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Poster #126 DOPAMINERGIC FUNCTION IN TREATMENT RESISTANT SCHIZOPHRENIA: NEW EVIDENCE FROM AN [18]-DOPA PET STUDY
Abstracts of the 3rd Biennial Schizophrenia International Research Conference / Schizophrenia Research 136, Supplement 1 (2012) S1–S375
toxic effects of CNS proline elevation, which is supported by our data from a mouse model system. We also propose that vitamin D supplementation targeted to hyperprolinemic patients, will be useful in the treatment of schizophrenia.
Poster #126 DOPAMINERGIC FUNCTION IN TREATMENT RESISTANT SCHIZOPHRENIA: NEW EVIDENCE FROM AN [18 ]-DOPA PET STUDY Arsime Demjaha 1,2 , Robin Murray 1, Shitij Kapur 1 , Oliver Howes 1,2 1 Institute of Psychiatry, London, United Kingdom; 2 Imperial College, London, United Kingdom Background: Molecular imaging studies have consistently reported presynaptic striatal dopaminergic elevation in schizophrenia, but no such studies have investigated the dopaminergic function in treatment resistant patients, and it remains unknown whether the neurobiology of treatment resistance is linked to dopamine dysregulation. We thus examined the dopaminergic function in a cohort of treatment resistant patients with schizophrenia by means of [18 F]-DOPA uptake and a high sensitivity 3 dimensional positron emission tomography. Methods: Tweleve patients with treatment resistant schizophrenia, twelve patients who responded to treatment, and twelve healthy volunteers matched for gender, age, ethnicity, weight and cigarette smoking underwent [18 F]-DOPA PET scanning. Striatal dopamine uptake influx rate constants (Ki values) were measured for the whole striatal region of interest (ROI) and for the functional subdivisions relative to uptake in the reference region. Results: There were no significant differences between treatment resistant patients and healthy volunteers for striatal [18 F]-DOPA uptake Ki values. Striatal [18 F]-DOPA uptake was, however, significantly increased in responders compared to non-responders for the whole striatum (P=0.01; ES=1.11) and for its associative (P=0.004; ES=1.31), and limbic (P=0.01; ES=1.01) subdivisions. There was no significant difference in sensorimotor striatum Discussion: Our findings suggest that the dopaminergic dysregulation may not be the main neurochemical abnormality in treatment resistance.This may indicate that treatment resistant schizophrenia constitutes a distinct neurobiological subtype of psychotic illness.
Poster #127 ANALYSES OF MONOAMINE METABOLITES IN THE CEREBROSPINAL FLUID OF PATIENTS WITH SCHIZOPHRENIA Kotaro Hattori 1,2 , Daimei Sasayama 1 , Toshiya Teraishi 1 , Takashi Fujii 1 , Hiroshi Kunugi 1 1 Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry Kodaira, Tokyo, Japan; 2 Translational Medical Center, National Center of Neurology and Psychiatry Kodaira, Tokyo, Japan Background: Monoamine neurotransmitters such as dopamine and serotonin play crucial roles in psychiatric disorders including schizophrenia. The levels of monoamine metabolites, i.e., homovanillic acid (HVA), 3methoxy-4-hydroxyphenylglycol (MHPG) and 5-hydroxyindole acetic acid (5-HIAA) in the cerebrospinal fluid (CSF), reflect the releases of dopamine, noradrenalin and serotonin respectively in the brain. Thus, in the present study, we aimed to examine the possible use of CSF monoamine metabolites as biomarkers for schizophrenia. Methods: Subjects were 52 patients with schizophrenia diagnosed according to the DSM-IV criteria (35 males and 17 females, age 41.1±9.8), and 40 healthy controls (25 males and 15 females, age 41.6±16.5). All subjects were biologically unrelated Japanese individuals. Patients except three cases had been under chronic treatments of antipsychotic medication. After psychiatric and neurologic examinations, a lumbar puncture was done in a standardized manner and CSF was analyzed by HPLC for each metabolite. Results: The average CSF HVA level was higher in the schizophrenic group compared to the control group (38.1±16.7 vs 31.0±12.9), though the difference was not statistically significant. CSF levels of 5-HIAA or MHPG did not differ between the schizophrenic group and the control group. Among the schizophrenic subjects, MHPG levels were significantly correlated with the severities of symptoms (PANSS total score, r=0.46, p=0.0034; hallucination,
S137
r=0.47, p=0.0027; suspiciousness, r=0.34, p=0.035; emotional withdrawal, r=0.43, p=0.0076; mannerisms and posturing, r=0.42, p=0.009). We also found that the levels of HVA and 5-HIAA in the schizophrenic subjects negatively correlated with the severity of an extra pyramidal symptom, rigidity (HVA, r=-0.35, p=0.033; 5-HIAA, r=-0.57, p=0.0002). No significant correlation was detected between HVA levels and antipsychotic dose. Discussion: Most previous studies on CSF HVA levels in unmedicated schizophrenic patients reported that there was no significant difference between patients and controls and that the HVA levels in the patients were increased after chronic antipsychotics treatment. Therefore the observed higher HVA levels in our schizophrenic patients might have resulted in part from antipsychotic medication. The correlation between MHPG levels and psychotic symptoms is in accordance with several previous studies. Thus, the present study supports the possibility of CSF MHPG levels as a good biomarker for schizophrenic symptoms, and suggests noradrenaline dysfunction in the pathogenesis of schizophrenia.
