Nobumi Miyake

Imaging Changes in Glutamate Transmission In Vivo with the Metabotropic Glutamate Receptor 5 Tracer [11C] ABP688 and N-Acetylcysteine Challenge

BACKGROUND An imaging method to probe glutamate levels in vivo would allow the study of glutamate transmission in disease states and in response to therapeutic interventions. Here we demonstrate the feasibility of this approach for the first time using positron emission tomography and [(11)C] ABP688, a radiotracer for an allosteric site on the metabotropic glutamate receptor 5. METHODS We conducted two sets of experiments in anesthetized baboons: test and retest without pharmacologic challenge and in combination with N-acetylcysteine (NAC), a promoter of the cystine-glutamate antiporter that increases extrasynaptic glutamate release. The goal was to assess whether NAC-induced changes in [(11)C] ABP688 binding potential, ΔBP(ND), could be detected above the noise in the measurement. RESULTS Linear mixed modeling comparing ΔBP(ND) from test-retest to ΔBP(ND) from NAC challenge across all brain regions showed a highly significant effect of treatment [F(1,40) = 21.2, p < .001]. ΔBP(ND) was significantly different from zero following NAC [F(1,20) = 76.6, p < .001] but not after test-retest studies. CONCLUSIONS NAC induced decrease in [(11)C] ABP688 ΔBP(ND) may be the result of allosteric modulation, although other mechanisms may be at play. We outline steps needed to replicate and validate this method as a new tool to measure in vivo glutamate transmission.

Presynaptic Dopamine in Schizophrenia

Presynaptic dopamine (DA) transmission has been measured in schizophrenia using different paradigms aimed at providing estimates of the integrity or the activity of the presynaptic dopaminergic neuron. Researchers have measured: (1) DA synthesis capacity with [18F]DOPA, a measure of the activity of dopa decarboxylase, (2) DA release with studies measuring the impact of a DA releasing stimulant challenge on the binding of a D2 receptor radiotracer, (3) D2 baseline occupancy by DA, a measure of baseline intrasynaptic DA, assessed by the changes in binding of D2 radiotracer induced by DA depletion, and (4) the DA and the vesicular monoamine transporters, to assess the integrity of presynaptic terminals. The relationship between DA release and D2 receptor occupancy at baseline by DA has also been assessed in the same patients. Overall, these different imaging modalities have converged to show a dysregulation of presynaptic dopaminergic activity in schizophrenia, leading to excessive DA release in the striatum, particularly in the projection to the associative striatum, an area of integration between cognitive and limbic cortical inputs. Excessive striatal presynaptic DA is linked to the emergence of acute psychotic symptoms and to their response to treatment in schizophrenia. Understanding the etiology of this dysregulation and its consequences on the rest of the circuitry is important for future drug development.

Effects of discontinuation of long-term biperiden use on cognitive function and quality of life in schizophrenia

BACKGROUND The high use of long-term antiparkinsonian anticholinergic drugs with antipsychotics has been identified as an important issue in the treatment of schizophrenia in Japan. The aim of this study was to evaluate the effects of gradual discontinuation of biperiden, an anticholinergic drug, on cognitive function and quality of life (QOL) in schizophrenia. METHODS Thirty-four schizophrenic patients who had received a second-generation antipsychotic (SGA) with concomitant biperiden for at least 3 months were enrolled. Before and 4 weeks after discontinuation of biperiden, the Japanese version of the Brief Assessment of Cognition in Schizophrenia (BACS-J) and the Schizophrenia Quality of Life Scale (SQLS-J) were administered. Clinical evaluation also included the Positive and Negative Syndrome Scale (PANSS). To compare the practice effect on BACS-J, 10 chronic patients with schizophrenia were assessed without tapering biperiden. RESULTS Biperiden was discontinued safely in most patients, and no emergent extrapyramidal symptoms were observed. Significant improvements were shown in attention, processing speed, and composite score, as measured by the BACS-J without practice effect. In addition, the psychosocial condition score on the SQLS-J and the general psychopathology score on the PANSS significantly improved after biperiden discontinuation. CONCLUSION Discontinuation of long-term biperiden use may be warranted in patients with schizophrenia treated with SGAs, as it may improve cognitive function, subjective QOL, and psychiatric symptoms with no significant adverse effects.

