Neurobiologie der Schizophrenie

Abstract

Schizophrenia is a severe and chronic disease, leading to important social and physical consequences. Up to 80% of individuals with schizophrenia are unemployed, and their life expectancy is reduced by 10 to 25 years. All available and effective antipsychotic drugs block the dopamine D2 receptor. Consistently, the dopamine hypothesis posits that a hyperactive dopamine systems underlies schizophrenia. However, this hypothesis mainly explains positive symptoms and does not take into account the full complexity of the disorder, including cognitive and negative symptoms. There is growing evidence from genome-wide scans and pharmacological studies using phencyclidine that the glutamate system is importantly involved in the pathogenesis of schizophrenia. This hypothesis has the power to explain both, positive and negative symptoms. In addition, hypofunction of the glutamate system may be a key factor in the disrupted brain development leading to schizophrenia. Compounds targeting the glutamate system, including glycine reuptake inhibitors, mGluR2/3 antagonists, mGluR5 agonists, D-serine, N-acetylcysteine and omega-3 fatty acids, have a huge therapeutic and preventative potential. However, none of these drugs have shown consistent efficacy in clinical trials. Biomarkers that predict treatment response, allowing for sample stratification, and treatment onset in early stages of the illness, may considerably improve efficacy of glutamatergic drugs. Bleuler considered schizophrenia as an inhibitory dysfunction. Recent research on epigenetic mechanisms in the pathogenesis of schizophrenia confirm Bleuler’s hypothesis. It suggests that gene-environment and environment-environment interactions at the GAD67 gene (which produces 80% of central GABA) contribute to inhibitory dysfunction, underlying many facets of schizophrenia symptoms. In summary, there is considerable progress in the understanding of the neurobiology and genetics of schizophrenia. This progress offers promising leads for the discovery of biomarkers and provides novel targets for drug development.