Although the duration of untreated psychosis (DUP) plays an important role in the short-term prognosis of patients with schizophrenia, their long-term prognosis generally is not determined by DUP alone. It is important to explore how other clinical factors in the early stage are related to DUP and consequent disease courses.
A total of 664 patients with untreated psychosis were surveyed for this study. At the first examination, we divided them into the severe positive symptoms cases (SC) or the less severe cases (NonSC) and compared the prognosis among the two groups after a 10-year follow-up. In all, 113 patients in the SC group and 43 patients in the NonSC group were follow-up completers.
Whereas DUP was not different between the two groups, patients with nonacute onset in both groups had significantly longer DUP than those in patients with acute onset. For all clinical measures, there was no difference in prognosis between the two groups or among the four groups classified by mode of onset (MoO) and initial severity of positive symptoms. However, the degree of improvement of global assessment of functioning (GAF) was significantly smaller in the NonSC-nonacute group than in the SC-acute and SC-nonacute groups.
These results suggest that neither DUP nor MoO alone necessarily affects the initial severity of positive symptoms. Moreover, it is possible that patients with low impetus of positive symptoms onset within long DUP experience profound pathologic processes. Therefore, the current study results indicated that long DUP and nonacute onset were related to poor long-term prognosis, regardless of initial positive symptoms.
D-Serine, an endogenous co-agonist of the N-methyl-D-aspartate (NMDA) receptor, is synthesized from L-serine by serine racemase (SRR). Given the role of D-serine in both neurodevelopment and the pathophysiology of schizophrenia, we examined whether neonatal disruption of D-serine synthesis by SRR inhibition could induce behavioral abnormalities relevant to schizophrenia, in later life.
Neonatal mice (7–9 days) were injected with vehicle or phenazine methosulfate (Met-Phen: 3 mg/kg/day), an SRR inhibitor. Behavioral evaluations, such as spontaneous locomotion, novel object recognition test (NORT), and prepulse inhibition (PPI) were performed at juvenile (5–6 weeks old) and adult (10–12 weeks old) stages. In addition, we tested the effects of D-serine on PPI deficits in adult mice after neonatal Met-Phen exposure. Finally, we assessed whether D-serine could prevent the onset of schizophrenia-like behavior in these mice. Neonatal Met-Phen treatment reduced D-serine levels in the brain, 24 hours after the final dose. Additionally, this treatment caused behavioral abnormalities relevant to prodromal symptoms in juveniles and to schizophrenia in adults. A single dose of D-serine improved PPI deficits in adult mice. Interestingly, chronic administration of D-serine (900 mg/kg/day from P35 to P70) significantly prevented the onset of PPI deficits after neonatal Met-Phen exposure.
This study shows that disruption of D-serine synthesis during developmental stages leads to behavioral abnormalities relevant to prodromal symptoms and schizophrenia, in later life. Furthermore, early pharmacological intervention with D-serine may prevent the onset of psychosis in adult.
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.
This case report details the therapeutic effects of tandospirone on two patients with anorexia nervosa, one with the restricting subtype (ANR), and another with the binge-eating/purging subtype (ANBP). A 22-year-old female patient with ANR and a 23-year-old female patient with ANBP were treated successfully with the 5-HT1A partial agonist tandospirone. After treatment, not only did both patients gain weight, they also showed improved scores on the Eating Disorder Examination Questionnaire. In addition, a 6-month follow-up showed maintenance of these effects. In this disorder, tandospirone may be an effective drug for long-term use with good patient compliance.
Anorexia nervosa; Pharmacotherapy; Treatment; Serotonin 1A receptor; Tandospirone
Cognitive behavior therapy (CBT) is regarded as an effective treatment for social anxiety disorder (SAD) in Europe and North America. Individual CBT might be acceptable and effective for patients with SAD even in non-Western cultures; therefore, we conducted a feasibility study of individual CBT for SAD in Japanese clinical settings. We also examined the baseline predictors of outcomes associated with receiving CBT.
This single-arm trial employed a 14-week individual CBT intervention. The primary outcome was the self-rated Liebowitz Social Anxiety Scale, with secondary measurements of other social anxiety and depressive severity. Assessments were conducted at baseline, after a waiting period before CBT, during CBT, and after CBT.
