Terumichi Takahashi

Single prolonged stress increases contextual freezing and the expression of glycine transporter 1 and vesicle-associated membrane protein 2 mRNA in the hippocampus of rats

Rats subjected to single prolonged stress (SPS) show enhanced HPA negative feedback, exaggerated acoustic startle response, and enhanced contextual freezing 7 days after SPS, and accordingly, SPS is an animal model of PTSD. To elucidate the influence of contextual fear on gene expression in the hippocampus of SPS rats, we used cDNA microarray followed by real-time quantitative PCR analyses to compare the hippocampal gene expression profiles between rats that were or were not subjected to SPS during exposure to contextual fear. In the behavioral experiments, spontaneous locomotor activity was measured 7 days after SPS. Twenty-four hours after footshock conditioning (7 days after SPS), freezing behavior was measured during re-exposure to the chamber in which footshock was delivered. Based on the behavioral analysis, rats subjected to SPS exhibited a significant enhancement of contextual freezing compared to rats not subjected to SPS, without any changes in locomotor activity. Analyses using cDNA microarray and RT-PCR showed that the hippocampal levels of glycine transporter 1 (Gly-T1) and vesicle-associated membrane protein 2 (VAMP2) mRNA in rats subjected to SPS were significantly increased relative to sham-treated rats. Administration of SPS alone did not affect the expression of these 2 genes. These findings suggest that the upregulation of Gly-T1 and VAMP2 in the hippocampus may be, at least in part, involved in the enhanced susceptibility to contextual fear in rats subjected to SPS.

Quetiapine Treatment for Behavioral and Psychological Symptoms in Patients with Senile Dementia of Alzheimer Type

The purpose of this study was to assess the effect of quetiapine in the treatment of behavioral and psychological symptoms of dementia (BPSD) in patients with senile dementia of Alzheimer type (SDAT). Sixteen SDAT patients with BPSD were recruited and quetiapine (25– 200 mg/day) was prescribed for 8 weeks. BPSD were evaluated with the Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD) and Cohen-Mansfield Agitation Inventory (CMAI) at week 0 (baseline) and week 8 (endpoint). The severity of the extrapyramidal symptoms was also assessed by the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) at baseline and endpoint. Significant improvements were seen in the CMAI total score and in the BEHAVE-AD subscales of delusions, activity disturbances, aggressiveness, diurnal rhythm disturbances and in the BEHAVE-AD overall severity. There was no significant difference between the baseline and endpoint in the DIEPSS score. These data indicate that quetiapine is effective in controlling BPSD with favorable adverse-event profiles.

Predictors of quality of life in inpatients with schizophrenia

Shortening hospital stays has become a key focus in psychiatric care in recent years. However, patients with schizophrenia account for about 60% of inpatients in psychiatry departments in Japan. This study was designed to investigate the relationship between quality of life (QOL) and key indicators for long-term hospital stays among schizophrenia inpatients. A further aim was to elucidate the clinical determinants of QOL among long-stay inpatients. The study sample consisted of 217 inpatients with schizophrenia. Age, duration of illness, duration of hospitalization, years of education, body mass index, neurocognitive function, drug-induced extrapyramidal symptoms, involuntary movements, psychiatric symptoms, and dose equivalents of antipsychotics and anticholinergic agents were used as index factors. Pearson linear correlation and regression analyses were performed to examine the associations between QOL and the above-mentioned factors. Negative symptoms, psychological discomfort, and resistance as rated on the Brief Psychiatric Rating Scale (BPRS) were correlated with all subscale scores of the Japanese version of the Schizophrenia Quality of Life Scale (JSQLS). Stepwise regression showed that negative symptoms, psychological discomfort, and resistance predicted the dysfunction of psycho-social activity score and the dysfunction of motivation and energy score on the JSQLS. This study shows that active treatment for negative symptoms, psychological discomfort, and resistance should be recommended to improve QOL among inpatients with schizophrenia.

Association of Typical versus Atypical Antipsychotics with Symptoms and Quality of Life in Schizophrenia

