Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study.
OBJECTIVE
Minimum therapeutic doses of paroxetine and citalopram produce 80% occupancy for the serotonin (5-HT) transporter (5-HTT). The authors used [(11)C]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.


METHODS
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.
Meyer
Jeffrey H
JH
Clarke Site, Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, 250 College St., Toronto, Ont. M5T 1R8, Canada. jmeyer@camhpet.on.ca
Wilson
Alan A
AA
Sagrati
Sandra
S
Hussey
Doug
D
Carella
Anna
A
Potter
William Z
WZ
Ginovart
Nathalie
N
Spencer
Edgar P
EP
Cheok
Andy
A
Houle
Sylvain
S
D000328:Adult; D001596:Benzylamines; D002250:Carbon Radioisotopes; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D015283:Citalopram / Q000493:pharmacokinetics / Q000627:therapeutic use; D003342:Corpus Striatum / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism*; D003511:Cyclohexanols / Q000493:pharmacokinetics / Q000627:therapeutic use; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D005260:Female; D005473:Fluoxetine / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism*; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009419:Nerve Tissue Proteins; D017374:Paroxetine / Q000493:pharmacokinetics / Q000627:therapeutic use; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020280:Sertraline / Q000493:pharmacokinetics / Q000627:therapeutic use; D014055:Tomography, Emission-Computed; D000069470:Venlafaxine Hydrochloride
D001596:Benzylamines; D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D015283:Citalopram; D003511:Cyclohexanols; D003692:Delayed-Action Preparations; D005473:Fluoxetine; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D017374:Paroxetine; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline; D000069470:Venlafaxine Hydrochloride; C420885:N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine; C493230:SLC6A4 protein, human