Serotonergic mechanisms in schizophrenia: Evolution and current concepts

Abstract

Serotonin (5-HT) was once thought to have a role in visual hallucinations based on the findings that lysergic acid diethylamide was found to be a serotonin agonist. This led to a search for endogenous indole hallucinogens in schizophrenia, which ultimately proved unsuccessful. Studies of 5-HT receptor subtypes opened up the issue in several ways, with the 5-HT2A, 5-HT2C, and 5-HT1A receptors seeming to be of greatest importance, and 5-HT6 and 5-HT7 receptors of secondary importance. Linkages between 5-HT, dopamine (DA), glutamate, acetylcholine, and brain-derived neurotrophic factor, have provided some important leads as to how 5-HT may be involved in schizophrenia. It has been found that 5-HT2A rather than 5-HT2C receptor stimulation is the most likely basis for the hallucinogenic effects of lysergic acid diethylamide, but recent neurochemical and genetic studies have raised the possibility that the 5-HT2C receptor may also be important in psychosis based on its ability to regulate tonic dopaminergic function. The discovery that 5-HT2A receptor blockade was an important component of the action of clozapine and other atypical antipsychotic drugs also restored interest in a primary role of 5-HT2A receptors in the etiology of psychosis. 5-HT1A receptors also have been found to enhance DA release in the cortex and hippocampus and are primary factor in the regulation of DA release in both of these regions. Postmortem studies have found some evidence of non-drug-induced increased density of 5-HT1A receptors. Genetic studies are ongoing to link single nucleotide polymorphisms of the 5-HT2A, 5-HT2C, and 5-HT1A receptors to some schizophrenia phenotypes. It is likely that serotonergic function will become even more important in developing genetic and other markers for schizophrenia novel therapies, particularly for psychosis and cognition.