Osamu Shirakawa

Abnormal expression of brain-derived neurotrophic factor and its receptor in the corticolimbic system of schizophrenic patients.

Previous neuropathological studies have revealed that the corticolimbic system of schizophrenic patients expresses abnormal levels of various synaptic molecules, which are known to be influenced by the neuronal differentiation factors, neurotrophins. Therefore, we determined levels of neurotrophins and their receptors in the postmortem brains of schizophrenic patients and control subjects in relation to molecular impairments in schizophrenia. Among the neurotrophins examined, levels of brain-derived neurotrophic factor (BDNF) were elevated specifically in the anterior cingulate cortex and hippocampus of schizophrenic patients, but levels of nerve growth factors and neurotrophin-3 showed no change in any of the regions examined. In parallel, the expressions of TrkB receptor and calbindin-D, which are both influenced by BDNF, were reduced significantly in the hippocampus or the prefrontal cortex. However, neuroleptic treatment did not appear to mimic the neurotrophic change. Neither withdrawal of drug treatment in patients nor chronic administration of haloperidol to rats altered levels of BDNF. These findings suggest that neurotrophic abnormality is associated with the corticolimbic structures of schizophrenic patients and might provide the molecular substrate for pathological manifestations of the illness.

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.

Differential changes in serotonin 5-HT1A and 5-HT2 receptor binding in patients with chronic schizophrenia.

Serotonin 5-HT1A and 5-HT2 receptors were examined in the postmortem brains of controls and patients with chronic schizophrenia. In the prefrontal cortex from patients with schizophrenia, 5-HT1A receptor binding was increased, while 5-HT2 receptor binding was decreased, when compared to controls. The increased 5-HT1A receptor binding or the decreased 5-HT2 receptor binding was observed in both the patients who had been medicated with neuroleptics at time of death and those who had not, at least 2 months prior to death. Thus, abnormalities of 5-HT receptor subtypes seem to exist in the brains of patients with chronic schizophrenia. 5-HT related agents might be beneficial for the treatment of schizophrenia.

Selective reduction of a PDZ protein, SAP-97, in the prefrontal cortex of patients with chronic schizophrenia

Many postsynaptic density proteins carrying postsynaptic density‐95/discs large/zone occludens‐1 (PDZ) domain(s) interact with glutamate receptors to control receptor dynamics and synaptic plasticity. Here we examined the expression of PDZ proteins, synapse‐associated protein (SAP) 97, postsynaptic density (PSD)‐95, chapsyn‐110, GRIP1 and SAP102, in post‐mortem brains of schizophrenic patients and control subjects, and evaluated their contribution to schizophrenic pathology. Among these PDZ proteins, SAP97 exhibited the most marked change: SAP97 protein levels were decreased to less than half that of the control levels specifically in the prefrontal cortex of schizophrenic patients. In parallel, its binding partner, GluR1, similarly decreased in the same brain region. The correlation between SAP97 and GluR1 levels in control subjects was, however, altered in schizophrenic patients. SAP102 levels were also significantly reduced in the hippocampus of schizophrenic patients, but this reduction was correlated with sample storage time and post‐mortem interval. There were no changes in the levels of the other PDZ proteins in any of the regions examined. In addition, neuroleptic treatment failed to mimic the SAP97 change. These findings suggest that a phenotypic loss of SAP97 is associated with the postsynaptic impairment in prefrontal excitatory circuits of schizophrenic patients.

Striatal enlargement in rats chronically treated with neuroleptic

BACKGROUND Striatal enlargement with chronic neuroleptic treatment in schizophrenic patients has been reported by several investigators. Longitudinal magnetic resonance imaging studies of patients suggest that changes in striatal volume may be caused by treatment with antipsychotic medication. METHODS We have examined the effects of chronic neuroleptic treatment on postmortem striatal volume in the laboratory rat and have examined the relationship between striatal volume and vacuous chewing movements (VCMs). Autoradiographs of 50 rats treated with haloperidol (1.5 mg/kg/day) or drug free for varying durations of time (1-12 months) were utilized in this analysis. RESULTS Chronic treatment with neuroleptics (1 month or greater) was associated with larger striatal volumes. The increase in striatal volume was present at 1 month of treatment and was sustained to 12 months of treatment. Rats that developed the high-VCM syndrome had larger striatal volumes than both drug-free and low-VCM rats, while low-VCM rats had larger striatal volumes than drug-free rats. CONCLUSIONS These data suggest that chronic neuroleptic treatment is the cause of striatal enlargement in the laboratory rat, and that this enlargement is most prominent in rats that have the high-VCM syndrome.

