[Show abstract][Hide abstract] ABSTRACT: Objective:
Glutamatergic neurotransmission via the N-methyl-d-aspartate (NMDA) receptor is integral to the pathophysiology of depression. This study was performed to examine whether amino acids related to NMDA receptor neurotransmission are altered in the serum of patients with depression.
We measured the serum levels of d-serine, l-serine, glycine, glutamate and glutamine in patients with depression (n=70), and age-matched healthy subjects (n=78).
Serum levels of d-serine and l-serine in patients with depression were significantly higher than those of healthy controls (p<0.001). In contrast, serum levels of glycine, glutamate and glutamine did not differ between the two groups. Interestingly, the ratio of l-serine to glycine in patients was significantly higher than that of healthy controls (p<0.001).
This study suggests that serine enantiomers may be peripheral biomarkers for depression, and that abnormality in the d-serine-l-serine-glycine cycle plays a role in the pathophysiology of depression.
[Show abstract][Hide abstract] ABSTRACT: Background:
Defective decision-making is a symptom of impaired cognitive function observed in patients with schizophrenia. Impairment on the Iowa Gambling Task (IGT) has been reported in patients with schizophrenia, but these results are inconsistent among studies.
We differentiated subjects based on whether they expressed certainty at having deciphered an advantageous strategy in the course of the task. We investigated this impairment using the IGT in patients with schizophrenia and performed analysis different to standard advantageous decks minus disadvantageous decks in all 100 card choices, [C+D]-[A+B](1-100). We examined the effects on behavior after receiving a big penalty.
Results were dependent on participants utilizing with or without certainty, the best strategy for positive gain. Schizophrenic patients without certainty failed to show card choice shift, from disadvantageous to advantageous decks. Differences in card choices on the IGT were clearly shown between patients with schizophrenia and normal controls by the use of improvement from block 1 to blocks 3-5, [C+D]-[A+B]([41-100]-[1-20]) (P<0.001), rather than by the composite value of blocks 3-5, [C+D]-[A+B](41-100) (P=0.011). The deficit of emotion-based learning in schizophrenia without uncertainty were related to scores on the SANS and S5 attention. In addition, S1 affective flattering and S4 anhedonia-asociality were also related to these deficits. For a while, normal controls showed a smooth shift from disadvantageous to advantageous decks after big penalties, with or without a certainty for strategy. However, patients with schizophrenia failed to show switching from disadvantageous to advantageous decks, even after big penalties, under the same conditions.
Our results highlight certainty of strategy and behavior after a big penalty, as two points of difference between patients with schizophrenia and normal controls in the accumulation of net scores.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 03/2015; 57. DOI:10.1016/j.pnpbp.2014.10.007 · 3.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction:
The genetic background of antidepressant response represents a unique opportunity to identify biological markers of treatment outcome. Encouraging results alternating with inconsistent findings made antidepressant pharmacogenetics a stimulating but often discouraging field that requires careful discussion about cumulative evidence and methodological issues.
The present review discusses both known and less replicated genes that have been implicated in selective serotonin reuptake inhibitors (SSRIs) efficacy and side effects. Candidate genes studies and genome-wide association studies (GWAS) were collected through MEDLINE database search (articles published till January 2014). Further, GWAS signals localized in promising genetic regions according to candidate gene studies are reported in order to assess the general comparability of results obtained through these two types of pharmacogenetic studies. Finally, a pathway enrichment approach is applied to the top genes (those harboring SNPs with p < 0.0001) outlined by previous GWAS in order to identify possible molecular mechanisms involved in SSRI effect.
In order to improve the understanding of SSRI pharmacogenetics, the present review discusses the proposal of moving from the analysis of individual polymorphisms to genes and molecular pathways, and from the separation across different methodological approaches to their combination. Efforts in this direction are justified by the recent evidence of a favorable cost-utility of gene-guided antidepressant treatment.
