Koki Ito

Tone duration mismatch negativity deficits predict impairment of executive function in schizophrenia

Impairment in mismatch negativity (MMN) potentials is a robust finding in schizophrenia. There are few studies which examined the correlation between MMN deficits and neuropsychological performances. The purpose of this study was to investigate the relationship between deficits of tone duration MMN and various neuropsychological measures in schizophrenic patients (n=23). The results demonstrated a significant correlation between low MMN amplitude and poor performances of executive function in Wisconsin Card Sorting Test, Stroop Test and Trail Making Test. Our finding suggests MMN deficits in schizophrenia predict deficits of executive function and might reflect ongoing functional abnormality of fronto-temporal interaction.

Role of the simultaneous enhancement of NMDA and dopamine D1 receptor-mediated neurotransmission in the effects of clozapine on phencyclidine-induced acute increases in glutamate levels in the rat medial prefrontal cortex

Clozapine (CLZ) can improve both the positive and negative symptoms of treatment-resistant schizophrenia (TRS), which does not respond to typical antipsychotics. This suggests that elucidation of the pharmacological mechanism for CLZ could lead to further clarification of the pathophysiology of TRS. This study examined the effects of CLZ on phencyclidine (PCP)-induced hyperlocomotion and on the acute increases in glutamate levels that occur in the medial prefrontal cortex (mPFC) in order to test the hypothesis that CLZ effect is associated with the simultaneous enhancement of N-methyl-d-aspartate (NMDA) and dopamine D1 receptor-mediated neurotransmission. CLZ effect on PCP-induced hyperlocomotion and increases in glutamate levels were examined by using behavioral rating scores and in vivo microdialysis, respectively. CLZ and haloperidol (HAL) dose-relatedly attenuated PCP-induced hyperlocomotion, and concentration-relatedly blocked PCP-induced acute increases in glutamate levels in the mPFC, with the decrease in saline-induced locomotor activity induced by CLZ being much weaker than that induced by HAL. CLZ also blocked, in a dose-related manner, acute increases in glutamate levels in the mPFC that were induced by local perfusion with a competitive NMDA receptor antagonist, CPP, in this region. Although an enhanced blocking effect of the sub-threshold concentration of NMDA perfusion on PCP-induced acute increases in glutamate levels in the mPFC was noted after co-perfusion with a dopamine D1 receptor agonist, SKF-38393, perfusion with SKF-38393 did not reverse the CLZ blocking of PCP-induced increases in glutamate levels. Therefore, CLZ may block PCP-induced acute increases in glutamate levels in the mPFC by an enhancement of the NMDA receptor-mediated neurotransmission that is not accelerated by an enhanced dopaminergic transmission via dopamine D1 receptors. This blocking effect may partially explain the CLZ-induced attenuation of PCP-induced hyperlocomotion.

Olanzapine and risperidone block a high dose of methamphetamine-induced schizophrenia-like behavioral abnormalities and accompanied apoptosis in the medial prefrontal cortex

This study aims to propose a comprehensive new model for schizophrenia, which shows PPI disruption at baseline state as an endophenotype, the development of cross-sensitization to an NMDA receptor antagonist, MK-801 as a clinical phenotype of the progression into treatment-resistance, and accompanied induction of apoptosis in the medial prefrontal cortex as a critical possibility during the progression. Repeated administration of a high dose of methamphetamine (METH) (2.5 mg/kg), which could increase glutamate levels in the medial prefrontal cortex (mPFC), induced TUNEL-positive cells in this region, accompanied development of behavioral cross-sensitization to MK-801 in response to a challenge injection of MK-801, and PPI disruption at baseline state without a challenge injection. Olanzapine (OLZ) (1.0 mg/kg) and risperidone (RIS) (0.1 mg/kg), which inhibited and remarkably attenuated METH (2.5 mg/kg)-induced increases in glutamate levels, respectively, blocked not only the induction of TUNEL-positive cells in the mPFC but also the accompanied development of above behavioral abnormalities. These findings suggest that repeating the METH-induced glutamate release produces behavioral abnormalities as a clinical phenotype of schizophrenia, accompanied apoptosis as a critical possibility during the progression, and suggest that sufficient dose of olanzapine and risperidone can block the development of these behavioral abnormalities and accompanied apoptosis during the progression.

