Keiko Kanno-Nozaki

Influence of -141C Ins/Del Polymorphism in DRD2 Gene on Clinical Symptoms and Plasma Homovanillic Acid Levels in the Treatment of Schizophrenia With Aripiprazole.

FIGURE 1. Mean change in PANSS total (A), positive (B), negative (C), and plasmaHVA levels (D) of 2 genetic subgroups. There were no time genotype interactions on PANSS scores (total: P = 0.63, positive: P = 0.92, negative: P = 0.29) or plasma HVA levels (P = 0.61). B ecause the dopamine D2 receptor (DRD2) plays an important role in schizophrenia, genetic studies have been focused on this gene. A meta-analysis demonstrated a significant association between the −141C Ins/Del polymorphism in DRD2 and the response to antipsychotics, whereas the Taq1A polymorphism was not associated with the response. The −141C Ins/Del represents a deletion of cytosine at position −141, located in the 5′ promoter region of DRD2. The −141C Ins/Del polymorphism has effects on DRD2 density in the brain; however, the function of this polymorphism in schizophrenia remains unclear. Homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are major metabolites of dopamine and noradrenaline, respectively. In this study, we investigated the effect of the −141C Ins/Del polymorphism on clinical symptoms and plasma levels of HVA and MHPG during treatment with aripiprazole in antipsychoticfree patients with schizophrenia. Subjects were 34 Japanese patients (men, 22; women, 12; mean [SD] age, 41.2 [12.6] years) whose conditions were diagnosed with schizophrenia or schizoaffective disorder according to theDiagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Thirty of 34 patients were the same subjects from our previous study, and a previous report contains detailed descriptions of the study design. The −141C Ins/Del genotype was determined with the polymerase chain reaction method as previously described. This study was approved by the ethics committee of FukushimaMedical University, and the patients consented to participate after having been informed of the purpose of the study. Student t test (unpaired) and Pearson χ test were used for comparisons between the 2 genotype groups. Student t test (paired) was used to compare measures from before and after the aripiprazole treatment. Analysis of variance with repeated measures was used to evaluate changes in the Positive and Negative Syndrome Scale (PANSS) score and

Associations between five-factor model of the Positive and Negative Syndrome Scale and plasma levels of monoamine metabolite in patients with schizophrenia

The five-factor model of the Positive and Negative Syndrome Scale (PANSS) for schizophrenia symptoms is the most common multiple-factor model used in analyses; its use may improve evaluation of symptoms in schizophrenia patients. Plasma monoamine metabolite levels are possible indicators of clinical symptoms or response to antipsychotics in schizophrenia. We investigated the association between five-factor model components and plasma monoamine metabolites levels to explore the models biological basis. Plasma levels of homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) were measured using high-performance liquid chromatography in 65 Japanese patients with schizophrenia. Significant negative correlation between plasma 5-HIAA levels and the depression/anxiety component was found. Furthermore, significant positive correlation was found between plasma MHPG levels and the excitement component. Plasma HVA levels were not correlated with any five-factor model component. These results suggest that the five-factor model of the PANSS may have a biological basis, and may be useful for elucidating the psychopathology of schizophrenia. Assessment using the five-factor model may enable understanding of monoaminergic dysfunction, possibly allowing more appropriate medication selection. Further studies of a larger number of first-episode schizophrenia patients are needed to confirm and extend these results.

Impacts of age on plasma monoamine metabolite concentrations in a large cohort of healthy individuals.

The measurement of plasma concentrations of monoamine metabolites is a useful method for inferring the dynamics of monoamine metabolites in the brain. To clarify effects of age and sex on plasma monoamine metabolites levels, we used high-performance liquid chromatography to measure plasma levels of homovanillic acid (HVA), free and total 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) in healthy men and women of various ages (n=214). In all plasma monoamine metabolites, there were significant differences across the age groups, and multiple comparisons revealed that older subjects had higher levels than younger subjects. Moreover, significant positive correlations were found between age and plasma levels of HVA, free MHPG, total MHPG, and 5-HIAA. On the other hand, plasma concentrations of monoamine metabolites were not influenced by sex, except for total MHPG for which the plasma levels were significantly higher in men than in women. Age-related changes in monoamine oxidase and renal function might affect our results. This large cohort survey provides further evidence to be cautiously aware of age effects when regarding plasma monoamine metabolites levels as reflections of central activity.

Effects of Shakuyaku-Kanzo-to on Extrapyramidal Symptoms During Antipsychotic Treatment: A Randomized, Open-Label Study.

