In vivo imaging of serotonin transporter occupancy by means of SPECT and [123I]ADAM in healthy subjects administered different doses of escitalopram or citalopram.
BACKGROUND
Escitalopram is a dual serotonin reuptake inhibitor (SSRI) approved for the treatment of depression and anxiety disorders. It is the S-enantiomer of citalopram, and is responsible for the serotonin reuptake activity, and thus for its pharmacological effects. Previous studies pointed out that clinically efficacious doses of other SSRIs produce an occupancy of the serotonin reuptake transporter (SERT) of about 80% or more. The novel radioligand [123I]ADAM and single photon emission computer tomography (SPECT) were used to measure midbrain SERT occupancies for different doses of escitalopram and citalopram.


METHODS
Twenty-five healthy subjects received a single dose of escitalopram [5 mg (n=5), 10 mg (n=5), and 20 mg (n=5)] or citalopram [(10 mg (n=5) and 20 mg (n=5)]. Midbrain SERT binding was measured with [(123)I]ADAM and SPECT on two study days, once without study drug and once 6 h after single dose administration of the study drug. The ratio of midbrain-cerebellum/cerebellum was the outcome measure (V3") for specific binding to SERT in midbrain. Subsequently, SERT occupancy levels were calculated using the untreated baseline level for each subject. An Emax model was used to describe the relationship between S-citalopram concentrations and SERT occupancy values. Additionally, four subjects received placebo to determine test-retest variability.


RESULTS
Single doses of 5, 10, or 20 mg escitalopram led to a mean SERT occupancy of 60+/-6, 64+/-6, and 75+/-5%, respectively. SERT occupancies for subjects treated with single doses of 10 and 20 mg citalopram were 65+/-10 and 70+/-6%, respectively. A statistically significant difference was found between SERT occupancies after application of 10 and 20 mg escitalopram, but not for 10 and 20 mg citalopram. There was no statistically significant difference between the SERT occupancies of either 10 mg citalopram or 10 mg escitalopram, or between 20 mg citalopram and 20 mg escitalopram. Emax was slightly higher after administration of citalopram (84%) than escitalopram (79%). In the test-retest study, a mean SERT "occupancy" of 4% was found after administration of placebo, the intraclass correlation coefficient was 0.92, and the repeatability coefficient was 0.25.


CONCLUSIONS
SPECT and [123I]ADAM were used to investigate SERT occupancies after single doses of escitalopram or citalopram. The test-retest study revealed good reproducibility of SERT quantification. Similar SERT occupancies were found after administration of equal doses (in respect to mg) of escitalopram and citalopram, giving indirect evidence for a fractional blockade of SERT by the inactive R-citalopram.
Klein
N
N
Department of General Psychiatry, University Hospital for Psychiatry, Währinger Gürtel, 18-20A-1090, Vienna, Austria.
Sacher
J
J
Geiss-Granadia
T
T
Attarbaschi
T
T
Mossaheb
N
N
Lanzenberger
R
R
Pötzi
C
C
Holik
A
A
Spindelegger
C
C
Asenbaum
S
S
Dudczak
R
R
Tauscher
J
J
Kasper
S
S
D000284:Administration, Oral; D000328:Adult; D017109:Akathisia, Drug-Induced / Q000209:etiology; D019540:Area Under Curve; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D002928:Cinanserin / Q000008:administration & dosage / Q000031:analogs & derivatives; D015283:Citalopram / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D008636:Mesencephalon / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D008657:Metabolic Clearance Rate; D009325:Nausea / Q000139:chemically induced; D011485:Protein Binding; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D012893:Sleep Wake Disorders / Q000139:chemically induced; D013237:Stereoisomerism; D013997:Time Factors; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*; D014987:Xerostomia / Q000139:chemically induced
D002928:Cinanserin; D015283:Citalopram; D007457:Iodine Radioisotopes; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C413491:2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine