Hajime Kazamatsuri

Multi-institutional study on the teratogenicity and fetal toxicity of antiepileptic drugs: a report of a collaborative study group in Japan.

Summary: A multi‐institutional collaborative study was conducted concerning the course of pregnancy and delivery and the incidence of abnormal infants delivered of epileptic women. Of 657 women receiving antiepileptic drugs, 73% delivered live infants, 14% had miscarriage or stillbirth, and 13% underwent induced abortion. In contrast to the above findings, 80% of 162 patients not receiving antiepileptic drugs delivered live infants and 4% had miscarriage or stillbirth. The latter outcome was significantly increased in the medicated patients. In this series, 63 (9.9%) of 638 live births were malformed, 55 (11.5%) being from medicated mothers and 3 (2.3%) from nonmedicated mothers. The incidence of fetal malformation in medicated mothers was thus five times as high as that in nonmedicated mothers. Cleft lip and/or palate and malformations involving the cardiovascular system were found frequently in the infants from medicated mothers. General background factors that might exert teratogenic effects on pregnant patients with epilepsy were studied, and the potential toxicity of antiepileptic drugs to the fetus was also analyzed. In this regard, consideration should be given to whether the patient has partial epileptic seizures, whether the patient herself exhibits any malformation, or whether her previous pregnancy resulted in an abnormal outcome. The incidence of fetal malformation was the highest (12.7%) in the medicated patients who had epileptic seizures during the pregnancy. It is presumed on the basis of the results of analysis of the data that a combination of more than three drugs and a daily dose greater than a certain minimal level is likely to produce malformed infants.

A study of the association between schizophrenia and the dopamine D3 receptor gene

A study of the genetic association between schizophrenia and aBalI polymorphism in exon 1 of the dopamine D3 (DRD3) gene, a candidate gene for schizophrenia, was conducted. The polymorphism was examined in 91 patients whose symptoms satisfied DSM-III-R for schizophrenia and 90 controls. There were no significant differences between the groups in allele frequencies or genotype counts. Contrary to a previous report, the patients were no more likely to be homozygous than controls. Moreover, no association with the presence of illness could be demonstrated when the patients were grouped according to sex, age of onset, history of admission to psychiatric institutions or positive family history.

Neurotrophin-3 gene polymorphism associated with schizophrenia.

The recent possible neurodevelopmental etiology of schizophrenia makes the neurotrophin‐3 (NT‐3) gene an interesting candidate locus. We studied the allelic distributions of dinucleotide repeat polymorphism at the NT‐3 gene locus in 70 patients with schizophrenia and in 70 controls. A highly significant difference between the two groups was observed at the allele A3. Even Bonferronis correction was used, the difference was still significant. Individuals with homozygous or heterozygous for the allele A3 had a 2.4‐fold increased risk of schizophrenia. Determination of NT‐3 genotype may help to identify those at greater risk of schizophrenia. Furthermore, this finding supports evidence implicating neurodevelopmental deficit in the pathogenesis of this disorder.

Smoking and tardive dyskinesia

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Association of apolipoprotein E4 with sporadic Alzheimer's disease is more pronounced in early onset type

Apolipoprotein E genotypes in 88 unrelated Japanese patients with NINCDS-ADRDA sporadic Alzheimers disease (AD) were examined and compared with those of 93 healthy controls. Frequency of epsilon 4 allele was increased in patients with AD (31%) compared with controls (10%), as was reported previously. Individuals homozygous or heterozygous for the allele epsilon 4 had a 5.9-fold increased risk of AD. This tendency was more pronounced in early onset sporadic (= non-familial) type than late onset type. The relative risk was also greater for early onset type (RR = 11.7; 95% CI, 4.9-28.3) than late onset type (RR = 4.3; 95% CI, 2.1-8.8). Moreover, patients with homozygote for the allele epsilon 4 had a 14.7-fold increased risk of early onset sporadic AD (P < 0.005, chi 2 = 9.0, df = 1, 95% CI, 2.5-85.1). Our findings indicated that association of apolipoprotein epsilon 4 with sporadic Alzheimers disease is more pronounced in early onset type than in late onset type.

