Kitajima Tsuyoshi

Background: Abnormality of the V-akt murine thymoma viral oncogene homologue 1 (AKT1) may be a predisposing factor in schizophrenia. Recent evidence supporting this hypothesis showed decreased AKT1 protein levels in patients with schizophrenia and significant association of AKT1 haplotypes according to the transmission disequilibrium test. Methods. We provide the first replication of this evidence using a relatively large case-control sample (507 Japanese schizophrenia and 437 control subjects). We genotyped five single nucleotide polymorphisms (SNTs) from the original study and one additional SNP. Results: We found a positive association with an SNP (SNP5) different from the original study's findings (SNP3) and also significance in the haplotypes constructed from the combination of SNP5. Linkage disequilibrium around SNP5 was complex and may produce this positive association. Conclusions: Our study provides support for the theory that AKT1 is a susceptibility gene for japanese schizophrenia. Fine linkage disequilibrium mapping is required for a conclusive result.

Recent studies have shown that functional variations in clock genes, which generate circadian rhythms through interactive positive/ negative feedback loops, contribute to the development of circadian rhythm sleep disorders in humans. Another potential candidate for rhythm disorder susceptibility is casein kinase I epsilon (CKIepsilon), which phosphorylates clock proteins and plays a pivotal role in the circadian clock. To determine whether variations in CKIe induce vulnerability to human circadian rhythm sleep disorders, such as delayed sleep phase syndrome (DSPS) and non-24-hsleep-wake syndrome (N-24), we analyzed all of the coding exons of the human CKIe gene. One of the variants identified encoded an amino-acid substitution S408N, eliminating one of the putative autophosphorylation sites in the carboxyl-terminal extension of CKIepsilon. The N408 allele was less common in both DSPS ( p = 0.028) and N-24 patients ( p = 0.035) compared to controls. When DSPS and N-24 subjects were combined, based on an a priori prediction of a common mechanism underlying both DSPS and N-24, the inverse association between the N408 allele and rhythm disorders was highly significant ( p = 0.0067, odds ratio = 0.42, 95% confidence interval: 0.22 - 0.79). In vitro kinase assay revealed that CKIe with the S408N variation was similar to1.8-fold more active than wild-type CKIepsilon. These results indicate that the N408 allele in CKIe plays a protective role in the development of DSPS and N-24 through alteration of the enzyme activity.

Previous studies show that genetic haplotype within the neuregulin 1 gene (NRG1) increase the risk of developing schizophrenia. The authors described a negative replication that a haplotype of NRG1 did not associate with schizophrenia. Of 607 Japanese schizophrenic patients and 515 controls, the estimated frequency of the core at-risk haplotype had no difference between patients (4.5%) and controls (4.3%). The data suggests that NRG1 haplotype is unlikely to be associated with increased risk of schrizophrenia.

It is known that benzodiazepines have a hypotensive effect, but the mechanism has not been well elucidated yet. To clarify whether this effect is due to central or peripheral mechanism, we administered 5 mg of diazepam or saline intravenously to healthy volunteers and assessed the change in blood pressure, heart rate, muscle sympathetic nerve activity and heart rate variability. After diazepam administration, systolic and mean blood pressure decreased significantly. Muscle sympathetic nerve activity was also significantly reduced but heart rate did not change, whereas the variables of spectral analysis of heart rate variability did not show significant change. We concluded that the hypotensive effect of diazepam in human is mainly due to the central mechanism. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

