Open Access
and Olanzapine Treatment on Prefrontal Cortical Function in Patients With Schizophrenia
Alessandro Bertolino,Giuseppe Blasi,Mariapia De Candia,Vittoria Petruzzella,Mario Altamura,Gaetano Nappi,Sergio Papa,Joseph H. Callicott,Venkata S. Mattay,Antonello Bellomo,Tommaso Scarabino,Daniel R. Weinberger,Marcello Nardini +12 more
- 01 Jan 2004
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TL;DR: Evaluated patients with schizophrenia with acute untreated schizophrenia suggest that a genetically determined variation in prefrontal dopamine catabolism impacts the therapeutic profile of olanzapine.
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Abstract: Objective: Deficits in working memory and in prefrontal cortical physiology are important outcome measures in schizophrenia, and both have been associated with dopamine dysregulation and with a functional polymorphism (Val 108/158 Met) in the catechol O-methyltransferase (COMT) gene that affects dopamine inactivation in the prefrontal cortex. The purpose of the present study was to evaluate in patients with schizophrenia the effect of COMT genotype on symptom variation, working memory performance, and prefrontal cortical physiology in response to treatment with an atypical antipsychotic drug. Method: Thirty patients with acute untreated schizophrenia were clinically evaluated with the Positive and Negative Syndrome Scale, underwent COMT Val/Met genotyping, and entered an 8-week prospective study of olanzapine treatment. Twenty patients completed two 3-T functional magnetic resonance imaging scans at 4 and 8 weeks during performance of N-back working memory tasks. Results: There was a significant interaction of COMT genotype and the effects of olanzapine on prefrontal cortical function. Met allele load predicted improvement in working memory performance and prefrontal physiology after 8 weeks of treatment. A similar effect was found also for negative symptoms assessed with the Positive and Negative Syndrome Scale. Conclusions: These results suggest that a genetically determined variation in prefrontal dopamine catabolism impacts the therapeutic profile of olanzapine.
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Citations
Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond.
TL;DR: Preliminary data indicating that catechol-o-methyltransferase is a promising therapeutic target for ameliorating the cognitive deficits associated with schizophrenia are outlined.
724
Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder
Hamid Mostafavi Abdolmaleky,Kuang-hung Cheng,Stephen V. Faraone,Marsha A. Wilcox,Stephen J. Glatt,Fangming Gao,Cassandra L. Smith,Rahim Shafa,Batol Aeali,Julie Carnevale,Hongjie Pan,Panagiotis Papageorgis,Jose F. Ponte,Vadivelu Sivaraman,Ming T. Tsuang,Ming T. Tsuang,Sam Thiagalingam +16 more
TL;DR: It is suggested that MB-COMT over-expression due to promoter hypomethylation and/or hyperactive allele of COMT may increase dopamine degradation in the frontal lobe providing a molecular basis for the shared symptoms of schizophrenia and bipolar disorder.
Cognitive Impairment in Schizophrenia
TL;DR: Cognitive remediation programs have generated considerable interest as these methods are far less costly than pharmacologic treatment and are likely to be safer and the efficacy of the various methods used has not been empirically investigated.
451
From maps to mechanisms through neuroimaging of schizophrenia
TL;DR: Characterizing the neural risk architecture of schizophrenia provides a translational research strategy for future treatments and defines neural systems that mediate heritable risk linked to candidate and genome-wide-supported common variants.
Site-specific role of catechol-O-methyltransferase in dopamine overflow within prefrontal cortex and dorsal striatum.
TL;DR: The present findings represent the first demonstration of the significant contribution of COMT in modulating the dynamics of dopamine overflow in the cortex and underscore the therapeutic potential of manipulating COMT activity to alter dopaminergic neurotransmission in the prefrontal cortex.
298
References
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TL;DR: During performance of working memory tasks, deficits in prefrontal activation, including dorsolateral regions, are more severe in participants with schizophrenia than in unmedicated outpatients with acute nonpsychotic major depression.
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Prefrontal cortex dysfunction mediates deficits in working memory and prepotent responding in schizophrenia.
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TL;DR: In this paper, a resolution between the suggestion of functional dopamine (DA) "depletion" in the prefrontal cortex and enhanced subcortical DA function was offered by studies of Carter, Pycock, and associates.
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Relative Risk of Attention Deficits in Siblings of Patients With Schizophrenia
Michael F. Egan,Terry E. Goldberg,Tonya Gscheidle,Mary Weirich,Lewellyn Bigelow,Daniel R. Weinberger +5 more
TL;DR: Given the ease of administering the Continuous Performance Test, the use of impaired attention as an intermediate phenotype could increase the power of genetic studies of schizophrenia.
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