Attitude of patients with mood disorder toward clinical trials in Japan.
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Adult↗
Biomedical subjects
Teruhiko Higuchi
Publications and source records attributed to Teruhiko Higuchi.
Expression analysis of actin-related genes as an underlying mechanism for mood disorders.
In this study, we explored the newly postulated 'disturbed cytoskeletal' theory of mood disorders. Firstly, we identified Cap1, a gene for important mediator of actin turnover, as a cogent quantitative trait gene for depressive trait of mice by combining the results of our prior genetic and current genome-wide expression analyses. Then we rigorously examined 'core' actin-related gene expression in the frontal cortex of C57BL/6 (B6) (prone to depression) and C3H/He (C3) (resistant to depression) mice. We confirmed that Cap1 was down-regulated at both transcript and protein levels in B6. Other differentially regulated genes included cofilin1 and profilin1 (up-regulated in B6), and a Rho-family GTPase member (Pak1) (down-regulated in B6). Thirdly, we investigated the 'core' actin-pathway components in human postmortem prefrontal cortices, and observed trend for CAP1 reduction in the bipolar brains. These data suggest that the balance of actin dynamics might be altered towards actin depolymerization in mood disorders.
Actins↗
Genome-wide expression analysis detects eight genes with robust alterations specific to bipolar I disorder: relevance to neuronal network perturbation.
The limited number of genome-wide transcriptome analyses using the postmortem brains of bipolar disorder sufferers has not produced a clear consensus on the molecular pathways affected by the disorder. To expand the knowledge in this area, we examined the expression levels of more than 12 000 genes in Brodmann's Area (BA), 46 (dorsolateral prefrontal cortex) from bipolar I disorder and control samples using Affymetrix GeneChips. This analysis detected 108 differentially expressed genes in bipolar brains. Validation studies using quantitative RT-PCR on the two original diagnostic cohorts plus tissue from schizophrenic subjects, confirmed the differential expressions of eight genes (RAP1GA1, SST, HLA-DRA, KATNB1, PURA, NDUFV2, STAR and PAFAH1B3) in a bipolar-specific manner and one gene (CCL3) which was downregulated in both bipolar and schizophrenic brains. Of these, protein levels of RAP1GA1 (RAP1 GTPase activating protein 1) showed a trend of increase in BA46 from bipolar brains, in keeping with mRNA transcript levels. Transmission disequilibrium analysis of the nine genes using 43 single nucleotide polymorphisms (SNPs) in 229 National Institute of Mental Health bipolar trios exposed nominal SNP association and modest empirical haplotypic association (P=0.033) between SST (somatostatin) and disease. Finally, gene network analysis using the currently obtained expression data highlighted cellular growth and nervous system development pathways as potential targets in the molecular pathophysiology of bipolar disorder.
1-Alkyl-2-acetylglycerophosphocholine Esterase↗
Distinguishable haplotype blocks in the HTR3A and HTR3B region in the Japanese reveal evidence of association of HTR3B with female major depression.
BACKGROUND: Genetic variations in the serotonin receptor 3A (HTR3A) and 3B (HTR3B) genes, positioned in tandem on chromosome 11q23.2, have been shown to be associated with psychiatric disorders in samples of European ancestry. But the polymorphisms highlighted in these reports map to different locations in the two genes, therefore it is unclear which gene exerts a stronger effect on susceptibility. METHODS: To determine the haplotype block structure in the genomic regions of HTR3A and HTR3B, and to examine whether genetic variations in the region show evidence of association with schizophrenia and affective disorder in the Japanese, we performed haplotype-based case-control analysis using 29 polymorphisms. RESULTS: Two haplotype blocks each were revealed for HTR3A and HTR3B in Japanese samples. In HTR3B, haplotype block 2 that included a nonsynonymous single nucleotide polymorphism (SNP), yielded evidence of association with major depression in females (global p = .0023). Analysis employing genome-wide SNPs using the STRUCTURE program did not detect population stratification in the samples. CONCLUSIONS: Our results suggest an important role for HTR3B in major depression in women and also raise the possibility that previously proposed disease-associated SNPs in the HTR3A/B region in Caucasians are in linkage disequilibrium with haplotype block 2 of HTR3B in the Japanese.
Adult↗
Assessment of the dexamethasone/CRH test as a state-dependent marker for hypothalamic-pituitary-adrenal (HPA) axis abnormalities in major depressive episode: a Multicenter Study.
