Abnormal microstructures of the basal ganglia in schizophrenia revealed by diffusion tensor imaging.

There has been a hypothesis that deficits in the basal ganglia-thalamic system may play an important role in the dysfunctional goal-directed behaviour in schizophrenia. By using diffusion tensor imaging, we measured fractional anisotropy (FA) values in the basal ganglia-thalamic system in 42 schizophrenics and 42 matched controls to investigate microstructural tissue alterations in the basal ganglia-thalamic system in schizophrenia. Schizophrenics had significantly lower FA values in the bilateral globus pallidus and left thalamus compared to controls, suggesting that schizophrenics might have microstructural abnormalities in globus pallidus and thalamus. These data support the notion that myelination abnormalities in basal ganglia-thalamic system are related to the pathophysiology of schizophrenia.

Risk of developing schizophrenia among Japanese high-risk offspring of affected parent: outcome of a twenty-four-year follow up.

AIMS: Prospective follow-up studies of high-risk children may help clarify the etiological factors in schizophrenia. While studies from North America, Europe and Israel have estimated the risk of schizophrenia at 7-16% in the offspring of an affected parent, no data have been reported for Asian populations. METHOD: We started a follow up of the offspring of Japanese schizophrenia patients in 1978. We investigated the estimated risk of schizophrenia in 51 high-risk offspring at the 24-year follow up. The effects of the parents' status, including history of psychiatric hospitalization and social functioning, on the risk in the offspring were also investigated. RESULTS: The cumulative incidence of schizophrenia was 13.7 % and the lifetime prevalence was estimated to be 13.5 +/- 4.8%. The association between the psychiatric hospitalization in the probands and the risk of schizophrenia in the offspring was not significant, and the Global Assessment of Functioning score was significantly lower in the probands with a history of psychiatric hospitalization than in those without such a history. CONCLUSIONS: The risk of developing schizophrenia in Japanese high-risk offspring might be comparable with the Western results. The present study suggests that the severity of the disease or the level of social functioning may not significantly affect the risk in Japanese offspring.

The association between the Val158Met polymorphism of the catechol-O-methyl transferase gene and morphological abnormalities of the brain in chronic schizophrenia.

The catechol-O-methyl transferase (COMT) gene is considered to be a promising schizophrenia susceptibility gene. A common functional polymorphism (Val158Met) in the COMT gene affects dopamine regulation in the prefrontal cortex (PFC). Recent studies suggest that this polymorphism contributes to poor prefrontal functions, particularly working memory, in both normal individuals and patients with schizophrenia. However, possible morphological changes underlying such functional impairments remain to be clarified. The aim of this study was to examine whether the Val158Met polymorphism of the COMT gene has an impact on brain morphology in normal individuals and patients with schizophrenia. The Val158Met COMT genotype was obtained for 76 healthy controls and 47 schizophrenics. The diagnostic effects, the effects of COMT genotype and the genotype-diagnosis interaction on brain morphology were evaluated by using a voxel-by-voxel statistical analysis for high-resolution MRI, a tensor-based morphometry. Patients with schizophrenia demonstrated a significant reduction of volumes in the limbic and paralimbic systems, neocortical areas and the subcortical regions. Individuals homozygous for the Val-COMT allele demonstrated significant reduction of volumes in the left anterior cingulate cortex (ACC) and the right middle temporal gyrus (MTG) compared to Met-COMT carriers. Significant genotype-diagnosis interaction effects on brain morphology were noted in the left ACC, the left parahippocampal gyrus and the left amygdala-uncus. No significant genotype effects or genotype-diagnosis interaction effects on morphology in the dorsolateral PFC (DLPFC) were found. In the control group, no significant genotype effects on brain morphology were found. Schizophrenics homozygous for the Val-COMT showed a significant reduction of volumes in the bilateral ACC, left amygdala-uncus, right MTG and left thalamus compared to Met-COMT schizophrenics. Our findings suggest that the Val158Met polymorphism of the COMT gene might contribute to morphological abnormalities in schizophrenia.

Antipsychotic medication and cognitive function in schizophrenia.

Antipsychotic polypharmacy and excessive dosing still prevail worldwide in the treatment of schizophrenia, while their possible association with cognitive function has not well been examined. We examined whether the "non-standard" use of antipsychotics (defined as antipsychotic polypharmacy or dosage >1,000 mg/day of chlorpromazine equivalents) is associated with cognitive function. Furthermore, we compared cognitive function between patients taking only atypical antipsychotics and those taking only conventionals. Neurocognitive functions were assessed in 67 patients with chronic schizophrenia and 92 controls using the Wechsler Memory Scale-Revised (WMS-R), the Wechsler Adult Intelligence Scale-Revised (WAIS-R), the Wisconsin Card Sorting Test (WCST), and the Advanced Trail Making Test (ATMT). Patients showed markedly poorer performance than controls on all these tests. Patients on non-standard antipsychotic medication demonstrated poorer performance than those on standard medication on visual memory, delayed recall, performance IQ, and executive function. Patients taking atypical antipsychotics showed better performance than those taking conventionals on visual memory, delayed recall, and executive function. Clinical characteristics such as duration of medication, number of hospitalizations, and concomitant antiparkinsonian drugs were different between the treatment groups (both dichotomies of standard/non-standard and conventional/atypical). These results provide evidence for an association between antipsychotic medication and cognitive function. This association between antipsychotic medication and cognitive function may be due to differential illness severity (e.g., non-standard treatment for severely ill patients who have severe cognitive impairment). Alternatively, poorer cognitive function may be due in part to polypharmacy or excessive dosing. Further investigations are required to draw any conclusions.

