Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders

Recently, the addition of drugs with prominent 5-HT2 receptor antagonist properties (risperidone, olanzapine, mirtazapine, and mianserin) to selective serotonin reuptake inhibitors (SSRIs) has been shown to enhance therapeutic responses in patients with major depression and treatment-refractory obsessive-compulsive disorder (OCD). These 5-HT2 antagonists may also be effective in ameliorating some symptoms associated with autism and other pervasive developmental disorders (PDDs). At the doses used, these drugs would be expected to saturate 5-HT2A receptors. These findings suggest that the simultaneous blockade of 5-HT2A receptors and activation of an unknown constellation of other 5-HT receptors indirectly as a result of 5-HT uptake inhibition might have greater therapeutic efficacy than either action alone. Animal studies have suggested that activation of 5-HT1A and 5-HT2C receptors may counteract the effects of activating 5-HT2A receptors. Additional 5-HT receptors, such as the 5-HT1B/1D/5/7 receptors, may similarly counteract the effects of 5-HT2A receptor activation. These clinical and preclinical observations suggest that the combination of highly selective 5-HT2A antagonists and SSRIs, as well as strategies to combine high-potency 5-HT2A receptor and 5-HT transporter blockade in a single compound, offer the potential for therapeutic advances in a number of neuropsychiatric disorders.