Does stimulation of 5-HT(1A) receptors improve cognition in schizophrenia?

Cognitive impairment is a key feature of schizophrenia and may be the most important determinant of outcome in schizophrenia. This impairment is diffuse and may reflect abnormalities in frontal cortex, hippocampus and other brain regions. While deficits in glutamatergic, GABAergic, dopaminergic and cholinergic impairment have received the most attention as the basis of this impairment, there are many reasons for considering the role of serotonin (5-HT) in contributing to these deficits. This may be via its influence on dopaminergic, cholinergic, glutamatergic and GABAergic function, as well as various growth factors that have been implicated in schizophrenia. Of the 14 known serotonin receptors, the 5-HT(1A) receptor is a key candidate for mediating at least some of the influence 5-HT has on cognition. 5-HT(1A) receptors are upregulated in postmortem specimens from patients with schizophrenia, suggesting a deficit in 5-HT(1A) function in this disorder. Atypical but not typical antipsychotic drugs stimulate the efflux of dopamine from cortex by a 5-HT(1A)-dependent mechanism. A series of studies from this laboratory involving the 5-HT(1A) partial agonists tandospirone and buspirone have reported a modest ability of these agents to improve some domains of cognition in patients receiving typical or atypical antipsychotic drugs. Preclinical studies have been mixed in regard to the ability of 5-HT(1A) partial agonists to improve cognition in various paradigms; some studies report that 5-HT(1A) antagonists are effective to improve cognition. Aripiprazole, clozapine, olanzapine, perospirone, quetiapine risperidone, and ziprasidone are examples of atypical antipsychotic drugs which are either direct or indirect 5-HT(1A) agonists which have been shown to improve cognitive function in patients with schizophrenia. Further study is needed to determine the role of the 5-HT(1A) receptor to improve cognitive function in schizophrenia.