• Top
• Oral presentation

Oral presentation

Schizophrenia is a major psychotic disorder of unknown aetiology. The lifetime risk to develop schizophrenia lies at about 1% in the world population. Schizophrenia has an early onset, a chronic nature and a high mortality with a suicide rate of 10-15%, with consequent substantial adverse impact upon family, social, and occupational life. Characteristic features are hallucinations and delusions, disorders of thought, speech, and behaviour, disturbance of emotions and affect, cognitive deficits and avolition. According to the major current classification systems, diagnosis is solely based on characteristic phenotypic symptoms and a minimum duration of these symptoms. Already Eugen Bleuler, who coined the term schizophrenia at the beginning of the nineteenth century, considered schizophrenia not as a unitary disease but rather as a group of diseases that share a number of clinical features but have different aetiologies.

During the last century, major efforts has been made to identify the underlying causes of schizophrenia. Although no causal factor has been identified so far, the development of antipsychotic medication has been quite successful. Today, antipsychotics form the mainstay of treatment for schizophrenia. There is strong evidence to suggest that genetic variation plays not only a role in the aetiology of the disorder but also in the way patients respond to treatment.

In the search for those genes two strategies have been applied: the candidate gene and the linkage approach. In pharmacogenetic studies, the first strategy is applied, given that the latter approach is difficult to realise because it requires the comparison of at least two affected family members. Candidate genes are generally chosen according to the hypothesised role of the gene product in the aetiology of the disorder. Major candidates for pharmacogenetic studies have so far been genes encoding for the CYP450 system (pharmacokinetic level) and for neurotransmitter receptors and transporters (pharmacodynamic level). These candidates have most intensively been studied in the context of a.) tardive dyskinesia, the most common side-effect of classical neuroleptics, and b.) response to the atypical neuroleptic agent clozapine.

The results of these studies are multi-layered. They show that 1.) none of the genes investigated has a major effect on response or side-effects 2.) large patient samples are required for the identification of these genes and their interaction with each other and environmental factors 3.) phenotype characterisation warrants standardisation to ensure valid replication studies 3.) knowledge about the aetiology of the disorder is still limited, which has implication on the selection of candidate genes.

In the search for the vulnerability genes in schizophrenia, both strategies have been applied. Due to the abundant number of possible candidates (>10000) and the limited knowledge about the pathophysiology of the disorder, results were erratic. Today, the intensive search for vulnerability genes concentrates on those chromosomal regions that have been repeatedly identified by independent linkage studies to host vulnerability genes. This method proved to be successful: recently, variations in four genes, Dysbindin on chromosome 6p, G72 on 13q, DAAO on 12q, and Neuregulin on 8p have been found to be associated with schizophrenia in independent samples by independent groups. Knowledge about vulnerability genes will hopefully soon provide insight into the pathophysiology of the disorder and lead to new targets for the development of causal drugs.

Have something to say? Post a comment on this article!