Of the 19 subjects screened, 15 were eligible for the study and completed the outcome measures at all assessment points. Receiving CBT led to significant improvements in primary and secondary SAD severity (ps < .001). The mean total score on the Liebowitz Social Anxiety Scale improved from 91.8 to 51.7 (before CBT to after CBT), and the within-group effect size at the end-point assessment was large (Cohen’s d = 1.71). After CBT, 73% of participants were judged to be treatment responders, and 40% met the criteria for remission. We found no significant baseline predictors of those outcomes.
Despite several limitations, our treatment—which comprises a 14-week, individual CBT program—seems feasible and may achieve favorable treatment outcomes for SAD in Japanese clinical settings. Further controlled trials are required in order to address the limitations of this study.
Cognitive behavioral therapy; CBT; Social anxiety disorder; Social phobia; SAD; Japanese
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
Yokukan-san, a Japanese traditional herbal (Kampo) prescription, has recently gathered increasing attention due to accumulating reports showing its remarkable efficacy in treating a wide variety of diseases refractory to conventional medicine as well as the behavioral and psychological symptoms of dementia. As yokukan-san has become broadly integrated with conventional medicine, augmentation therapy with other Kampo prescriptions has become necessary when the yokukan-san has been only partially efficacious. In this paper, we report three cases in which the addition of orengedoku-to, another Kampo formula, to yokukan-san was remarkably effective.
Case 1 was an 85-year-old man with Alzheimer-type dementia who had become aggressive during the past 2 years. Three milligrams of aripiprazole completely suppressed his problematic behaviors but had to be stopped because of extrapyramidal symptoms. In the second case, a 44-year-old man with methamphetamine-induced psychosis had suffered from serious tardive dystonia for 2 years. No conventional approach had improved his tardive dystonia. The third case was a 29-year-old engineer who often failed to resist aggressive impulses and was diagnosed with intermittent explosive disorder. He was prescribed 5 mg of olanzapine, which did not suppress his extraordinary anger and caused somnolence even though the dose was low.
Interventions and outcomes
Yokukan-san was complementarily added to the patients’ regular medication and exerted a definitive but partial effect in all cases. The addition of orengedoku-to to yokukan-san exerted the same efficacy as aripiprazole in controlling aggressiveness in Case 1, improved the tardive dystonia by 80% in Case 2, and was completely effective in controlling the patient’s aggressive impulses in Case 3.
Together with empirical evidence demonstrating the effectiveness of both yokukansan and orengedoku-to in reducing irritability, impulsivity, and aggression, these three cases suggest that orengedoku-to augmentation can be an effective option in cases that are partially responsive to yokukan-san treatment.
traditional medicine; aggressiveness; tardive dystonia; intermittent explosive disorder
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.
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.
Agonists of α7-nicotinic acetylcholine receptors (nAChRs) have been developed as potential therapeutic drugs for neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. Positron emission tomography (PET) is a noninvasive brain imaging technique to measure receptor occupancy in the living human brain. Although much effort has been expended to create specific PET radioligands for α7-nAChRs in the brain, only 4-[11C]methylphenyl-1,4-diazabicyclo[3.2.2.]nonane-4-carboxylate ([11C]CHIBA-1001) is currently available for clinical studies. In contrast, two 5-hydroxytryptamine-3 (5-HT3) receptor antagonists, tropisetron and ondansetron, have been used to treat patients with chemotherapy-induced or postoperative nausea and vomiting. Furthermore, tropisetron, but not ondansetron, possesses high affinity for α7-nAChRs. In the present study, we evaluated the receptor occupancy in the human brain after a single oral administration of tropisetron and ondansetron using [11C]CHIBA-1001 and PET.
Two serial dynamic PET scans using [11C]CHIBA-1001 in healthy non-smoking male subjects were performed before and after receiving an oral administration of these medications.
A single oral administration of tropisetron, but not ondansetron, decreased the total distribution volume of [11C]CHIBA-1001 in the human brain.