Expert Opinion on Drug Metabolism & Toxicology 06/2014; 10(8):1-26. DOI:10.1517/17425255.2014.928693 · 2.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Accumulating evidence suggests that patients with schizophrenia are exposed to a high risk of osteoporosis/osteopenia caused by long-term antipsychotic treatment. The degree of bone mineral density (BMD) loss that a given antipsychotic may cause is not known. Examinations using a bone turnover marker may more accurately predict the ongoing bone states in psychiatric patients. We measured prolactin, estradiol, testosterone, and bone resorption marker (TRACP-5b) levels in 167 patients with schizophrenia and 60 normal controls. The patients showed significantly higher levels of prolactin and lower levels of TRACP-5b compared to the controls. Moreover, prolactin was negatively correlated with estradiol and testosterone in the group of all male subjects and the male patients. TRACP-5b was positively correlated with prolactin in the female patients and negatively correlated with estradiol in the group of all female subjects. The results show that the bone resorption rate was rather attenuated in the patients compared to the normal controls, suggesting a complicated etiology of BMD loss in schizophrenia patients. Several meaningful correlations between key factors in this study confirmed that hyperprolactinemia induced the suppression of sex hormones, and possibly led to the higher bone turnover. These results indicate that measurement of the resorption marker TRACP-5b might be useful to clarify the pathology of BMD loss.
Schizophrenia Research 05/2014; 157(1-3). DOI:10.1016/j.schres.2014.05.009 · 3.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Several lines of evidence suggest that glial cell-line derived neurotrophic factor (GDNF) plays an important role in the pathophysiology of neuropsychiatric and neurodegenerative disorders. In this study, we investigated the association between GDNF serum levels and the clinical status of medicated patients with schizophrenia. Sixty-three medicated patients with schizophrenia and 52 age- and sex-matched healthy controls were recruited. Patients were evaluated using the Brief Psychiatry Rating Scale, the Scale for the Assessment of Negative Symptoms (SANS) and neuropsychological tests. Serum levels of GDNF were determined using an ELISA method. Serum levels of GDNF did not differ between schizophrenia patients and controls. Higher GDNF serum levels were associated with better performances on the Digit Span in healthy controls but not in schizophrenics. At the same time, higher GDNF serum levels were associated with severe attention deficits on the SANS subscale, in schizophrenics. Our preliminary study suggests that serum levels of GDNF may be an unsuitable biomarker for schizophrenia, although it may be associated with working memory in healthy controls and the pathophysiology of attention deficits in schizophrenia.
[Show abstract][Hide abstract] ABSTRACT: Background
The psychological impact of dual-disasters (earthquakes and a nuclear accident), on affected communities is unknown. This study investigated the impact of a dual-disaster (earthquakes and radioactive contamination) on the prevalence of psychological distress in a landlocked city within the Tohoku area, Japan.
A cross-sectional mail-in survey with a random sample of inhabitants from Ichinoseki city was conducted eleven months after the disasters, and data from 902 respondents were analyzed by logistic regression models, with multiple imputation methodology. The K6 was used to determine psychological distress.
The estimated prevalence of psychological distress was 48.0 percent. House damage due to earthquakes and anxiety about radioactive contamination were significantly associated with psychological distress (p < 0.05), while an interactive effect between house damage and anxiety about radioactive contamination was not significant. Being female, middle-to-low educational status and unemployed were additional risk factors for psychological distress.
This dual-disaster was associated with a moderate prevalence of psychological distress in the area. The impact of the earthquake and radioactive contamination appeared additive.
BMC Research Notes 05/2014; 7(1):307. DOI:10.1186/1756-0500-7-307
[Show abstract][Hide abstract] ABSTRACT: A meta-analysis study reported serum brain-derived neurotrophic factor (BDNF) levels as a potential biomarker for schizophrenia. However, at the time, commercially available human ELISA kits were unable to distinguish between pro-BDNF (precursor BDNF) and mature BDNF, because of limited antibody specificity. Here, we used new ELISA kits, to examine serum levels of mature BDNF and matrix metalloproteinase-9 (MMP-9), which converts pro-BDNF to mature BDNF in schizophrenia. Sixty-three patients with chronic schizophrenia and 52 age- and sex-matched healthy controls were enrolled. Patients were evaluated using the Brief Psychiatry Rating Scale, the Scale for the Assessment of Negative Symptoms (SANS) and neuropsychological tests. Neither serum mature BDNF nor MMP-9 levels differed between patients and controls. In male subgroups, serum MMP-9 levels of smoking patients were higher than those of non-smoking patients, but this was not observed in male controls or the female subgroup. In patients, serum mature BDNF levels were associated with SANS total scores and the Information subtest scores of the Wechsler Adult Intelligence Scale Revised (WAIS-R), while serum MMP-9 levels were associated with smoking and category fluency scores. These findings suggest that neither mature BDNF nor MMP-9 is a suitable biomarker for schizophrenia, although further studies using large samples are needed.
