Neurobiology of treatment-resistant schizophrenia: New insights and new models

In an attempt to understand schizophrenia, four important fields have been implicated in the disease process and are reviewed here. Early findings that antipsychotic drugs were dopamine antagonists led to a dopaminergic theory of schizophrenia. However, it now appears that a primary dopaminergic abnormality is an unlikely explanation. The cortex has always been thought to be involved in the development of schizophrenia and recent data from neuropsychological, postmortem and imaging studies have indicated that connections between the prefrontal and temporolimbic areas within the brain may be abnormal. Traditionally, schizophrenia has been considered to be a disease with an adult onset pathology. This theory has now been challenged by data suggesting that in schizophrenia, anatomical changes in the adult brain are non-progressive and occurred prior to the onset of illness. Finally, studies on neuronal gene expression have indicated that all antipsychotic drugs modulate DNA transcription in the shell of the nucleus accumbens and that newer antipsychotics produce a quite different pattern of expression from conventional neuroleptics. These recent approaches provide new opportunities in the understanding of schizophrenia, its treatment and prevention.