This study shows that tropisetron, but not ondansetron, could bind to α7-nAChRs in the human brain after a single oral administration. Therefore, [11C]CHIBA-1001 may be a useful PET radioligand to measure the occupancy of α7-nAChRs in the human brain.
α7-nicotinic acetylcholine receptor; Positron-emission tomography; Tropisetron; Ondansetron; [11C]CHIBA-1001
Several investigations suggested abnormalities in circadian rhythms are related to the pathophysiology of psychiatric disorders, including drug addiction. Recently, orphan nuclear receptor rev-erb alpha and glycogen synthase kinase-3 β (GSK-3β) were shown to be important circadian components. In addition, the orphan nuclear receptor rev-erb alpha is a key negative feedback regulator of the circadian clock. These evidences indicate that rev-erb alpha gene (NR1D1) is a good candidate gene for the pathogenesis of methamphetamine dependence. To evaluate the association between NR1D1 and methamphetamine dependence, we conducted a case-control study of Japanese samples (215 methamphetamine dependence and 232 controls) with three tagging SNPs selected by HapMap database. Written informed consent was obtained from each subject. This study was approved by the ethics committees at Fujita Health University, Nagoya University Graduate School of Medicine and each participating member of the Institute of the Japanese Genetics Initiative for Drug Abuse (JGIDA). We did not detect an association between NR1D1 and Japanese methamphetamine dependence patients in allele/genotype-wise analysis, or the haplotype analysis. Our findings suggest that NR1D1 does not play a major role in the pathophysiology of methamphetamine dependence in the Japanese population.
Orphan nuclear receptor Rev-erb alpha gene (NR1D1); methamphetamine dependence; tagging SNPs; linkage disequilibrium.
Disruption of circadian rhythms may be involved in the pathophysiology of psychiatric disorders, including drug addiction. Recently, we detected the significant association between prokineticin 2 receptor gene (PROKR2) and Japanese methamphetamine dependence patients. Also, prokineticin 2 (PK2) gene deficient mice showed reduced physiological and behavioral parameters, including circadian locomotor activity, circulating glucocorticoid, glucose levels and the expression of peripheral clock genes compared with WT mice. These evidences indicate that PK2 gene (PROK2) is a good candidate gene for the pathogenesis of methamphetamine dependence. To evaluate the association between PROK2 and methamphetamine dependence, we conducted a case-control study of Japanese samples (215 methamphetamine dependence and 232 controls) with four tagging SNPs selected by HapMap database. The age and sex of the control subjects did not differ from those of the methamphetamine dependence patients. Written informed consent was obtained from each subject. This study was approved by the ethics committees at Fujita Health University, Nagoya University Graduate School of Medicine and each participating member of the Institute of the Japanese Genetics Initiative for Drug Abuse (JGIDA). We did not detect an association between PROK2 and Japanese methamphetamine dependence patients in allele/genotype-wise analysis, or the haplotype analysis. Our findings suggest that PROK2 does not play a major role in the pathophysiology of methamphetamine dependence in the Japanese population.
Prokineticin 2 gene (PROK2); methamphetamine dependence; tagging SNPs; linkage disequilibrium.
Several lines of evidence suggest that the dopaminergic nervous system contributes to methamphetamine (METH) dependence, and there is increasing evidence of antagonistic interactions between dopamine and adenosine receptors in METH abusers. We therefore hypothesized that variations in the A1 adenosine receptor (ADORA1) gene modify genetic susceptibility to METH dependence/psychosis. In this study, we identified 7 single nucleotide polymorphisms (SNPs) in exons and exon-intron boundaries of the ADORA1 gene in a Japanese population. A total of 171 patients and 229 controls were used for an association analysis between these SNPs and METH dependence/psychosis. No significant differences were observed in either the genotypic or allelic frequencies between METH dependent/psychotic patients and controls. A global test of differentiation among samples based on haplotype frequencies showed no significant association. In the clinical feature analyses, no significant associations were observed among latency of psychosis, prognosis of psychosis, and spontaneous relapse. These results suggest that the ADORA1 gene variants may make little or no contribution to vulnerability to METH dependence/psychosis.
