Klein N, Sacher J, Geiss-Granadia T, Attarbaschi T, Mossaheb N, Lanzenberger R et al. In vivo imaging of serotonin transporter occupancy by means of SPECT and [123I]ADAM in healthy subjects administered different doses of escitalopram or citalopram. Psychopharmacology (Berl) 188: 263-272

Department of General Psychiatry, University Hospital for Psychiatry, Währinger Gürtel, 18-20A-1090, Vienna, Austria.
Psychopharmacology (Impact Factor: 3.88). 11/2006; 188(3):263-72. DOI: 10.1007/s00213-006-0486-0
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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.
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.
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.
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.

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    • "is complex, but based on animal studies (Cremers et al., 2009; Karlsson et al., 2013) and observed midbrain SERT occupancy in healthy human volunteers (Klein et al., 2006), we expected peak CNS levels over this timeframe. Mean plasma levels after citalopram, measured by a specific validated high performance chromatographic method, were 38.6 ng/ml (range 23.8– 55.7 ng/ml) and after placebo, 0 ng/ml. "
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    • "Therefore, SERT binding could be a state marker for patients with MDD, and dynamic changes in SERT binding might be associated with pathophysiology of MDD and its treatment response. Previous studies that examined the antidepressant occupancy of SERT and its relationship to treatment response have reliably shown an 80% striatal occupancy of the SERT after a 4-week treatment with selective serotonin reuptake inhibitors (SSRIs; Meyer et al., 2001, 2004b; Erlandsson et al., 2005; Klein et al., 2006; Parsey et al., 2006c). Nonetheless, these findings cannot explain the individual differences observed in antidepressant efficacy and treatment dropout rate. "
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    • "The extent to which R-citalopram inhibits the S-enantiomer occupancy of SERT is greater with multiple dosing, because of the slower metabolism and elimination of R-citalopram, thereby reducing the effectiveness of escitalopram at the primary SERT-binding site. These post-hoc pooled analysis, together with the results of the studies by Klein et al. (2006, 2007) provide additional evidence to support the putative time-dependent physiological mechanisms by which escitalopram achieves superior clinical effectiveness over citalopram. "
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