Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study

Am J Psychiatry. 2004 May;161(5):826-35. doi: 10.1176/appi.ajp.161.5.826.

Abstract

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.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Benzylamines
  • Carbon Radioisotopes
  • Carrier Proteins / drug effects
  • Carrier Proteins / metabolism*
  • Citalopram / pharmacokinetics
  • Citalopram / therapeutic use
  • Corpus Striatum / diagnostic imaging*
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism*
  • Cyclohexanols / pharmacokinetics
  • Cyclohexanols / therapeutic use
  • Delayed-Action Preparations
  • Dose-Response Relationship, Drug
  • Female
  • Fluoxetine / pharmacokinetics
  • Fluoxetine / therapeutic use
  • Humans
  • Male
  • Membrane Glycoproteins / drug effects
  • Membrane Glycoproteins / metabolism*
  • Membrane Transport Proteins*
  • Middle Aged
  • Nerve Tissue Proteins*
  • Paroxetine / pharmacokinetics
  • Paroxetine / therapeutic use
  • Serotonin / metabolism*
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors / pharmacokinetics
  • Serotonin Uptake Inhibitors / therapeutic use*
  • Sertraline / pharmacokinetics
  • Sertraline / therapeutic use
  • Tomography, Emission-Computed*
  • Venlafaxine Hydrochloride

Substances

  • Benzylamines
  • Carbon Radioisotopes
  • Carrier Proteins
  • Cyclohexanols
  • Delayed-Action Preparations
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine
  • Nerve Tissue Proteins
  • SLC6A4 protein, human
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • Citalopram
  • Serotonin
  • Paroxetine
  • Venlafaxine Hydrochloride
  • Sertraline