Postmortem and PET studies indicate increased serotonin (5-HT)-5-HT1A receptor density in frontal and temporal cortices in schizophrenia, suggesting up-regulation secondary to diminished 5-HT1A-receptor stimulation. We previously conducted a series of pilot studies of the effects of the addition of tandospirone, a 5-HT1A partial agonist and azapirone derivative, to ongoing treatment with small to moderate doses of typical antipsychotic drugs, on cognitive function in patients with schizophrenia. The addition of tandospirone (30 mg/day), but not placebo, for 4 to 6 weeks was found to improve executive function and verbal learning and memory.

We have conducted a randomly-assigned placebo-controlled double-blind study to investigate the ability of the addition of buspirone to enhance cognitive function in subjects with schizophrenia treated with atypical antipsychotic drugs (AAPDs). Buspirone, 30 mg/day, outperformed placebo in improving the performance on a measure of attention/speeded motor performance and index of general cognitive function. The distinct cognition-enhancing ability of buspirone suggests its usefulness for patients who have large deficits in attention in spite of treatment with AAPDs.

The findings from these clinical studies indicate 5-HT1A receptors are a promising target for the management of psychotic symptoms and cognitive disturbances of schizophrenia. This concept has prompted the development of novel antipsychotic compounds with agonist actions at 5-HT1A receptors, e.g. F156063, SLV313, SSR181507, and bifeprunox. Evidence from basic studies with these drugs suggests an optimal balance of activity at 5-HT1A and dopamine-D2 receptors is required to gain cognitive benefits, which deserves further investigations.