Abstract Extrapyramidal symptoms (EPS) are common adverse effects of antipsychotic treatment. This study examined the effects of the traditional Japanese herbal medicine (kampo) shakuyaku-kanzo-to on EPS during antipsychotic treatment. Twenty-two Japanese patients with psychiatric disorders who had developed EPS during antipsychotic treatment were randomly allocated to receive either shakuyaku-kanzo-to (7.5 g/d) or biperiden (3 mg/d) for 2 weeks. Extrapyramidal symptoms were evaluated using the Drug-Induced Extrapyramidal Symptom Scale (DIEPSS) and the Barnes Akathisia Rating Scale. Plasma levels of the monoamine metabolite homovanillic acid and serum prolactin levels were measured to investigate the mechanisms of action of shakuyaku-kanzo-to. Twenty of the 22 patients completed the study (10 patients in the shakuyaku-kanzo-to group and 10 patients in the biperiden group). There was a time effect on the Drug-Induced Extrapyramidal Symptom Scale total score (P < 0.01), suggesting that both shakuyaku-kanzo-to and biperiden decreased EPS. Notably, there was a time × drug interaction in dystonia, suggesting that shakuyaku-kanzo-to had a greater effect on dystonia compared with biperiden. No significant changes were observed in plasma homovanillic acid or serum prolactin levels after 2 weeks of treatment in either group. The effects of shakuyaku-kanzo-to on abnormal muscle tonus and dopamine D2 receptors may have contributed to improve EPS. These results suggest that shakuyaku-kanzo-to may be useful in decreasing EPS, especially dystonia, in patients undergoing treatment with antipsychotic agents.

Near-infrared spectroscopy and plasma homovanillic acid levels in bipolar disorder: a case report.

Misdiagnosis of bipolar disorder is a serious, but not unusual problem for patients. Nevertheless, there are few biomarkers for distinguishing unipolar and bipolar disorder. Near-infrared spectroscopy (NIRS) is a noninvasive and useful method for the measurement of hemoglobin concentration changes in the cortical surface area, which enables the assessment of brain function. We measured NIRS and plasma monoamine metabolite levels in a patient with bipolar disorder. A 22-year-old man was admitted due to major depression. At admission, NIRS findings showed oxygenated hemoglobin reincrease in the posttask period, which is characteristic of schizophrenia. After treatment with paroxetine, he became manic with psychotic symptoms. His plasma level of homovanillic acid just before the manic switch was ten times higher than that just after paroxetine initiation. Treatment with lithium and antipsychotics was successful, and plasma homovanillic acid decreased after treatment. In this case, the NIRS findings may predict a possible risk of a manic switch, which is likely induced by paroxetine. NIRS may be able to help distinguish unipolar and bipolar disorder in clinical settings.

Switching antipsychotics to aripiprazole or blonanserin and plasma monoamine metabolites levels in patients with schizophrenia

Blonanserin is a novel atypical antipsychotic drug that has efficacy equal to risperidone. We investigated the effects of aripiprazole and blonanserin on clinical symptoms and plasma levels of homovanillic acid (pHVA) and 3‐methoxy‐4hydroxyphenylglycol in the switching strategy of schizophrenia.

The Relationship between Mismatch Negativity and the COMT Val108/158Met Genotype in Schizophrenia

Mismatch negativity (MMN) is a component of auditory event-related potentials that reflects automatic change detection in the brain, showing qualities of endophenotypes in schizophrenia. MMN deficiency is one of the robust findings in patients, and it reflects both cognitive and functional decline. Catechol-o-methyltransferase (COMT) is a key enzyme involved in regulating dopamine transmission within the prefrontal cortex. A preliminary study suggested that the COMTVal108/158Met genotype (rs4680) is related to cognitive function in schizophrenia. Both the COMTVal108/158Met genotype and MMN are related to cognitive function, but no studies have reported on the relationship between MMN and the COMTVal108/158Met genotype in schizophrenia. This study therefore examined the relationship between COMTVal108/158Met genotype and MMN. The duration of MMN was measured, and the COMTVal108/158Met polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism in 49 Japanese schizophrenia patients (Val/Val, n = 21; Met carriers, n = 28). Amplitude and latency of MMN were compared between Val/Val and Met carriers.

