Improving the treatment of schizophrenia: Focus on serotonin (5-HT)(1A) receptors

Although antagonism of mesolimbic dopamine D-2 receptors by neuroleptics su ch as haloperidol attenuates positive symptoms of schizophrenia, a signific ant population of "resistant" patients fails to respond while negative and cognitive symptoms are little modified. Furthermore, concomitant blockade o f striatal D-2 receptors is associated with extrapyramidal motor side effec ts. The superior "atypical" antipsychotic profile of clozapine appears to r eside in its broad pattern of interaction with D-2 receptors and a diversit y of other monoaminergic sites. In this regard, serotonergic mechanisms are of particular relevance both in view of their modulation of dopaminergic t ransmission and their key role in the control of mood, cognition, and motor behavior. While most attention has focused on potential advantages of pref erential 5-HT2A versus D-2 receptor blockade, 5-HT1A receptors likewise rep resent a valid target for improved antipsychotic agents. In this regard, ra ther than selective agents, ligands interacting with both 5-HT1A and D-2 re ceptors appear of interest. A modest level of efficacy appears optimal, tha t is, sufficient to engage highly sensitive 5-HT1A autoreceptors while bloc king their low-sensitivity postsynaptic counterparts. Such a profile may co unter negative and cognitive symptoms, improve mood, diminish extrapyramida l 5-HT1A motor side effects, and, perhaps, enhance efficacy in refractory p atients. Notably, "partial agonist" properties of clozapine at 5-HT1A recep tors may contribute to its distinctive functional profile. However, notwith standing this compelling body of experimental data, clinical studies of ant ipsychotics interacting with 5-HT1A receptors are required to establish the ir genuine pertinence to the - hopefully improved - treatment of schizophre nia.