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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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.

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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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    ABSTRACT: Disinhibition is a cardinal feature of the behavioural variant of frontotemporal dementia, presenting as impulsive and impetuous behaviours that are often difficult to manage. The options for symptomatic treatments are limited, but a potential target for therapy is the restoration of serotonergic function, which is both deficient in behavioural variant frontotemporal dementia and closely associated with inhibitory control. Based on preclinical studies and psychopharmacological interventions in other disorders, we predicted that inhibition would be associated with the right inferior frontal gyrus and dependent on serotonin. Using magnetoencephalography and electroencephalography of a Go-NoGo paradigm, we investigated the neural basis of behavioural disinhibition in behavioural variant frontotemporal dementia and the effect of selective serotonin reuptake inhibition on the neural systems for response inhibition. In a randomized double-blinded placebo-controlled crossover design study, 12 patients received either a single 30 mg dose of citalopram or placebo. Twenty age-matched healthy controls underwent the same magnetoencephalography/electroencephalography protocol on one session without citalopram, providing normative data for this task. In the control group, successful NoGo trials evoked two established indices of successful response inhibition: the NoGo-N2 and NoGo-P3. Both of these components were significantly attenuated by behavioural variant frontotemporal dementia. Cortical sources associated with successful inhibition in control subjects were identified in the right inferior frontal gyrus and anterior temporal lobe, which have been strongly associated with behavioural inhibition in imaging and lesion studies. These sources were impaired by behavioural variant frontotemporal dementia. Critically, citalopram enhanced the NoGo-P3 signal in patients, relative to placebo treatment, and increased the evoked response in the right inferior frontal gyrus. Voxel-based morphometry confirmed significant atrophy of inferior frontal gyrus, alongside insular, orbitofrontal and temporal cortex in our patient cohort. Together, these data suggest that the dysfunctional prefrontal cortical systems underlying response inhibition deficits in behavioural variant frontotemporal dementia can be partially restored by increasing serotonergic neurotransmission. The results support a translational neuroscience approach to impulsive neurological disorders and indicate the potential for symptomatic treatment of behavioural variant frontotemporal dementia including serotonergic strategies to improve disinhibition. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.
    Brain 05/2015; 138(7). DOI:10.1093/brain/awv133 · 9.20 Impact Factor
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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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    ABSTRACT: Many lines of evidence suggest the role of serotonin transporter (SERT)-mediated reuptake of serotonin in the pathophysiology and treatment of major depressive disorder (MDD). The study aimed to examine whether the pretreatment SERT binding potential or SERT binding ratio between terminal projection regions relative to the midbrain raphe nuclei was associated with treatment outcome to SERT-targeted antidepressants. We recruited 39 antidepressant-naïve patients with MDD and 39 heathy controls. Positron emission tomography with N,N-dimethyl-2-(2-amino-4-[(18)F]fluorophenylthio)benzylamine (4-[(18)F]-ADAM) was used to measure in vivo SERT availability prior to antidepressant treatment. The 21-item Hamilton Depression Rating Scale (HDRS) was use to assess the severity of depression from baseline to week 6. All the patients with MDD had HDRS scores of 18 or more. Pretreatment SERT binding in the thalamus and striatum positively correlated with an early reduction in HDRS scores at week 3. Non-responders and dropout patients showed a proportionate reduction in SERT binding in the terminal projection regions and midbrain compared to healthy controls. In contrast, a disproportionate reduction in SERT binding in the terminal projection regions relative to midbrain was observed in responders. The results of this study suggested that a disproportionate reduction in SERT binding between terminal projection regions and midbrain may predict better treatment outcome in patients with MDD. © The Author 2015. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 01/2015; 18(7). DOI:10.1093/ijnp/pyu120 · 4.01 Impact Factor
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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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    ABSTRACT: Escitalopram the S-enantiomer of the racemate citalopram, is clinically more effective than citalopram in the treatment of major depressive disorder. However, the precise mechanism by which escitalopram achieves superiority over citalopram is yet to be determined. It has been hypothesized that the therapeutically inactive R-enantiomer competes with the serotonin-enhancing S-enantiomer at a low-affinity allosteric site on serotonin reuptake transporters (SERTs), and reduces the effectiveness of the S-enantiomer at the primary, high-affinity serotonin-binding site. This study summarizes the results of two recent single-photon emission computerized tomography studies measuring SERT occupancy in citalopram-treated and escitalopram-treated healthy volunteers, after a single dose and multiple doses (i.e. under steady-state conditions). The single-dose study showed no attenuating effect of R-citalopram. After multiple dosing, however, SERT occupancy was significantly reduced in the presence of R-citalopram. Under steady-state conditions, R-enantiomer concentrations were greater than for the S-enantiomer because of slower clearance of R-citalopram. A pooled analysis suggests that build-up of the R-enantiomer after repeated citalopram dosing may lead to increased inhibition of S-enantiomer occupancy of SERT. This review adds to the growing body of evidence regarding differences in the dynamics of SERT occupancy, that is, molecular mechanisms underlying the often-observed superior clinical efficacy of escitalopram compared with citalopram in major depressive disorder.
    International clinical psychopharmacology 06/2009; 24(3):119-25. DOI:10.1097/YIC.0b013e32832a8ec8 · 2.46 Impact Factor
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