COMT Val 108/158 Met polymorphism and treatment response to aripiprazole in patients with acute schizophrenia

Introduction The COMT Val 108/158 Met polymorphism (rs4680) may affect treatment response to antipsychotics, as well as metabolism and dynamics of neurotransmitters during the treatment of schizophrenia. We investigated the effects of the COMT Val 108/158 Met polymorphism on treatment response to aripiprazole and plasma monoamine metabolite levels in patients with acute schizophrenia. Materials and methods Forty patients with schizophrenia were treated with aripiprazole for 6 weeks. We measured Positive and Negative Syndrome Scale (PANSS) and plasma levels of homovanillic acid (HVA) and plasma MHPG (3-methoxy-4-hydroxyphenethyleneglycol) at baseline and endpoint. The COMT Val 108/158 Met polymorphism was genotyped with the polymerase chain reaction and restriction fragment length polymorphism. Results There were significant genotype–time interactions on PANSS total and general psychopathology scores, with Met/Met genotype showing greater improvement. The response rate to aripiprazole did not differ between COMT Val 108/158 Met genotype groups. We found a significant time effect on plasma MHPG levels, but no time effect on plasma HVA levels or time–genotype interactions in the plasma levels of HVA and MHPG. Although the responder rate did not differ among the 3 genotype groups. Conclusion Our results suggest that individuals with the Met/Met genotype had greater improvement in PANSS score after the treatment with aripiprazole. On the other hand, the Val 108/158 Met polymorphism may not induce changes in plasma levels of monoamine metabolites during aripiprazole treatment. Because of the small sample size, further studies are needed to confirm and to extend our results.

DNA methylation of ANKK1 and response to aripiprazole in patients with acute schizophrenia: A preliminary study

Epigenetic modification including DNA methylation may affect pathophysiology and the response to antipsychotic drugs in patients with schizophrenia. The objective of the present study was to investigate the effect of the DNA methylation of ANKK1 (ankyrin repeat and kinase domain containing 1) on the response to aripiprazole and plasma levels of monoamine metabolites in antipsychotic-free acute schizophrenia patients. The subjects were 34 Japanese patients with schizophrenia who had been treated with aripiprazole for 6 weeks. Comprehensive DNA methylation of ANKK1 was determined using a next-generation sequencer. DNA methylation levels at CpG site 387 of ANKK1 were higher in responders to treatment with aripiprazole and correlated with the changes in Positive and Negative Syndrome Scale scores, although the associations did not remain significant after Bonferroni correction. In responders, methylation at all CpG sites was significantly correlated with plasma levels of homovanillic acid (r = 0.587, p = 0.035) and 3-methoxy-4hydroxyphenylglycol (r = 0.684, p = 0.010) at baseline. Despite our non-significant results after multiple correction, our preliminary findings suggest that methylation levels at CpG site 387 of ANKK1 may be associated with treatment response to aripiprazole. Furthermore, methylation of ANKK1 may affect dopaminergic neural transmission in the treatment of schizophrenia, and may influence treatment response. Caution is needed in interpreting these findings because of the small sample size, and further studies are needed to confirm and expand our preliminary results.

Hashimoto encephalopathy with high plasma monoamine metabolite levels: a case report

Hashimoto encephalopathy (HE) is believed to be an immune-mediated disorder associated with Hashimoto’s thyroiditis. It was suggested that neuropsychiatric symptoms, the presence of antithyroid antibody, and good response to steroids were important for the diagnosis of HE. It has been reported that homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), which are monoamine metabolites of dopamine and noradrenaline, respectively, are the possible biomarkers of neuropsychiatric diseases. We report a case of Hashimoto encephalopathy, in which we longitudinally measured the plasma levels of monoamine metabolites. A 52-year-old woman developed acute psychosis, and was admitted to the psychiatric ward of our hospital due to psychotic state, 6 days after a traffic accident. An extensive evaluation showed no remarkable findings, except an increase in antithyroglobulin antibodies. Plasma levels of HVA and MHPG were extremely high at 66.5 and 41.8 ng/mL, respectively. On day 16, 50 mg/day oral prednisolone was administered, which improved her psychotic symptoms. Plasma levels of HVA and MHPG decreased to 7.2 and 9.9 ng/mL, respectively, on day 19. After the temporary worsening of psychosis and increase in plasma levels of HVA and MHPG, the dosage of prednisolone was tapered and low-dose risperidone was started. Her psychiatric symptoms gradually improved and plasma monoamine metabolite levels decreased again (HVA: 17.9 ng/mL; MHPG: 7.7 ng/mL). Although autoimmune mechanism has been suggested to be involved in HE, neural mechanism and pathogenesis of HE remain unknown. Our findings suggest that monoaminergic neural activity might be associated with psychotic symptoms in patients with HE and plasma levels of monoamine metabolites might be useful as state markers.