The Mechanism of Anti-Epileptogenesis by Levetiracetam Treatment is Similar to the Spontaneous Recovery of Idiopathic Generalized Epilepsy during Adolescence

Hiroki Kikuyama,Tadahito Hanaoka,Tetsufumi Kanazawa,Yasushi Yoshida,Takafumi Mizuno,Hirotaka Toyoda,Hiroshi Yoneda 대한신경정신의학회 2017 PSYCHIATRY INVESTIGATION Vol.14 No.6

Objective: The anti-epileptogenic drug levetiracetam has anticonvulsant and anti-epileptogenesis effects. Synergy between cell death and inflammation can lead to increased levels of apoptosis inhibitory factors and brain-derived neurotrophic factor, aberrant neurogenesis and extended axon sprouting. Once hyperexcitation of the neural network occurs, spontaneous seizures or epileptogenesis develops. This study investigated whether the anti-epileptogenic effect of levetiracetam is due to its alternate apoptotic activity. Methods: Adult male Noda epileptic rats were treated with levetiracetam or vehicle control for two weeks. mRNA quantification of Bax, Bcl-2 and GAPDH expression were performed from prefrontal cortex and hippocampus tissue samples. Results: The levetiracetam-treated group showed a significant increase of Bax/Bcl-2 mRNA expression ratio in the prefrontal cortex than the control group, but no change in the Bax/Bcl-2 mRNA expression ratio in hippocampus. Conclusion: Idiopathic generalized epilepsy including childhood absence epilepsy develop at childhood and recover spontaneously during adolescence. The aberrant neural excitable network is pruned by a neural-maturing action. This study suggests the mechanism of acquired anti-epileptogenesis by levetiracetam treatment may be similar to spontaneous recovery of idiopathic generalized epilepsy during adolescence.

Association between Medication Adherence and Duration of Outpatient Treatment in Patients with Schizophrenia

Seiichiro Tarutani,Hiroki Kikuyama,Munehiro Ohta,Tetsufumi Kanazawa,Takehiko Okamura,Hiroshi Yoneda 대한신경정신의학회 2016 PSYCHIATRY INVESTIGATION Vol.13 No.4

ObjectiveaaMedication adherence is important in the treatment of schizophrenia, and critical periods during treatment may be associated with relapse. However, the relationship between adherence and duration of outpatient treatment (DOT) remains unclear. The authors aimed to clarify the relationship between adherence and DOT at a psychiatric hospital in Japan. MethodsaaFor outpatients with schizophrenia who regularly visit Shin-Abuyama hospital, the authors conducted a single questionnaire survey (five questions covering gender, age, DOT, medication shortages, and residual medication) over one month period. Participants were divided into two groups whether DOT were from more than one year to within five years or not. Mantel-Haenszel analysis and logistic regression analysis were performed on the data regarding the medication adherence. ResultsaaEffective answers were received for 328 patients. The residual medication rate was significantly higher among those receiving outpatient treatment from more than one year to within five years than five years than those receiving outpatient treatment for more than five years or less than one year (p=0.016). ConclusionaaThis survey suggests that there are critical periods during which patients are most prone to poor adherence. Because poor adherence increases the risk of relapse, specific measures must be taken to improve adherence during these periods.

Increases in iPS Transcription Factor (Oct4, Sox2, c-Myc, and Klf4) Gene Expression after Modified Electroconvulsive Therapy

Masaki Nishiguchi,Hiroki Kikuyama,Tetsufumi Kanazawa,Atsushi Tsutsumi,Takao Kaneko,Hiroyuki Uenishi,Yasuo Kawabata,Seiya Kawashige,Jun Koh,Hiroshi Yoneda 대한신경정신의학회 2015 PSYCHIATRY INVESTIGATION Vol.12 No.4

ObjectiveaaElectroconvulsive therapy (ECT) is a reasonable option for intractable depression or schizophrenia, but a mechanism of action has not been established. One credible hypothesis is related to neural plasticity. Three genes (Oct4, Sox2, c-Myc) involved in the induction of induced pluripotent stem (iPS) cells are Wnt-target genes, which constitute a key gene group involved in neural plasticity through the TCF family. Klf4 is the other gene among Yamanaka’s four transcription factors, and increases in its expression are induced by stimulation of the canonical Wnt pathway. MethodsaaWe compared the peripheral blood gene expression of the four iPS genes (Oct4, Sox2, c-Myc, and Klf4) before and after modified ECT (specifically ECT with general anesthesia) of patients with intractable depression (n=6) or schizophrenia (n=6). Using Thymatron ten times the total bilateral electrical stimulation was evoked. ResultsaaBoth assessments of the symptoms demonstrated significant improvement after mECT stimulation. Expression of all four genes was confirmed to increase after initial stimulation. The gene expression levels after treatment were significantly different from the initial gene expression in all twelve cases at the following treatment stages: at the 3rd mECT for Oct4; at the 6th and 10th mECT for Sox2; and at the 3rd, 6th and 10th mECT for c-Myc. ConclusionaaThese significant differences were not present after correction for multiple testing; however, our data have the potential to explain the molecular mechanisms of mECT from a unique perspective. Further studie should be conducted to clarify the pathophysiological involvement of iPS-inducing genes in ECT.

