To the Editor: Fumihiko Yasuno, M.D., Ph.D., et al. (1) reported a negative correlation between verbal memory function and the binding potential of serotonin 1A (5-HT_1A) receptors in the hippocampus, as well as an inhibitory effect of acute administration of a relatively high dose of tandospirone (60 mg/day), a 5-HT_1A partial agonist, on verbal memory in healthy volunteers. Based on these findings, they concluded that antagonists at postsynaptic 5-HT_1A receptors might be beneficial for the treatment of memory disturbances.

Their results extend our previous observations with schizophrenic patients (2, 3), which provided the first evidence, to our knowledge, for the ability of 5-HT_1A agonists to modulate memory performance in human subjects. In their Discussion, Dr. Yasuno et al. presented the reason for the ability of the lower dose of tandospirone (30 mg/day) to improve verbal memory performance, as demonstrated by our studies (2, 3), i.e., preferential stimulation of presynaptic 5-HT_1A autoreceptors, leading to the decreased release of 5-HT acting on postsynaptic 5-HT_1A receptors. Still, they failed to mention the discrepant results regarding the effect of the lower dose (30 mg/day) of tandospirone on memory performance, i.e., the facilitative influence in our studies versus the partially inhibitory effects in their study.

Here we would like to provide further discussion of this issue. First, the apparent difference between the two studies is that they focused on the acute effect of tandospirone (60 minutes after administration) while we assessed its long-term effect (over 6 weeks). It is possible that some adaptive changes in 5-HT_1A receptor function occur during prolonged administration of the drug, leading to altered response of 5-HT_1A receptors to intrinsic 5-HT or the 5-HT_1A agonist.

The second difference was that their study (1) used normal subjects while our studies (2, 3) concerned patients with schizophrenia. There is a strong consensus for the up-regulation of 5-HT_1A receptors in the brains of subjects with schizophrenia (4). The augmented tonic stimulation of postsynaptic 5-HT_1A receptors, as a result of the increased number of these receptors, may be a reason for impaired cognitive function in patients with schizophrenia. Activation of presynaptic 5-HT_1A autoreceptors by low-dose tandospirone, by means of inhibition of 5-HT neuronal activity, would produce a greater degree of decrease in the stimulation of postsynaptic 5-HT_1A receptors in patients with schizophrenia compared to psychiatrically normal subjects. Thus, the low-dose tandospirone improved memory function in patients with schizophrenia but not in normal subjects.

We propose that agents that activate presynaptic 5-HT_1A receptors, as well as drugs that work as antagonists at postsynaptic 5-HT_1A receptors, may be of value in treating some of the cognitive deficits in schizophrenia and possibly other psychiatric disorders as well.