Background Several reports on patients with chronic schizophrenia suggest that atypical versus typical antipsychotics are expected to lead to better quality of life (QOL) and cognitive function. Our aim was to examine the association of chronic treatment with typical or atypical antipsychotics with cognitive function, psychiatric symptoms, QOL, and drug-induced extrapyramidal symptoms in long-hospitalized patients with schizophrenia. Methodology and Principal Findings The Hasegawa Dementia Scale-Revised (HDS-R), Brief Psychiatric Rating Scale (BPRS), the Schizophrenia Quality of Life Scale, translated into Japanese (JSQLS), and the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) were used to evaluate cognitive function, psychiatric symptoms, QOL, and drug-induced extrapyramidal symptoms. We examined the correlation between the dose of antipsychotics and each measure derived from these psychometric tests. The student t-test was used to compare scores obtained from psychometric tests between patients receiving typical and atypical antipsychotics. Results showed significant correlations between chlorpromazine (CPZ)-equivalent doses of typical antipsychotics and atypical antipsychotics, and the total BPRS score and BPRS subscale scores for positive symptoms. CPZ-equivalent doses of typical antipsychotics were correlated with the JSQLS subscale score for dysfunction of psycho-social activity and DIEPSS score. Furthermore, the total BPRS scores, BPRS subscale score for positive symptoms, the JSQLS subscale score for dysfunction of psycho-social activity, and the DIEPSS score were significantly higher in patients receiving typical antipsychotics than atypical antipsychotics. Conclusion and Significance These findings suggest that long-term administration of typical antipsychotics has an unfavorable association with feelings of difficulties mixing in social situations in patients with chronic schizophrenia.

Negative Correlation between Affective Symptoms and Prefrontal Activation during a Verbal Fluency Task: A Near-Infrared Spectroscopy Study

Only a few studies have examined the relationships between affective symptoms, cognitive function (e.g. verbal fluency), quality of life (QOL), and brain activation in a nonclinical population. The aim of the present study was to assess these relationships and examine the underlying cortical mechanisms in a nonclinical population. Fifty-two healthy male volunteers were assessed for depressive symptoms using the Zung Self-Rating Depression Scale (SDS), for apathy using the Apathy Scale, and QOL using the Medical Outcomes Study short-form 36-item questionnaire (SF36). The volunteers also performed a verbal fluency test (VFT) while hemoglobin concentration changes were assessed on the surface of the frontal cortex using 24-channel near-infrared spectroscopy (NIRS). The SDS and Apathy Scale scores showed significant negative correlations with the scores of most of the SF36 subscales. Frontal activation had a significant negative correlation with the SDS scores and the Apathy Scale. These results suggest that the degree of affective symptoms is associated with a lower QOL in a nonclinical population, and that cortical hypoactivation during a VFT measured by NIRS may objectively identify individuals with a high degree of affective symptoms.

Depressive symptoms and apathy are associated with psychomotor slowness and frontal activation

Affective symptoms, such as depression and apathy, and cognitive dysfunction, such as psychomotor slowness, are known to have negative impacts on the quality of life (QOL) of patients with mental and physical diseases. However, the relationships among depressive symptoms, apathy, psychomotor slowness, and QOL in a non-clinical population are unclear. The aim of the present study was to assess these relationships and examine the underlying cortical mechanisms in a non-clinical population. Fifty-two healthy male volunteers were assessed for depressive symptoms using the Zung Self-rating Depression Scale (SDS), for apathy measured using the Apathy Scale, and QOL using the Short-Form 36 item questionnaire (SF36). The volunteers also performed the Trail Making Test Part A (TMT-A) while undergoing assessment of hemoglobin concentration changes in the frontal cortical surface using 24-channel near-infrared spectroscopy (NIRS). The scores of the SDS and Apathy Scale showed significant negative correlations with the scores of most of subscales of the SF36. In addition, the SDS score had a significant positive correlation with the time to complete the TMT-A. Further, activation of several frontal cortical areas had a significant positive correlation with the scores of the SDS and Apathy Scale. These results suggest that the degree of depressive symptoms and apathy are associated with a lower QOL in a non-clinical population and that cortical hyperactivation during a psychomotor task measured by NIRS may identify objectively individuals with a high degree of depressive symptoms and apathy.

Reduction in levels of amphiphysin 1 mRNA in the hippocampus of aged rats subjected to repeated variable stress.

Various neurobiological studies of aging indicate that elevated levels of circulating glucocorticoids lead to hippocampal vulnerability to stress, though little is known about the molecular mechanism underlying stress vulnerability in the elderly. We have compared the gene expression profiles in the hippocampus of aged (20 months) and adult (3 months) rats in response to repeated variable stress (RVS) for 4 days, using a cDNA array technique and real-time quantitative PCR, to identify putative genes involved in the mechanism of stress vulnerability in the elderly. We found a significant decrease in the levels of amphiphysin 1 mRNA in aged rats subjected to RVS compared with treated and untreated adult rats or to untreated aged rats. Similarly, we found a significant decrease in hippocampal levels of amphiphysin 1 mRNA in aged rats subjected to RVS for 8 days, but not in those subjected to a single VS. These findings suggest that the decrease in the hippocampal levels of amphiphysin 1 mRNA in response to repeated stress may be involved in the stress vulnerability in the elderly, and may lead to the disturbance of learning and memory under stressful conditions in the elderly.