Poster #128 NITRIC OXIDE SYNTHASE ACTIVITY IS DIFFERENTIALLY ALTERED BETWEEN ACUTE AND SUBCHRONIC PHENCYCLIDINE TREATMENTS IN DISCRETE MOUSE BRAIN REGIONS Graham Lee 1,2,3,4 , David M. Thomson 1,3,4 , Allan McVie 1,4 , Colin J. Suckling 2,3,5 , Brian J. Morris 1,4 , Judith A. Pratt 1,2,3 1 Psychiatric Research Institute of Neuroscience in Glasgow (PsyRING), Glasgow, United Kingdom; 2 Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom; 3 Centre for Neuroscience, University of Strathclyde (CeNsUS), Glasgow, United Kingdom; 4 Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, United Kingdom; 5 WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow, United Kingdom Background: Experimental and clinical findings have identified a potential role of neuronal nitric oxide synthase (nNOS) in schizophrenia. For example, in rodents NOS inhibitors reverse behavioural deficits induced by the NMDA receptor antagonist phencyclidine (PCP) that have relevance to cognitive deficits seen in schizophrenia. Here, we elucidate the activity of NOS in brain regions important in cognition of mice following acute and subchronic PCP treatment. Methods: To determine NOS activity in the brain following PCP-treatment, semiquantitative NADPH-diaphorase histochemistry was used with cryostat-sectioned brains of adult male C57BL6J mice. This assay was also adapted for use with tissue homogenates in order to provide a more rapid and quantitative assessment of NOS activity. NOS activity was assessed following acute or subchronic PCP treatment. Brains were collected 30 mins following acute PCP treatment (5 mg kg-1 , i.p.) or vehicle (0.9% saline, i.p.). Subchronic drug administration consisted of two daily (circa 10 am and 4 pm) injections of vehicle (Veh/Veh), 5 mg kg-1 PCP and vehicle (PCP/Veh), or two doses of 5 mg kg-1 PCP (PCP/PCP). Subchronic drug-treated mouse brains were collected 67 hours following the final injection. The S-nitrosylation of proteins, and activities of caspase and thioredoxin reductase enzymes were also investigated in brain regions of mice with acute PCP treatment. Data were analysed using Mann-Whitney or Kruskal-Wallis with Dunn’s multiple comparisons tests, as appropriate. Results: NADPH-diaphorase activity was increased in the hippocampi of mice with acute PCP treatment in histological sections (CA1, 112.1±6.1% of vehicle, n.s., n=6; dentate gyrus, 113.4±5.8% of vehicle, n.s., n=6) and significantly increased in whole-hippocampus homogenates (133.9±8.5% of vehicle, p=0.02, n=6). Whereas, NADPH-diaphorase activity in the hippocampus was marginally decreased following subchronic PCP/Veh (87.5±3.9% of Veh/Veh, n.s., n=6) or subchronic PCP/PCP (84.0±8.9% of Veh/Veh, n.s., n=6). There was decreased NADPH-diaphorase activity in prefrontal cortex homogenates of mice with subchronic treatment in PCP/Veh-treated mice (64.2±6.4% of Veh/Veh, p=0.05, n=6), and in PCP/PCP mice (57.8±8.2% of Veh/Veh, p=0.02, n=6). However, these changes were not observed in the prefrontal cortex following acute PCP treatment with either histological (104.5±2.2% of vehicle, n.s., n=6), or homogenate (104.7±17.8% of vehicle, n.s., n=6) approaches. Discussion: These data suggest a differential effect of acute and subchronic NMDA receptor blockade on NOS activity in discrete brain regions. The altered activity of NOS in the brain regions investigated may contribute
toxic effects of CNS proline elevation, which is supported by our data from a mouse model system. We also propose that vitamin D supplementation targeted to hyperprolinemic patients, will be useful in the treatment of schizophrenia.
