Clozapine markedly affects glucose metabolic rate in the striatum and cortex

Potkin, S.G.; Buchsbaum, Monte S.; Jin, Yi; Costa, Jerome; Richmond, G.; Telford, J.; Tang, Charmaine; Najafi, Ahmad; Lottenberg, Stephen; Gulasekaram, Bala; Bunney, W. E.

doi:10.1016/0920-9964(93)90441-k

Cited by 17 publications

(25 citation statements)

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“…Although the antipsychotic clozapine has been shown to attenuate cognitive deficits (Jentsch et al, 1997a), we found that neither clozapine nor haloperidol could modulate the PCP-induced hypometabolism within the prelimbic cortex of the rat. The fact that the antipsychotics do not modulate the decreased metabolic activity induced by PCP in the prelimbic cortex is consistent with clinical data from imaging studies of schizophrenic patients, with metabolic hypofunction being observed in both medicated and nonmedicated patients (Hazlett et al, 2000;Cohen et al, 1997;Schroeder et al, 1994;Potkin et al, 1994;Buchsbaum et al, 1990Buchsbaum et al, , 1992. The inability of clozapine and haloperidol to attenuate this metabolic hypofunction within the prefrontal cortex is contrary to the ability of clozapine to attenuate the metabolic hyperfunction induced by acute NMDA receptor antagonist treatment (Duncan et al, 1998).…”

supporting

confidence: 69%

“…These studies have frequently revealed an absolute or relative metabolic hypofunction within particular brain areas that have been shown to have altered neuropathology and neurochemical deficits in schizophrenia (Hazlett et al, 2000;Buchsbaum and Hazlett, 1998;Cohen et al, 1997;Buchsbaum et al, 1996;Nordahl et al, 1996;Schroder et al, 1996Schroder et al, , 1994Potkin et al, 1994;Wolkin et al, 1992;Andreasen et al, 1992;Tamminga et al, 1992;Buchsbaum et al, 1990). In particular, the altered metabolic activity in the prefrontal cortex in the schizophrenic brain has been shown to correlate with the presence and severity of negative symptoms and cognitive deficits (Hazlett et al, 2000;Volz et al, 1999;Buchsbaum and Hazlett, 1998;Schroder et al, 1996;Schroeder et al, 1994;Wolkin et al, 1992;Tamminga et al, 1992;Andreasen et al, 1992;Buchsbaum et al, 1990), while altered metabolic activities within the temporal lobe and thalamus have been shown to correlate with positive symptomology (Buchsbaum and Hazlett, 1998;Buchsbaum et al, 1996;Nordahl et al, 1996;Schroder et al, 1996;Tamminga et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

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Induction of Metabolic Hypofunction and Neurochemical Deficits after Chronic Intermittent Exposure to Phencyclidine: Differential Modulation by Antipsychotic Drugs

Cochran

Kennedy

McKerchar

et al. 2003

Neuropsychopharmacol

216

176

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Numerous human imaging studies have revealed an absolute or relative metabolic hypofunction within the prefrontal cortex, thalamus and temporal lobes of schizophrenic patients. The former deficit correlates with cognitive deficits and negative symptoms, whereas the latter correlates with positive symptomologies. There is also general consensus that schizophrenia is associated with decreased parvalbumin expression in the prefrontal cortex. Since the drug phencyclidine can induce a psychosis resembling schizophrenia in humans, we have examined whether repeated phencyclidine (PCP) treatment to rats could produce similar metabolic and neurochemical deficits to those occurring in schizophrenia and whether these deficits could be modulated by antipsychotic drugs. We demonstrate here that chronic intermittent exposure to PCP (2.58 mg kg À1 i.p.) elicits a metabolic hypofunction, as demonstrated by reductions in the rates of glucose utilization, within the prefrontal cortex, reticular nucleus of thalamus and auditory system, key structures displaying similar changes in schizophrenia. Moreover, chronic PCP treatment according to this regime also decreases parvalbumin mRNA expression in the rat prefrontal cortex and reticular nucleus of the thalamus. Chronic coadministration of haloperidol (1 mg kg À1 day À1 ) or clozapine (20 mg kg À1 day À1) with PCP did not modulate PCP-induced reductions in metabolic activity in the rat prefrontal cortex, but reversed deficits in the structures of the auditory system. Clozapine, but not haloperidol, reversed PCP-induced decreases in parvalbumin expression in prefrontal cortex GABAergic interneurons, whereas both drugs reversed the deficits in the reticular nucleus of the thalamus. These data provide important new information, which strengthen the validity of chronic PCP as a useful animal model of schizophrenia, when administered according to this protocol. Furthermore, we propose that reversal of PCP-induced reductions in parvalbumin expression in the prefrontal cortex may be a potential marker of atypical antipsychotic activity in relation to amelioration of cognitive deficits and negative symptoms of schizophrenia.

