problematic in the treatment of schizophrenia. Therefore, the simultaneous analysis of their plasma concentrations is required. In this study, we developed a simultaneous liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for analyzing plasma antipsychotics approved in Japan for therapeutic drug monitoring (TDM) applications. First, we counted the prescriptions for 16 antipsychotics and concomitant drugs used at the Tohoku University Hospital. LC-MS/MS was used for the simultaneous analysis of 16 antipsychotics and four drug metabolites. This analysis was conducted using a combination of selected reaction monitoring mode and reversed-phase chromatography. Following the examination of the MS/MS and LC conditions, an analytical method validation test was conducted. The developed method was used to analyze plasma antipsychotic levels in patients with schizophrenia. One-third of the patients received treatment with multiple antipsychotics. Under LC-MS/MS conditions, LC separation was performed using a combination of a C18 column and ammonium formate-based mobile phases with a gradient flow. The calibration curves were optimized by adjusting the ion abundance, and 11 compounds met the criteria for intra- and inter-day reproducibility tests. Some stability test results did not meet these criteria; therefore, further investigation is required. The developed method permitted the measurement of all the plasma parameters, including concentrations above the therapeutic range. Therefore, this method may be useful in the daily TDM practice of antipsychotics.

Associations among plasma markers for N-methyl-d-aspartate receptor hypofunction, redox dysregulation, and insufficient myelination in patients with schizophrenia.

Background: Several hypotheses regarding the pathomechanisms of schizophrenia have been proposed. If schizophrenia is a unitary disease, then these pathological processes must be linked; however, if such links do not exist, schizophrenia may best be considered a group of disorders. Only a few studies have examined the relationships among these pathomechanisms. Herein, we examined the relationships among deficient myelination, NMDA receptor hypofunction, and metabolic dysregulation by measuring various plasma markers and examining their correlations. Methods: Plasma samples were collected from 90 patients with schizophrenia and 68 healthy controls. Concentrations of nardilysin (N-arginine dibasic convertase, NRDC), a positive regulator of myelination, the NMDA receptor co-agonist d-serine and glycine, various additional amino acids related to NMDA receptor transmission (glutamate, glutamine, and l-serine), and homocysteine (Hcy), were measured. Concentrations were compared using independent samples t-test or logistic regression, and associations were evaluated using Pearson's correlation coefficients. Results: Plasma glycine (t = 2.05, p = 0.042), l-serine (t = 2.25, p = 0.027), and homocysteine (t = 3.71, p < 0.001) concentrations were significantly higher in patients with schizophrenia compared to those in healthy controls. Logistic regression models using age, sex, smoking status, glutamine, glutamate, glycine, l-serine, d-serine, homocysteine, and NRDC as independent variables revealed significantly lower plasma d-serine (p = 0.024) and NRDC (p = 0.028), but significantly higher l-serine (p = 0.024) and homocysteine (p = 0.001) in patients with schizophrenia. Several unique correlations were found between NMDA receptor-related amino acids and NRDC in patients with schizophrenia compared to those in healthy controls, while no correlations were found between plasma homocysteine and other markers. No associations were found between plasma marker concentrations and disease status or cognitive function in patients with schizophrenia, except for a significant correlation between plasma glycine and full intelligence quotient. Conclusion: Reduced myelination and NMDA receptor hypofunction may be related to pathological mechanisms in schizophrenia, while homocysteine dysregulation appears to be an independent pathological process. These results suggest that schizophrenia may be a group of disorders with unique or partially overlapping etiologies.

Management of Pregnant Women with Mental Disorders Requires Attention to Gestational Diabetes Mellitus.

Background: Psychiatric interventions may be required during pregnancy. In the aspect of the management of psychiatric symptoms and the consideration of the need for pharmacotherapy, possibly to manage the effects on the fetus, pregnant women with mental disorders are considered high risk as other physical illnesses. Objective: We investigated the characteristics of pregnant women with psychiatric disorders compared with high-risk pregnant women with physical illnesses at our university hospital and the effects of psychotropic drug use on pregnant women with mental disorders and their children. Materials and Methods: In a multivariate analysis of 1282 pregnant women, excluding those with multiple pregnancies who gave birth at our hospital between January 2017 and the end of December 2019, we evaluated the effects of mental disorders and the use of psychotropic drugs throughout at least the third trimester up to the day of delivery on obstetric complications and infants. All data were collected retrospectively. Results: Ninety-nine pregnant women had mental disorders and 62 took psychotropic drugs. Among multiple factors, pregnant women with mental disorders were associated with significantly higher rates of smoking and gestational diabetes mellitus (GDM) and significantly lower child abnormalities. The cause or effect was difficult to determine; however, the use of antipsychotics or antidepressants was also significantly associated with GDM, while psychotropic use was not related to any of the other factors investigated in this study. Conclusions: Attention to GDM might be important in the management of pregnant women with mental disorders.

