Taku Furuno

Association in Japanese patients between neuroleptic malignant syndrome and functional polymorphisms of the dopamine D 2 receptor gene

A genetic predisposition to the development of neuroleptic malignant syndrome (NMS) has been suggested by clinical studies. Although the molecular basis of NMS is unclear, a dopaminergic blockade mechanism has been considered the main cause. We therefore investigated the association between NMS and three functional polymorphisms of the dopamine D2 receptor (DRD2) gene: TaqI A, −141C Ins/Del, and Ser311Cys. Subjects included 32 Japanese patients, previously diagnosed with NMS, and 132 schizophrenic patients treated with neuroleptics without occurrence of NMS. Polymerase chain reaction and restriction fragment length polymorphism analyses were performed to determine each genotype. We found significant differences in genotypic and allelic frequencies of the –141C Ins/Del polymorphism between patients with and without NMS. The −141C Del allele was significantly more frequent in the NMS group (23.4 vs 11.7%, P=0.026). Similarly, the proportion of −141C Del allele carriers was significantly higher in the NMS group (40.6 vs 20.5%, P=0.022). No significant differences between the two groups were seen for allelic and genotypic frequencies of the TaqI A and Ser311Cys polymorphisms. This result suggests that the −141C Ins/Del polymorphism is likely to predispose toward the development of NMS, probably together with other unidentified factors.

Psychiatric assessment of suicide attempters in Japan: a pilot study at a critical emergency unit in an urban area

BackgroundThe incidence of suicide has increased markedly in Japan since 1998. As psychological autopsy is not generally accepted in Japan, surveys of suicide attempts, an established risk factor of suicide, are highly regarded. We have carried out this study to gain insight into the psychiatric aspects of those attempting suicide in Japan.MethodsThree hundred and twenty consecutive cases of attempted suicide who were admitted to an urban emergency department were interviewed, with the focus on psychosocial background and DSM-IV diagnosis. Moreover, they were divided into two groups according to the method of attempted suicide in terms of lethality, and the two groups were compared.ResultsNinety-five percent of patients received a psychiatric diagnosis: 81% of subjects met the criteria for an axis I disorder. The most frequent diagnosis was mood disorder. The mean age was higher and living alone more common in the high-lethality group. Middle-aged men tended to have a higher prevalence of mood disorders.ConclusionThis is the first large-scale study of cases of attempted suicide since the dramatic increase in suicides began in Japan. The identification and introduction of treatments for psychiatric disorders at emergency departments has been indicated to be important in suicide prevention.

Interventions to prevent repeat suicidal behavior in patients admitted to an emergency department for a suicide attempt: a meta-analysis

BACKGROUND A huge number of patients with self-harm and suicide attempt visit emergency departments (EDs). We systematically reviewed studies and examined the effect of interventions to prevent repeat suicidal behavior in patients admitted to EDs for a suicidal attempt. METHOD We searched the databases of MEDLINE, PsychoINFO, CINAHL, and EMBASE through August 2013. Eligible studies were randomized controlled trials assessing the effects on repeat suicidal behavior of interventions initiated in suicidal patients admitted to EDs. Interventions in each trial were classified into groups by consensus. Meta-analyses were performed to determine pooled relative risks (RRs) and 95% confidence intervals (CIs) of repetition of suicide attempt for interventions in each group. RESULTS Out of 5390 retrieved articles, 24 trials were included and classified into four groups (11 trials in the Active contact and follow-up, nine in the Psychotherapy, one in the Pharmacotherapy, and three in the Miscellaneous). Active contact and follow-up type interventions were effective in preventing a repeat suicide within 12 months (n=5319; pooled RR=0.83; 95% CI: 0.71 to 0.97). However, the effect at 24 months was not confirmed (n=925; pooled RR=0.98; 95% CI: 0.76-1.22). The effects of the other interventions on preventing a repetition of suicidal behavior remain unclear. LIMITATION Caution is needed regarding the heterogeneity of the effects. CONCLUSION Interventions of active contact and follow-up are recommended to reduce the risk of a repeat suicide attempt at 12 months in patients admitted to EDs with a suicide attempt. However, the long-term effect was not confirmed.

