Estimation of the optimal dosing regimen of escitalopram in dogs: A dose occupancy study with [11C]DASB

Abstract

Although the favourable characteristics of escitalopram as being the most selective serotonin reuptake inhibitor and having an increased therapeutic efficacy via binding on an additional allosteric binding site of the serotonin transporter, its dosing regimen has not yet been optimized for its use in dogs. This study aimed to estimate the optimal dosing frequency and the required dose for achieving 80% occupancy of the serotonin transporters in the basal ganglia. The dosing frequency was investigated by determining the elimination half-life after a four day oral pre-treatment period with 0.83 mg/kg escitalopram (3 administrations/day) and a subsequent i.v. injection 0.83 mg/kg. Blood samples were taken up to 12 hours after i.v. injection and the concentration of escitalopram in plasma was analysed via LC-MSMS. The dose-occupancy relationship was then determined by performing two PET scans in five adult beagles: a baseline PET scan and a second scan after steady state conditions were achieved following oral treatment with a specific dose of escitalopram ranging from 0.5 to 2.5 mg/kg/day. As the elimination half-life was determined to be 6.7 hours a dosing frequency of three administrations a day was proposed for the second part of the study. Further it was opted for a treatment period of four days, which well exceeded the minimum period to achieve steady state conditions. The optimal dosing regimen to achieve 80% occupancy in the basal ganglia and elicit a therapeutic effect, was calculated to be 1.85 mg/kg/day, divided over three administrations. Under several circumstances, such as insufficient response to other SSRIs, concurrent drug intake or in research studies focused on SERT, the use of escitalopram can be preferred over the use of the already for veterinary use registered fluoxetine, however, in case of long-term treatment with escitalopram, regularly cardiac screening is recommended.

Accelerated HF-rTMS Modifies SERT Availability in the Subgenual Anterior Cingulate Cortex: A Canine [11C]DASB Study on the Serotonergic System

“…First, we hypothesized that [ 11 C]-DASB binding alterations occurred in the regions with high SERT density. In line with antidepressant intake, a higher dose resulted in higher occupancy of the SERT binding sites [ 6 ], we expected SERT decreases, more pronounced with the active 20 sessions as compared to the 5-session aHF-rTMS protocol. We expected no influences on any of the measurements following sham aHF-rTMS.…”

“…Consequentially, by administering SSRIs, a decreased 5-HT re-uptake speed is acquired, which is accompanied by an improvement of depression [ 2 ]. As such, SSRIs mediate a decrease in the SERT density by regulation of SERT expressions [ 3 , 4 , 5 ] or by direct occupancy, which can account for the long-term clinical effects of this kind of antidepressant treatment [ 6 ]. Unsurprisingly, brain regions with the highest density of SERT are involved in the regulation of mood, anxiety, and fear, and they comprise the thalamus, hypothalamus, amygdalae, raphe nuclei, caudate, and putamen [ 2 , 7 ].…”

“…In a former study in humans and non-human primates, by measuring the changes of 5-HT1B receptor binding induced by escitalopram, they found the serotonin concentration decreases in serotonergic projection areas after a single, but clinically relevant dose of escitalopram, which may contribute to the understanding of the time-lag between SERT occupancy and the clinical effect of SSRIs [ 8 ]. In dogs, areas with high and moderate SERT binding were affected by repeated oral escitalopram administration but cortical binding was not influenced [ 6 ]. Another study using single IV-administered vortioxetine and citalopram in non-human primates reported a decrease in SERT binding in the caudate nucleus and putamen [ 9 ].…”

The use of anxiolytic drugs for the correction of behavioral disorders in mammals

“…For many years, selective serotonin reuptake inhibitors have been taking the leading position in the treatment of emotional disorders in animals. Among them, a prominent place is occupied by escitalopram, which acts by blocking the serotonin transporter (Taylor et al, 2017).…”

Dogs aren’t jealous – they are just asking for accurate information

“…The types of imaging studies pursued by Berns and colleagues, especially when coupled with the imaging studies of behavioral pathologies (Peremans et al, 2003(Peremans et al, , 2005(Peremans et al, , 2006Vermeire et al, 2011Vermeire et al, , 2012 and interventional studies that show how dogs with specific suites of behaviors respond to psychopharmacological interventions (Overall, 1994(Overall, , 2001King et al, 2000;Simpson et al, 2007;Korpivaara et al, 2017;Taylor et al, 2017), can be our window into dogs in translation, as translated by native speakers. For this to happen, we need to let the dogs speak without anthropomorphism or anthropocentrism -and we need to listen without labels.…”