Can 5-HT3 antagonists contribute toward the treatment of schizophrenia?

In one of his earlier papers, Lex Cools stated that the 'concept of an impaired balance between the in series connected […] dopamine system, […] 5-HT system and […] noradrenaline system offers a single coherent and integrated theory of schizophrenia' (Cools, 1975). Since then, considerable attention has focused on the interaction between dopamine and 5-HT and it is now well accepted that most antipsychotics (especially the second-generation drugs) modulate both dopaminergic and serotonergic receptors. However, the vast majority of research has focused on the 5-HT1A, 5-HT2A and 5-HT2C receptors. In the present paper, we review the literature pertaining to the 5-HT3 receptor, the only ionotropic 5-HT receptor. We discuss both the interactions between 5-HT3 receptors and dopamine, and the animal and human literature investigating the role of 5-HT3 receptors in schizophrenia. The results show that the interactions between 5-HT3 receptors and dopamine are complex, but that 5-HT3 receptors do not have a strong influence on the positive symptoms of schizophrenia. However, when added to standard antipsychotic medication, several recent studies have found that 5-HT3 receptor antagonists can induce a statistically significantly improvement in negative and cognitive symptoms. The implications of these findings in relation to animal modelling and drug development are discussed.