Dopamine D2 receptor gene polymorphisms are associated with suicide attempt in the Japanese population.

Background: Some reports have suggested the involvement of the D2 dopaminergic function in the expression of suicidal behavior. Here, we examined associations between suicide attempts and two kinds of functional polymorphisms in the dopamine D2 receptor (DRD2) gene, namely, TaqIA and –141C Ins/Del. Methods: Subjects included 120 suicide attempters and 123 unrelated volunteers. Those who attempted suicide were severely injured and were transferred to the emergency unit in our university hospital. To determine each genotype, we performed polymerase chain reaction and restriction fragment length polymorphism analyses. Results: We found significant differences in genotypic and allelic frequencies of –141C Ins/Del and TaqIA polymorphisms between suicide attempters and healthy controls (–141C Ins/Del, p = 0.01; TaqIA,p = 0.036). The Ins allele of –141C Ins/Del was significantly more frequent in suicide attempters (p = 0.011), as well as the A2 allele of TaqIA (p = 0.017). Haplotype analysis revealed no significant linkage disequilibrium between –141C Ins/Del and TaqIA polymorphisms (D′ = 0.226, r2 = 0.016, p = 0.10). Conclusions: These findings suggest that DRD2 gene polymorphisms may be involved in the biological susceptibility to suicide.

Trait aggression in suicide attempters: a pilot study.

Suicide attempt is a potent risk factor of subsequent suicide. Understanding the characteristics of suicide attempters is important for preventing suicide. The authors investigated aggression in medically serious suicide attempters at an emergency department. Trait aggression was evaluated in 55 suicide attempters and 71 healthy individuals as a control group using the Japanese version of the Buss‐Perry Aggression Questionnaire (BAQ). Total BAQ scores (t = 2.782, P = 0.006) and the hostility scores (t = 3.735, P < 0.001) were significantly higher in the suicide attempters than the controls. It suggested that to focus on aggression and its management is one of the key components for preventing suicide.

Effects of CYP2D6 polymorphisms on neuroleptic malignant syndrome

ObjectiveNeuroleptic malignant syndrome (NMS) is one of the most serious adverse reactions to antipsychotic medications. We accumulated data on Japanese NMS patients and, in a study designed to examine the effects of drug metabolism on the occurrence of NMS, tested the possibility of association between NMS and CYP2D6 polymorphisms.MethodsWe studied 53 patients who had experienced NMS and 112 healthy individuals. We determined what drugs the patients with NMS had been given and retrospectively identified candidates for drugs causing NMS. We screened the prevalence of CYP2D6 genotypes using polymerase chain reaction and restriction fragment length polymorphism analyses.ResultsThe prevalence of *5 alleles in the group of all patients with NMS was higher than that in the controls, though this difference was not statistically significant (10.4% vs. 5.4%; P = 0.107; odds ratio (OR) 2.05; 95% confidence interval (CI) 0.87–4.80). No association was found between the frequency of *10 alleles and the occurrence of NMS. We found *4 and duplicated alleles in only one patient each among the patients with NMS. A total of 29 patients appeared to have developed NMS as a result of having taking CYP2D6 substrates. The prevalence of *5 alleles in these 29 patient was significantly higher than that in the controls (15.5% vs. 5.4%; P = 0.020; OR 3.25; 95% CI 1.30–8.13).ConclusionOur findings suggest that the CYP2D6*5 allele is likely to affect vulnerability to development of NMS.

Dose-dependent effect of antipsychotic drugs on autonomic nervous system activity in schizophrenia

