Serotonin Transporter Occupancy of Five Selective Serotonin Reuptake Inhibitors at Different Doses: An [11C]DASB Positron Emission Tomography Study

• Published in: The American journal of psychiatry 2004-05, Vol.161 (5), p.826-835
• Main Authors: Meyer, Jeffrey H., Wilson, Alan A., Sagrati, Sandra, Hussey, Doug, Carella, Anna, Potter, William Z., Ginovart, Nathalie, Spencer, Edgar P., Cheok, Andy, Houle, Sylvain
• Format: Article
• Language: English
• Subjects: Adult; Antidepressants; Benzylamines; Biological and medical sciences; Carbon Radioisotopes; Carrier Proteins - drug effects; Carrier Proteins - metabolism; Citalopram - pharmacokinetics; Citalopram - therapeutic use; Clinical outcomes; Corpus Striatum - diagnostic imaging; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Cyclohexanols - pharmacokinetics; Cyclohexanols - therapeutic use; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug therapy; Female; Fluoxetine - pharmacokinetics; Fluoxetine - therapeutic use; Humans; Male; Medical sciences; Membrane Glycoproteins - drug effects; Membrane Glycoproteins - metabolism; Membrane Transport Proteins; Mental disorders; Middle Aged; Nerve Tissue Proteins; Neuropharmacology; Paroxetine - pharmacokinetics; Paroxetine - therapeutic use; Pharmacology. Drug treatments; Psychiatry; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Serotonin - metabolism; Serotonin Plasma Membrane Transport Proteins; Serotonin Uptake Inhibitors - pharmacokinetics; Serotonin Uptake Inhibitors - therapeutic use; Sertraline - pharmacokinetics; Sertraline - therapeutic use; Tomography; Tomography, Emission-Computed; Venlafaxine Hydrochloride
• ISSN: 0002-953X; 1535-7228
• DOI: 10.1176/appi.ajp.161.5.826

OBJECTIVE: Minimum therapeutic doses of paroxetine and citalopram produce 80% occupancy for the serotonin (5-HT) transporter (5-HTT). The authors used [11C]DASB positron emission tomography to measure occupancies of three other selective serotonin reuptake inhibitors (SSRIs) at minimum therapeutic doses. The relationship between dose and occupancy was also investigated. METHOD: Striatal 5-HTT binding potential was measured in 77 subjects before and after 4 weeks of medication administration. Binding potential is proportional to the density of receptors not blocked by medication. Subjects received citalopram, fluoxetine, sertraline, paroxetine, or extended-release venlafaxine. Healthy subjects received subtherapeutic doses; subjects with mood and anxiety disorders received therapeutic doses. Percent reduction in 5-HTT binding potential for each medication and dose was calculated. To obtain test-retest data, binding potential was measured before and after 4 weeks in six additional healthy subjects. RESULTS: Substantial occupancy occurred at subtherapeutic doses for all SSRIs. Compared to test-retest data, each drug at the minimum therapeutic dose had a significant effect on striatal 5-HTT binding potential. Mean occupancy at this dose was 76%-85%. At higher plasma SSRI concentrations, 5-HTT occupancy tended to increase above 80%. For each drug, as the dose (or plasma level) increased, occupancy increased nonlinearly, with a plateau for higher doses. CONCLUSIONS: At tolerable doses, SSRIs have increasing occupancy with increasing plasma concentration or dose. Occupancy of 80% across five SSRIs occurs at minimum therapeutic doses. This suggests that 80% 5-HTT blockade is important for therapeutic effect. Occupancy should be measured during development of antidepressant compounds targeting the 5-HTT.