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Bhikram T.P.,University of Toronto | Bhikram T.P.,Center for Addiction and Mental Health | Farb N.A.,University of Toronto | Farb N.A.,Rotman Research Institute | And 9 more authors.
Journal of Neuropsychiatry and Clinical Neurosciences | Year: 2016

This study investigated the effect of an intravenous serotonin reuptake inhibitor on the neural substrates of obsessivecompulsive disorder (OCD), as intravenous agents may be more effective in treating OCD than conventional oral pharmacotherapy. Eight OCD subjects and eight control subjects received alternate infusions of citalopram and placebo during functional magnetic resonance imaging, in a randomized, symptom-provocation, crossover design. Compared with baseline, OCD subjects displayed significant changes in prefrontal neural activity after the citalopram infusion relative to placebo, and these changes correlated with reductions in subjective anxiety. © 2016 American Psychiatric Association. All rights reserved.


Iwata Y.,Multimodal Imaging Group | Iwata Y.,University of Toronto | Iwata Y.,Keio University | Nakajima S.,Multimodal Imaging Group | And 18 more authors.
Molecular Psychiatry | Year: 2015

Hypofunction of N-methyl-d-Aspartate (NMDA) receptors has been proposed to have an important role in the cognitive impairments observed in schizophrenia. Although glutamate modulators may be effective in reversing such difficult-to-treat conditions, the results of individual studies thus far have been inconsistent. We conducted a systematic review and meta-Analysis to examine whether glutamate positive modulators have beneficial effects on cognitive functions in patients with schizophrenia. A literature search was conducted to identify double-blind randomized placebo-controlled trials in schizophrenia or related disorders, using Embase, Medline, and PsycINFO (last search: February 2015). The effects of glutamate positive modulators on cognitive deficits were evaluated for overall cognitive function and eight cognitive domains by calculating standardized mean differences (SMDs) between active drugs and placebo added to antipsychotics. Seventeen studies (N=1391) were included. Glutamate positive modulators were not superior to placebo in terms of overall cognitive function (SMD=0.08, 95% confidence interval=-0.06 to 0.23) (11 studies, n=858) nor each of eight cognitive domains (SMDs=-0.03 to 0.11) (n=367-940) in this population. Subgroup analyses by diagnosis (schizophrenia only studies), concomitant antipsychotics, or pathway of drugs to enhance the glutamatergic neurotransmission (glycine allosteric site of NMDA receptors or α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors) suggested no procognitive effect of glutamate positive modulators. Further, no effect was found in individual compounds on cognition. In conclusion, glutamate positive modulators may not be effective in reversing overall cognitive impairments in patients with schizophrenia as adjunctive therapies. © 2015 Macmillan Publishers Limited All rights reserved.


Nakajima S.,Multimodal Imaging Group Research Imaging Center | Nakajima S.,Center for Addiction and Mental Health | Nakajima S.,University of Toronto | Nakajima S.,Keio University | And 24 more authors.
Schizophrenia Research | Year: 2015

Background: Recent developments in neuroimaging have advanced the understanding of biological mechanisms underlying schizophrenia. However, neuroimaging correlates of treatment-resistant schizophrenia (TRS) and superior effects of clozapine on TRS remain unclear. Methods: Systematic search was performed to identify neuroimaging characteristics unique to TRS and ultra-resistant schizophrenia (i.e. clozapine-resistant [URS]), and clozapine's efficacy in TRS using Embase, Medline, and PsychInfo. Search terms included (schizophreni*) and (resistan* OR refractory OR clozapine) and (ASL OR CT OR DTI OR FMRI OR MRI OR MRS OR NIRS OR PET OR SPECT). Results: 25 neuroimaging studies have investigated TRS and effects of clozapine. Only 5 studies have compared TRS and non-TRS, collectively providing no replicated neuroimaging finding specific to TRS. Studies comparing TRS and healthy controls suggest that hypometabolism in the prefrontal cortex, hypermetabolism in the basal ganglia, and structural anomalies in the corpus callosum contribute to TRS. Clozapine may increase prefrontal hypoactivation in TRS although this was not related to clinical improvement; in contrast, evidence has suggested a link between clozapine efficacy and decreased metabolism in the basal ganglia and thalamus. Conclusion: Existing literature does not elucidate neuroimaging correlates specific to TRS or URS, which, if present, might also shed light on clozapine's efficacy in TRS. This said, leads from other lines of investigation, including the glutamatergic system can prove useful in guiding future neuroimaging studies focused on, in particular, the frontocortical-basal ganglia-thalamic circuits. Critical to the success of this work will be precise subtyping of study subjects based on treatment response/nonresponse and the use of multimodal neuroimaging. © 2015 Elsevier B.V.


