chapter  25
15 Pages

How antipsychotics work: Examining trans-synaptic realities

WithSRIDHAR NATESAN, SHITIJ KAPUR

Introduction The dopamine hypothesis of schizophrenia, modified since its initial version, has been the most defensible argument put forward in explaining the symptomatology of this chronic mental disorder (Carlsson & Lindqvist, 1963; Davis, Kahn, Ko, & Davidson, 1991; Howes & Kapur, 2009; Snyder, 1976; van, van der, & Hurkmans, 1962). The current hypothesis states that both subcortical hyperdopaminergia and cortical hypodopaminergia co-exist and these lead to the manifestation of both positive and negative symptoms, respectively. Although antipsychotic agents were initially discovered by serendipity, they fit into this hypothesis as they block the dopamine D2 receptors and thus inhibit excessive dopamine transmission in subcortical areas (Seeman, Chau-Wong, Tedesco, & Wong, 1975; Snyder, Creese, & Burt, 1975). However, the use of antipsychotics for over half a century has revealed their limitations: motor side effects, emergence of treatment resistance, lack of effects on negative symptoms and metabolic abnormalities (Kapur & Mamo, 2003). In this chapter, we discuss the history of antipsychotic discovery and how it led to understanding their mechanism of action, the role of dopamine D2 receptors, mismatch of treatment that is currently targeted at the wrong end of the synapse, and steps needed to be taken towards rational treatment.