[Show abstract][Hide abstract] ABSTRACT: Pharmacotherapies for the behavioural and psychological symptoms of dementia are limited; novel agents for the symptoms are still needed. Herein, we report the case of an 80-year-old male patient with Alzheimer's disease whose severe agitation, insomnia and sexual delusions were successfully treated with a traditional natural Japanese (Kampo) medicine, keishi-ka-ryukotsu-borei-to. We found that administrating keishi-ka-ryukotsu-borei-to increased his serum luteinizing hormone level, which could be inversely associated with his behavioural and psychological symptoms. This report suggests that keishi-ka-ryukotsu-borei-to is a possible alternative treatment for the behavioural and psychological symptoms of dementia, especially sexual delusions.
[Show abstract][Hide abstract] ABSTRACT: A number of candidate gene studies focused on major depression (MD) and antidepressant (AD) efficacy have been carried out, but results mainly remain inconclusive. We performed a comprehensive meta-analysis of published candidate gene studies focused on AD efficacy in MD to evaluate the cumulative evidence. A random-effect model was applied to study the polymorphisms with genotypic counts available from at least three independent studies. On the base of previous evidence, the analysis was stratified by ethnicity (Caucasian, Asian, and other/mixed), and AD class (SSRIs and mixed/other ADs). Genotypic data were available for 16 polymorphisms in 11 genes. After the exclusion of 5-HTTLPR in SLC6A4 included in another recent meta-analysis, 15 polymorphisms in 11 genes were included in the present meta-analysis (BDNF rs6265, SLC6A4 STin2, HTR1A rs6295, HTR2A rs6311, rs6313 and rs7997012, HTR6 rs1805054, TPH1 rs1800532, SLC6A2 rs5569, COMT rs4680, GNB3 rs5443, FKBP5 rs1360780 and rs3800373, and ABCB1 rs1045642 and rs2032582). Our results suggested that BDNF rs6265 (Val66Met) heterozygous genotype was associated with better SSRIs response compared to the homozygous genotypes, particularly in Asians (OR=1.53, 95%CI 1.12-2.07, p=0.007). SLC6A4 STin2, HTR2A rs6311 and rs7997012, GNB3 rs5443, FKBP5 rs1360780 and rs3800373, and ABCB1 rs2032582 showed associations with AD efficacy, but these results were highly dependent on one or two single studies. In conclusion, our findings suggested the BDNF Val66Met as the best single candidate involved in AD response, with a selective effect in SSRI treatment. Our overall results supported no major effect of any single gene variant on AD efficacy.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 05/2013; 45. DOI:10.1016/j.pnpbp.2013.05.011 · 3.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Several studies have proposed an optimal dopamine D2 receptor occupancy by antipsychotics (OOc) to establish optimal pharmacological treatment of schizophrenia. However, there are limitations to the use of the OOc, especially in application to patients with treatment-resistant schizophrenia, including dopamine supersensitivity psychosis (DSP) or late-onset psychosis (LOP). It has been suggested that D2 receptor density is up-regulated by chronic treatment of antipsychotics in DSP, whereas it may be low in LOP owing to age-related reduction. In estimation of the proposed OOc, these alterations have not been taken into account, which may be one of the factors contributing to the limited application of this index. We here hypothesize that there is an optimal range in the number of D2 receptors available for dopamine binding to elicit adequate neurotransmission in the treatment of patients with schizophrenia. We then estimated the OOc under the assumption that the range is constant while D2 density is variable. The results showed that the OOc and plasma level of antipsychotics increase with an increase in the D2 density but decrease with a decrease in the D2 density. That is, if the range of OOc is 65% to 78% in a standard D2 density, it becomes 82% to 89% under 2-fold up-regulated density and 42% to 63% under a 40% reduced density. The results also indicated that the reduction of the plasma antipsychotic level is greater during a given time period in patients with higher D2 density, as they need a higher antipsychotic dose to achieve the raised OOc, which would account for the clinical features of DSP, for example, acute exacerbation after a discontinuation of antipsychotics. On the other hand, in patients with lower D2 density, only a lower antipsychotic dose will achieve the OOc, and a small increase in the dose will result in a greater increase in occupancy and induce extrapyramidal adverse effects more easily. Furthermore, the reduction of the plasma antipsychotic level during the time period is smaller, which prolongs extrapyramidal adverse effects after discontinuation of antipsychotics in LOP. We also attempted to develop a strategy for the prevention and treatment of patients with DSP or LOP by focusing on D2 density.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study is to clarify the symptomatology of the eating disorders examining the prefrontal function and activity associated with self-regulation among participants with or without eating disorders.