Delayed regional metabolic actions of phencyclidine

Phencyclidine (PCP), a psychotomimetic drug of abuse, produces mental changes and manifestations in humans which are reminiscent of schizophrenia, though the mechanism of these actions remains unknown. We report here a biphasic time course of PCP action on regional cerebral glucose metabolism extending over 48 h. A single dose of PCP (8.6 mg/kg) produces an initial increase in glucose metabolism (at 3 h) and a later decrease in glucose metabolism (at 24 h) without a return to baseline until 48 h. A single lower dose of PCP (0.86 mg/kg), a dose which is considered selective for action at the NMDA-PCP receptor, produces no early metabolic change (at 3 h), but replicates the regional hypometabolism albeit less intense at 24 h. The delayed cerebral hypometabolism does not appear to be related to PCP-induced intracellular vacuolization, seen in the retrosplenial cortex. These metabolic changes may be associated with the psychotomimetic effects of PCP and thus may be relevant to psychosis in humans.

Association between 5HT2A receptor gene promoter region polymorphism and eating disorders in Japanese patients

BACKGROUND Evidence from family and twin studies suggests a genetic contribution to the etiology of eating disorders (EDs). Recently, researchers have reported genetic associations between the MspI polymorphism (-1438A/G) of the promoter region of the 5HT2A receptor gene and EDs; however, reports of evidence against these findings make the association controversial. METHODS The authors examined the prevalence of the -1438A/G polymorphism of the 5HT2A receptor gene among 182 Japanese patients with EDs and 374 normal control subjects. Interactions of the association of this polymorphism with subtypes of anorexia nervosa (AN), bulimia nervosa (BN), and various clinical characteristics were also assessed. RESULTS In contrast to previous studies reporting elevated A allele frequencies in patients with AN, the G allele had a significantly higher frequency in patients with BN but not in patients with AN, than in control subjects. Examination of the interactions revealed that the presence of the binge eating and/or purging behavior and comorbid borderline personality disorder (BPD) tended to be associated with increased frequency of the G allele. CONCLUSIONS Though preliminary, these results can be interpreted as suggesting that the G allele of the 5HT2A receptor gene -1438A/G polymorphism may be associated with pathological features that EDs and BPD have in common, especially disinhibition in eating behavior and personality trait.

Association between Catechol-O-Methyltransferase Functional Polymorphism and Male Suicide Completers

Suicide has been suggested to involve catecholaminergic dysfunction and to be related to genetics. Catechol-O-methyltransferase (COMT) 158Val/Met polymorphism (GenBank Accession No. Z26491) is a polymorphism of the gene encoding COMT, a major enzyme in catecholamine inactivation. The COMT 158Val/Met polymorphism affects COMT activity, that is, the alleles encoding Val and Met are associated with relatively high and relatively low COMT activity, respectively. In this study, we hypothesized that the COMT 158Val/Met polymorphism is associated with suicide. The study population consisted of 163 suicide completers (112 males and 51 females). We found that the genotype distribution of the COMT 158Val/Met polymorphism was significantly different between male suicide completers and male controls (p=0.036), while the frequency of the Val/Val genotype, a high-activity COMT genotype, was significantly less in male suicide completers than in male controls (OR: 0.52; 95% CL: 0.31–0.89; p=0.016). However, this was not the case in females. Our results suggest that the Val/Val genotype is a protective factor against suicide in males.

Serotonin transporter regulatory region polymorphism is associated with anorexia nervosa.

Several lines of evidence support possible serotonin transporter (5‐HTT) involvement in modulating eating disorders (ED). The 5‐HTT gene is a good candidate for genetic studies on the course of ED, despite controversy concerning the association between polymorphism in the 5‐HTT gene promoter region (5‐HTTLPR) and ED. Comparison of 5‐HTTLPR distribution in 195 female Japanese ED patients and 290 age‐ and gender‐matched control subjects facilitated examining the association between the course of the disease and 5‐HTTLPR in 138 of 195 ED subjects. The 5‐HTTLPR S allele frequency was significantly higher in subjects with anorexia nervosa (AN) than in control subjects. Among subjects observed ≥3 years, the S allele frequency was significantly higher in those diagnosed as AN at ED onset than in those diagnosed as AN in this study. The 5‐HTTLPR S allele might play some role in the development of AN with persistent disease.

Tryptophan hydroxylase immunoreactivity is altered by the genetic variation in postmortem brain samples of both suicide victims and controls.

Several lines of evidence suggest that a partly genetically controlled serotonergic dysfunction is involved in the biological pathogenesis of suicide. In this study, we measured tryptophan hydroxylase (TPH) immunoreactivity as a pre-synaptic marker, and serotonin receptor 2A (5HT2A receptor) density as a post-synaptic marker in the serotonergic system in 10 postmortem brains of suicide victims. We also examined whether TPH gene polymorphisms (A218C and A-6526G polymorphisms) could affect TPH immunoreactivity and 5HT2A receptor gene polymorphism (A-1438G polymorphism) could affect 5HT2A receptor density in 28 postmortem brain samples. No significant differences were found in TPH immunoreactivity or 5HT2A receptor density between suicide victims and controls. The AA genotype of the A218C polymorphism of the TPH gene showed higher TPH immunoreactivity along with lower 5HT2A receptor density than did any other genotypes in the postmortem brains of both suicide victims and controls. Our findings suggest that the A218C polymorphism of the TPH gene can be expected to provide new insights not only for neurobiological studies of suicide, but also for research into the behavioral characteristics that may be associated with serotonergic dysfunction.