Nakajima S.,Research Imaging Center | Nakajima S.,Center for Addiction and Mental Health | Nakajima S.,University of Toronto | Nakajima S.,Keio University | And 28 more authors.
Schizophrenia Research | Year: 2015

Background: No study has examined dopamine D2/3 receptor (D2/3R) availability in antipsychotic-free older patients with schizophrenia. Methods: We included patients with schizophrenia 50years or older who were antipsychotic-free for at least 3months. We compared non-displaceable binding potential (BPND) of [11C]-raclopride in the caudate, putamen, ventral striatum, and globus pallidus between patients and age- and sex-matched healthy controls. Results: Ten patients participated (antipsychotic-naive=4). No differences in BPND were found between patients and controls in any ROIs (F(1, 72)=42, p=52). Conclusion: The preliminary results suggest no differences in D2/3R availability between antipsychotic-free older patients with schizophrenia and controls. © 2015 Elsevier B.V.


Nakajima S.,Multimodal Imaging Group Research Imaging Center | Nakajima S.,Center for Addiction and Mental Health | Nakajima S.,University of Toronto | Nakajima S.,Keio University | And 23 more authors.
Journal of Cerebral Blood Flow and Metabolism | Year: 2015

Positron emission tomography with antagonist radiotracers has showed that striatal dopamine D 2/3 receptor (D 2/3 R) availability decreases with age. However, no study has specifically assessed whether D 2/3 R availability decreases with age in healthy persons as measured with agonist radiotracers. Moreover, it is unknown whether D 3 R availability changes with age in healthy humans. Thus, we explored the relationship between age and D 2/3 R availability in healthy humans using the D 3 receptor (D 3 R)-preferential agonist radiotracer [11C]-(+)-PHNO (n=72, mean±s.d. age=40±15, range=18 to 73) and the antagonist [11C]-Raclopride (n=70, mean±s.d. age =40±14, range=18 to 73) (both, n=33). The contribution of D 3 R to the [11C]-(+)-PHNO signal varies across regions of interest; the substantia nigra and hypothalamus represent D 3 R-specific regions, the ventral pallidum, globus pallidus, and ventral striatum represent D 2/3 R-mixed regions, and the caudate and putamen represent D 2 receptor (D 2 R)-specific regions. With [11C]-(+)-PHNO, a negative correlation was observed between age and nondisplaceable binding potential (BP ND) in the caudate (r(70)=-0.32, P=0.005). No correlations were observed in the other regions. With [11C]-Raclopride, negative correlations were observed between age and BP ND in the caudate (r(68)=-0.50, P<0.001), putamen (r(68)=-0.41, P<0.001), and ventral striatum (r(68)=-0.43, P<0.001). In conclusion, in contrast with the age-dependent decrease in D 2 R availability, these findings suggest that D 3 R availability does not change with age. © 2015 ISCBFM.


Nakajima S.,Multimodal Imaging Group | Nakajima S.,Center for Addiction and Mental Health | Nakajima S.,University of Toronto | Nakajima S.,Keio University | And 29 more authors.
Schizophrenia Research | Year: 2015

Background: The comparative antidepressant effects of clozapine and other atypical antipsychotics for schizophrenia remain elusive, leading us to examine this question using the data from the Clinical Antipsychotic Trials of Intervention Effectiveness phase 2E. Methods: Ninety-nine patients who discontinued treatment with olanzapine, quetiapine, risperidone, or ziprasidone because of inadequate efficacy were randomly assigned to open-label treatment with clozapine (n = 49) or double-blind treatment with another atypical antipsychotic not previously received in the trial (olanzapine [n = 19], quetiapine [n = 15], or risperidone [n = 16]). The primary outcome was the Calgary Depression Scale for Schizophrenia (CDSS) total score. Antidepressant effects of clozapine and the other atypical antipsychotics were compared in patients with chronic schizophrenia and those with a major depressive episode (MDE) at baseline (i.e. ≥ 6 on the CDSS), using mixed models. Results: No differences in the baseline CDSS total scores were found between the treatment groups regardless of presence of an MDE. Clozapine was more effective than quetiapine in antidepressant effects for chronic schizophrenia (p < .01 for the whole sample and p = .01 for those with an MDE), and comparable to olanzapine and risperidone. Conclusion: The present findings suggest that clozapine demonstrates superior antidepressant effects to quetiapine and comparable effects to olanzapine and risperidone in chronic schizophrenia regardless of presence of MDE. Given the indication of clozapine for treatment-resistant schizophrenia (TRS) and the negative impacts of depressive symptoms on clinical outcomes in schizophrenia, further research is warranted to investigate antidepressant effects of clozapine in TRS with an MDE. © 2014 Elsevier B.V.


