In vivo imaging of serotonin transporter occupancy by means of SPECT and [123I]ADAM in healthy subjects administered different doses of escitalopram or citalopram.

Department of General Psychiatry, University Hospital for Psychiatry, Währinger Gürtel, 18-20A-1090, Vienna, Austria.
Psychopharmacology (Impact Factor: 3.99). 11/2006; 188(3):263-72. DOI: 10.1007/s00213-006-0486-0
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Summary form only given, as follows. The authors explored the possibility that the correct encoding of the information at the input-layer level in a neural network (not at the hidden-layer level, as usually assumed) is a requisite for its correct representation. They proposed a mechanism that calculates the psychophysical function of the input data to obtain the canonical coordinates with which the network will operate and then filters the resulting values using a maximum entropy algorithm to eliminate the spurious information that inevitably arises using psychophysical functions. They considered the possible implications of the proposed model, especially the last part, which could be viewed as a primitive model of consciousness
  • [Show abstract] [Hide abstract]
    ABSTRACT: Escitalopram appears to be a superior antidepressant to racemic citalopram. It has been hypothesized that binding of R-citalopram to the serotonin transporter (SERT) antagonizes escitalopram binding to and inhibition of the SERT, thereby curtailing the elevation of extracellular 5-hydroxytryptamine (5-HTExt), and hence antidepressant efficacy. Further, it has been suggested that a putative allosteric binding site is important for binding of escitalopram to the primary, orthosteric, site, and for R-citalopram's inhibition hereof. Primary: Investigate at the human (h)SERT, at clinical relevant doses, whether R-citalopram antagonizes escitalopram-induced 5-HTExt elevation. Secondary: Investigate whether abolishing the putative allosteric site affects escitalopram-induced 5-HTExt elevation and/or modulates the effect of R-citalopram. Recombinant generation of hSERT transgenic mice; in vivo microdialysis; SERT binding; pharmacokinetics; 5-HT sensitive behaviors (tail suspension, marble burying). We generated mice expressing either the wild-type human SERT (hSERT(WT)) or hSERT carrying amino acid substitutions (A505V, L506F, I507L, S574T and I575T) collectively abolishing the putative allosteric site (hSERT(ALI/VFL+SI/TT)). One mg/kg escitalopram yielded clinical relevant plasma levels and brain levels consistent with therapeutic SERT occupancy. The hSERT mice showed normal basal 5-HTExt levels. Escitalopram-induced 5-HTExt elevation was not decreased by R-citalopram co-treatment and was unaffected by loss of the allosteric site. The behavioral effects of the clinically relevant escitalopram dose were small and tended to be enhanced by R-citalopram co-administration. We find no evidence that R-citalopram directly antagonizes escitalopram or that the putative allosteric site is important for hSERT inhibition by escitalopram.
    Psychopharmacology 05/2014; · 3.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The presence of depression in patients with diabetes mellitus is reported to be associated with poor glycemic control and an increased risk of diabetic complications. Treatment of depression with selective serotonin reuptake inhibitors (SSRIs) may improve glycemic control and may be beneficial for patients with comorbid depression and diabetes. To study the effect of Escitalopram (SSRI) in patients with diabetes mellitus with comorbid depression and the relationship of treatment response for depression and glycemic control. 40 patients received open-label Escitalopram therapy for up to 12 weeks. Clinical outcome measures included Hamilton Depression rating scale (HAM-D) assessment at 3, 6, and 12 weeks. In addition, fasting and post-prandial plasma glucose level, weight and waist circumference, glycosylated hemoglobin level (HbA1C), lipid profile, renal function test and fundus examination were done before and during Escitalopram therapy. A significant decline in mean HAM-D scores was observed 3 weeks onwards till the end of the study during Escitalopram therapy. There was a corresponding decline in mean fasting and post-prandial plasma glucose level at 6 and 12 weeks respectively and glycosylated hemoglobin level at 12 weeks was observed. Escitalopram is effective in treating depression in patients with diabetes mellitus, and has beneficial effects on glycemic control.
    Asian journal of psychiatry. 10/2013; 6(5):364-8.

Full-text (2 Sources)

Available from
May 22, 2014