Single nucleotide polymorphism; SNP; variation; human; Japanese; MAP; abuse; dopamine.
The neuronal nitric oxide synthase gene (NOS1) is located at 12q24, a susceptibility region for schizophrenia, and produces nitric oxide (NO). NO has been reported to play important roles as a gaseous neurotransmitter in brain. NO is a second messenger for the N-methyl-D aspartate (NMDA) receptor and is related to the dopaminergic system. Because the symptomatology of methamphetamine (METH) use disorder patients with psychosis is similar to that of patients with schizophrenia, NOS1 is a good candidate gene for METH-induced psychosis. Therefore, we conducted a case-control association study between NOS1 and METH-induced psychosis with Japanese subjects (183 with METH-induced psychosis patients and 519 controls). We selected seven SNPs (rs41279104, rs3782221, rs3782219, rs561712, rs3782206, rs6490121, rs2682826) in NOS1 from previous reports. Written informed consent was obtained from each subject. This study was approved by the Ethics Committee at Fujita Health University School of Medicine and each participating institute of the Japanese Genetics Initiative for Drug Abuse (JGIDA). No significant association was found between NOS1 and METH-induced psychosis in the allele/genotype-wise or haplotype-wise analyses. In conclusion, we suggest that NOS1 might not contribute to the risk of METH-induced psychosis in the Japanese population.
Methamphetamine-induced psychosis; neuronal nitric oxide synthase 1 gene (NOS1); case-control association study.
Several investigations have suggested that abnormalities in glutamate neural transmission play a role in the pathophysiology of psychiatric disorders, including schizophrenia. The metabotropic glutamate 3 receptor (mGluR3) gene was reported to be associated with schizophrenia, and paranoid type schizophrenia has symptoms that are similar to those of methamphetamine-induced psychosis. This suggests that mGluR3 gene (GRM3) is a good candidate gene for the pathogenesis of methamphetamine-induced psychosis. To evaluate the association between GRM3 and methamphetamine-induced psychosis, we conducted a case-control study of Japanese samples (181 methamphetamine-induced psychosis and 232 controls).
We selected one functional SNP (rs6465084), reported to be associated with prefrontal brain functioning, for an association analysis. Written informed consent was obtained from each subject. This study was approved by the ethics committees at Fujita Health University, Nagoya University Graduate School of Medicine and each participating member of the Institute of the Japanese Genetics Initiative for Drug Abuse (JGIDA).
We did not detect an association between rs6465084 in GRM3 and Japanese methamphetamine-induced psychosis.
Our findings suggest that rs6465084 in GRM3 does not play a major role in the pathophysiology of methamphetamine-induced psychosis in the Japanese population. However, because we did not perform an association analysis based on linkage disequilibrium (LD) or a mutation scan of GRM3, a replication study using a larger sample and based on LD may be required for conclusive results.
GRM3; Methamphetamine-Induced Psychosis; case-control study.
There is a growing evidence that serotoninergic systems modulate dopaminergic neurotransmission. We analyzed the association between the variations in the brain tryptophan hydroxylase 2 (TPH2) gene, a rate limiting enzyme for serotonin biosynthesis, and methamphetamine (METH) dependence/psychosis in a Japanese population. We found ten single nucleotide polymorphisms (SNPs) and two polynucleotide polymorphisms in TPH2 gene exons and exon-intron boundaries. A total of 162 patients and 243 controls were used for the association analysis between these polymorphisms and METH dependence/psychosis. No significant differences were observed in either genotypic or allelic frequencies between METH dependent/psychotic patients and controls. A global test of differentiation among samples based on haplotype frequencies showed no significant association. With respect to latency of psychosis, prognosis of psychosis, and spontaneous relapse, we found no significant association with these SNPs. These results suggest that the TPH2 gene variants may not be a factor in vulnerability to METH dependence/psychosis.
Single nucleotide polymorphism; SNP; variation; serotonin; human; Japanese; MAP; abuse.
The CogState Schizophrenia Battery (CSB), a computerized cognitive battery, covers all the same cognitive domains as the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery but is briefer to conduct. The aim of the present study was to evaluate the criterion and construct validity of the Japanese language version of the CSB (CSB-J) in Japanese patients with schizophrenia.