In vivo binding of antipsychotics to D3 and D2 receptors: a PET study in baboons with [11C]-(+)-PHNO.

Measuring the in vivo occupancy of antipsychotic drugs at dopamine D2 and D3 receptors separately has been difficult because of the lack of selective radiotracers. The recently developed [11C]-(+)-PHNO is D3-preferring, allowing estimates of the relative D2 and D3 binding of antipsychotic drugs. We used positron emission tomography (PET) imaging in baboons with [11C]-(+)-PHNO to examine the binding of clozapine and haloperidol to D2 and D3 receptors. Four animals were scanned with dynamically acquired PET and arterial plasma input functions. Test and retest scans were acquired in single scanning sessions for three subjects to assess the reproducibility of [11C]-(+)-PHNO scans. Four additional scans were acquired in each of three subjects following single doses of antipsychotic drugs (clozapine 0.5534 mg/kg, haloperidol 0.0109 mg/kg, two administrations per drug per subject) and compared with baseline scans. The percent change in binding (ΔBPND) following challenges with antipsychotic drugs was measured. A regression model, based on published values of regional D2 and D3 fractions of [11C]-(+)-PHNO BPND in six brain regions, was used to infer occupancy at D2 and D3 receptors. BPND following antipsychotic challenge decreased in all regions. Estimated D2 : D3 selectivity was 2.38 for haloperidol and 5.25 for clozapine, similar to published in vitro values for haloperidol (3.03), but slightly higher for clozapine (2.82). These data suggest that acute doses of clozapine and haloperidol bind to D3 receptors in vivo, and that the lack of D3 occupancy by antipsychotics observed in some recent imaging studies may be because of other phenomena.

In vivo binding of antipsychotics to D3 and D2 receptors

Measuring the in vivo occupancy of antipsychotic drugs at dopamine D2 and D3 receptors separately has been difficult because of the lack of selective radiotracers. The recently developed [11C]-(+)-PHNO is D3-preferring, allowing estimates of the relative D2 and D3 binding of antipsychotic drugs. We used positron emission tomography (PET) imaging in baboons with [11C]-(+)-PHNO to examine the binding of clozapine and haloperidol to D2 and D3 receptors. Four animals were scanned with dynamically acquired PET and arterial plasma input functions. Test and retest scans were acquired in single scanning sessions for three subjects to assess the reproducibility of [11C]-(+)-PHNO scans. Four additional scans were acquired in each of three subjects following single doses of antipsychotic drugs (clozapine 0.5534 mg/kg, haloperidol 0.0109 mg/kg, two administrations per drug per subject) and compared with baseline scans. The percent change in binding (ΔBPND) following challenges with antipsychotic drugs was measured. A regression model, based on published values of regional D2 and D3 fractions of [11C]-(+)-PHNO BPND in six brain regions, was used to infer occupancy at D2 and D3 receptors. BPND following antipsychotic challenge decreased in all regions. Estimated D2 : D3 selectivity was 2.38 for haloperidol and 5.25 for clozapine, similar to published in vitro values for haloperidol (3.03), but slightly higher for clozapine (2.82). These data suggest that acute doses of clozapine and haloperidol bind to D3 receptors in vivo, and that the lack of D3 occupancy by antipsychotics observed in some recent imaging studies may be because of other phenomena.