Case report: Impact of hyperthyroidism on psychotic symptoms in schizophrenia comorbid with Graves' disease.

Introduction: Auditory hallucinations are the most common type of hallucinations observed in schizophrenia; however, visual hallucinations are not uncommon. In Graves' disease, depression, hypomania, and psychosis can occur. While the association between Graves' disease and psychosis has been explored, understanding of the specific impact of thyroid dysfunction severity on psychiatric symptom severity is limited. Here, we present a case report of a patient with schizophrenia comorbid with Graves' disease whose psychotic symptoms were impacted by hyperthyroidism. Case: The patient was a 32-year-old Japanese woman who presented with auditory and visual hallucinations, agitation, and pressured speech. The patient was diagnosed with schizophrenia comorbid with Graves' disease and thyroid storm. The patient's psychotic symptoms were found to be associated with fluctuations in thyroid hormone levels, and visual hallucinations were observed only during thyroid storms. Treatment involved dexamethasone, potassium iodide, bisoprolol fumarate, and methimazole for thyrotoxicosis, and a blonanserin transdermal patch, paliperidone, and paliperidone palmitate for psychotic symptoms. The patient's auditory and visual hallucinations improved with antipsychotic treatment and decreased thyroid hormone levels. Conclusion: This case highlights the importance of monitoring thyroid function in patients with schizophrenia, particularly those with comorbid Graves' disease. The correlation between psychiatric symptoms and thyroid hormone levels was demonstrated on an individual level over time, with symptoms worsening as thyroid hormone levels increased. Additionally, our case suggests that abnormally high thyroid hormone levels may trigger visual hallucinations in individuals with schizophrenia. Further studies are needed to elucidate the underlying mechanisms and potential treatment implications of this association.

Deep exome sequencing identifies enrichment of deleterious mosaic variants in neurodevelopmental disorder genes and mitochondrial tRNA regions in bipolar disorder.

Bipolar disorder (BD) is a global medical issue, afflicting around 1% of the population with manic and depressive episodes. Despite various genetic studies, the genetic architecture and pathogenesis of BD have not been fully resolved. Besides germline variants, postzygotic mosaic variants are proposed as new candidate mechanisms contributing to BD. Here, we performed extensive deep exome sequencing (DES, ~300×) and validation experiments to investigate the roles of mosaic variants in BD with 235 BD cases (194 probands of trios and 41 single cases) and 39 controls. We found an enrichment of developmental disorder (DD) genes in the genes hit by deleterious mosaic variants in BD (P = 0.000552), including a ClinVar-registered pathogenic variant in ARID2. An enrichment of deleterious mosaic variants was also observed for autism spectrum disorder (ASD) genes (P = 0.000428). The proteins coded by the DD/ASD genes with non-synonymous mosaic variants in BD form more protein-protein interaction than expected, suggesting molecular mechanisms shared with DD/ASD but restricted to a subset of cells in BD. We also found significant enrichment of mitochondrial heteroplasmic variants, another class of mosaic variants, in mitochondrial tRNA genes in BD (P = 0.0102). Among them, recurrent m.3243 A > G variants known as causal for mitochondrial diseases were found in two unrelated BD probands with allele fractions of 5-12%, lower than in mitochondrial diseases. Despite the limitation of using peripheral tissues, our DES investigation supports the possible contribution of deleterious mosaic variants in the nuclear genome responsible for severer phenotypes, such as DD/ASD, to the risk of BD and further demonstrates that the same paradigm can be applied to the mitochondrial genome. These results, as well as the enrichment of heteroplasmic mitochondrial tRNA variants in BD, add a new piece to the understanding of the genetic architecture of BD and provide general insights into the pathological roles of mosaic variants in human diseases.