Changes of Immunological Functions after Acute Exacerbation in Schizophrenia

We investigated the changes of immunological functions in 14 schizophrenic patients (DSM-III-R; six men and eight women) who were hospitalized due to acute exacerbation of schizophrenia. The following immunological functions were studied on admission, 4 and 8 weeks after admission: serum immunoglobulins (Ig)G, A, and M; serum complement CH50; lymphocyte responses to mitogens (phytohemagglutinin, concanavalin A, and pokeweed mitogen); lymphocyte subpopulations (CD3%, 4%, 8%, 16%, 20%, 25%, and 56%); and natural killer cell (NK) activity. Psychological status of the patients, which was assessed by using Brief Psychiatric Rating Scale, improved gradually after admission. Changes in immune functions were analyzed using one-way analysis of variance and a randomized block analysis of variance with multiple comparison. NK activity on admission was significantly lower than those at 4 and 8 weeks after admission (p < .03). Serum IgG levels on admission and at 4 weeks after admission were significantly decreased as compared with those at 8 weeks after admission (p < .05); they were also lower than those in controls (p < .05). CD56% on admission and CD25% 4 weeks after admission were significantly increased as compared with controls (p < .05). These results indicate that several immunological functions might change related to time course after acute exacerbation. It is suggested that clinical conditions be carefully taken into consideration to evaluate immunological studies in schizophrenia.

Linkage studies between affective disorder and dopamine D2, D3, and D4 receptor gene loci in four Japanese pedigrees

Dopamine antagonists are effective in the treatment of episodes of acute mania. Conversely, drugs which increase dopamine activity can induce a switch to mania. Therefore, disturbances in dopamine transmission and dopamine receptors might be implicated in the pathophysiology of bipolar affective disorder. We have carried out linkage studies between the susceptibility gene for effective disorder and polymorphisms of dopamine DRD2, DRD3, and DRD4 receptor genes in four Japanese pedigrees. Linkages of both DRD2 and DRD3 have been excluded, at least for dominant and intermediate models. The result for DRD2 was consistent with previous studies. For DRD3 this is the first exclusion of affective disorder from this locus in the 3q13.3 where DRD3 has been localized. On the other hand, our data could not exclude linkage of DRD4.

Early parental loss and depressive disorder in Japan.

The aim of this study is to determine in a Japanese sample whether or not the permanent loss of a parent by death or separation in childhood is aetiologically associated with unipolar major depressive disorder (according to RDC). We compared the incidence of parental loss before 17 years of age by death or separation between 122 depressed inpatients and 94 non- and never-depressed medical controls. Early maternal death was found to be significantly more common in the depressives than in the controls. Separation from either parent also showed a trend towards an increased incidence in the depressive group. No significant difference in the incidence of early paternal death was found.

Pericentric region of chromosome 9 is a possible candidate region for linkage study of schizophrenia

We have undertaken a systematic G-banding survey to find structural chromosomal abnormalities among patients with schizophrenia. Of 120 patients with DSM-III-R schizophrenia, four (3.3%) had a pericentric inversion of chromosome 9 and three (2.5%) had a X/XX mosaicism. The frequency of pericentric inversion of chromosome 9 among patients with schizophrenia was statistically higher than those among newborns and Asian populations. Our results indicate that the pericentric region of chromosome 9 might be one of the potential regions of interest for linkage analysis of schizophrenia.

Overnight Effects of Triazolam on Cognitive Function: An Event-Related Potentials Study

The effects of triazolam on cognitive function and vigilance on the morning following a nocturnal administration were investigated using event-related potentials (ERP) measurement and a sleep latency test (SLT). We previously reported a significant reducing effect on target N1 amplitude on the morning following triazolam administration, suggesting a residual effect of triazolam. In order to demonstrate, which aspect of cognitive function alteration caused the reducing effect on N1 amplitude, we added the ignore condition for ERP measurement, which enabled us to separate mismatch negativity (MMN) from other subcomponents overlapping N1. As a result, MMN was attenuated and sleep latency was shortened on the morning following triazolam administration. Two possibilities were suggested for the mechanism of MMN attenuation. One is GABAergic activation caused by the residual effect of triazolam per se, and the other is the lowered vigilance level demonstrated in the SLT. Further studies are necessary to determine whether this alteration in physiological bases underlying mismatch detection is specific to triazolam and/or other benzodiazepines or related to nonspecific vigilance level.