Ten patients with anorexia nervosa, fourteen with bulimia nervosa, and fourteen healthy control participants performed two cognitive tasks assessing self-regulatory functions, an auditorily distracted word fluency task and a rock-paper-scissors task under the measurements on prefrontal oxyhemoglobin concentration with near infrared spectroscopy. The psychiatric symptoms of patient groups were assessed with several questionnaires.
Patients with bulimia nervosa showed decreased performances and prefrontal hyper activation patterns. Prefrontal activities showed a moderate negative correlation with task performances not in the patient groups but only in the healthy participants. The prefrontal activities of the patient groups showed positive correlations with some symptom scale aspects.
The decreased cognitive abilities and characteristic prefrontal activation patterns associated with self-regulatory functions were shown in patients with bulimia nervosa, which correlated with their symptoms. These findings suggest inefficient prefrontal self-regulatory function of bulimia nervosa that associate with its symptoms.
PLoS ONE 03/2013; 8(3):e59324. DOI:10.1371/journal.pone.0059324 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Pharmacotherapy and cognitive behavioural therapy (CBT) are consistently effective as first-line treatments for social anxiety disorders (SADs). Nevertheless, pharmacotherapy is often the first choice in clinical practice. In many countries, the first line of pharmacotherapy involves the administration of a selective serotonin reuptake inhibitor (SSRI). Although a significant proportion of patients with SAD fail to respond to the initial SSRI administration, there is no standard approach to the management of SSRI-resistant SAD. This paper describes the study protocol for a randomised controlled trial to evaluate the clinical effectiveness of CBT as a next-step strategy, concomitant with conventional treatment, for patients with SSRI-resistant SAD.
Methods and analysis:
This Prospective Randomized Open Blinded End-point study is designed with two parallel groups, with dynamic allocation at the individual level. The interventions for the two groups are conventional treatment, alone, and CBT combined with conventional treatment, for 16 weeks. The primary end-point of SAD severity will be assessed by an independent assessor using the Liebowitz Social Anxiety Scale, and secondary end-points include severity of other social anxieties, depressive severity and functional impairment. All measures will be assessed at weeks 0 (baseline), 8 (halfway point) and 16 (postintervention) and the outcomes will be analysed based on the intent-to-treat. Statistical analyses are planned for the study design stage so that field materials can be appropriately designed.
Ethics and dissemination:
This study will be conducted at the academic outpatient clinic of Chiba University Hospital. Ethics approval was granted by the Institutional Review Board of Chiba University Hospital. All participants will be required to provide written informed consent. The trial will be implemented and reported in accordance with the recommendations of CONSORT.
Clinical trial registration number:
BMJ Open 01/2013; 3(2). DOI:10.1136/bmjopen-2012-002242 · 2.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cognitive impairments in schizophrenia are associated with suboptimal psychosocial performance. Several lines of evidence have suggested that endoplasmic reticulum protein sigma-1 receptors were involved in cognitive impairments in patients with schizophrenia and that the sigma-1 receptor agonist fluvoxamine was effective in treating cognitive impairments in animal models of schizophrenia and in some patients with schizophrenia. A randomized, double-blind, placebo-controlled, parallel trial of fluvoxamine adjunctive therapy in patients with schizophrenia was performed. A total of 48 patients with chronic schizophrenia were enrolled. Subjects were randomly assigned to an 8-week administration of add-on fluvoxamine (n = 24, titrated up to 150 mg/d) or placebo (n =24) in a total 12-week double-blind trial. The primary outcome measure was the Cambridge Neuropsychological Test Automated Battery (CANTAB), assessing visual memory, working memory, attention, and executive function. The secondary outcome measures were the Positive and Negative Syndrome Scale, the Scale for the Assessment of Negative Symptoms, the Quality of Life Scale, and the Montgomery-Åsberg Depression Rating Scale. Fluvoxamine was well tolerated. No significant time × group interaction effects were observed in the scores of the CANTAB, Positive and Negative Syndrome Scale, Scale for the Assessment of Negative Symptoms, Quality of Life Scale, or the Montgomery-Åsberg Depression Rating Scale. However, in secondary analyses, the change from baseline to end point on the Spatial Working Memory strategy score (executive function) of CANTAB improved in the fluvoxamine group. This study suggests no major benefit of fluvoxamine adjunctive therapy to improve cognitive impairments in patients with schizophrenia. Nevertheless, a further study using a large sample size will be needed to confirm the secondary analyses findings.