Effect of antipsychotic use by patients with schizophrenia on deceleration capacity and its relation to the corrected QT interval.

OBJECTIVE: Schizophrenia patients treated with antipsychotics are at higher risk of sudden cardiac death. Decreased deceleration capacity (DC) of the heart rate is an accurate predictor of cardiac mortality. We evaluated the risk of sudden cardiac death due to antipsychotic use by assessing DC and examining the association between DC and the corrected QT interval (QTc) in schizophrenia patients. METHODS: We measured the DC and QTc of 138 schizophrenia patients. We then compared the DC of 86 age- and sex-matched healthy controls with that of 86 schizophrenia patients. We investigated the correlation of DC of approximately 138 schizophrenia patients with prescribed doses of antipsychotics using linear regression analysis. We compared the DC of schizophrenia patients with and without prolonged QT intervals. RESULTS: We found DC significantly differed between schizophrenia patients on antipsychotic medication and healthy controls. Additionally, DC was negatively correlated with antipsychotic use, especially chlorpromazine, zotepine, olanzapine and clozapine, in a dose-dependent manner. There was no significant association between DC and the QTc. CONCLUSION: Assessing DC could facilitate monitoring and identification of increased risk of cardiac mortality in patients with schizophrenia that take antipsychotics. Assessing both DC and the QTc may enhance the accuracy of predicting sudden cardiac death.

Patient with bipolar I disorder who presented with low blood lithium levels after receiving crushed tablets via a nasogastric tube: A case report.

In clinical psychiatric cases, the placement of a nasogastric tube is occasionally considered. If a patient who presents with mania or other psychiatric conditions refuses to take drugs, they are administered via the nasogastric tube. The tablet is crushed, suspended, passed via the nasogastric line, and reaches the stomach directly. However, the effects of these processes on blood drug concentrations remain unclear. Herein, we report a patient with bipolar I disorder who presented with low blood lithium carbonate (Li) concentrations after receiving the drug via the nasogastric tube. Case: A 26-year-old woman developed manic symptoms with grandeur delusion. She was admitted to a psychiatric hospital three times after diagnosis. Her manic symptoms with delusion improved with Li and aripiprazole (ARP). Her condition stabilized with Li 800 mg/day and ARP 9 mg/day. After the Li dose was reduced to 600 mg/day, she maintained remission, with the blood level range of Li being 0.31 ∼ 0.42 mEq/L. After 1 year, she was admitted to our hospital due to a jaw deformity. During the perioperative period, treatment with oral Li was discontinued by the surgeons, and her manic symptoms recurred. During therapy with olanzapine 20 mg and Li 800 mg, her blood Li concentration was 0.67 mEq/L. The symptoms remained. Hence, the Li dose increased to 1,000 mg/day. However, she refused to take the medication. Thus, a nasogastric tube was used to administer medicines. Thereafter, the blood Li concentration decreased to 0.43 mEq/L, which was lesser than 800 mg/day. Each blood sample was collected approximately 18 h after the administration. Her symptoms remained. Thereafter, she agreed to take the medication, and the Li concentration reached 0.78 mEq/L. Then, the symptoms partly improved. Conclusion: After the administration of Li via the nasogastric tube, the Li concentration decreased, which was lower than expected. This phenomenon could be attributed to the fact that the medication was crushed, suspended, and administered via the nasogastric tube. Therefore, pulverizing and administering Li tablets via the nasogastric tube can be applied for the management of mania, however, caution should be observed because of the risk of fluctuations in blood Li levels, as in this case.

Systematic analysis of exonic germline and postzygotic de novo mutations in bipolar disorder.

Bipolar disorder is a severe mental illness characterized by recurrent manic and depressive episodes. To better understand its genetic architecture, we analyze ultra-rare de novo mutations in 354 trios with bipolar disorder. For germline de novo mutations, we find significant enrichment of loss-of-function mutations in constrained genes (corrected-P = 0.0410) and deleterious mutations in presynaptic active zone genes (FDR = 0.0415). An analysis integrating single-cell RNA-sequencing data identifies a subset of excitatory neurons preferentially expressing the genes hit by deleterious mutations, which are also characterized by high expression of developmental disorder genes. In the analysis of postzygotic mutations, we observe significant enrichment of deleterious ones in developmental disorder genes (P = 0.00135), including the SRCAP gene mutated in two unrelated probands. These data collectively indicate the contributions of both germline and postzygotic mutations to the risk of bipolar disorder, supporting the hypothesis that postzygotic mutations of developmental disorder genes may contribute to bipolar disorder.

