Alternative approaches to the discovery of novel antipsychotic agents.

Abstract

Currently used drugs that are effective treatments for schizophrenia have one single factor in common — their ability to antagonise the actions of dopamine at post-synaptic dopamine D2 receptors [1–4]. This action is at the cornerstone of the dopamine hypothesis of schizophrenia and has served as the basis of the primary screen for the discovery of structurally diverse antipsychotic compounds for almost twenty years. However, general blockade of D2 receptors in the CNS is associated with two major side effects: (i) the induction of abnormal movement syndromes [5] and (ii) the stimulation of prolactin secretion [6, 7]. Furthermore, most antipsychotic drugs are effective treatments for the positive symptoms of schizophrenia (delusions, hallucinations, thought disorders), but their efficacy against the negative symptoms associated with the disease (flattening of affect, poverty of speech, loss of volition) is less easy to demonstrate [8]. Many compounds also have autonomic and cardiovascular effects that can limit their usefulness [9]. Thus, much effort has been, and is currently being, expended in the search for ways of attenuating dopaminergic function without inducing motor, hormonal or other potentially harmful side-effects, yet retaining or improving clinical efficacy.