Nakao Iwata

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.

Diffuse neurofibrillary tangles with calcification (DNTC) is an atypical dementia and is characterized pathologically by diffuse neurofibrillary tangles (NFTs) without senile plaques (SPs). In this study, we investigated the distribution of human leukocyte antigen (HLA)-DR-positive activated microglia in postmortem brain tissue of six patients with DNTC and six patients with Alzheimer disease (AD). HLA-DR-positive activated microglia were observed to associate with SPs in AD. In the DNTC brain, which lacks SPs, HLA-DR-positive microglia were mainly accumulated around weakly tau-positive NFTs, which were also positive for anti-amyloid-P and anti-C3d antibodies. The results of this study suggest that the complement pathway is also activated in the DNTC brain and that immune and inflammatory responses, including microglia activation, may occur around extracellular NFTs in DNTC patients.

In the rat, variation in alcohol and benzodiazepine sensitivity has been correlated with an inherited variant of the GABA(A)alpha 6 receptor. Our goal was to identify polymorphisms in the human GABA(A)alpha 6 receptor gene and determine whether a variant of the receptor is associated with alcoholism. The GABA(A)alpha 6 receptor gene coding region was screened in 80 unrelated patients with alcoholism using single strand conformational polymorphism analysis. For rapid genotyping, a Polymerase Chain Reaction-Restriction Fragment Length polymorphism (PCR-RFLP) assay was developed. A relatively abundant amino acid substitution and three synonymous DNA substitutions were detected. The synonymous variants, 35A > G, 665A > G, and 1031 > G > C had rare-allele frequencies of 0,25, 0,02, and 0,47, respectively. The Pro38-5Ser substitution is located in the second intracellular domain of the receptor adjacent to a putative phosphorylation site. Pro385Ser has rarer allele frequencies of 3.3% and 4.8% in 196 Finnish alcoholic patients and 189 controls, respectively (P = NS). A naturally occurring non-conservative Pro385Ser was detected in the GABA(A)alpha 6 receptor. The variant is not associated with alcoholism.

Objective: In humans, interindividual variation in sensitivity to benzodiazepine drugs may correlate with behavioral variation, including vulnerability to disease states such as alcoholism. In the rat, variation in alcohol and benzodiazepine sensitivity has been correlated with an inherited variant of the GABA(A)alpha 6 receptor. The authors detected a Pro385Ser [1236C>T] amino acid substitution in the human GABA(A)alpha 6 that may influence alcohol sensitivity. In this pilot study, they evaluated the contribution of this polymorphism to benzodiazepine sensitivity. Method: Sensitivity to diazepam was assessed in 51 children of alcoholics by using two eye movement measures: peak saccadic velocity and average smooth pursuit gain. Association analysis was performed with saccadic velocity and smooth pursuit gain as dependent variables and comparing Pro385/Ser385 heterozygotes and Pro385/Pro385 homozygotes. Results: The Pro385Ser genotype was associated with less diazepam-induced impairment of saccadic velocity but not with smooth pursuit gain. Conclusions: The Pro385Ser genotype may play a role in benzodiazepine sensitivity and conditions, such as alcoholism, that may be correlated with this trait.

Background: The vulnerability to alcohol dependence appears to be genetically influenced through a variety of mechanisms. One potentially genetically mediated channel may be a low level of response (LR) to alcohol, which has been seen in children of alcoholics and noted to predict future alcohol abuse and dependence. This pilot study uses a case and control genetic association approach to evaluate the possible role of five genotypes in both LR and alcoholism in informative subgroups of men with high and low LR scores documented 15 years earlier. Methods: As part of a larger study, 41 men, about 39 years old, were selected from among the first 113, completed 15-year follow-ups in a prospective study. The 17 subjects whose LRs at age 20 were in the lower third were compared on five polymorphisms of four genes with 24 men whose reactions to alcohol had been above the median, Results: The 14 men with the LL genotype of the serotonin transporter (5-HTT) polymorphism and the seven with the Pro/Ser genotype of the GAB(A alpha 6) polymorphism had demonstrated lower LR scores at about age 20, and had significantly higher proportions of alcoholics than the other genotypes for those loci. All four subjects with combined LL and Pro/Ser genotypes had developed alcoholism and demonstrated the lowest LR scores overall, There was no evidence that two polymorphisms of the 5-HT2A receptor gene and one of the 5-HT2C receptor gene were related to LR or alcoholism in this sample. Conclusions: These results are consistent with animal and human studies suggesting a possible role for genetic variation in the GABA(A alpha 6) and the serotonin transporter in the reaction to alcohol and the alcoholism risk. Biol Psychiatry 1999;45:647-651 (C) 1999 Society of Biological Psychiatry.

We screened the serotonin(5A) receptor gene coding region in 186 unrelated alcoholic patients and 187 controls. A relatively abundant amino acid substitution and two synonymous DNA substitutions were detected. Two synonymous variants, A12T and C789T, had rarer-allele frequencies of 23% and 1%, respectively. The Pro15Ser substitution is located in the amino terminal, extracellular domain of the receptor adjacent to a putative phosphorylation site. Pro15Ser had rarer-allele frequencies of 8.1% and 5.9% in Finnish alcoholic patients and controls, respectively (p = n.s.). (C) 1998 Elsevier Science B.V. All rights reserved.

The relationship between role stress at work and mental health status, and the moderating effect of social support, were examined in a sample of Japanese bank workers. Hierarchical moderated multiple regression analyses revealed that role overload had the largest association with mental health status and its interaction with co-worker support was also significantly associated with mental health status. Visual inspection indicated that this interaction should be regarded as a convergent relationship; i.e. high co-worker support would be effective to keep mental health status at low to medium levels of role overload, but become less effective at a higher level of role overload. This relationship was replicated for male clerks. but varied for female clerks, and was not significant for male chief clerks or higher. This might suggest that contradictions in the moderating effects of social support reported in earlier literature from Western countries could, at least in part, be explained by differences in the types of stress, strain, and social support, as well as the situational context of the samples.

The mouse tyrosine hydroxylase (TH) gene was isolated from a genomic library by cross-hybridization with human TH cDNA probe. Nucleotide sequence analysis of two overlapping genomic clones showed that this gene is split into 13 exons distributed about 7.5 kb in length. The transcription initiation site was determined by primer extension analysis with mouse adrenal gland poly(A)+RNA. The structure of the mouse TH gene was similar to that of the human TH gene, but it contained neither the alternative splice donor site around the 3′-end of the first exon nor an independent exon corresponding to the second exon of the human TH gene. There were the canonical TATA and GC boxes, cyclic AMP responsive element (CRE), and AP1 binding site in the 5′-flanking region of the mouse TH gene. © 1992 Academic Press, Inc.