Genetic Polymorphisms in Dopamine- and Serotonin-Related Genes and Treatment Responses to Risperidone and Perospirone

Atsushi Tsutsumi,Tetsufumi Kanazawa,Hiroki Kikuyama,Gaku Okugawa,Hiroyuki Uenishi,Toshio Miyamoto,Naoki Matsumoto,Jun Koh,Kazuhiro Shinosaki,Toshifumi Kishimoto,Hiroshi Yoneda,Toshihiko Kinoshita 대한신경정신의학회 2009 PSYCHIATRY INVESTIGATION Vol.6 No.3

We investigated the possible association between genetic polymorphisms in the dopamine receptor and serotonin transporter genes and the responses of schizophrenic patients treated with either risperidone or perospirone. The subjects comprised 27 patients with schizophrenia who were clinically evaluated both before and after treatment. The genotyping of the polymorphisms of the dopamine D2 receptor gene (DRD2) (rs1801028 and rs6277), the dopamine D4 receptor gene (DRD4) (120-bp tandem repeats and rs1800955), and serotonin transporter gene (5HTT)(variable number of tandem repeats; VNTR) were performed using the real-time polymerase chain reaction and sequencing. In DRD2 and 5HTT-VNTR, there were no significant correlations between clinical response and polymorphism in the case of risperidone, and for perospirone treatment it was impossible to analyze the clinical evaluation due to the absence of genotype information. On the other hand, in DRD4 there were significant correlations in the two-factor interaction effect on the Positive and Negative Syndrome Scale (PANSS) between the two drugs [120-bp tandem repeat, p=0.003; rs1800955, p=0.043]. Although the small sample represents a serious limitation, these results suggest that variants in DRD4 are a predictor of whether treatment will be more effective with risperidone or with perospirone in individual patients. We investigated the possible association between genetic polymorphisms in the dopamine receptor and serotonin transporter genes and the responses of schizophrenic patients treated with either risperidone or perospirone. The subjects comprised 27 patients with schizophrenia who were clinically evaluated both before and after treatment. The genotyping of the polymorphisms of the dopamine D2 receptor gene (DRD2) (rs1801028 and rs6277), the dopamine D4 receptor gene (DRD4) (120-bp tandem repeats and rs1800955), and serotonin transporter gene (5HTT)(variable number of tandem repeats; VNTR) were performed using the real-time polymerase chain reaction and sequencing. In DRD2 and 5HTT-VNTR, there were no significant correlations between clinical response and polymorphism in the case of risperidone, and for perospirone treatment it was impossible to analyze the clinical evaluation due to the absence of genotype information. On the other hand, in DRD4 there were significant correlations in the two-factor interaction effect on the Positive and Negative Syndrome Scale (PANSS) between the two drugs [120-bp tandem repeat, p=0.003; rs1800955, p=0.043]. Although the small sample represents a serious limitation, these results suggest that variants in DRD4 are a predictor of whether treatment will be more effective with risperidone or with perospirone in individual patients.

An Association Study of the Signal Transducer and Activator of Transcription 6 Gene With Periodic Psychosis

Seiya Kawashige,Tetsufumi Kanazawa,Atsushi Tsutsumi,Hiroki Kikuyama,Hiroyuki Uenishi,Jun Koh,Hiroshi Yoneda 대한신경정신의학회 2008 PSYCHIATRY INVESTIGATION Vol.5 No.1

Objective: Recent molecular and genetic investigations have suggested that the current nosology for major psychiatric disorders, based on the “two-entities-principal” is not accurate with respect to clinical observations; patient groups that do not fit to the current operative diagnostic boundaries are readily identified. We aimed to perform an investigation of the signal transducer and activator of transcription 6 (STAT6) gene (located on 12q13), which has an important role in the apoptotic cascade, with patients suffering from periodic psychosis. Methods: Genetic association study has been employed for the current work. Investigated six tag-SNPs were chosen from Hapmap database. Results: Among six tag-SNPs, one marker (rs10783813), located in the STAT6 gene, showed modest association (p<0.05), although no marker or haplotype block showed association after Bonferroni’s correction. Conclusion: Future studies will reveal the etiological role of STAT6, and of other genes of the apoptotic cascade, in major psychiatric disorders. Objective: Recent molecular and genetic investigations have suggested that the current nosology for major psychiatric disorders, based on the “two-entities-principal” is not accurate with respect to clinical observations; patient groups that do not fit to the current operative diagnostic boundaries are readily identified. We aimed to perform an investigation of the signal transducer and activator of transcription 6 (STAT6) gene (located on 12q13), which has an important role in the apoptotic cascade, with patients suffering from periodic psychosis. Methods: Genetic association study has been employed for the current work. Investigated six tag-SNPs were chosen from Hapmap database. Results: Among six tag-SNPs, one marker (rs10783813), located in the STAT6 gene, showed modest association (p<0.05), although no marker or haplotype block showed association after Bonferroni’s correction. Conclusion: Future studies will reveal the etiological role of STAT6, and of other genes of the apoptotic cascade, in major psychiatric disorders.