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supporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Induction of Metabolic Hypofunction and Neurochemical Deficits after Chronic Intermittent Exposure to Phencyclidine: Differential Modulation by Antipsychotic Drugs

Cochran

Kennedy

McKerchar

et al. 2003

Neuropsychopharmacol

216

176

View full text Add to dashboard Cite

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“…19 Furthermore, we have shown that the phenotype of brain metabolic response to clozapine is stable over 12 weeks (Potkin et al, unpublished data). In the present study, we have demonstrated that brain metabolic response and clinical response to clozapine are related to DRD1 receptor genotype.…”

mentioning

confidence: 99%

D1 receptor alleles predict PET metabolic correlates of clinical response to clozapine

et al. 2003

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A goal of pharmacogenetics is to clarify associations between allelic variation and risk factors in psychiatric illness. We report changes in regional brain metabolism based on dopamine alleles. Treatment-resistant schizophrenic subjects were positron emission tomography scanned with 18F-fluorodeoxyglucose after 5 weeks each of placebo and clozapine treatment. Significant regional brain metabolic effects were found for the D1 receptor genotypes (Po0.05), adjusted for multiple comparisons. Metabolic decreases for the 2,2 genotype but not the 1,2 genotype were observed in all major sectors of the brain, with the exception of the ventral parts of the caudate and putamen. Frontal, temporal, parietal, and occipital neocortices showed decreased metabolism as did the cingulate juxta-allocortex and the parahippocampal allocortex. Decreases were also observed in the thalamus, amygdala, and cerebellum bilaterally. No significant metabolic differences by genotype were observed for D3, 5HT 2A , and 5HT 2C polymorphisms. In terms of clinical response, the DRD1 2,2 genotype significantly improved with clozapine treatment, demonstrating a 30% decrease in the Brief Psychiatric Rating Scale positive symptoms in contrast to a 7% worsening for the 1,2 genotype (Po0.05). In this preliminary study, brain metabolic and clinical response to clozapine are related to the D1 receptor genotype. Molecular Psychiatry (2003) an association between parietal lobe, but not other major brain regions, volumes, and brain-derived neurotrophic factor (BDNF) alleles. 6 Laruelle et al 7 failed to find an association between D2 receptor binding and alleles at the TaqI-A RFLP site in the D2 receptor gene using single-photon emission computed tomography (SPECT) imaging. Despite their small sample sizes, these preliminary studies provide intriguing data regarding the ability of brain imaging to serve as an intermediate phenotype in pharmacogenetic studies. These studies, however, did not examine the relationship between allelic variation, clinical response to pharmacological treatment, and the intermediate phenotypes as revealed by brain imaging. The relationship between dopamine and serotonin receptor genotypes, regional brain metabolism, and clinical response to clozapine treatment was the focus of this study.We report the changes in brain metabolism based on dopamine and serotonin alleles following treatment with clozapine. Positron emission tomography scanning using 18 F-fluorodeoxyglucose (FDG PET) has the ability to measure regional brain metabolic response while the subject is performing an activation task. PET has the ability to resolve individual gyri and distinguish subcortical regions from each other. PET can measure brain work because of the close coupling between glucose utilization and neuronal activity. 8,9 During the FDG uptake, the subject performed an attentional task, the degraded continuous performance task (CPT), activating brain systems related to essential elements of the illness. In this task, subjects view a series of blurred num...

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“…Clozapine, the gold standard among the atypical neuroleptics, has a pharmacological profile with weaker blockade of DA D2 receptors and broader actions for multiple receptors than other atypical antipsychotics, and these characteristics are presumed to be related to its superior clinical efficacy relative to other neuroleptics. Interestingly, several previous studies have reported that clozapine induced a significant reduction in blood flow/metabolism in the prefrontal cortex (Potkin et al, 1994(Potkin et al, , 2003Cohen et al, 1997;Lahti et al, 2003;Molina et al, 2005dMolina et al, , 2008. On the other hand, increases in several parts of the prefrontal cortex, including the ACC (Lahti et al, 2003) and decreases in the hippocampus (Lahti et al, 2003;Potkin et al, 2003) have been shown by some studies, supporting the drug's clinical actions such as ameliorations of delusions/hallucinations and cognitive impairments.…”

Section: Impacts Of Antipsychotics On Blood Flow and Metabolismmentioning

confidence: 81%