[Show abstract][Hide abstract] ABSTRACT: Meta-analyses have identified serum levels of brain-derived neurotrophic factor (BDNF) as a potential biomarker for major depressive disorder (MDD). However, at the time, commercially available human ELISA kits are unable to distinguish between proBDNF (precursor of BDNF) and mature BDNF because of limited BDNF antibody specificity. In this study, we examined whether serum levels of proBDNF, mature BDNF, and matrix metalloproteinase-9 (MMP-9), which converts proBDNF to mature BDNF, are altered in patients with MDD.
Sixty-nine patients with MDD and 78 age- and gender-matched healthy subjects were enrolled. Patients were evaluated using 17 items on the Structured Interview Guide for the Hamilton Depression Rating Scale. Cognitive impairment was evaluated using the CogState battery. Serum levels of proBDNF, mature BDNF, and MMP-9 were measured using ELISA kits. Serum levels of mature BDNF in patients with MDD were significantly lower than those of normal controls. In contrast, there was no difference in the serum levels of proBDNF and MMP-9 between patients and normal controls. While neither proBDNF nor mature BDNF serum levels was associated with clinical variables, there were significant correlations between MMP-9 serum levels and the severity of depression, quality of life scores, and social function scores in patients.
These findings suggest that mature BDNF may serve as a biomarker for MDD, and that MMP-9 may play a role in the pathophysiology of MDD. Further studies using larger sample sizes will be needed to investigate these results.
PLoS ONE 08/2012; 7(8):e42676. DOI:10.1371/journal.pone.0042676 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This case is of 54-year-old female with catatonic schizophrenia, characterized by treatment resistance to the pharmacotherapy with olanzapine, risperidone, flunitrazepam, and ECT. Olanzapine and risperidone and flunitrazepam did not improve her catatonic and psychotic symptoms, and induced the extrapyramidal symptoms. The effects of ECT did not continue even for a month. However, the treatment with low-dose aripiprazole dramatically improved the patient's psychotic symptoms and extrapyramidal symptoms. The mechanisms underlying the effects of low-dose aripiprazole in this case remain unclear, but unlike other antipsychotics, aripiprazole is a dopamine D2 partial agonist. In this regard, our results suggest that aripiprazole has numerous advantages, especially in cases of stuporous catatonia and a defective general status.
Annals of General Psychiatry 05/2012; 11(1):12. DOI:10.1186/1744-859X-11-12 · 1.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Eating disorders (EDs) manifest as abnormal patterns of eating behavior and weight regulation driven by low self-esteem due to weight preoccupation and perceptions toward body weight and shape. Two major groups of such disorders are anorexia nervosa (AN) and bulimia nervosa (BN). The etiology of EDs is complex and evidence indicates that both biological/genetic and psychosocial factors are involved. Several lines of evidence indicate that brain-derived neurotrophic factor (BDNF) plays a critical role in regulating eating behaviors and cognitive impairments in the EDs. BDNF is involved in neuronal proliferation, differentiation, and survival during development. BDNF and its tyrosine kinase receptor (TrkB) are expressed in hypothalamic nuclei associated with eating behaviors. A series of studies using BDNF knockout mice and the human BDNF gene indicate an association of BDNF and EDs with predisposition and vulnerability. In the previous studies, serum BDNF levels in subjects with EDs are reduced significantly compared with healthy controls, hence, we proposed that levels of serum BDNF would be a useful diagnostic indicator for EDs.
International Union of Biochemistry and Molecular Biology Life 05/2012; 64(5):355-61. DOI:10.1002/iub.1012 · 3.14 Impact Factor