Forty Japanese patients with schizophrenia and 40 Japanese healthy controls with matching age, gender, and premorbid intelligence quotient were enrolled. The CSB-J and the Brief Assessment of Cognition in Schizophrenia, Japanese-language version (BACS-J) were performed once. The structure of the CSB-J was also evaluated by a factor analysis. Similar to the BACS-J, the CSB-J was sensitive to cognitive impairment in Japanese patients with schizophrenia. Furthermore, there was a significant positive correlation between the CSB-J composite score and the BACS-J composite score. A factor analysis showed a three-factor model consisting of memory, speed, and social cognition factors.
This study suggests that the CSB-J is a useful and rapid automatically administered computerized battery for assessing broad cognitive domains in Japanese patients with schizophrenia.
In Japan, hospitalization for the assessment of mentally disordered offenders under the Act on Medical Care and Treatment for the Persons Who Had Caused Serious Cases under the Condition of Insanity (the Medical Treatment and Supervision Act, or the MTS Act) has yet to be standardized.
We conducted a written survey that included a questionnaire regarding hospitalization for assessment; the questionnaire consisted of 335 options with 9 grades of validity for 60 clinical situations. The survey was mailed to 50 Japanese forensic mental health experts, and 42 responses were received.
An expert consensus was established for 299 of the options. Regarding subjects requiring hospitalization for assessment, no consensus was reached on the indications for electroconvulsive therapy (ECT) or for confronting the offenders regarding their offensive behaviors.
The consensus regarding hospitalization for assessment and its associated problems were clarified. The consensus should be widely publicized among practitioners to ensure better management during the hospitalization of mentally disordered offenders for assessment.
Background: Long-term treatment of schizophrenia with antipsychotics is crucial for relapse prevention, but a prolonged blockade of D2 dopamine receptors may lead to the development of supersensitivity psychosis. We investigated the chronic effects of aripiprazole (ARI) on dopamine sensitivity. Methods: We administered ARI (1.5 mg/kg/d), haloperidol (HAL; 0.75 mg/kg/d), or vehicle (VEH) via minipump for 14 days to drug-naive rats or to rats pretreated with HAL (0.75 mg/kg/d) or VEH via minipump for 14 days. On the seventh day following treatment cessation, we examined the effects of the treatment conditions on the locomotor response to methamphetamine and on striatal D2 receptor density (N = 4-10/condition/experiment). Results: Chronic treatment with HAL led to significant increases in locomotor response and D2 receptor density, compared with the effects of chronic treatment with either VEH or ARI; there were no significant differences in either locomotor response or D2 density between the VEH- and ARI-treated groups. We also investigated the effects of chronic treatment with HAL, ARI, or VEH preceded by HAL or VEH treatment on locomotor response and D2 density. ANOVA analysis indicated that the rank ordering of groups for both locomotor response and D2 density was HAL-HAL > HAL-VEH > HAL-ARI > VEH-VEH. Conclusions: Chronic treatment with ARI prevents development of dopamine supersensitivity and potentially supersensitivity psychosis, suggesting that by reducing excessive sensitivity to dopamine and by stabilizing sensitivity for an extended period of time, ARI may be helpful for some patients with treatment-resistant schizophrenia.
D2 dopamine receptor; locomotor activity; partial agonist; radioligand binding assay; rat; striatum
Neuropeptide S (NPS) and its cognate receptor were reported to mediate anxiolytic-like and arousal effects. NPS receptors are predominantly expressed in the brain, especially in limbic structures, including amygdala, olfactory nucleus, subiculum and retrosplenial cortex. In contrast, the NPS precursor is expressed in only a few brainstem nuclei where it is co-expressed with various excitatory transmitters, including glutamate. The current study investigates interactions of the NPS system with glutamatergic neurotransmission. It has been suggested that dysfunctions in glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) receptors might be involved in the pathophysiology of schizophrenia since NMDA receptor antagonists, such as MK-801, have been shown to induce psychotic-like behavior in humans and animal models. Also, MK-801 is known to produce histological changes such as cytoplasmic vacuoles in retrosplenial cortex neurons where NPS receptors are highly expressed. In this study we show that NPS is able to alleviate neuropathological, neurochemical and behavioral changes produced by NMDA receptor antagonists. NPS treatment attenuated MK-801-induced vacuolization in the rat retrosplenial cortex in a dose dependent manner that can be blocked by an NPS receptor-selective antagonist. NPS also suppressed MK-801-induced increases of extracellular acetylcholine levels in the retrosplenial cortex. In the prepulse inhibition (PPI) assay, animals pretreated with NPS recovered significantly from MK-801-induced disruption of PPI. Our study suggests that NPS may have protective effects against the neurotoxic and behavioral changes produced by NMDA receptor antagonists and that NPS receptor agonists may elicit antipsychotic effects.
