COMT, neuropsychological function and brain structure in schizophrenia: a systematic review and neurobiological interpretation

COMT, neuropsychological function and brain structure in schizophrenia: a systematic review and neurobiological interpretation

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J Psychiatry Neurosci 2013; 38(6): 366-380

Elisa Ira, PhD; Martina Zanoni, PhD; Mirella Ruggeri, MD, PhD; Paola Dazzan, MD, PhD;* Sarah Tosato, MD, PhD*

Ira, Zanoni, Ruggeri, Tosato — Section of Psychiatry, University of Verona, Verona, Italy; Dazzan — Institute of Psychiatry, Department of Psychosis Studies, King’s College, London, United Kingdom

*These authors contributed equally to this work.

Abstract

Background: Endophenotypes in genetic psychiatry may increase our understanding of the molecular mechanisms underlying disease risk and its manifestations. We sought to investigate the link between neuropsychological impairments and brain structural abnormalities associated with the COMT Val158Met polymorphism in patients with schizophrenia to improve understanding of the pathophysiology of this disorder.

Methods: We performed a systematic review using studies identified in PubMed and MEDLINE (from the date of the first available article to July 2012). Our review examined evidence of an association between the COMT Val158Met polymorphism and both neuropsychological performance and brain structure in patients with psychosis, in their relatives and in healthy individuals (step 1). The review also explored whether the neuropsychological tasks and brain structures identified in step 1 met the criteria for an endophenotype (step 2). Then we evaluated evidence that the neuropsychological endophenotypes identified in step 2 are associated with the brain structure endophenotypes identified in that step (step 3). Finally, we propose a neurobiological interpretation for this evidence.

Results: A poorer performance on the n-back task and the Continuous Performance Test (CPT) and smaller temporal and frontal brain areas were associated with the COMT Val allele in patients with schizophrenia and their relatives and met most of the criteria for an endopheno type. It is possible that the COMT Val158Met polymorphism therefore contributes to the development of these neuropsychological and brain structural endophenotypes of schizophrenia, in which the prefrontal cortex may represent the neural substrate underlying both n-back and CPT performances.

Limitations: The association between a single genetic variant and an endophenotype does not necessarily imply a causal relationship between them.

Conclusion: This evidence and the proposed interpretation contribute to explain, at least in part, the biological substrate of 4 important endophenotypes that characterize schizophrenia.


Submitted Sept. 6, 2012; Revised Jan. 9, 15, 2013; Accepted Jan. 16, 2013.

Competing interests: None declared for M. Zanoni and P. Dazzan. As below for E. Ira, M. Ruggeri and S. Tosato.

Contributors: S. Tosato designed the review. E. Ira acquired the data and analyzed it with M. Zanoni, M. Ruggeri and P. Dazzan. E. Ira and M. Zanoni wrote the article, which M. Ruggeri, P. Dazzan and S. Tosato reviewed. All authors approved its publication.

Funding: This study was supported by Veneto Region, Italy, with the FSE grant “Acquisizione nuove tecniche automatizzate di studio di immagini di risonanza magnetica nucleare cerebrali” to E. Ira and by Fondazione Cariverona with the grant “Disabilità cognitiva e comportamentale nelle demenze e nelle psicosi. Sotto-obiettivo A.9. Basi morfofunzionali cognitive e genetiche delle psicosi maggiori: uno studio integrato longitudinale” to M. Ruggeri and S. Tosato.

DOI: 10.1503/jpn.120178

Correspondence to: E. Ira, Department of Public Health and Community Medicine, Section of Psychiatry, University of Verona, Policlinico G.B. Rossi, P.le L.A. Scuro 10, 37134 Verona, Italy; elisa.ira@univr.it