Study Objectives: Sleep deprivation has a profound effect on cardiovascular regulation through the autonomic nervous system. This study examined the effect of 24-hour total sleep deprivation on muscle sympathetic nerve activity (MSNA), which is a direct measurement of the postganglionic sympathetic efferent innervating the vascular bed in the skeletal muscle and other circulatory structures. Design: The study was performed on 6 young healthy men. The factors exerting influence on MSNA, such as aging, obesity, body posture, activity, intensity of illumination, and food and beverage consumption were strictly controlled. Burst rate and burst incidence were used as parameters of MSNA. The burst rate, burst incidence, heart rate, and systolic and diastolic blood pressure were measured after total sleep deprivation and control sleep. To perform a linear regression analysis of arterial baroreflex (ABR), the incidence of MSNA bursts corresponding to a given diastolic blood pressure (%MSNA) was examined. Measurement and Results: The diastolic blood pressure was significantly higher after total sleep deprivation than after control sleep (66.5 +/- 1.7 vs 57.4 +/- 3.3 mm Hg). The burst rate (9.6 +/- 1.8 vs 13.3 +/- 2.7 bursts/min) and burst incidence (21.6 +/- 4.5 vs 30.3 +/- 8.9 bursts/100 heart beats) of MSNA were significantly lower after total sleep deprivation than after control sleep (P < .05). Analysis of the ABR disclosed a significant linear regressive relation between %MSNA and diastolic blood pressure in every subject after both total sleep deprivation and control sleep. This result implies that the ABR regulates the occurrence of MSNA bursts under different diastolic blood pressure conditions. The threshold (X-axis intercept) of the blood pressure regression line (ie, an indicator of the ABR set point) shifted by 12 +/- 4.3 mm Hg toward a higher blood pressure level after total sleep deprivation (P < .05). The ABR sensitivity, or the slope of the regression line, tended to be less steep after total sleep deprivation than after control sleep, although it was not statistically significant (P = .09). Conclusions: The diastolic blood pressure increased and both burst rate and burst incidence of MSNA decreased after total sleep deprivation. The results show that resetting of the ABR toward a higher blood pressure level occurred after total sleep deprivation. This ABR resetting probably brings about an increase in arterial blood pressure after total sleep deprivation.

The serotonin 5-HT4 receptor (5-HT4) is implicated in cognitive function, of which impairment is hypothesized as one of the core disturbances of schizophrenia. Linkage analysis shows that 5q33.2, in which HTR4 is located, is schizophrenia-susceptibility loci. We therefore hypothesized that variation in the 5-HT4 receptor gene (HTR4) modifies genetic susceptibility to schizophrenia. HTR4 coding regions and introns that include the branch sites of HTR4 were investigated in 96 unrelated Japanese schizophrenics using denaturing high-performance liquid chromatography analysis. One silent single nucleotide polymorphism (SNP) within the coding region and six intronic SNPs were detected. 353 + 6G > A was located in the branch site that could be effect to RNA splicing. None of the four SNPs, in which rare-allele frequencies were more than 10% was associated with 189 schizophrenics, in comparison to 299 controls. However, a highly significant association between schizophrenia and haplotype A-T (OR = 0.13 [0.03-0.58]) was detected. These findings suggest that haplotype A-T itself may inhibit the occurrence of schizophrenia, or that another susceptible genetic variants may exist within linkage disequilibrium. © 2003 Wiley-Liss, Inc.

The serotonin 5-HT4 receptor (5-HT4) is implicated in cognitive function, of which impairment is hypothesized as one of the core disturbances of schizophrenia. Linkage analysis shows that 5q33.2, in which HTR4 is located, is schizophrenia-susceptibility loci. We therefore hypothesized that variation in the 5-HT4 receptor gene (HTR4) modifies genetic susceptibility to schizophrenia. HTR4 coding regions and introns that include the branch sites of HTR4 were investigated in 96 unrelated Japanese schizophrenics using denaturing high-performance liquid chromatography analysis. One silent single nucleotide polymorphism (SNP) within the coding region and six intronic SNPs were detected. 353 + 6G > A was located in the branch site that could be effect to RNA splicing. None of the four SNPs, in which rare-allele frequencies were more than 10% was associated with 189 schizophrenics, in comparison to 299 controls. However, a highly significant association between schizophrenia and haplotype A-T (OR = 0.13 [0.03-0.58]) was detected. These findings suggest that haplotype A-T itself may inhibit the occurrence of schizophrenia, or that another susceptible genetic variants may exist within linkage disequilibrium. © 2003 Wiley-Liss, Inc.

A pilot study using actigraph was conducted to assess the effects of a 1-week repeated administration of 15 mg of quazepam on the sleep and daytime activity of six healthy adults. The nocturnal sleep time gradually increased during quazepam administration, and a significant difference from the baseline was noted on the seventh day of administration. There was no significant difference in the daytime activity before and after the administration. Quazepam and its active metabolites appear to have acted on the level not affecting the daytime activity but prolonging the nocturnal sleep time through their interactions.

