Improving the treatment of schizophrenia: role of 5-HT receptors in modulating cognitive and extrapyramidal motor functions.

Patients with schizophrenia exhibit various clinical symptoms including positive and negative symptoms, neurocognitive impairments and mood disturbances. Although a series of second generation antipsychotics (SGAs) (e.g., risperidone, olanzapine and quetiapine) have been developed in the past two decades, clinical reports do not necessarily show advantages over first generation antipsychotics (FGAs) in the treatment of schizophrenia, especially in their efficacy against cognitive impairment and ability to cause extrapyramidal side effects (EPS). Recently, several lines of studies have revealed therapeutic roles of 5-HT receptors in modulating cognitive impairments and extrapyramidal motor disorders. Specifically, inhibition of 5-HT1A, 5-HT3 and 5-HT6 receptors or activation of 5-HT4 receptors alleviates cognitive impairments (e.g., deficits in learning and memory). In addition, stimulation of 5-HT1A receptors or inhibition of 5-HT3 and 5-HT6 receptors as well as 5-HT2A/2C receptors can ameliorate extrapyramidal motor disorders. Thus, controlling the activity of 5-HT1A, 5-HT3 or 5-HT6 receptors seems to provide benefits by both alleviating cognitive impairments and reducing antipsychotic-induced EPS. This article reviews the functional roles and mechanisms of 5-HT receptors in the treatment of schizophrenia, focusing on the serotonergic modulation of cognitive and extrapyramidal motor functions, and illustrates future therapeutic strategies.