Impact of a Psychiatric Nurse Specialist as a Liaison for Pregnant Women with Mental Disorders.

A number of scholarly reports have shown the importance of mental health care during pregnancy, especially for women with mental disorders. Nevertheless, the postpartum mortality rate due to mental disorders has been a serious issue in Japan. Therefore, since January 2015, our hospital has implemented a liaison system in which one psychiatric nurse specialist contributes to perinatal care. The aim of this study is to explore the impacts of a psychiatric nurse specialist as a liaison for pregnant women with mental disorders. More specifically, the investigation was retrospectively performed from January 2011 to December 2019 using medical records from a single university medical hospital in Japan. Participants comprised pregnant women with mental disorders. Of the 4,066 total deliveries completed during the study period, 152 women were detected as being exposed to the liaison system (2015-2019), while 92 were recognized as controls (2011-2014). We then conducted a comparative analysis between those who were exposed to the liaison system and the control group. Except for Apgar scores taken five minutes after birth, there were no intergroup differences in the patient characteristics or perinatal psychiatric outcomes. We found that the liaison system was associated with an increased rate of referral to the local public health center (p = 0.003). The system also significantly delayed the time at which patients first visited a psychiatrist because a psychiatric nurse could determine the urgency through interviews with the patients. Overall, our results suggest that the liaison system is helpful for pregnant women with mental disorders.

Effects of Antipsychotics on Arrhythmogenic Parameters in Schizophrenia Patients: Beyond Corrected QT Interval.

PURPOSE: Antipsychotic drugs have been implicated as risk factors for QT prolongation, which is a predictor of sudden cardiac death. However, the QT interval is considered an imperfect marker for proarrhythmic risk. Recently, improved methods, namely, QT dispersion (QTD), QTD ratio (QTDR), T wave peak-to-end interval (Tp-e), Tp-e/QT ratio and Tp-e/QTc ratio, have been regarded as proarrhythmic risk markers. We attempted to reevaluate the risk of sudden cardiac death due to antipsychotics use by measuring these improved evaluation methods. PATIENTS AND METHODS: We retrospectively evaluated QTc, QTD, QTDR, Tp-e, Tp-e/QT ratio and Tp-e/QTc ratio from the medical records of 410 patients with schizophrenia diagnosed by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision, or 5th Edition. Information on drugs administered was obtained from medical records. We investigated the correlation between each index on ECG and medication, such as antipsychotics, prescribed to participants with linear regression analysis. We also compared each index between 235 healthy controls and 235 patients matched for age and sex. RESULTS: Positive correlations between QTc and levomepromazine and brexpiprazole were identified. Levomepromazine and lithium were positively correlated with QTD. Levomepromazine, quetiapine, asenapine, clozapine and carbamazepine were positively correlated with QTDR. Levomepromazine, olanzapine, brexpiprazole and lithium were positively correlated with Tp-e. Olanzapine, brexpiprazole and lithium were positively correlated with the Tp-e/QT ratio. Olanzapine, brexpiprazole and lithium were positively correlated with Tp-e/QTc ratio. Significant differences in all indexes were noted between the patients and healthy controls. CONCLUSION: According to our results, the prediction of the risk of sudden cardiac death by each index was inconsistent. We should evaluate the predictive factor of ventricular arrhythmia according to various electrocardiogram indexes because QTc alone could not identify the risk of sudden cardiac death.

Structural Determination of Lysosphingomyelin-509 and Discovery of Novel Class Lipids from Patients with Niemann-Pick Disease Type C.