Nakajima S.,Multimodal Imaging Group Research Imaging Center | Nakajima S.,Center for Addiction and Mental Health | Nakajima S.,University of Toronto | Nakajima S.,Keio University | And 25 more authors.
European Neuropsychopharmacology | Year: 2013

Currently available treatments have limited pro-cognitive effects for neuropsychiatric disorders, such as schizophrenia, Parkinson's disease and Alzheimer's disease. The primary objective of this work is to review the literature on the role of dopamine D3 receptors in cognition, and propose dopamine D3 receptor antagonists as possible cognitive enhancers for neuropsychiatric disorders. A literature search was performed to identify animal and human studies on D3 receptors and cognition using PubMed, MEDLINE and EMBASE. The search terms included "dopamine D3 receptor" and "cognition". The literature search identified 164 articles. The results revealed: (1) D3 receptors are associated with cognitive functioning in both healthy individuals and those with neuropsychiatric disorders; (2) D3 receptor blockade appears to enhance while D3 receptor agonism seems to impair cognitive function, including memory, attention, learning, processing speed, social recognition and executive function independent of age; and (3) D3 receptor antagonists may exert their pro-cognitive effect by enhancing the release of acetylcholine in the prefrontal cortex, disinhibiting the activity of dopamine neurons projecting to the nucleus accumbens or prefrontal cortex, or activating CREB signaling in the hippocampus. These findings suggest that D3 receptor blockade may enhance cognitive performance in healthy individuals and treat cognitive dysfunction in individuals with a neuropsychiatric disorder. Clinical trials are needed to confirm these effects. © 2013 Elsevier B.V. and ECNP.


Zhang H.,Campbell Research Institute | Li T.,Campbell Research Institute | Li T.,Xi'an Jiaotong University | Li S.,Campbell Research Institute | And 3 more authors.
Journal of Proteomics | Year: 2016

Functional regulation of NMDA receptor (NMDAR) by the activation of α7 nicotinic acetylcholine receptor (α7nAChR) has been reported, although the molecular signaling pathway underlying this process remains largely unknown. We employed a label-free quantitative proteomics approach to identify potential intracellular molecules and pathways that might be involved in the functional cross-talk between NMDAR and α7nAChR. 43 proteins showed significantly expression changes after choline treatment in which 35 out of 43 proteins was significantly altered by co-treatment with NMDA. Western blot analysis verified proteins expression determined by LC-MS. Furthermore, protein expression in vivo in neurons from fetal rats were visualized and quantified by Confocal microscopy,which showed consistency of relative changes of AHA-1 expressionmeasured by LC-MS and Western blot. Biological network analysis of differently expressed proteins found 21 kind of biological pathways involved. Of those pathways, 6 pathways were directly involved in regulation of neurotransmitters. Lastly, the levels of neurotransmitters (dopamine, glutamate, GABA and 5-HT) were measured by HPLC-ECD. Co-treatment choline/NMDA significantly enhances the release of dopamine, glutamate and GABA and dramatically decrease 5-HT to only 65% of control level, which is consist with this protein interaction network analysis, providing an additional evidence for the cross-talk between NMDAR and α7nAChR. © 2015 Elsevier B.V.


PubMed | Campbell Research Institute, Xi'an Jiaotong University and University of Toronto
Type: | Journal: Journal of proteomics | Year: 2015

Functional regulation of NMDA receptor (NMDAR) by the activation of 7 nicotinic acetylcholine receptor (7nAChR) has been reported, although the molecular signaling pathway underlying this process remains largely unknown. We employed a label-free quantitative proteomics approach to identify potential intracellular molecules and pathways that might be involved in the functional cross-talk between NMDAR and 7nAChR. 43 proteins showed significantly expression changes after choline treatment in which 35 out of 43 proteins was significantly altered by co-treatment with NMDA. Western blot analysis verified proteins expression determined by LC-MS. Furthermore, protein expression in vivo in neurons from fetal rats were visualized and quantified by Confocal microscopy,which showed consistency of relative changes of AHA-1 expressionmeasured by LC-MS and Western blot. Biological network analysis of differently expressed proteins found 21 kind of biological pathways involved. Of those pathways, 6 pathways were directly involved in regulation of neurotransmitters. Lastly, the levels of neurotransmitters (dopamine, glutamate, GABA and 5-HT) were measured by HPLC-ECD. Co-treatment choline/NMDA significantly enhances the release of dopamine, glutamate and GABA and dramatically decrease 5-HT to only 65% of control level, which is consist with this protein interaction network analysis, providing an additional evidence for the cross-talk between NMDAR and 7nAChR.


PubMed | Research Imaging Center, University of Toronto, University of Malta, Campbell Research Institute and Keio University
Type: Journal Article | Journal: Schizophrenia research | Year: 2015

No study has examined dopamine D/ receptor (D/R) availability in antipsychotic-free older patients with schizophrenia.We included patients with schizophrenia 50 years or older who were antipsychotic-free for at least 3 months. We compared non-displaceable binding potential (BPND) of [(11)C]-raclopride in the caudate, putamen, ventral striatum, and globus pallidus between patients and age- and sex-matched healthy controls.Ten patients participated (antipsychotic-naive=4). No differences in BPND were found between patients and controls in any ROIs (F(1, 72)=.42, p=.52).The preliminary results suggest no differences in D/R availability between antipsychotic-free older patients with schizophrenia and controls.

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