Improving the Treatment of Schizophrenia: Focus on Serotonin (5-HT)(1A) Receptors

Although antagonism of mesolimbic dopamine D(2) receptors by neuroleptics such as haloperidol attenuates positive symptoms of schizophrenia, a significant population of "resistant" patients fails to respond while negative and cognitive symptoms are little modified. Furthermore, concomitant blockade of striatal D(2) receptors is associated with extrapyramidal motor side effects. The superior "atypical" antipsychotic profile of clozapine appears to reside in its broad pattern of interaction with D(2) receptors and a diversity of other monoaminergic sites. In this regard, serotonergic mechanisms are of particular relevance both in view of their modulation of dopaminergic transmission and their key role in the control of mood, cognition, and motor behavior. While most attention has focused on potential advantages of preferential 5-HT(2A) versus D(2) receptor blockade, 5-HT(1A) receptors likewise represent a valid target for improved antipsychotic agents. In this regard, rather than selective agents, ligands interacting with both 5-HT(1A) and D(2) receptors appear of interest. A modest level of efficacy appears optimal, that is, sufficient to engage highly sensitive 5-HT(1A) autoreceptors while blocking their low-sensitivity postsynaptic counterparts. Such a profile may counter negative and cognitive symptoms, improve mood, diminish extrapyramidal 5-HT(1A) motor side effects, and, perhaps, enhance efficacy in refractory patients. Notably, "partial agonist" properties of clozapine at 5-HT(1A) receptors may contribute to its distinctive functional profile. However, notwithstanding this compelling body of experimental data, clinical studies of antipsychotics interacting with 5-HT(1A) receptors are required to establish their genuine pertinence to the-hopefully improved-treatment of schizophrenia.