Niemann-Pick disease type C (NPC) is an autosomal recessive disorder caused by the mutation of cholesterol-transporting proteins. In addition, early treatment is important for good prognosis of this disease because of the progressive neurodegeneration. However, the diagnosis of this disease is difficult due to a variety of clinical spectrum. Lysosphingomyelin-509, which is one of the most useful biomarkers for NPC, was applied for the rapid and easy detection of NPC. The fact that its chemical structure was unknown until recently implicates the unrevealed pathophysiology and molecular mechanisms of NPC. In this study, we aimed to elucidate the structure of lysosphingomyelin-509 by various mass spectrometric techniques. As our identification strategy, we adopted analytical and organic chemistry approaches to the serum of patients with NPC. Chemical derivatization and hydrogen abstraction dissociation-tandem mass spectrometry were used for the determination of function groups and partial structure, respectively. As a result, we revealed the exact structure of lysosphingomyelin-509 as N-acylated and O-phosphocholine adducted serine. Additionally, we found that a group of metabolites with N-acyl groups were increased considerably in the serum/plasma of patients with NPC as compared to that of other groups using targeted lipidomics analysis. Our techniques were useful for the identification of lysosphingomyelin-509.

Association of genetic variants at 22q11.2 chromosomal region with cognitive performance in Japanese patients with schizophrenia.

22q11.2 heterozygous multigene deletions confer an increased risk of schizophrenia with marked impairment of cognition. We explored whether genes on 22q11.2 are associated with cognitive performance in patients with idiopathic schizophrenia. A total of 240 schizophrenia patients and 240 healthy controls underwent the Japanese-language version of the Brief Assessment of Cognition in Schizophrenia (BACS) and were genotyped for 115 tag single-nucleotide polymorphisms (tag SNPs) at the 22q11.2 region using the golden gate assay (Illumina®). Associations between z-scores of the BACS cognitive domains and SNPs and haplotypes were analyzed using linear regression in PLINK 1.07. An additional set of 149 patients with bipolar disorder were included for cognitive assessment and selected SNPs were genotyped using real-time PCR. Patients with schizophrenia and bipolar disorder showed qualitatively comparable profiles of cognitive impairment across BACS subdomains, as revealed by significant correlation between the two groups in the resulting cognitive effect sizes relative to controls. rs4819522 (TBX1) and rs2238769 (UFD1L) were significantly and nominally associated, respectively, with symbol coding in patients with schizophrenia. Haplotype analyses revealed that haplotypes containing the A allele at rs4819522 and G allele at rs2238769 showed significant negative associations with symbol coding in patients with schizophrenia. There was no effect of any haplotypes on cognition in patients with bipolar disorder. Our results have implications for the understanding of the role of haplotypes of UFD1L and TBX1 genes associated with symbol coding in patients with schizophrenia. Further replication studies in a cohort of newly diagnosed patients and other ethnicities are warranted.

Investigation of the Proarrhythmic Effects of Antidepressants according to QT Interval, QT Dispersion and T Wave Peak-to-End Interval in the Clinical Setting.

OBJECTIVE: Some antidepressants have been implicated as risk factors for QT prolongation, which is a predictor of sudden cardiac death. However, the QT interval is considered an imperfect biomarker for proarrhythmic risk. Therefore, we reevaluated the risk of sudden cardiac death due to antidepressants using improved. METHODS: , namely, QT dispersion (QTD), T wave peak-to-end interval (Tp-e), and Tp-e/QT ratio. METHODS: We compared the effects of antidepressants on QTc (QT/RR1/3), QTD, Tp-e, and Tp-e/QT ratio in 378 patients with mood disorder. We also compared each index between 165 healthy controls and 215 randomly selected age-matched patients. RESULTS: Age (p<0.01), sex (p<0.05), tricyclic antidepressant (TCA) use (p<0.05), and clomipramine (p<0.01) and mianserin (p<0.05) use in particular, significantly associated with a prolonged QTc. We also found that age (p<0.01), TCA use (p<0.05), and clomipramine (p<0.01) and mianserin (p<0.05) use in particular, significantly prolonged QTD. However, there was no correlation between each variable and Tp-e or Tp-e/QT ratio. Significant differences in QTc and QTD were found between the patients and healthy controls. CONCLUSION: From our results, prediction of risk of sudden cardiac death by QTD, Tp-e, or Tp-e/QT ratio was inconsistent. Increased QTD may be more suitable for predicting sudden cardiac death due to antidepressants.

Cognitive function, treatment response to lithium, and social functioning in Japanese patients with bipolar disorder.