There is compelling evidence for the involvement of hypothalamic-pituitary-adrenal (HPA) axis abnormalities in depression. Growing evidence has suggested that the combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test is highly sensitive to detect HPA axis abnormalities. We organized a multicenter study to assess the DEX/CRH test as a state-dependent marker for major depressive episode in the Japanese population. We conducted the DEX/CRH test in 61 inpatients with major depressive episode (Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV)) and 57 healthy subjects. In all, 35 patients were repeatedly assessed with the DEX/CRH test on admission and before discharge. The possible relationships between clinical variables and the DEX/CRH test were also examined. Significantly enhanced pituitary-adrenocortical responses to the DEX/CRH test were observed in patients on admission compared with controls. Such abnormalities in patients were significantly reduced after treatment, particularly in those who underwent electroconvulsive therapy (ECT) in addition to pharmacotherapy. Age and female gender were associated with enhanced hormonal responses to the DEX/CRH test. Severity of depression correlated with DEX/CRH test results, although this was explained, at least in part, by a positive correlation between age and severity in our patients. Medication per se was unrelated to DEX/CRH test results. These results suggest that the DEX/CRH test is a sensitive state-dependent marker to monitor HPA axis abnormalities in major depressive episode during treatment. Restoration from HPA axis abnormalities occurred with clinical responses to treatment, particularly in depressed patients who underwent ECT.
Adult↗
Nurses' collaboration with physicians in managing medication improves patient outcome in acute psychiatric care.
The aim of the present paper was to examine the impact of nurses' collaboration with physicians in medication management on patient outcome in acute psychiatric care. Data for 143 patients with schizophrenia were assessed based on information given by nurses and physicians in charge. Twenty-two patients were defined as a collaborative group when physicians changed medication after receiving reports that nurses perceived the necessity to change. A control group was formed from the 50 patients when nurses perceived the necessity to change medication but did not tell physicians, or nurses advised of the necessity to physicians but medication was not changed. Physicians retrospectively evaluated patients' social functioning and acceptance of medication at admission and discharge. Social functioning was measured by Global Assessment of Functioning (GAF), and acceptance of medication by a single item using Japanese version of Schedule for Assessment of Insight (SAI-J). Changes in the scores from admission to discharge on GAF and acceptance of medication were defined as outcome measures. Nurses recognized the necessity to change medication for patients with frequent aggressive behavior and younger age. Compared with the control group, the collaborative group had less instruction for use of drugs, and more perceived necessity to decrease the current dose or the number of drugs because of stable symptoms. The collaborative group demonstrated significantly greater improvement in social functioning. The collaborative group improved acceptance of medication, although there were no significant differences between the two groups. Nurses' collaboration with physicians in medication management improved patient outcome in acute psychiatric care.
Acute Disease↗
Induction of neuroserpin expression in rat frontal cortex after chronic antidepressant treatment and electroconvulsive treatment.
Using expressed sequence tag (EST) analysis, we previously identified certain molecular machinery that mediates antidepressant effects. To date, several partial cDNA fragments, termed antidepressant-related genes (ADRGs), have been isolated as ESTs from rat brain. In the present study, we identified two of the ADRGs to be rat neuroserpin. Using real-time quantitative PCR, we demonstrated increased neuroserpin mRNA expression in rat frontal cortex after chronic treatment with several classes of antidepressants, including imipramine, fluoxetine, sertraline, and venlafaxine. Electroconvulsive treatment (ECT), another therapeutic treatment for depression, also increased neuroserpin expression in rat frontal cortex. Neuroserpin is a serine protease inhibitor that is implicated in the regulation of synaptic plasticity, neuronal migration, and axogenesis in the central nervous system. In conclusion, our results support the hypothesis that neuroserpin-mediated plastic changes in frontal cortex may underlie the therapeutic action of antidepressants and ECT.
Animals↗
Identification and expression of frizzled-3 protein in rat frontal cortex after antidepressant and electroconvulsive treatment.