Effects of aripiprazole and haloperidol on progression to schizophrenia-like behavioural abnormalities and apoptosis in rodents

Aripiprazole (APZ) is considered a first-line medication for treating first and multiple episodes of schizophrenia, but its effect on preventing the progressive pathophysiology of schizophrenia remains unclear. This study examined the hypothesis that APZ blocks enhanced glutamate release in the medial prefrontal cortex (mPFC) during psychotic episodes of schizophrenia, thereby preventing progression of the pathophysiology. We examined effects of APZ on methamphetamine (METH)-induced increases in glutamate levels in the mPFC, and on repeatedly administered METH-induced progression to schizophrenia-like behavioural abnormalities involving cross-sensitization to the N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, deficit of prepulse inhibition (PPI), and expression of TUNEL-positive cells. Additionally, we compared the preventive effects of APZ to those of a conventional antipsychotic: haloperidol (HPD). Results show that APZ (1.0 and 3.0 mg/kg) and HPD (0.1 mg/kg) each blocked METH (2.5 mg/kg)-induced increases in glutamate levels in the mPFC. Furthermore, APZ (3.0 mg/kg) and HPD (0.1 mg/kg), when co-administered repeatedly with METH, each prevented progression to schizophrenia-like behavioural and neuropathological abnormalities. Repeated co-administration of APZ (3.0 mg/kg) with saline did not induce apoptosis, although HPD (0.1 mg/kg) with saline did induce apoptosis. These results indicate that APZ and HPD prevented progressive pathophysiology, which is related to increased glutamate levels, and indicate that repeated administration of HPD, but not APZ, induced apoptosis under conditions without increased glutamate levels. These findings suggest the importance of using APZ and HPD in the appropriate stages of the glutamate-related pathophysiology of schizophrenia.

The Role of Benzodiazepine Receptors in the Acquisition and Expression of Behavioral Sensitization to Methamphetamine

The GABA-benzodiazepine neurotransmission has been reported to be implicated in various forms of plasticity such as kindling and learning. In a previous study, we have shown that clonazepam (CZP), a GABA-benzodiazepine agonist, prevents the acquisition of behavioral sensitization to methamphetamine (MA). The present study was conducted to extend this finding by examining the effect of flumazenil (Flu), a GABA-benzodiazepine antagonist on the prevention by CZP. Rats (male Wistar-King rats) treated with MA (1 mg/kg, SC) for 10 days showed significantly enhanced motor activity compared to those treated with saline when tested with MA (1 mg/kg) after a 7-8-day withdrawal, indicating the acquisition of behavioral sensitization. Representing the previous finding, pretreatment with CZP (0.5 mg/kg) prior to MA administration prevented the acquisition of the phenomenon. Pretreatment with Flu (10 mg/kg) prior to MA administration has no influence on the acquisition of sensitization. However, pretreatment with Flu prior to CZP administration reversed the inhibitory effect of CZP. CZP showed no effect on the expression of sensitization in the sensitized rats when given prior to the MA readministration. These results strengthen the suggestion that stimulation of GABA-benzodiazepine receptors plays a role in the acquisition but not in the expression of behavioral sensitization to MA.

Clonazepam Prevents the Development of Sensitization to Methamphetamine

The GABA-benzodiazepine neurotransmission has been implicated in various forms of plasticity such as kindling and learning. The present study examined the effects of clonazepam (CZP), a GABA-benzodiazepine agonist, on the development of behavioral sensitization to methamphetamine (MA). Rats treated with MA (1 mg/kg, S.C.) for 10 days displayed significantly enhanced motor activity when tested with MA (1 mg/kg) after a 7-8-day withdrawal, indicating the development of behavioral sensitization. Pretreatment with CZP (0.5 and 2.0 mg/kg) prior to MA administration prevented the development of the phenomenon. Rats treated with CZP alone showed no difference in the motor activity compared to those treated with saline. These results suggest that stimulation of GABA-benzodiazepine receptors plays a role in the development of behavioral sensitization.

Screening for diabetes using Japanese monitoring guidance in schizophrenia patients treated with second‐generation antipsychotics: A cross‐sectional study using baseline data

Aim:  The Japanese blood glucose monitoring guidance for patients receiving second‐generation antipsychotics has been newly developed. We aimed to report a cross‐sectional study using the baseline data of the Japanese monitoring guidance to find undiagnosed hyperglycemia systematically as a routine clinical practice and to quantify the frequency of glucose abnormalities in schizophrenia patients treated with second‐generation antipsychotics.

