New mechanisms of action in the development of antipsychotics: Evidence from a clinical perspective

Abstract

For 60 years since the discovery of antipsychotics, their action has been linked to blockade of Dopamine D2 receptors. New neuroscientific insights have led to antipsychotics with different mechanisms of action, yet still related to Dopamine D2 receptors. This group includes the second-generation antipsychotics, which, in addition to affinity for Dopamine D2 receptors, also have affinity for serotonin 5-HT2 receptors. Further progress came with partial Dopamine D2 agonists. These drugs constitute the third generation of antipsychotics. In this way, the story of antipsychotics that act primarily through effects on Dopamine receptors has been completed. Nevertheless, many patients show an unsatisfactory response to these antipsychotics, together with substantial adverse effects and, ultimately, a virtual lack of efficacy against negative and, above all, cognitive symptoms of schizophrenia, which necessitates the development of new antipsychotics. In addition, all mechanisms of action on Dopamine receptors are practically of postsynaptic localization, whereas scientific evidence indicates that the dominant dysfunction is localized presynaptically, on the cell body of the Dopamine neuron. All of this calls for the development of new antipsychotics with different mechanisms of action. This lecture provides a critical review of novel pharmacological approaches and the available clinical evidence. Particular attention is devoted to muscarinic agonists, primarily the combination of xanomeline-trospium. Its efficacy in short-term studies in acute schizophrenia has been confirmed, along with a different adverse-effect profile that is predominantly gastrointestinal and cholinergic. TAAR1 receptor agonists, modulators of glutamatergic neurotransmission (including glycine transporter inhibitors), and agents targeting serotonin receptors are also discussed.