S-65-01

Glutamate psychopharmacology of schizophrenia and bipolar disorder: A neuroscientific dissection

S. Dursun. Neuroscience + Psychiatry Unit University of Manchester. Manchester, United Kingdom

Objective: There is growing evidence indicating a possible common neuronal-pathway dysfunction in Schizophrenia(Sch)and bipolar disorder (BD.

Methods: The evidence for the common-pathway dysfunction in Sch and BD comes from preclinical-healthy volunteer-and clinical trials data. This common pathway involves pedominantly the glutamate-GABA connectivity dysfunction.

Results: Gultamate GABA common pathway connectivity dysfunction is supported by the well established efficacy of atypical antipsychotic drugs and also anitconvulsant drugs such as lamotrigine and divalproex sodium (add-on) in both Sch and BD

Conclusion: The aim of the presentation will be, to dissect the neuroscientific evidence which indicates a common pathway dysfunction of glutamate & GABA in Sch and BD.

S-65-02

Neurotrophic factors in schizophrenia and affective disorders: Basis for novel therapeutic approaches?

H. Ehrenreich. Max Planck Institute for Experimental Medicine, G6ttingen, Germany

Objective: Schizophrenia and affective disorders are increasingly recognized as organic brain diseases involving degenerative processes. These processes, once turned on, are not disease-specific but part of a final common deleterious pathway characterized by disturbed neurotrophic/neuroprotective capacity. Neuroprotective therapy in these diseases should reduce degeneration and enhance regeneration. As an example, erythropoietin (EPO) is a candidate compound for neuroprotection in neuropsychiatric disorders. We have prepared the ground for its application in a first neuroprotective add-on strategy in schizophrenia, aiming at improvement of cognitive function as well as prevention/slowing of degeneration.

Methods: Methods and Results: Using rodent studies, immunohistochemical analysis of human post mortem brain tissue and nuclear imaging technology in man, we demonstrate that: (1) peripherally applied recombinant human (rh) EPO efficiently penetrates into the brain, (2) rbEPO is enriched intracranially in healthy men and more distinctly in schizophrenic patients, (3) EPO receptors are densely expressed in hippocampus and cortex of schizophrenic patients but less in healthy controls, (4) rhEPO attenuates haloperidol-induced neuronal death in vitro, and (4) peripherally administered rhEPO enhances cognitive functioning in mice in the context of an aversion task involving cortical and subcortical pathways believed to be affected in schizophrenia. These observations, together with the known safety of EPO, render it an interesting compound for neuroprotective add-on strategies in schizophrenia and other human diseases characterized by a progressive decline in cognitive performance. A multicenter proofof principle trial on "EPO in chronic schizophrenia" will be unblinded in April 2005.

S-65-03

Gene expression profiling: Disease-specific or common patterns?

P. Falkai, Dept. of Psychiatry Saarland University, Homburg, Germany

Objective: Recently risk genes for schizophrenia like dysbindin and neuregulin and for bipolar disorders like G 72 were described. Interestingly G 72 seems to be involved into the pathophysiology of schizophrenia and bipolar disorder as well. Gene expression studies give important information of the specific distribution of these risk genes in the pathophysiologically relevant brain structures in the mentioned disorders.

Methods: Using Medline and PubMed with the keywords "affective disorders, psychotic and gene expression" 197 references were found. Based on the abstracts 16 articles were identified dealing with the outlined topic. There are only a few studies where post-mortem tissue from patients with bipolar disorders and schizophrenia in comparison to control subjects were researched at the same time. Therefore the results from different papers are summarized and used for a comparison of gene expression profiles between the two disorders.

Results: Interestingly neuregulin shows a specific distribution in the frontal cortex in schizophrenia depending on the specific isoform. Dysbindin was found to be reduced in the glutamatergic terminals of the hippocampal formation in schizophrenia. These and other results are discussed in view of the pathophysiology of schizophrenia.

S-65-04

Are antipsychotics effective in schizophrenia and affective disorders?

W. Fleischhacker. Psychiatrische University Klinik Innsbruck, Innsbruck, Austria

New generation antipsychotics have been evaluated against a host of psychiatric disorders and syndromes beyond those of the schizophrenia spectrum. With regard to affective disorders they have been studied in acute bipolar mania, bipolar depression as well as in long-term recurrence prophylaxis. Some evidence is also available concerning treatment refractory depression. Within the schizophrenia spectrum, these agents, next to demonstrating antipsychotic efficacy, also appear to have advantages over traditional neuroleptics in treating concomitant depressive symptoms, especially during the actue phases of the illness. Aripiprazole, olanzapine, quetiapine, risperidone and ziprasidone have demonstrated good antimanic effects either as monotherapy or in combination with mood stabilizers. Recurrence prevention trials are still scarce but at least olanzapine has been shown to prevent both manic and depressive episodes. Clozapine has been suggested to be helpful in treatment resistant bipolar patients and very recent results point to antidepressant effects of quetiapine. A combination of fluoxetine and olanzapine has helped patients with treatment refractory depression. All in all, the evidence is most convincing for antipsychotic and antimanic properties of second generation medications. Whether or not these drugs also have true antidepressant effects, both during acute and maintenance treatment remains to be seen.

S-65-05

Synthesis of part I and part II

W. Maier. Department of Psychiatry, University, Bonn, Germany