In-Ho Paik

OBSERVATION OF METABOLIC CHANGES IN CHRONIC SCHIZOPHRENIA AFTER NEUROLEPTIC TREATMENT BY IN VIVO HYDROGEN MAGNETIC RESONANCE SPECTROSCOPY

RATIONALE AND OBJECTIVES The authors investigate: (1) whether there is a lateral effect of hydrogen (1H) magnetic resonance (MR) spectroscopy observable metabolite ratios between the right and the left prefrontal lobe in chronic schizophrenia; (2) whether there is a change of proton metabolite ratios in chronic schizophrenia after neuroleptic treatment; (3) whether there is a relation between changes in 1H MR spectra and the clinical assessment of Brief Psychiatric Rating Scale (BPRS); and (4) to investigate a hypofrontality hypothesis in schizophrenia in terms of neurochemical aspects. METHODS Localized in vivo 1H MR spectroscopy was used to measure the metabolite levels in the prefrontal lobes of control persons (n = 20) and of chronic patients before and after neuroleptic treatment (n = 34). The MR spectra of 8 cm3 voxels were compared with clinical assessment of BPRS in each subject. RESULTS No significant metabolic lateral effect was established in both schizophrenia and control groups (P > 0.05). After neuroleptic treatment, chronic schizophrenic patients generally demonstrated a decrease of the complex of gamma-aminobutyric acid (GABA) and glutamate (Glu) containing (GABA + Glu)/creatine (Cr) ratio. CONCLUSIONS The current follow-up 1H MR spectroscopy study shows a significant correlation between alterations of (GABA + Glu)/Cr ratio and BPRS, and supports a hypofrontality hypothesis in chronic schizophrenia. The reduction of (GABA + Glu)/Cr ratio after neuroleptic treatment may implicate the recovery of normal neuronal function in neurotransmitters. In vivo 1H MR spectroscopy may be a useful modality in follow-up evaluation of neuroleptic treatment in chronic schizophrenia.

TPH Gene May Be Associated with Suicidal Behavior, but Not with Schizophrenia in the Korean Population

Tryptophan hydroxylase (TPH) is a rate-limiting enzyme in the biosynthesis of serotonin. This study was designed to examine whether A218C polymorphism, which has been identified in intron 7 of the TPH gene, may be associated with schizophrenia or the suicidal behavior of schizophrenics in the Korean population. TPH genotypes were determined in DNA samples from 217 schizophrenics and 236 healthy volunteers. Among the schizophrenic group, 27 patients had a history of suicidal behavior. Genomic DNA was amplified by a polymerase-chain-reaction-based method and restricted by NheI. A218C polymorphism was associated with a history of suicidal behavior in schizophrenics. This finding suggests that the TPH gene or a gene in its vicinity may influence suicidal behavior in schizophrenics. However, genotypic and allelic distrubutions of this polymorphism did not significantly differ between schizophrenics and controls.

An estimation of the first positive Lyapunov exponent of the EEG in patients with schizophrenia.

We studied the complexity of the electroencephalogram (EEG) in schizophrenic patients by estimating the first Lyapunov exponent (L1), which might serve as an indicator of the specific brain function in schizophrenia. We recorded the EEG from 25 schizophrenic patients (12 male, 13 female; age=25.1+/-7.0 years) fulfilling DSM-IV criteria and 15 healthy controls (9 male, 6 female; age=27. 8+/-4.2 years) at 16 electrodes, different from previous studies which recorded the EEGs at limited electrodes. We employed a method with an optimal embedding dimension to calculate the L1s. For limited noisy data, this algorithm was strikingly faster and more accurate than previous ones. Our results showed that the schizophrenic patients had lower values of the L1 at the left inferior frontal and anterior temporal regions compared with normal controls. These results for L1 in non-linear analysis have some differences from those for power ratios in linear analysis. These suggest that the non-linear analysis of the EEGs such as the estimation of the L1 might be a useful tool in analyzing EEG data to explore the neurodynamics of the brains of schizophrenic patients.

Quinone oxidoreductase (NQO1) gene polymorphism (609C/T) may be associated with tardive dyskinesia, but not with the development of schizophrenia.

The association between the quinone oxidoreductase gene (NQO1) polymorphism (609C/T) and schizophrenia was examined to replicate and extend the findings of a previous study (Hori et al., 2003). The study sample was 107 schizophrenia in-patients and 106 healthy controls. The distributions of the NQO1 genotypes and alleles were not different between the schizophrenia patients and the controls. However, the frequency of the variant genotype was significantly higher in the subgroup with tardive dyskinesia (TD) than in the subgroup without (p=0.019). The subjects with allele T were significantly more frequent in the TD patients than in those without (odds ratio 2.256, 95% confidence interval 1.235-4.133). In addition, the Abnormal Involuntary Movement Scale (AIMS) score was significantly higher in the variant genotype group (T/T) than in other genotypic groups (C/C and C/T) (p=0.004). This study suggests that the NQO1 gene polymorphism (609C/T) may confer susceptibility to the development of TD in schizophrenia, at least in the Korean population.

Glutathione S-transferase M1 polymorphism may contribute to schizophrenia in the Korean population.