glutamate; NMDA; microdialysis; neuropeptide; schizophrenia; prepulse inhibition; retrosplenial cortex
Benzodiazepines carry the risk of inducing cognitive impairments, which may go unnoticed while profoundly disturbing social activity. Furthermore, these impairments are partly associated with the elimination half-life (EH) of the substance from the body. The object of the present study was to examine the effects of etizolam and ethyl loflazepate, with EHs of 6 h and 122 h, respectively, on information processing in healthy subjects.
Healthy people were administered etizolam and ethyl loflazepate acutely and subchronically (14 days). The auditory P300 event-related potential and the neuropsychological batteries described below were employed to assess the effects of drugs on cognition. The P300 event-related potential was recorded before and after drug treatments. The digit symbol test, trail making test, digit span test and verbal paired associates test were administered to examine mental slowing and memory functioning.
Acute administration of drugs caused prolongation in P300 latency and reduction in P300 amplitude. Etizolam caused a statistically significant prolongation in P300 latency compared to ethyl loflazepate. Furthermore, subchronic administration of etizolam, but not ethyl loflazepate, still caused a weak prolongation in P300 latency. In contrast, neuropsychological tests showed no difference.
The results indicate that acute administration of ethyl loflazepate induces less effect on P300 latency than etizolam.
Several lines of evidence suggest that the dopaminergic nervous system contributes to methamphetamine (METH) dependence, and there is increasing evidence of antagonistic interactions between dopamine and adenosine receptors. We therefore hypothesized that variations in the A2A adenosine receptor (ADORA2A) gene modify genetic susceptibility to METH dependence/psychosis.
We first analyzed variations in the exons and exon-intron boundaries of the ADORA2A gene in METH dependent/psychotic patients. Then an association analysis between these single nucleotide polymorphisms and METH dependence/psychosis was performed using a total of 171 METH dependent/psychotic patients and 229 controls.
We found 6 variations, of which one single nucleotide polymorphism (SNP) was novel. Significant associations were observed between the allelic and genotypic frequencies of the Exon2+751 (rs5751876) SNP and METH dependence/psychosis. These associations were observed especially in females. In the clinical feature analyses, significant associations were observed between the SNP and the patient subgroup using METH alone (i.e., without concomitant use of other substances of abuse).
These results suggest that the ADORA2A gene could be a vulnerability factor for METH dependence/psychosis, especially in females and/or in patients using only METH.
Set-shifting is impaired in people with anorexia nervosa (AN), but the underlying physiological and biochemical processes are unclear. Animal studies have established that glutamatergic pathways in the prefrontal cortex play an important role in set-shifting ability. However, it is not yet understood whether levels of serum glutamatergic amino acids are associated with set-shifting performance in humans. The aim of this study was to determine whether serum concentrations of amino acids related to glutamatergic neurotransmission (glutamine, glutamate, glycine, l-serine, d-serine) are associated with set-shifting ability in people with acute AN and those after recovery.
Serum concentrations of glutamatergic amino acids were measured in 27 women with current AN (AN group), 18 women recovered from AN (ANRec group) and 28 age-matched healthy controls (HC group). Set-shifting was measured using the Wisconsin Card Sorting Test (WCST) and the Trail Making Task (TMT). Dimensional measures of psychopathology were used, including the Eating Disorder Examination Questionnaire (EDEQ), the Maudsley Obsessive-Compulsive Inventory (MOCI) and the Hospital Anxiety and Depression Scale (HADS).