Poster #126 DOPAMINERGIC FUNCTION IN TREATMENT RESISTANT SCHIZOPHRENIA: NEW EVIDENCE FROM AN [18 ]-DOPA PET STUDY Arsime Demjaha 1,2 , Robin Murray 1, Shitij Kapur 1 , Oliver Howes 1,2 1 Institute of Psychiatry, London, United Kingdom; 2 Imperial College, London, United Kingdom Background: Molecular imaging studies have consistently reported presynaptic striatal dopaminergic elevation in schizophrenia, but no such studies have investigated the dopaminergic function in treatment resistant patients, and it remains unknown whether the neurobiology of treatment resistance is linked to dopamine dysregulation. We thus examined the dopaminergic function in a cohort of treatment resistant patients with schizophrenia by means of [18 F]-DOPA uptake and a high sensitivity 3 dimensional positron emission tomography. Methods: Tweleve patients with treatment resistant schizophrenia, twelve patients who responded to treatment, and twelve healthy volunteers matched for gender, age, ethnicity, weight and cigarette smoking underwent [18 F]-DOPA PET scanning. Striatal dopamine uptake influx rate constants (Ki values) were measured for the whole striatal region of interest (ROI) and for the functional subdivisions relative to uptake in the reference region. Results: There were no significant differences between treatment resistant patients and healthy volunteers for striatal [18 F]-DOPA uptake Ki values. Striatal [18 F]-DOPA uptake was, however, significantly increased in responders compared to non-responders for the whole striatum (P=0.01; ES=1.11) and for its associative (P=0.004; ES=1.31), and limbic (P=0.01; ES=1.01) subdivisions. There was no significant difference in sensorimotor striatum Discussion: Our findings suggest that the dopaminergic dysregulation may not be the main neurochemical abnormality in treatment resistance.This may indicate that treatment resistant schizophrenia constitutes a distinct neurobiological subtype of psychotic illness.
Poster #127 ANALYSES OF MONOAMINE METABOLITES IN THE CEREBROSPINAL FLUID OF PATIENTS WITH SCHIZOPHRENIA Kotaro Hattori 1,2 , Daimei Sasayama 1 , Toshiya Teraishi 1 , Takashi Fujii 1 , Hiroshi Kunugi 1 1 Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry Kodaira, Tokyo, Japan; 2 Translational Medical Center, National Center of Neurology and Psychiatry Kodaira, Tokyo, Japan Background: Monoamine neurotransmitters such as dopamine and serotonin play crucial roles in psychiatric disorders including schizophrenia. The levels of monoamine metabolites, i.e., homovanillic acid (HVA), 3methoxy-4-hydroxyphenylglycol (MHPG) and 5-hydroxyindole acetic acid (5-HIAA) in the cerebrospinal fluid (CSF), reflect the releases of dopamine, noradrenalin and serotonin respectively in the brain. Thus, in the present study, we aimed to examine the possible use of CSF monoamine metabolites as biomarkers for schizophrenia. Methods: Subjects were 52 patients with schizophrenia diagnosed according to the DSM-IV criteria (35 males and 17 females, age 41.1±9.8), and 40 healthy controls (25 males and 15 females, age 41.6±16.5). All subjects were biologically unrelated Japanese individuals. Patients except three cases had been under chronic treatments of antipsychotic medication. After psychiatric and neurologic examinations, a lumbar puncture was done in a standardized manner and CSF was analyzed by HPLC for each metabolite. Results: The average CSF HVA level was higher in the schizophrenic group compared to the control group (38.1±16.7 vs 31.0±12.9), though the difference was not statistically significant. CSF levels of 5-HIAA or MHPG did not differ between the schizophrenic group and the control group. Among the schizophrenic subjects, MHPG levels were significantly correlated with the severities of symptoms (PANSS total score, r=0.46, p=0.0034; hallucination,
S137
r=0.47, p=0.0027; suspiciousness, r=0.34, p=0.035; emotional withdrawal, r=0.43, p=0.0076; mannerisms and posturing, r=0.42, p=0.009). We also found that the levels of HVA and 5-HIAA in the schizophrenic subjects negatively correlated with the severity of an extra pyramidal symptom, rigidity (HVA, r=-0.35, p=0.033; 5-HIAA, r=-0.57, p=0.0002). No significant correlation was detected between HVA levels and antipsychotic dose. Discussion: Most previous studies on CSF HVA levels in unmedicated schizophrenic patients reported that there was no significant difference between patients and controls and that the HVA levels in the patients were increased after chronic antipsychotics treatment. Therefore the observed higher HVA levels in our schizophrenic patients might have resulted in part from antipsychotic medication. The correlation between MHPG levels and psychotic symptoms is in accordance with several previous studies. Thus, the present study supports the possibility of CSF MHPG levels as a good biomarker for schizophrenic symptoms, and suggests noradrenaline dysfunction in the pathogenesis of schizophrenia.
