Molekulare Grundlagen der Schizophrenie

Zusammenfassung

Der Serotonin_2A-Rezeptor (5-HT_2AR) wird sowohl mit der Pathologie der Schizophrenie als auch mit dem Wirkungsmechanismus vieler atypischer Antipsychotika in Verbindung gebracht. Da atypische Antipsychotika wie Clozapin den 5-HT_2AR blockieren und die 5-HT_2AR-Dichte reduzieren, stellt sich die Frage, ob die in Post-mortem-Untersuchungen schizophrener Patienten festgestellte Abnahme der 5-HT_2AR-Dichte ein Indikator der zu Grunde liegenden Erkrankung oder ein sekundärer medikamentöser Effekt ist. Zur Klärung dieser Frage sind Studien über den In-vivo-Status des 5-HT_2AR bei der Schizophrenie erforderlich, die vor Erstmanifestation der Erkrankung und vor Beginn einer pharmakologischen Therapie durchgeführt werden. Dieser Überlegung trägt unsere Pilotstudie Rechnung, bei der unter Verwendung des Radioliganden [18F]Altanserin und der Positronenemissionstomographie (PET) Verminderungen der 5-HT_2AR-Verfügbarkeit im orbitofrontalen und dorsolateralen präfrontalen Kortex bei Patienten mit Symptomen psychosenaher und psychoseferner Prodromalzustände der Schizophrenie festgestellt wurden. Diese Ergebnisse sprechen für eine erkrankungsbedingte serotonerge Dysregulation in Hirnarealen, deren frühe Störung an der Entstehung affektiver und kognitiver Symptome der Schizophrenie beteiligt sein könnte.

Summary

The brain serotonin_2A receptor (5-HT_2AR) has been implicated in both the pathology of schizophrenia and the therapeutic action of many atypical antipsychotics. As atypical antipsychotics like clozapine antagonize the 5-HT_2AR and reduce 5-HT_2AR density, it cannot be ruled out that a prefrontal decrease of 5-HT_2AR density observed in postmortem brains from patients with schizophrenia is triggered by antipsychotic drug effects. Today, little is known about the 5-HT_2AR in vivo status before the first psychotic episode and before the exposure to antipsychotics. Into this void comes our pilot study in which we used the radioligand [18F]altanserin and positron emission tomography (PET) to investigate individuals at increased risk of developing schizophrenia. We identified decreases of 5-HT_2AR availability in orbitofrontal cortex and dorsolateral prefrontal cortex, suggesting that disease-related abnormalities of serotonergic neurotransmission emerge in brain areas involved in affective and cognitive processes, dysfunctions of which are core representations of the schizophrenic phenotype.

Schlüsselwörter

Schizophrenie - Prodrom - PET - Serotonin - 5-HT_2A-Rezeptor

Keywords

Schizophrenia - at-risk mental state - PET - serotonin - 5-HT_2A-receptor

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