Possible Dose-Side Effect Relationship of Antipsychotic Drugs: Relevance to Cognitive Function in Schizophrenia

Tomiki Sumiyoshi

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Expert Rev Clin Pharmacol. 2008;1(6):791-802. 

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As mentioned earlier, treatment with atypical antipsychotic drugs has been shown to be associated with improvement in various types of cognitive function in patients with schizophrenia.[27,29,56,83–86] However, the effect size of the cognitive benefit of atypical agents has been found to be small to moderate in a recent meta-analysis.[86,87] For example, the ability of the atypical drugs to improve attention/vigilance (effect size 0.12) was less than their ability to improve learning and memory (0.24) or verbal fluency (0.16).[87] Therefore, efforts to identify additional means to improve cognition in schizophrenia, especially attention/vigilance and executive function, another domain of cognition that is relatively unresponsive to atypical agents, are needed.

Findings from basic research indicate that clozapine, ziprasidone and aripiprazole, which are partial agonists at 5-HT1A receptors, decreased kainic acid (an excitotoxin)-induced striatal lesion volumes, an effect reversed by pretreatment with WAY100635, a 5-HT1A receptor antagonist.[88] By contrast, haloperidol, which is devoid of 5-HT1A agonist properties, did not show such an effect. These results suggest that some atypical antipsychotics with 5-HT1A agonist properties may protect against excitotoxic insults that may be responsible for progression to psychosis.[88] Using in vivo microdialysis methods, we reported that the 5-HT1A partial agonist tandospirone increased extracellular concentrations of the energy substrate lactate in the prefrontal cortex,[89] a brain region governing higher cognitive functions, such as social cognition.[90] The advantage of 5-HT1A receptor stimulation for reducing excitotoxic burden in the brain and improving cognition, as revealed by these basic studies, is consistent with our clinical observations that tandospirone and buspirone, 5-HT1A partial agonists, enhance cognitive performance in patients with schizophrenia treated with typical or atypical antipsychotic drugs.[71–73,91]

There is a strong consensus for the upregulation of 5-HT1A receptors in the brains of subjects with schizophrenia.[19,92] The augmented tonic stimulation of postsynaptic 5-HT1A 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-HT1A 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-HT1A receptors in patients with schizophrenia compared with psychiatrically normal subjects. Thus, low-dose tandospirone improved memory function in patients with schizophrenia[71,72,91,92] but not in normal subjects Figure 6.[92,93] Additional discussions of this issue have been reported.[92,94] Further studies are needed to determine the role of the 5-HT1A receptor to improve cognitive function in schizophrenia.[94]

Mechanism for the ability of 5-HT1A agonism to enhance cognitive function in subjects with schizophrenia. There is a strong consensus for the upregulation of 5-HT1A receptors in the brains of subjects with schizophrenia. The augmented tonic stimulation of postsynaptic 5-HT1A 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-HT1A autoreceptors by low-dose 5-HT1A partial agonists, by means of inhibition of 5-HT neuronal activity, would produce a greater degree of decrease in the stimulation of postsynaptic 5-HT1A receptors in patients with schizophrenia compared with psychiatrically normal subjects. Thus, low-dose 5-HT1A agonists improve memory function in patients with schizophrenia but not in normal subjects. 5-HT: 5-hydroxytryptamine. Redrawn from.[92]

Other investigators have reported that buspirone may be efficacious in the treatment of tardive dyskinesia[95] but not acute akathisia.[96] Our preliminary analysis suggests buspirone 30 mg/day added to treatment with atypical antipsychotic drugs, such as olanzapine and risperidone, produced limited change in these neurologic signs in a randomly assigned double-blind placebo-controlled study [Sumiyoshi T et al., Unpublished Data].

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