Poster #128 NITRIC OXIDE SYNTHASE ACTIVITY IS DIFFERENTIALLY ALTERED BETWEEN ACUTE AND SUBCHRONIC PHENCYCLIDINE TREATMENTS IN DISCRETE MOUSE BRAIN REGIONS Graham Lee 1,2,3,4 , David M. Thomson 1,3,4 , Allan McVie 1,4 , Colin J. Suckling 2,3,5 , Brian J. Morris 1,4 , Judith A. Pratt 1,2,3 1 Psychiatric Research Institute of Neuroscience in Glasgow (PsyRING), Glasgow, United Kingdom; 2 Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom; 3 Centre for Neuroscience, University of Strathclyde (CeNsUS), Glasgow, United Kingdom; 4 Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, United Kingdom; 5 WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow, United Kingdom Background: Experimental and clinical findings have identified a potential role of neuronal nitric oxide synthase (nNOS) in schizophrenia. For example, in rodents NOS inhibitors reverse behavioural deficits induced by the NMDA receptor antagonist phencyclidine (PCP) that have relevance to cognitive deficits seen in schizophrenia. Here, we elucidate the activity of NOS in brain regions important in cognition of mice following acute and subchronic PCP treatment. Methods: To determine NOS activity in the brain following PCP-treatment, semiquantitative NADPH-diaphorase histochemistry was used with cryostat-sectioned brains of adult male C57BL6J mice. This assay was also adapted for use with tissue homogenates in order to provide a more rapid and quantitative assessment of NOS activity. NOS activity was assessed following acute or subchronic PCP treatment. Brains were collected 30 mins following acute PCP treatment (5 mg kg-1 , i.p.) or vehicle (0.9% saline, i.p.). Subchronic drug administration consisted of two daily (circa 10 am and 4 pm) injections of vehicle (Veh/Veh), 5 mg kg-1 PCP and vehicle (PCP/Veh), or two doses of 5 mg kg-1 PCP (PCP/PCP). Subchronic drug-treated mouse brains were collected 67 hours following the final injection. The S-nitrosylation of proteins, and activities of caspase and thioredoxin reductase enzymes were also investigated in brain regions of mice with acute PCP treatment. Data were analysed using Mann-Whitney or Kruskal-Wallis with Dunn’s multiple comparisons tests, as appropriate. Results: NADPH-diaphorase activity was increased in the hippocampi of mice with acute PCP treatment in histological sections (CA1, 112.1±6.1% of vehicle, n.s., n=6; dentate gyrus, 113.4±5.8% of vehicle, n.s., n=6) and significantly increased in whole-hippocampus homogenates (133.9±8.5% of vehicle, p=0.02, n=6). Whereas, NADPH-diaphorase activity in the hippocampus was marginally decreased following subchronic PCP/Veh (87.5±3.9% of Veh/Veh, n.s., n=6) or subchronic PCP/PCP (84.0±8.9% of Veh/Veh, n.s., n=6). There was decreased NADPH-diaphorase activity in prefrontal cortex homogenates of mice with subchronic treatment in PCP/Veh-treated mice (64.2±6.4% of Veh/Veh, p=0.05, n=6), and in PCP/PCP mice (57.8±8.2% of Veh/Veh, p=0.02, n=6). However, these changes were not observed in the prefrontal cortex following acute PCP treatment with either histological (104.5±2.2% of vehicle, n.s., n=6), or homogenate (104.7±17.8% of vehicle, n.s., n=6) approaches. Discussion: These data suggest a differential effect of acute and subchronic NMDA receptor blockade on NOS activity in discrete brain regions. The altered activity of NOS in the brain regions investigated may contribute