Treatment of schizophrenia in the 21st Century: beyond the neurotransmitter hypothesis

Over the last six decades, the treatment of schizophrenia has focused primarily on interactions at monoamine neurotransmitter receptor sites, including those for dopamine and serotonin. While first-generation antipsychotics demonstrate antagonism at the dopamine 2 receptor, newer atypical agents involve multiple receptors at various neurotransmitter sites. Despite the advent of these newer agents, the treatment of schizophrenia continues to elude clinicians, perhaps owing to a lack of information about the factors contributing to the development of the disease. While the etiology is complex and not yet fully delineated, we suggest that treating clinicians be willing to look beyond neurotransmitters and entertain other potential factors involved in the pathogenesis of schizophrenia. One such factor that is often overlooked is the possible contribution of autoimmunity to disease development in at least a subset of patients. In this article we make an argument for consideration of immune dysfunction in the development of schizophrenia and suggest future directions for the field.