Profile of blonanserin for the treatment of schizophrenia

Blonanserin was developed as an antipsychotic drug in Japan and approved for the treatment of schizophrenia. It belongs to a series of 4-phenyl-2-(1-piperazinyl)pyridines and acts as an antagonist at dopamine D2, D3, and serotonin 5-HT2A receptors. Blonanserin has low affinity for 5-HT2C, adrenergic α1, histamine H1, and muscarinic M1 receptors, but displays relatively high affinity for 5-HT6 receptors. In several short-term double-blind clinical trials, blonanserin had equal efficacy as haloperidol and risperidone for positive symptoms in patients with chronic schizophrenia and was also superior to haloperidol for improving negative symptoms. Blonanserin is generally well tolerated and has a low propensity to cause metabolic side effects and prolactin elevation. We recently reported that blonanserin can improve some types of cognitive function associated with prefrontal cortical function in patients with first-episode and chronic schizophrenia. Taken together, these results suggest that blonanserin may be a promising candidate for a first-line antipsychotic for acute and maintenance therapy for schizophrenia. Further comparative studies are warranted to clarify the benefit/risk profile of blonanserin and its role in the treatment of schizophrenia.

Effects of N-Acetylcysteine on Cognitive Functions in Subjects With an At-Risk Mental State: A Case Series.

FIGURE 1. Changes in the BACS z scores. Significant improvements were observed in the BACS composite z score (−0.44 ± 1.06 to 0.19 ± 0.79; P = 0.043). BACS indicates Brief Assessment of Cognition in Schizophrenia. A ccumulating evidence suggests that psychosocial and pharmacologic intervention may be beneficial in delaying or preventing the onset of psychosis. However, at present, there is no established treatment for subjects with an at-risk mental state (ARMS) or a clinical high-risk state for psychosis. Particularly, the use of antipsychotics for the prevention of psychosis is controversial. To date, only a few studies have investigated the use of antipsychotics in subjects with an ARMS and the potential risks and benefits associated with their use at the prodromal phase of psychosis remain unclear. In view of the lack of evidence for effective and safe treatments, the safer approaches are warranted, such as psychological interventions and potential neuroprotective agents (eg, fish oil). N-acetylcysteine (NAC), a glutathione precursor, has been suggested to have potential benefits in chronic schizophrenia. In a developmental rodent model of schizophrenia which used the neonatal ventral hippocampal model, Cabungcal et al have recently reported that treatment with NAC during the juvenile period and adolescence can prevent the decrease of prefrontal parvalbumin interneuron activity, as well as schizophrenia-related electrophysiological and behavioral deficits. Given that NAC has antioxidative and neuroprotective effects, its use in subjects with an ARMS should merit investigation. Individuals meeting criteria of prodromal syndromes based on the structural interview for prodromal symptoms were recruited from St. Marianna University School of Medicine Hospital. Five subjects (19.8 ± 5.7 years, 4 men and 1 woman) were given NAC (2000 mg/d) as supplementation for 12 weeks. Clinical evaluations were conducted at baseline, 12 and 24 weeks (endpoint). The outcome measures were changes in the Scale of Prodromal Symptoms, the Brief Assessment of Cognition in Schizophrenia, the Schizophrenia Cognition Rating Scale, University of

Retraction: ‘Effect of blonanserin on cognitive function in antipsychotic-naïve first-episode schizophrenia’

The above article from Human Psychopharmacology, first published on 25 January 2012 in Wiley OnlineLibrary (onlinelibrary.wiley.com), and in Volume 90, pp. 90‐100, has been retracted by agreement between the authors, the journal Editor in Chief, David Baldwin, and John Wiley & Sons Ltd. The retraction has been agreed following an investigation by the St Marianna University Ethics Committee which determined that the paper was not as originally designed and approved.

Reproducibility and sensitivity to pharmacological challenge of [11C]-ABP688 in non-human primate brain

Purpose: 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-C-methyl-oxime ([C]-ABP688) is a highly-selective antagonist PET tracer for imaging the metabotropic glutamate receptor subtype 5 (mGluR5). The aims of this study were to test the reproducibility of outcome measures using this tracer with anesthetized baboons and to test the effect of challenge with the glutamate releaser N-acetylcysteine (NAC) on [C]-ABP688 specific binding.