Mariko Sugishita

Association of structural polymorphisms in the human period3 gene with delayed sleep phase syndrome

Recent progress in biological clock research has facilitated genetic analysis of circadian rhythm sleep disorders, such as delayed sleep phase syndrome (DSPS) and non‐24‐h sleep–wake syndrome (N‐24). We analyzed the human period3 (hPer3) gene, one of the human homologs of the Drosophila clock‐gene period (Per), as a possible candidate for rhythm disorder susceptibility. All of the coding exons in the hPer3 gene were screened for polymorphisms by a PCR‐based strategy using genomic DNA samples from sleep disorder patients and control subjects. We identified six sequence variations with amino acid changes, of which five were common and predicted four haplotypes of the hPer3 gene. One of the haplotypes was significantly associated with DSPS (Bonferronis corrected P = 0.037; odds ratio = 7.79; 95% CI 1.59–38.3) in our study population. Our results suggest that structural polymorphisms in the hPer3 gene may be implicated in the pathogenesis of DSPS.

Genetic polymorphisms of human melatonin 1b receptor gene in circadian rhythm sleep disorders and controls

Recent studies suggest that melatonin 1b (Mel1b) receptor, as well as melatonin 1a (Mel1a) receptor, is involved in the modulation of circadian rhythms in mammals. Mutational analysis was performed in the entire coding region of the human Mel1b receptor gene using genomic DNA from sleep disorder subjects. We have identified two missense mutations, G24E and L66F. However, neither is likely to be associated with sleep disorders in our study population. One of the subjects with non-24-h sleep-wake syndrome carries missense mutations in both the Mel1a and Mel1b receptor genes.

Certain Neuroleptics Reduce Bone Mineralization in Schizophrenic Patients

A significant increase of urinary Ca and hydroxyproline levels and a decrease of urinary alkaline phosphatase activity were found in 12 schizophrenic patients receiving certain neuroleptic drugs. In these patients, the levels of active metabolites of vitamin D3 were decreased, while the levels of midmolecule parathyroid hormone were within the normal range, except for 2 cases. These results suggest that certain neuroleptics induce the increased urinary Ca excretion through suppression of active vitamin D3 formation and that chronic treatment with certain neuroleptics may induce abnormal bone mineralization.

Multicenter Study on SAD in Japan: The 4th Year Report

Four years have passed since a multicenter study on seasonal affective disorder (SAD) started in 1988. Summarizing our previous observations, the characteristics of Japanese SAD are as follows: 1) The sex ratio is practically even; 2) Latitude dependency is not likely; 3) Atypical symptoms are less frequent; and 4) Phototherapy is effective. However, the etiology, clinical course and prognosis have been depicted to a referrable extent neither in Japan nor other countries. There have not been reports on the long-term time course of this disorder either. In this report, we present the results of the four-year-long multicenter study of SAD in Japan.

Study on Sleep‐Wake Rhythm Disorders in Two Outpatient Clinics

Recently, sleep-wake rhythm disorders such as delayed sleep phase syndrome (DSPS), non-24 hour sleep-wake cycle (non-24) and irregular sleep-wake cycle have been the focus of much attention in research on sleep disorders. However, neither their clinical characteristics nor the mechanisms underlying these disorders are well understood. Moreover, their treatment is very difficult, although several investigators reported a successful treatment with vitamin B,, (Vit. B12)1 2 or bright light therapy. Consequently, it is important to reveal the clinical characteristics and therapeutic effects of novel treatments in a large number of patients to clarify their pathogenesis and to develop useful treatments, We report here a preliminary result of the study on the sleepwake rhythm disorders in two clinics, which started in October 1990.

National Survey of Seasonal Affective Disorders and Phototherapy in Japan

During the past 5 years more than 10 research groups reported seasonal affective disorders (SAD) from various countries in North America and Europe. It has been demonstrated that these disorders have characteristic backgrounds and symptoms.12 In particular, a high incidence of female patients is equally observed in the studies reported. Moreover, genetical involvement is also suggested. As to symptoms, several unique vegetative symptoms are reported such as hyperphagia, hypersomnia, weight gain or carbohydrate craving. It would be interest to investigate whether or not Mongolian peoples are also sensitive to photoperiodism as well as Caucasian peoples. To our knowledge no systematic study concerning SAD in Mongolian people has been reported. It is well known that Mongolian people are more tolerant to sunlight because of the pigmentation in their skin. Such difference in photosensitivity might cause some difference in symptoms or incidence of SAD, which has been suggested to relate to photoperiodism. From this viewpoint, members of the Japanese research group on chronobiology, which has been organized since 1986, conducted a multi-center survey of SAD in Japan last year with the support of a research grant from the Ministry of Education, Science and Culture (The representative of the research group is Dr. Saburo Takahashi, Professor of Psychiatry at Shiga University of Medical Science). The 16 facilities from north to south throughout Japan took part in the project (Table 1). The patients were recruited either at the study clinics or through nationwide or local newspapers. Nineteen male and 27 female SAD were identified. Their background and symptoms are shown in Tables 2 and 3. The ratio of male patients was relatively high compared with reports from abroad. Percentage of changes in affect such as sadness, anxiety or irritability are less compared with psychomotor retardation such as decreased activity, difficulty in work and so on. Increased appetite was found mainly in females, while increased weight was seen in both sexes. Hypersomnia was also observed in both sexes. Phototherapy was conducted on 19 patients, 11 males and 8 females. In the present pilot study we intended to see only if the phototherapy is effective in Japanese SAD patients. So, we did not always observe the effect of dim light or withdrawal of light treatment, as

The Comparison between the Suppressive Effects on Nocturnal Melatonin Secretion with β‐Blocker, Atenolol, and by Bright Artificial Light in Healthy Subjects

As a result of our study conducted on the suppression of nocturnal melatonin secretion of healthy subjects by bright artificial light, we reported on the existence of two subject categories during the 3rd Workshop for the Clinical Research on Chronobiology (Tokyo, 1988), the suppressed group which has maximum suppression rates of over 40%, and the non-suppressed group with rates below 40%. Following on these results we proceeded to continue this study with the following two objectives. The study shall proceed to clarify whether or not differences emerge between individual subjects for the &antagonist, atenolol, suppressive effect, as was the case for suppression through illumination. If such a difference was found to exist in the case of P-antagonist administration, it would be possible to predict or “pre-evaluate” the effects of light therapy on a given individual by the prior use of atenolol. 2) Taking into consideration the fact that Vit.B,, is used in rhythm disorders, either by itself or with light therapy, a prediction was made that there would be a correlation between serum concentrations of Vit.B,, and the suppressive effect of light on melatonin secretion.