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Jussi Hirvonen, MD; Theo G. M. van Erp, MA; Jukka Huttunen, MD; Sargo Aalto, MSc; Kjell Någren, PhD; Matti Huttunen, MD, PhD; Jouko Lönnqvist, MD, PhD; Jaakko Kaprio, MD, PhD; Jarmo Hietala, MD, PhD; Tyrone D. Cannon, PhD

Arch Gen Psychiatry. 2005;62:371-378.

Context  Schizophrenia has a heritability of about 80%, but the detailed molecular genetic basis of the disorder has remained elusive. Relative hyperfunction of the subcortical dopamine system has been previously suggested to be one of the key pathophysiologic mechanisms in schizophrenic psychosis.

Objective  To examine the contributions of genetic vulnerability for schizophrenia to the dopamine system in the human brain.

Design  Population-based twin cohort study.

Setting  Finland.

Participants  Six monozygotic and 5 dizygotic unaffected co-twins of patients with schizophrenia were ascertained, along with 4 monozygotic and 3 dizygotic healthy control twins with no family history of psychotic disorders.

Main Outcome Measures  Striatal dopamine D₂ receptor availability estimated with positron emission tomographic imaging and carbon 11 (¹¹C)–labeled raclopride, and performance on neuropsychological tests sensitive to frontal lobe functioning and to schizophrenia vulnerability.

Results  Unaffected monozygotic co-twins had increased caudate D₂ density compared with unaffected dizygotic co-twins and healthy control twins. Higher D₂ receptor binding in caudate was associated with a poor performance on cognitive tasks related to schizophrenia vulnerability in the whole sample.

Conclusions  The caudate dopamine D₂ receptor up-regulation is related to genetic risk for schizophrenia. Higher dopamine D₂ receptor density in caudate is also associated with poorer performance on cognitive tasks involving corticostriatal pathways. This finding suggests that caudate dopamine dysregulation is also a trait phenomenon related to psychosis vulnerability. This pattern of results provides a theoretical rationale for early pharmacologic intervention approaches using dopamine D₂ receptor blocking drugs.

Author Affiliations: Departments of Pharmacology and Clinical Pharmacology (Dr Hirvonen) and Psychiatry (Drs J. Huttunen and Hietala), Centre for Cognitive Neuroscience (Mr Aalto), and Turku PET Centre (Drs Hirvonen, J. Huttunen, Någren, and Hietala), University of Turku, Turku, Finland; Departments of Psychology, Psychiatry, and Human Genetics, University of California at Los Angeles School of Medicine (Mr van Erp and Dr Cannon); Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland (Drs M. Huttunen, Lönnqvist and Kaprio); and Department of Public Health, University of Helsinki (Dr Kaprio).

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