The biological basis for the therapeutic mechanisms of depression are still unknown. While performing EST (expressed sequence tag) analysis to identify some molecular machinery responsible for the antidepressant effect, we determined the full-length nucleotide sequence of rat frizzled-3 protein (Frz3) cDNA. Interestingly, Northern blot analysis demonstrated that elevated levels of Frz3 were expressed continually from embryonic day 20.5 to postnatal 4 weeks in developing rat brain. In adult rat brain, Frz3 mRNA was expressed predominantly in the cerebral cortex and hypothalamus and moderately in the hippocampus. Using real-time quantitative PCR, we demonstrated that chronic treatment with two different classes of antidepressants, imipramine and sertraline, reduced Frz3 mRNA expression significantly in rat frontal cortex. Electroconvulsive treatment (ECT) also reduced Frz3 expression. In contrast, antidepressants and ECT failed to reduce Frz2 expression. Additionally, chronic treatment with the antipsychotic drug haloperidol did not affect Frz3 expression. Recently, the Frz/Wingless protein pathway has been proposed to direct a complex behavioral phenomenon. In conclusion, the Frz3-mediated signaling cascade may be a component of the molecular machinery targeted by therapeutics commonly used to treat depression.
Amino Acid Sequence↗
Expression of Ndrg2 in the rat frontal cortex after antidepressant and electroconvulsive treatment.
Although the therapeutic action of antidepressants most likely involves the regulation of serotonergic and noradrenergic signal transduction, no consensus has been reached concerning their precise molecular or cellular mechanisms of action. In the present study, we demonstrated that chronic treatment with a tricyclic antidepressant (imipramine) and a selective serotonin reuptake inhibitor (sertraline) reduced the expression of Ndrg2 mRNA and protein in the rat frontal cortex. Ndrg2 is a member of the N-Myc downstream-regulated genes. Interestingly, repeated ECT also significantly decreased Ndrg2 expression in this region of the brain. These data suggest that Ndrg2 may be a common functional molecule that is decreased after antidepressant treatment and ECT. Although, the functional role of Ndrg2 in the central nervous system remains unclear, our findings suggest that Ndrg2 may be associated with treatment-induced adaptive neural plasticity in the brain, a chronic target of antidepressant action. In conclusion, we have identified Ndrg2 as a candidate target molecule of antidepressants and ECT.
Analysis of Variance↗
Repetitive transcranial magnetic stimulation induces kf-1 expression in the rat brain.
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive approach used for stimulating the brain, and has proven effective in the treatment of depression, however the mechanism of its antidepressant action is unknown. Recently, we have reported the induction of kf-1 in rat frontal cortex and hippocampus after chronic antidepressant treatment and repeated electroconvulsive treatment (ECT). In this study, we demonstrated the induction of kf-1 after rTMS in the rat frontal cortex and hippocampus, but not in hypothalamus. Our data suggest that kf-1 may be a common functional molecule that is increased after antidepressant treatment, ECT and rTMS. In conclusion, it is proposed that induction of kf-1 may be associated with the treatment induced adaptive neural plasticity in the brain, which is a long-term target for their antidepressant action.
Animals↗
Antidepressant-elicited changes in gene expression: remodeling of neuronal circuits as a new hypothesis for drug efficacy.
Although antidepressants have been used clinically for more than 50 years, no consensus has been reached concerning their precise molecular mechanism of action. Pharmacogenomics is a powerful tool that can be used to identify genes affected by antidepressants or by other effective therapeutic manipulations. Using this tool, others and we have identified as candidate molecular targets several genes or expressed sequence tags (ESTs) that are induced by chronic antidepressant treatment. In this article, we review antidepressant-elicited changes in gene expression, focusing especially on the remodeling of neuronal circuits that results. This refocusing motivates our hypothesis that this plasticity represents the mechanism for drug efficacy, and thus a causal event for clinical improvement. Defining the roles of these molecules in drug-induced neural plasticity is likely to transform the course of research on the biological basis of antidepressants. Such detailed knowledge will have profound effects on the diagnosis, prevention, and treatment of depression. Consideration of novel biological approaches beyond the "monoamine hypothesis" of depression is expected to evoke paradigm shifts in the future of antidepressant research.
Animals↗
Polypharmacy and excessive dosing: psychiatrists' perceptions of antipsychotic drug prescription.