Lamotrigine blocks apoptosis induced by repeated administration of high-dose methamphetamine in the medial prefrontal cortex of rats

Lamotrigine (LTG) is sometimes co-administered with antipsychotic drugs for the treatment of schizophrenia. Nevertheless, the pharmacological basis of LTG use for schizophrenia has not been reported. Our group recently proposed a new psychostimulant animal model that might reflect the progressive pathophysiology of schizophrenia. Results obtained using that model show that LTG blocks the initiation and expression of repeated high-dosage methamphetamine-induced prepulse inhibition deficit in rats (Nakato et al., 2010, Neurosci. Lett. [25]). Using the model, the effect of LTG (30 mg/kg) on methamphetamine (METH, 2.5 mg/kg)-induced increases in extracellular glutamate levels in the medial prefrontal cortex (mPFC) was examined in this study. Then the effect of repeated co-administration of LTG (30 mg/kg) on repeated METH (2.5 mg/kg)-induced apoptosis in this region of rats was investigated. Results show that LTG (30 mg/kg) blocked the METH (2.5 mg/kg)-induced glutamate increase in the mPFC. Repeated co-administration of LTG (30 mg/kg) blocked the development of apoptosis induced by repeated administration of METH (2.5 mg/kg) in the mPFC. The LTG blocks histological abnormalities induced by repeated administration of METH, which suggests a mechanism of LTG that protects against progressive pathophysiology in schizophrenia.

Lamotrigine blocks the initiation and expression of repeated high-dose methamphetamine-induced prepulse inhibition deficit in rats

Our group developed a new psychostimulant animal model reflecting some clinical aspects of schizophrenia better than the conventional model does. In this model, long-lasting prepulse inhibition (PPI) deficit at the basement state is induced via repeated administration of methamphetamine (METH, 2.5mg/kg) without challenge injection of this psychostimulant. This study elucidates the effects of lamotrigine (LTG, 30mg/kg) on the initiation and expression of a steady-state PPI deficit induced by the repeated METH administration. We assessed the effect of coadministration of LTG and METH on the initiation of PPI deficit. The LTG was injected 120min after each METH injection for 5 times on every alternate day and for an additional 5 times every day, amounting to a total of 10 times. After 11-13 days of the withdrawal period, we measured PPI using the SR-LAB system. Using other animals after 20min of LTG injection, we subsequently examined the effect of a single injection of LTG on the expression of PPI deficit caused by the repeated METH administration. The LTG blocked the initiation of PPI deficit induced by the repeated METH administration at 68dB of prepulse intensity, but had no effect on the startle amplitude. The LTG prevented the initiation and expression of neuroplastic PPI deficit detected at the baseline state without any METH challenge injection, which was induced by the repeated administration of this psychostimulant. Results suggest that LTG is useful for blocking progressive deterioration of neurocognitive function and recovering the neurocognitive deficit in schizophrenia.

Screening for diabetes using monitoring guidance in schizophrenia patients treated with second-generation antipsychotics: a 1-year follow-up study.

Second-generation antipsychotics (SGAs) tend to induce weight gain, dyslipidemia and diabetes mellitus. For those reasons, patients treated with SGAs should receive appropriate monitoring to avoid morbidity and mortality associated with cardiovascular disease. We conducted a one-year follow-up study using Japanese blood glucose monitoring guidance in schizophrenia patients treated with SGAs to evaluate the detection capability of the guidance in real clinical settings and to assess the importance of longitudinal monitoring. This retrospective cohort study included schizophrenia patients receiving at least one SGA, who were enrolled during June 2008-January 2009 at multiple sites and who had both baseline data and follow-up monitoring data at month 12. After one-year follow-up, the probable diabetes type (fasting blood glucose is higher than 125 mg/dL, casual blood glucose is higher than 179 mg/dL, or glycosylated hemoglobin (Hb(A1c)) is greater than 6.4%) was detected in 30 (8%) of the patients, and the pre-diabetes type (fasting blood glucose is 110-125 mg/dL, or casual blood glucose is 140-179 mg/dL, or Hb(A1c) is 6.0-6.4%) in 65 (17.4%) out of the total of 374 patients. During the follow-up period, 1.5% of patients had advanced from the normal (fasting blood glucose is less than 110 mg/dL, casual blood glucose is less than 140 mg/dL, or Hb(A1c) is less than 6.0%) to probable diabetes type and 42.4% had progressed from the pre-diabetes to probable diabetes type. Predictive factors for worsening of the diabetic state were a family history of diabetes, and high serum total-cholesterol and triglyceride levels at baseline. Not only cross-sectional baseline screening but also longitudinal follow-up screening is important to detect glucose abnormalities in patients treated with SGAs.