OBJECTIVES: Patients with bipolar disorder often suffer from cognitive impairment that significantly influences their functional outcome. However, it remains unknown whether lithium has a central role in cognition and functional outcome. We examined whether cognition and functional outcome were predicted by demographic and clinical variables, including the response to lithium, in lithium-treated patients with bipolar disorder. METHODS: We evaluated 96 lithium-treated euthymic patients with bipolar disorder and 196 age- and-gender-matched healthy controls, using the Brief Assessment of Cognition in Schizophrenia (BACS). The patients were also assessed using the Social Functioning Scale (SFS) and "The Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" (Alda) scale, which was evaluated as either a continuous measure of the total scale or a dichotomous criterion. RESULTS: Multiple regression analysis revealed two key findings: first, that the premorbid intelligence quotient, age, and number of mood episodes were predictors of the BACS composite score; and, second, that the BACS composite score, negative symptoms, and continuous measure on the total Alda scale (but not its dichotomy) predicted the total SFS score. Structural equation modeling (SEM) was used to confirm these findings, and additionally revealed that the Alda scale was significantly associated with negative symptoms and also the number of mood episodes, regardless of how it was evaluated. CONCLUSIONS: SEM delineated how demographic and clinical variables, cognitive performance, and response to lithium treatment were causally associated with, and converged on, social function. The putative role of the Alda scale for social function warrants further study.

Enrichment of deleterious variants of mitochondrial DNA polymerase gene (POLG1) in bipolar disorder.

AIM: Rare missense variants, which likely account for a substantial portion of the genetic 'dark matter' for a common complex disease, are challenging because the impacts of variants on disease development are difficult to substantiate. This study aimed to examine the impacts of amino acid substitution variants in the POLG1 found in bipolar disorder, as an example and proof of concept, in three different modalities of assessment: in silico predictions, in vitro biochemical assays, and clinical evaluation. We then tested whether deleterious variants in POLG1 contributed to the genetics of bipolar disorder. METHODS: We searched for variants in the POLG1 gene in 796 Japanese patients with bipolar disorder and 767 controls and comprehensively investigated all 23 identified variants in the three modalities of assessment. POLG1 encodes mitochondrial DNA polymerase and is one of the causative genes for a Mendelian-inheritance mitochondrial disease, which is occasionally accompanied by mood disorders. The healthy control data from the Tohoku Medical Megabank Organization were also employed. RESULTS: Although the frequency of carriers of deleterious variants varied from one method to another, every assessment achieved the same conclusion that deleterious POLG1 variants were significantly enriched in the variants identified in patients with bipolar disorder compared to those in controls. CONCLUSION: Together with mitochondrial dysfunction in bipolar disorder, the present results suggested deleterious POLG1 variants as a credible risk for the multifactorial disease.

Predictive value of premorbid IQ, negative symptoms, and age for cognitive and social functions in Japanese patients with schizophrenia: A study using the Japanese version of the Brief Assessment of Cognition in Schizophrenia.

Enduring cognitive impairment in patients with schizophrenia represents a global health burden. The Japanese-language version of the Brief Assessment of Cognition in Schizophrenia (BACS) and the Japanese Adult Reading Test were administered to 288 patients with chronic schizophrenia and 308 unrelated healthy control subjects. The Japanese version of self-reported Social Functioning Scale (SFS) was administered to a subpopulation of 157 patients with schizophrenia. In patients with schizophrenia, premorbid IQ and age were significantly related to most of the BACS subdomains, composite score, and intra-individual variability of BACS subdomains, whereas negative symptoms were significantly related to all BACS indices. Dosages of the first-generation antipsychotics had a significant negative impact on Tower of London task and intra-individual variability of BACS subdomains. The relationship of symbol coding with age was significantly lower in patients than in healthy control subjects. Multiple regression analysis revealed that negative symptoms were significantly negatively related to the total SFS scale, whereas better performance of token motor task was associated with higher total SFS. The present study revealed the role of premorbid IQ, age, and negative symptoms in predicting cognitive performance, and the significant correlation of negative symptoms and token motor task with social function in patients with schizophrenia.

Multi-regression analysis revealed a relationship between l-serine and methionine, a component of one-carbon metabolism, in the normal control but not in the schizophrenia.