BACKGROUND: Despite extensive research and recommendations regarding the optimal prescription of antipsychotic drugs, polypharmacy and excessive dosing still prevail. AIMS: To identify the factors associated with the polypharmacy and excessive dosing phenomena. METHOD: We studied 139 patients with schizophrenia, in 19 acute psychiatric units in Japanese hospitals, who were due to be discharged between October and December 2003. We examined patient characteristics, nurses' requests, and psychiatrists' characteristics and perceptions of prescribing practice and algorithms. RESULTS: Polypharmacy and excessive dosing were observed in 96 cases. Logistic regression analysis revealed that the use of multiple medications and excessive dosing were influenced by the psychiatrist's scepticism towards the use of algorithms, nurses' requests for more drugs and the patient's clinical condition. CONCLUSIONS: Educational interventions are necessary for psychiatrists and nurses to follow evidence-based guidelines or algorithms.
Adult↗
The inter-rater reliability of the Japanese version of the Montgomery-Asberg depression rating scale (MADRS) using a structured interview guide for MADRS (SIGMA).
The inter-rater reliability of the Japanese version of MADRS (MADRSJ) was examined using the structured interview guide for MADRS (SIGMA) developed by our group. Two or more psychiatrists attended the systematic interview sessions with each subject to evaluate MADRSJ independently, using SIGMA. A total of 18 interviews was carried out for seven patients with DSM-IV major depressive disorder. The severity of each item assessed by the raters ranged from 0 to 6 for nine items and from 0 to 4 for one item. The analysis of variance intraclass correlation coefficient inter-rater reliability values for the individual items carried out by two trained personnel ranged from 0.91 to 1.00, while those achieved by three raters ranged from 0.85 to 1.00. The present results suggest that SIGMA is a potentially useful interview guide for assessing ten symptoms of MADRSJ precisely in patients with a depressive disorder.
Adult↗
A questionnaire survey of ECT practice in university hospitals and national hospitals in Japan.
Although electroconvulsive therapy (ECT) is being performed in many hospitals in Japan, there is little information on its present practice. We surveyed ECT practice to improve the practice of ECT in Japan. A mail questionnaire survey of ECT practice was conducted between 1997 and 1999 in Japan. Of 84 university hospitals and 37 national hospitals, 86 respondents (71%) were obtained. ECT was performed in 56 hospitals (65%). Details of ECT practice were further surveyed in 46 hospitals. The number of patients per year receiving ECT varied according to hospitals from 0.5 to 120. Unmodified ECT was still used in two thirds of the hospitals. Modified ECT was mainly performed in an operating room. Unilateral ECT was seldom used. Japan is an under-developed country for ECT and the practice of ECT must be improved.
Depressive Disorder↗
Paroxetine in the treatment of obsessive-compulsive disorder: randomized, double-blind, placebo-controlled study in Japanese patients.
The efficacy of paroxetine in the treatment of obsessive-compulsive disorder in Western populations is well established. The present study compares the efficacy and safety of paroxetine with placebo in the treatment of obsessive-compulsive disorder in Japanese patients. Patients aged 16 years or older who met Diagnostic and Statistical Manual of Mental Disorders (4th edn; DSM-IV) criteria for obsessive-compulsive disorder and had a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score of >/=16 were randomized to receive 12 weeks' therapy in a double-blind manner. Paroxetine 20-50 mg/day or placebo was administered following a 1 week, placebo run-in phase. One hundred and ninety-one patients were randomized to either paroxetine or placebo, 188 patients were assessed as the full analysis set (FAS) and 144 patients completed the 12 week study. After adjustment for the Y-BOCS total score at baseline, reductions in obsessive-compulsive total score at week 6 and at the end of therapy were significantly greater in the paroxetine group than the placebo group. Most of the adverse events that occurred during the study were of mild to moderate intensity. Paroxetine is effective and well tolerated in Japanese adult patients with obsessive-compulsive disorder.
Adolescent↗
What are the diagnostic criteria, therapy and prophylaxis for discontinuation symptoms due to SSRIs?
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Diagnosis, Differential↗
[Treatment standard for bipolar disorders].
Lithium has clearly been the standard drug for treatment of acute mania, bipolar depression and for prophylaxis of manic and depressive phase. However, recent reviews show acute failure rates of lithium to be over 50%. It is well recognized mixed state, dysphoric mania or rapid cycler appears less likely to respond to lithium. It has also been clarified that in these subtypes of mania valproic acid and carbamazepine may be more efficacious than lithium. As for the treatment of bipolar depression, consensus seems to be emerging that combined treatment with a mood stabilizer and SSRI or SNRI is the first choice because TCA with a mood stabilizer increases the risk of switch to mania.
Algorithms↗
[Recent progress in the research of mood disorder].
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Aged↗