Risperidone is a widely used atypical antipsychotic with certain advantages over typical antipsychotics. Although variations in the efficacy of treatment with risperidone have been observed, no specific predictable marker has been identified as of yet. In all, 73 Japanese patients with schizophrenia were given risperidone for 8 weeks, and clinical symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS). Six candidate polymorphisms (HTR2A -1438G>A, 102T>C, H452Y; DRD2 -141delC, Taq I A; COMT V158M) were genotyped. The diplotype configuration for each individual was estimated by the maximum-likelihood method. Multiple linear regressions were used to analyze the effects of these haplotypes/genotype and other prognostic factors on PANSS scale performance. After adjustment for the effects of patient-related variables, HTR2A diplotype and COMT genotype, as well as other potential prognostic factors, did not significantly influence the clinical performance. A DRD2 haplotype tended to correlate with better clinical performance. Compared with patients who had Ins-A2/Ins-A2 diplotype (n=25), PANSS total scores of patients with Ins-A2/ Del-A1 diplotype (n=10) showed 40% greater improvement (P=0.03). The PANSS total scores of patients with HTR2A A-T/A-T diplotype (n=22) tended to show 15% worse improvement compared with A-T/G-C diplotype (n=33) (P-0.06). These results should be treated with caution because of limitations due to small sample size, heterogeneity of patients with respect to past antipsychotic use history, and no correction for multiple corrections. However, the present findings generate important hypotheses in a sample of Japanese schizophrenia patients that may lay the foundation for future pharmacogenomics investigations in other populations.

Mood disorders are common diseases and cause a big burden on society, including suicide. Because there are many treatment-resistant cases in mood disorders, it is very important to elucidate the pathophysiology of this condition to establish its prevention and its treatment. Genetic epidemiological studies have shown that genetic factors have an important role in the pathophysiology of mood disorders therefore the molecular genetics studies of this condition have been extensively performed, such as positional approach (i.e., linkage study) and candidate gene approach (i.e., association study). Linkage studies have shown some candidate locations that have been reproduced in two or more studies, such as 1q21-42, 4p16, 10q21-26, 11p15, 12q23-24, 13q11-32, 18p11, 18q21-22, 22q11-13, Xp11 and Xq24-28. Most association studies have until now focused on the neurotransmitter system as a candidate molecule including serotonin transporter, serotonin receptors, dopamine receptors, tyrosine hydroxylase, MAO-A, COMT, and tryptophan hydroxylase. Moreover, phamacogenetic studies also have been carried out in this field to develop new drugs as well as personalized medicine. Future molecular genetic studies will find out the mood-disorder susceptible genes and open the gate to true treatment and prevention of this disorder as the Human Genome Project attains its goal.

Yoku-kan-san-ka-chimpi-hange (YKCH) is a drug used for insomnia in Japanese traditional herbal medicine. The present study evaluated the effects of YKCH on sleep by all-night polysomnography using the double-blind method. Yoku-kan-san-ka-chimpi-hange increased the total sleep time significantly, and tended to cause an increase in sleep efficiency and of stage 2 sleep, as well as a decrease of sleep latency and of stage 3 + 4 sleep. There was no apparent influence on rapid eye movement (REM) sleep. In terms of non-REM sleep, the effects of YKCH exhibit a profile similar to those of benzodiazepines.

Donepezil (Aricept) is a therapeutic drug for the treatment of Alzheimer's disease (AD). However, there have been only two reports describing the effects of donepezil on sleep as assessed by nocturnal polysomnography (PSG). With this in mind, the effects of donepezil on the sleep of healthy subjects was evaluated using PSG. The results indicated that the percentage of rapid eye movement sleep to total sleep time was increased significantly by a single dose of 5 mg of donepezil when given to healthy subjects immediately before retiring to bed.

We investigated the influence of melatonin on the human autonomic functions by measuring muscle sympathetic nerve activity (MSNA). Five healthy male volunteers took 3 mg of melatonin, and their plasma melatonin concentration, blood pressure, heart rate, and burst rate of MSNA were then recorded. The peak level of melatonin concentration showed a marked interindividual variation. Blood pressure was reduced significantly: while heart rate and burst rate of MSNA did not change significantly. These results indicate that melatonin has a hypotensive effect on blood pressure, and the central cardiovascular regulatory mechanism such as lowering, of the baroreflex setpoint would be involved in the effect.

Polysomnography was used to assess the effect of thalidomide on human sleep. This compound significantly increased the time spent in REM and stage 3-4 sleep as compared with placebo. On the other hand, thalidomide significantly decreased the time spent in stage 1, while the time spent in stage 2 was unchanged. The effect of thalidomide on REM and stage 3-4 sleep is unique as compared with other hypnotics. Although the mode of action of this compound is unknown, further studies on thalidomide should help in our understanding of the mechanisms of sleep regulation.