BackgroundAntipsychotic drugs are considered a trigger factor for autonomic dysregulation, which has been shown to predict potentially fatal arrhythmias in schizophrenia. However, the dose-dependent effect of antipsychotic drugs and other psychotropic drugs on autonomic nervous system (ANS) activity remain unclear. The purpose of this study was to investigate the dose-dependent effect of antipsychotic drugs and other clinical factors on ANS activity in an adequate sample size of patients with schizophrenia.MethodsA total of 211 Japanese patients with schizophrenia and 44 healthy subjects participated in this study. ANS activity was assessed by means of heart rate variability (HRV) power spectral analysis. Antipsychotic drug treatment and various clinical factors were investigated for each participant. The patient group was categorized into three subgroups according to daily dose of antipsychotic drug, and HRV was compared between groups.ResultsThe results showed significantly decreased low-frequency and high-frequency components of HRV in the patient group compared to the control group. The high-dose group showed a significantly lower HRV than the medium-dose group and an even lower HRV than the low-dose group. In addition, a significant association between HRV and antipsychotic drug dose was identified by multiple regression analysis. HRV was not associated with age, sex, body mass index, duration of illness, or daily dose of other psychotropic drugs.ConclusionThese results suggest that antipsychotic drugs exert a significant dose-dependent effect on the extent of decline in ANS activity, and that optimal antipsychotic medication is required to avoid possible cardiovascular adverse events in patients with schizophrenia.

Knowledge and attitude towards suicide among medical students in Japan: preliminary study.

Abstract  Japan has one of the highest suicide rates in the world. Suicides numbered 32 863 in 1998 and have exceeded 30 000 in every subsequent year. Education of those involved in general and psychosocial patient care can contribute greatly to suicide prevention. The authors administered a brief knowledge and attitude assessment questionnaire concerning suicide to students in their first, third, and fifth years at a Japanese medical school. Participants numbered 160 (94 men with a mean age of 21.8 years, SD = 3.01, and 66 women with a mean age of 21.2 years, SD = 2.64); 59 first year, 52 third year, and 49 in their fifth year. The questionnaire consists of eight multiple‐choice questions asking knowledge of suicide and one open‐ended question asking attitude. In the knowledge part, only about half of the items were answered correctly (mean score was 4.21, SD = 1.28). A significant difference was observed in prevalence of attitudes as categorical variables between student years (P = 0.001). Sympathetic comments increased along with student years, while critical comments decreased. Given the frequent and interventional opportunities of primary‐care medical contacts, poor understanding of suicide from the medical viewpoint was of concern. Moreover, judgmental attitudes were common, especially in earlier school years. Better informed, more understanding physicians and other health professionals could contribute greatly to prevention.

No evidence of an association between CYP2D6 polymorphisms among Japanese and dementia with Lewy bodies

Abstract Dementia with Lewy bodies (DLB) is the second most frequent degenerative dementia among the elderly, following Alzheimer‐type dementia (ATD). An association of DLB with CYP2D6*4, one of the cytochrome P450IID6 (debrisoquine 4‐hydroxylase; CYP2D6) gene polymorphisms, was reported previously, but this is controversial. Moreover, these reports have been restricted to Caucasian populations. Therefore, we compared frequencies of CYP2D6*3, *4, and *10 mutant alleles in 17 Japanese DLB patients to those among Alzheimer‐type dementia (ATD) patients and healthy controls. Polymerase chain reaction amplification and restriction fragment length polymorphism analyses were used for genotyping. No significant difference of genotype or mutant allele frequencies was detected between DLB, ATD, and healthy controls. The present results do not support the suggestion that the CYP2D6 gene is related to DLB susceptibility, at least in the Japanese population.

Lack of association in Japanese patients between neuroleptic malignant syndrome and a debrisoquine 4-hydroxylase genotype with low enzyme activity.

Decreased activity of debrisoquine 4-hydroxylase (CYP2D6), which participates in hepatic metabolism of several frequently used neuroleptics and antidepressants, is inherited as an autosomal recessive trait through polymorphic CYP2D6 gene alleles. In eastern Orientals, a C --> T substitution at nucleotide 188 (Pro34Ser) is primarily responsible for decreased ability to metabolize CYP2D6 substrates. We therefore studied a possible association between neuroleptic malignant syndrome (NMS) and the C188T mutation. We examined the frequency of the C188T mutation by polymerase chain reaction and restriction fragment length polymorphism analysis in 36 Japanese patients previously diagnosed with NMS and 107 neuroleptic-treated schizophrenic patients with no NMS history. The C188T allele frequency was 0.417 in NMS patients and 0.463 in patients without NMS. No significant allele or genotype associations were observed. We cannot conclude that low CYP2D6 activity genotype causes susceptibility to NMS in Japanese patients.