BACKGROUND: Alterations in one-carbon metabolism (OCM) have been observed in patients with schizophrenia (SZ), but a comprehensive study of OCM has not yet been conducted. A carbon atom is transferred from l-serine to methionine during OCM, but the relationship between l-serine and methionine in SZ is not yet known. We investigated the relationship between l-serine and methionine to obtain a comprehensive understanding of OCM in SZ. METHODS: We recruited forty-five patients with SZ and thirty normal controls (NC). Whole blood, plasma, and DNA specimens were obtained from all participants. Plasma l-serine, d-serine, glycine, methionine, and total homocysteine levels were measured using high-performance liquid chromatography. Plasma vitamin B12 and total folate were measured using a chemiluminescent protein-binding immunoassay. Clinical symptoms were estimated using the positive and negative syndrome scale (PANSS). The methylenetetrahydrofolate reductase (MTHFR) C667T genotype and A298C genotype, which are involved in MTHFR activity, were determined using the TaqMan genotyping assay system. RESULTS: Analysis of variance was used to confirm that the SZ cohort has higher plasma homocysteine levels and lower plasma folate levels than the NC group. Multi-regression analysis revealed a relationship between l-serine and methionine in the NC group but not in the SZ group. The MTHFR genotype did not affect the relationship between l-serine and methionine in each group. The total PANSS score was significantly related to d-serine and folate levels and to age. Positive PANSS scores were significantly related to both glycine and sex. In addition, both glycine and d-serine were significantly correlated with negative PANSS scores. CONCLUSIONS: We found impairment of the relationship between l-serine and methionine in SZ. Clinical symptoms of SZ were partially correlated with the OCM components. These findings contributed to our understanding of OCM alteration in SZ and may explain why the alteration occurs.

Plasma concentrations of three methylated arginines, endogenous nitric oxide synthase inhibitors, in schizophrenic patients undergoing antipsychotic drug treatment.

Plasma concentration of three methylated arginines, endogenous nitric oxide synthase inhibitors, is not studied in schizophrenic patients. The purpose of this study was to determine plasma concentrations of N(G)-monomethyl-L-arginine (l-NMMA), N(G),N(G)-dimethyl-L-arginine (ADMA), N(G),N(G')-dimethyl-L-arginine (SDMA), and l-arginine in 56 male and 45 female schizophrenic patients undergoing antipsychotic drug treatment versus those of 39 male and 24 female healthy controls. Plasma concentrations of methylated arginines and l-arginine were measured using newly developed high performance liquid chromatography with fluorescence detection which we previously reported. Methylated arginine levels were slightly but significantly higher in schizophrenic patients. L-Arginine levels and the l-arginine/(ADMA+l-NMMA) ratio were higher in schizophrenic patients than in healthy controls. It is considered that pharmacological treatment of schizophrenic patients may lower methylated arginine levels that are increased by the disease, and increase L-arginine levels, eliciting an improvement in nitric oxide (NO) bioavailability.

Phosphoserine phosphatase activity is elevated and correlates negatively with plasma d-serine concentration in patients with schizophrenia.

The pathophysiology of schizophrenia may involve N-methyl-D-aspartate receptor (NMDAR) hypofunction. D-3serine and glycine are endogenous l-serine-derived NMDAR co-agonists. We hypothesized that the l-serine synthesis pathway could be involved in schizophrenia. We measured the activity of phosphoserine phosphatase (PSP), a rate-limiting enzyme in l-serine synthesis, in peripheral blood mononuclear cells of 54 patients with schizophrenia and 49 normal control subjects. Plasma amino acid (l-serine, d-serine, glycine, glutamine, and glutamate) levels were measured by high performance liquid chromatography. Peripheral blood mRNA expression levels of PHGDH, PSAT1, PSP, and SR, determined by quantitative real-time PCR were compared between patients and controls. PSP activity was higher in patients than in controls, especially in male patients. In male patients, the plasma l-serine concentration was higher than that in controls. In patients, PSP activity was negatively correlated with plasma d-serine and glycine levels. Furthermore, PSP activity was positively correlated with plasma l-serine concentration. These results were statistically significant only in male patients. PSP, PSAT1, and PHGDH mRNA levels were lower in patients than in controls, except when the PHGDH expression level was compared with ACTB expression. In summary, we found the l-serine synthesis system to be altered in patients with schizophrenia, especially in male patients.