The association between Glutathione S-Transferase M1 gene (GSTM1) polymorphism and schizophrenia was examined. One hundred and eleven in-patients with schizophrenia and 130 healthy controls were enrolled in this study. Genotyping was performed using a polymerase chain reaction-based method. The GSTM1 null genotype was significantly more frequent in the schizophrenia patients than in the controls (P=0.014, odds ratio=1.93, 95% confidence interval=1.115–3.351). On the other hand, the GSTM1 genotype variants were not associated with tardive dyskinesia or total abnormal involuntary movement scale scores. This study suggests that, at least in the Korean population, the GSTM1 polymorphism may confer susceptibility to the development of schizophrenia but not to tardive dyskinesia.

Monocyte chemoattractant protein-1 (MCP1) promoter -2518 polymorphism may confer a susceptibility to major depressive disorder in the Korean population.

We conducted a case-control association study of the monocyte chemoattractant protein-1 (MCP1) gene -2518 polymorphism in 90 patients with major depressive disorder. Genotyping was performed by polymerase chain reaction methods. We found significant differences in genotype and allele frequencies. The present study suggests that this polymorphism may confer a susceptibility to major depressive disorder in the Korean population.

BanI Polymorphism of the Cytosolic Phospholipase A2 Gene and Mood Disorders in the Korean Population

Membrane phospholipid abnormalities have been proposed to be involved in the pathogenesis of mood disorders, and in signal transduction and neurotransmitter uptake. Cytosolic phospholipase A2 (cPLA2) is not only an essential enzyme in the metabolism of fatty acids but also in signaling process. Therefore, we examined the association between the BanI polymorphism of the cPLA2 gene and mood disorders. Sixty-two patients with major depressive disorder (MDD), 50 patients with bipolar I disorder (BID) and 117 healthy controls participated in this study. Genotyping was performed by using PCR-based methods. Genotype and allele distributions in MDD patients were significantly different from those of the controls. In particular, the A2 allele was associated with increased risk of MDD development (p = 0.007, odds ratio = 1.827; confidence interval = 1.141–2.927). However, the polymorphism was not different between BID patients and controls in genotype and allele distribution. This preliminary study indicates the need for further studies on the potential role of the cPLA2 gene polymorphism in the susceptibility to mood disorders.

BanI polymorphism of the cytosolic phospholipase A2 gene may confer susceptibility to the development of schizophrenia.

Membrane phospholipid abnormalities have been proposed to be involved in the pathogenesis of schizophrenia. Cytosolic phospholipase A2 (cPLA2) plays a major role in the metabolism of fatty acids but is also found in abnormalities in patients with schizophrenia. This study examined the association between the cPLA2 gene BanI polymorphism and schizophrenia. Ninety-seven Korean schizophrenia patients and 117 healthy controls participated in this study. Genotyping was performed by using polymerase chain reaction (PCR)-based methods. Genotype and allele distributions were significantly different between the schizophrenia patients and controls. In particular, the A2 allele was associated with an increased risk of schizophrenia (p = 0.003; odds ratio (OR) = 1.799; confidence interval (CI) = 1.192-2.716). However, the polymorphism was not different when the patient group was subdivided by the presence or absence of family history and by positive and negative subgroups according to the positive and negative syndrome scale (PANSS) score on schizophrenia. The results of this study replicated those of previous findings from Western countries and indicates the need for further studies on the potential role of the cPLA2 gene polymorphism in the susceptibility to schizophrenia.

Decreased Plasma Antioxidants in Schizophrenia

An aberration in the level of antioxidants has been suggested in schizophrenia. Therefore, this study examined the difference in the antioxidant level between patients with schizophrenia and healthy controls, as well as the difference between the drug-naïve schizophrenic patients with a first episode (FSPR) and the risperidone-treated chronic schizophrenia (RCSPR) patients. The plasma albumin, bilirubin and uric acid levels were determined in 47 FSPR and 55 chronic schizophrenia patients who met the DSM-IV criteria for schizophrenia, and in 68 controls. The albumin and bilirubin levels were significantly lower in the schizophrenic patients compared to the controls, although there was no significant difference between the FSPR and RCSPR patients. The bilirubin level was significantly lower in the negative subgroup of the patient group. This study supports the hypothesis that an aberration in the antioxidant levels may be involved in schizophrenia. In addition, this study suggests that the antioxidant level may be associated with the clinical symptomatology as well as the treatment implications in schizophrenia, particularly the negative symptoms.

Manganese superoxide dismutase (MnSOD: Ala–9Val) gene polymorphism may not be associated with schizophrenia and tardive dyskinesia

There has been increasing evidence that the alteration of antioxidant enzymes such as manganese superoxide dismutase (MnSOD) might be implicated in the development of schizophrenia and/or tardive dyskinesia (TD). This study investigated the association of a MnSOD gene (MnSOD) polymorphism (Ala-9Val) with schizophrenia as well as its involvement in TD. Patients with schizophrenia (n=262) and healthy controls (n=263) were enrolled in this study and genotyped by a polymerase chain reaction-based method. The distribution of the MnSOD genotypes and alleles was not significantly different between patients and controls. Logistic regression analysis also failed to reveal any association between MnSOD genotypes and TD. Taken together, these results suggest that the MnSOD polymorphism does not contribute to the development of schizophrenia and/or TD, at least in the Korean population.