The Effect of Paroxetine on 5-HT_2A Receptors in Depression: An [¹⁸F]Setoperone PET Imaging Study

OBJECTIVE: In the cortex of animals, serotonin (5-HT) levels increase after several weeks of treatment with selective serotonin reuptake inhibitors (SSRIs). Studies using an intrasubject design to examine the effects of SSRI treatment on 5-HT_2A receptors in the cortex of drug-free depressed patients are needed. In theory, agonist stimulation of 5-HT_2A receptors could be relevant to SSRI treatment by promoting neuronal growth and survival as well as direct elevation of mood. The objective of this study was to evaluate the effect of 6 weeks of paroxetine treatment on 5-HT_2A receptors in depressed patients. METHOD: After a medication-free period of at least 3 months, 19 depressed patients were treated for 6 weeks with paroxetine, 20 mg/day. The authors used [¹⁸F]setoperone and positron emission tomography to assess 5-HT_2A receptor binding potential in the patients before and after treatment and in 19 age-matched healthy subjects. RESULTS: 5-HT_2A binding potential declined with age in all cortical regions in the depressed and healthy subjects. There was a significant interaction between age and treatment effect on 5-HT_2A binding potential in all cortical regions. Subjects aged 20 to 30 years had a 10% decrease in 5-HT_2A binding potential after treatment, whereas subjects aged 30 to 40 had no change. No regional differences in 5-HT_2A binding potential between depressed and healthy subjects were found. CONCLUSIONS: 5-HT_2A receptors down-regulate in young depressed subjects after treatment with paroxetine, but this down-regulation attenuates with age. This suggests that over 6 weeks paroxetine treatment increases 5-HT agonism on 5-HT_2A receptors in the cortex of young patients with depression.