Klinik und Poliklinik für Psychiatrie und Psychotherapie, Heinrich-Heine-University Duesseldorf

Project 2.3.2.1: Biological basis of pharmacological intervention

Klimke A, Coenen HH, Zilles K

Collaboration with: C. Boy, Institute for Medicine, HH Coenen, Institut for Nuclear Medicine, Research Centre Juelich

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Funded by :

SummaryThe present study of the German Research Network on Schizophrenia analyses the possible role of the central serotonergic system for the development of negative symptoms in schizophrenic patients. Negative symptoms are a determinant of cognitive and emotional deficits in the long-term course of schizophrenia. Using [18F] Altanserin-PET (a selective 5-HT2A receptor ligand), we investigate the possible diagnostic and predictive therapeutic value of the cortical 5-HT2A receptor density in schizophrenic patients with and without negative symptoms.

IntroductionThe development of persistent negative symptoms is a severe and frequent complication which leads to social and cognitive impairment of schizophrenic patients. Especially prominent are disturbances of emotional and social behavioural like flat affect, apathy and anhedonia (Gaebel & Woelwer, 1996). Up to now, there is still no experimental evidence about coherence between the serotonergic dysfunction and schizophrenic negative symptoms. Therefore, atypical neuroleptics modify negative and probably cognitive dysfunctions via antagonism of the 5HT2A-receptors and may provide treatment specifically for negative beside positive symptoms. As a consequence researching the serotonergic system is of relevance for understanding and treatment of negative symptoms of schizophrenia.In a cooperation between Medical Institute at Investigation Centre Juelich and Department of Psychiatry at the University of Duesseldorf (starting in 1994) several investigations regarding the functional relevance of selected neurotransmitter receptor subtypes were performed. Since 1997, the PET ligand [18F]-altanserin can be synthesized in Juelich and was used in several collaborative studies of affective disorders. The characteristics of 5HT2A receptor binding using PET and the radioligand [18F]-altanserin were already investigated in major depression in vivo (Larisch et al., 2001*). In this previous study, binding of [18F]-altanserin was about 38% lower in depressive patients than in healthy controls (Fig. 1).

MethodInpatients suffering from schizophrenia with or without negative symptoms treated with non-serotonergic antipsychotice drugs are included. 40 patients will be recruited - 20 patients with negative symptoms and 20 without. The psychopathological state is rated by an established rating scale (PANSS). Clinical relevant negative symptomatology is defined as a PANSS- negative symptom subscore > 30 (or < 7 in control group). PET is performed by using [18F]-altanserin to evaluate 5-HT2A receptor binding. Partial-volume correction of regional specific binding estimates is performed by using a method based on magnetic resonance imaging. The trial is executed in Medical Institute at Investigation Centre Juelich.

Status of the investigationThere was a long latency due to several discussions with the legal authorities for radiation protection and with the insurance company. All problems are solved now. As a consequence, the study could start in June 2002. 45 patients were screened since June 1st 2002 and August 31th, 2002 and 8 patients gave their informed consent to participate in the investigation. Up to yet, PET was performed by using [18F]-altanserin in 6 patients with schizophrenia (mean age = 32.5 years, SD = 5.3). Tab. 1 shows some patient data. Due to the low number of patients, a first analysis of the data is not appropriate at the moment.Our experiences with an increasing recruitment of probands and patients are promising and we believe that we can include 2 patients per week and therefore finish the study within 6 months as planned.

Networking – collaboration with other subprojects or institutions

*Larisch R, Klimke A, Mayoral F, Hamacher K, Herzog HR, Vosberg H, Tosch M, Gaebel W, Rivas F, Coenen HH, Muller-Gartner HW. Disturbance of serotonin 5HT2 receptors in remitted patients suffering from hereditary depressive disorder. Nuklearmedizin 2001 Aug; 40(4):129-34

Objectives

⇒ to demonstrate a 5HT2A receptor density in the prefrontal cortex in patients with negative symptoms which is significantly lower than in patients without these symptoms or in healthy comparison subjects

⇒ to demonstrate a correlation between 5HT2A-receptor density with the affective modulation of schizophrenic patients with negative symptoms (networking with project 2.3.2.2 – Functional brain indicators of emotional dysfunctions)

Fig. 1: 5HT2A-receptor status of a healthy comparison proband (left) and a patient with reduced 5-HT2A receptor density (right, suffering from bipolar affective disorder)

Age Diagnosis PANSS-Score

Negative PANSS-Score

PET MRI

1 34 F20.0 61 10 yes yes2 36 F20.0 70 30 yes yes3 30 F20.0 73 34 yes yes4 41 F20.0 93 45 yes yes5 30 F20.0 31 7 yes yes6 24 F20.0 69 35 yes yes

Tab. 1: Data of enrolled patients

Biological basis of Biological basis of pharmacological intervention - pharmacological intervention -

Altanserin-PET-Study Altanserin-PET-Study

(SP 2.3.2.1)

MEG-project (2.3.2.2)

sharing recruitment and MEG-examination

Medical Institute at Investigation Centre Juelich

synthesis of radioligand [18F]Altanserin, supply of the devices

Biological basis of early pharmacological intervention (1.1.3.1)interchange of information on methodological issues and mutual logistic support