[Treatment of substance dependence by a bio-cognitive model based on behavioral pharmacology].

We have introduced cognitive behavior therapy (CBT) into the treatment of substance dependence patients, which involves disease education and focused group therapy to obtain insight into the taking behavior and to establish concrete countermeasures to prevent relapse. We have created a bio-cognitive model based on biological aspects to explain the pathology of substance dependence. 'Dependence' is a term in behavioral pharmacology defined as reinforced drug seeking and taking behavior. Changes in taking behavior are thought to occur due to the repetition of the reinforcement action of psychoactive substances in the reward system of the brain. Therefore, when intake desire is strong, it is hard for patients to control themselves, and there is a feature of difficulties considering the process of thinking in CBT. In other words, when craving becomes strong, a chain of behavior happens spontaneously, without schema, involving automatic thoughts. We think that the improvement of protracted withdrawal syndrome (PWS) and entire frontal lobe function are important in learning to discern distortion of cognition. When PWS is improved, a conflict is easy to bring about in the process of drug seeking and taking behavior. And, it is easy to execute avoidance plans (coping skills) which are established to cope with craving in advance. We think that a goal for treatment is to discern drug seeking and taking behavior with natural emotion. The recovery of PWS and frontal lobe dysfunction takes a long time with a serious dependence, so we must perform repetition of CBT. As the treatment introduction of involuntary admission cases is adequate or cases of 1 to 3 months of admission treatment based on voluntary admission are hard to treat, treatment to obtain insights into patients while carrying out repeated CBT using a bio-cognitive model and to improve PWS could be a possibility as one treatment for the pathology of diversified substance dependence.

Immunogenicity of an inactivated adjuvanted whole-virion influenza A (H5N1, NIBRG-14) vaccine administered by intramuscular or subcutaneous injection.

The immunogenicity and safety profile of an inactivated whole-virion influenza A (H5N1, NIBRG-14) vaccine with alum adjuvant that was administered by IM or SC injection in a phase I clinical study involving 120 healthy Japanese men aged 20-40 years is described. The serological response of the IM group was stronger than that of the SC group. Local adverse events were less severe with IM injection than with SC injection, while similar systemic adverse events were seen in both groups. These results indicate that, when administering an inactivated whole virion vaccine with alum adjuvant for pandemic influenza, IM injection may achieve better immunogenicity and safety than SC injection.

A genetic variation in the dysbindin gene (DTNBP1) is associated with memory performance in healthy controls.

Schizophrenia is a common psychiatric disorder characterized by disturbances of cognition, emotion and social functioning. There are few studies investigating a possible genetic basis for the underlying mechanism of cognitive dysfunctions. A genetic variation in the dysbindin gene (DTNBP1: dystrobrevin binding protein 1), a susceptibility gene for schizophrenia, has been reported to be associated with general cognitive ability and cognitive decline in patients with schizophrenia. Although profound disturbances of memory performance are observed in schizophrenia, only one study has reported a relationship between this gene and spatial working memory in a Caucasian population. We examined a possible association between a protective haplotype of DTNBP1 for developing schizophrenia and memory performance measured by the Wechsler Memory Scale-Revised (WMS-R) and the Wechsler Adult Intelligence Scale-Revised (WAIS-R) in 165 healthy volunteers and 70 patients with schizophrenia in a Japanese population. Healthy controls that carry the protective haplotype showed higher performance in several memory domains measured by the WMS-R than those who did not. Genotype effect on memory performance was not observed in patients with schizophrenia. This haplotype did not affect IQ and its sub-scores as measured by the Wechsler Adult Intelligence Scale-Revised in both groups. These data suggest that DTNBP1 may have impact on parts of memory functions.

Factors associated with the development of panic attack and panic disorder: survey in the Japanese population.

Environmental factors, in addition to genetic factors, may be related to the development of panic attack (PA) and panic disorder (PD). Previous studies suggested that there may be seasonal variation in the onset of PA/PD and possibly a higher prevalence of PA/PD in colder areas. Also observed were lactate-induced PA and elevated serum cholesterol in PD patients. These suggest that living environment and lifestyle, such as weather conditions, preference of food and physical exercise, might play a role in the occurrence of PA and PD. The present study explored the association of such candidate factors with the development of PA and PD in 4000 Japanese subjects, using a questionnaire. The subjects were recruited from the general population of Japan, using stratified random sampling. Logistic regression with stepwise selection of variables was employed for statistical analysis. Variables including "dislike of physical exercise", mostly in female subjects, and "living in areas with longer winter", in male subjects, were suggested for associations with PA and PD among the candidate factors. The result is preliminary but indicates that lifestyle such as like/dislike of physical exercise and environmental factors including weather conditions could play a partial role in the development of PA and PD. Further investigations are required before firm conclusions can be reached.