Serum glutamine concentrations in the AN group (1,310.2 ± 265.6 μM, mean ± SD) were significantly higher (by approximately 20%) than those in the HC group (1,102.9 ± 152.7 μM, mean ± SD) (F(2, 70) = 6.3, P = 0.003, 95% CI 61.2 to 353.4). Concentrations of serum glutamine were positively associated with markers of the illness severity: a negative correlation was present between serum glutamine concentrations and body mass index (BMI) and lowest BMI and a positive correlation was found between duration of illness and EDEQ. The AN group showed significantly impaired set shifting in the WCST, both total errors, and perseverative errors. In the AN group, there were no correlations between serum glutamine concentrations and set shifting.
Serum concentrations of glutamine may be a biomarker of illness severity in people with AN. It does not appear to be directly associated with changes in executive function.
Cognitive deficits in schizophrenia are associated with psychosocial deficits that are primarily responsible for the poor long-term outcome of this disease. Auditory sensory gating P50 deficits are correlated with neuropsychological deficits in attention, one of the principal cognitive disturbances in schizophrenia. Our studies suggest that the α7 nicotinic acetylcholine receptor (α7 nAChR) agonist tropisetron might be a potential therapeutic drug for cognitive deficits in schizophrenia. Therefore, it is of particular interest to investigate the effects of tropisetron on the cognitive deficits in patients with schizophrenia.
A randomised, placebo-controlled trial of tropisetron in patients with schizophrenia was performed. A total of 40 patients with chronic schizophrenia who had taken risperidone (2 to 6 mg/day) were enrolled. Subjects were randomly assigned to a fixed titration of tropisetron (n = 20, 10 mg/day) or placebo (n = 20) in an 8-week double-blind trial. Auditory sensory gating P50 deficits and Quality of Life Scale (QLS), Cambridge Neuropsychological Test Automated Battery (CANTAB), and Positive and Negative Syndrome Scale (PANSS) scores were measured.
In all, 33 patients completed the trial. Tropisetron was well tolerated. Administration of tropisetron, but not placebo, significantly improved auditory sensory gating P50 deficits in non-smoking patients with schizophrenia. The score on the rapid visual information processing (sustained visual attention) task of CANTAB was significantly improved by tropisetron treatment. Total and subscale scores of PANSS were not changed by this trial. QLS scores in the all patients, but not non-smoking patients, were significantly improved by tropisetron trial.
This first randomised, double-blind, placebo-controlled trial supports the safety and efficacy of adjunctive tropisetron for treatment of cognitive deficits in schizophrenia.
The α7 nicotinic acetylcholine receptors (nAChRs) play an important role in the pathophysiology of neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. However, there are currently no suitable positron emission tomography (PET) radioligands for imaging α7 nAChRs in the intact human brain. Here we report the novel PET radioligand [11C]CHIBA-1001 for in vivo imaging of α7 nAChRs in the non-human primate brain.
A receptor binding assay showed that CHIBA-1001 was a highly selective ligand at α7 nAChRs. Using conscious monkeys, we found that the distribution of radioactivity in the monkey brain after intravenous administration of [11C]CHIBA-1001 was consistent with the regional distribution of α7 nAChRs in the monkey brain. The distribution of radioactivity in the brain regions after intravenous administration of [11C]CHIBA-1001 was blocked by pretreatment with the selective α7 nAChR agonist SSR180711 (5.0 mg/kg). However, the distribution of [11C]CHIBA-1001 was not altered by pretreatment with the selective α4β2 nAChR agonist A85380 (1.0 mg/kg). Interestingly, the binding of [11C]CHIBA-1001 in the frontal cortex of the monkey brain was significantly decreased by subchronic administration of the N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine (0.3 mg/kg, twice a day for 13 days); which is a non-human primate model of schizophrenia.
The present findings suggest that [11C]CHIBA-1001 could be a novel useful PET ligand for in vivo study of the receptor occupancy and pathophysiology of α7 nAChRs in the intact brain of patients with neuropsychiatric diseases such as schizophrenia and Alzheimer's disease.