Clinical doses of atomoxetine significantly occupy both norepinephrine and serotonin transports: Implications on treatment of depression and ADHD (original) (raw)
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NeuroImage, 2011
The objective of this study was to evaluate the suitability of [ 11 C]MRB for drug occupancy studies of NET using atomoxetine (ATX), a NET uptake inhibitor used in the treatment of depression and attention-deficit hyperactivity disorder (ADHD). A second goal of the study was identification of a suitable reference region. Ten PET studies were performed in three anesthetized rhesus monkeys following an infusion of ATX or placebo. [ 11 C]MRB arterial input functions and ATX plasma levels were also measured. A dosedependent reduction of [ 11 C]MRB volume of distribution was observed after correction for [ 11 C]MRB plasma free fraction. ATX IC 50 was estimated to be 31 ± 10 ng/mL plasma. This corresponds to an effective dose (ED 50) of 0.13 mg/kg, which is much lower than the therapeutic dose of ATX in ADHD (1.0-1.5 mg/kg). [ 11 C]MRB binding potential BP ND in the thalamus was estimated to be 1.8 ± 0.3. Defining a reference region for a NET radiotracer is challenging due to the widespread and relatively uniform distribution of NET in the brain. Three regions were evaluated for use as reference region: caudate, putamen and occipital cortex. Caudate was found to be the most suitable for preclinical drug occupancy studies in rhesus monkeys. The IC 50 estimate obtained using MRTM2 BP ND without arterial blood sampling was 21 ± 3 ng/mL (using caudate as the reference region). This study demonstrated that [ 11 C]MRB is suitable for drug occupancy studies of NET.
Molecular Psychiatry, 2021
Brain imaging techniques enable the visualization of serotonin transporter (SERT) occupancy as a measure of the proportion of SERT blocked by an antidepressant at a given dose. We aimed to systematically review the evidence on the relationship between antidepressant dose and SERT occupancy. We searched PubMed and Embase (last search 20 May 2021) for human in vivo, within-subject PET, or SPECT studies measuring SERT occupancy at any dose of any antidepressant with highly selective radioligands ([11C]-DASB, [123I]-ADAM, and [11C]-MADAM). We summarized and visualized the dose-occupancy relationship for antidepressants across studies, overlaying the plots with a curve based on predicted values of a standard 2-parameter Michaelis–Menten model fitted using the observed data. We included seventeen studies of 10 different SSRIs, SNRIs, and serotonin modulators comprising a total of 294 participants, involving 309 unique occupancy measures. Overall, following the Michaelis–Menten equation, S...
Pharmacological profile of antidepressants and related compounds at human monoamine transporters
European Journal of Pharmacology, 1997
Using radioligand binding assays, we determined the equilibrium dissociation constants (KD's) for 37 antidepressants, three of their metabolites (desmethylcitalopram, desmethylsertraline, and norfluoxetine), some mood stabilizers, and assorted other compounds (some antiepileptics, Ca2+ channel antagonists, benzodiazepines, psychostimulants, antihistamines, and monoamines) for the human serotonin, norepinephrine, and dopamine transporters. Among the compounds that we tested, mazindol was the most potent at the human norepinephrine and dopamine transporters with KD's of 0.45 +/- 0.03 nM and 8.1 +/- 0.4 nM, respectively. Sertraline (KD = 25 +/- 2 nM) and nomifensine (56 +/- 3 nM) were the two most potent antidepressants at the human dopamine transporter. We showed significant correlations for antidepressant affinities at binding to serotonin (R = 0.93), norepinephrine (R = 0.97), and dopamine (R = 0.87) transporters in comparison to their respective values for inhibiting uptake of monoamines into rat brain synaptosomes. These data are useful in predicting some possible adverse effects and drug-drug interactions of antidepressants and related compounds.
Psychopharmacology, 2006
Rationale To assess the paroxetine-induced serotonin transporter (SERT) occupancy (SERTocc) using in vivo 123I-ADAM SPECT. Objectives 123I-ADAM SPECT was used to investigate the SERTocc induced by paroxetine in major depression disorder (MDD) patients, to compare the SERT availability in drug-free MDD patients and healthy volunteers, and to study the relationship between paroxetine plasma concentrations (Cp) and SERTocc. Materials and methods Measures of SERT availability by means of 123I-ADAM SPECT were obtained in ten MDD patients before and after 4- to 6-week treatment with paroxetine 20 mg/day. 123I-ADAM SPECT measures of SERT availability from a group of ten previously studied age-matched healthy volunteers were used for comparison. The relationship between percentages of SERTocc and paroxetine Cp was studied using an E max model. Results Mean SERTocc values were 66.4 ± 9.5% in midbrain, 63.0 ± 9.6% in thalamus, and 61.3 ± 10.9% in striatum. No significant differences in SERTocc were found among these three regions. No significant differences in mean SERT availability were found in any region between drug-free MDD patients (midbrain = 1.14 ± 0.15; thalamus = 0.85 ± 0.13; striatum = 0.70 ± 0.07) and healthy volunteers (midbrain = 1.19 ± 0.22; thalamus = 0.96 ± 0.14; striatum = 0.67 ± 0.15). The E max model returned a SERToccmax = 70.5% and a Cp50 = 2.7 ng/ml. Conclusions Using 123I-ADAM SPECT, treatment with paroxetine 20 mg/day leads to more than 60% SERTocc on average in cerebral regions with known high SERT density. Data from this study do not support the existence of SERT availability differences between drug-free MDD patients and healthy volunteers. Finally, the E max model is suitable for the study of paroxetine Cp relationship to 123I-ADAM SPECT-measured SERTocc. This approach may be useful for pharmacokinetic–pharmacodynamic relationships in drug development.
Atomoxetine (ATX) is a non-stimulant drug approved for the treatment of children and adolescents with attention deficit/ hyperactivity disorder (ADHD). We aimed to study the excretion profile of ATX and its principal metabolites 4-hydroxyato-moxetine (4-OH-ATX) and N-desmethylatomoxetine (desmethyl-ATX) in oral fluid and plasma of ADHD paediatric subjects, after administration of different dosage regimens. Oral fluid and plasma samples were obtained from one child and five adolescents treated with different ATX doses (18–60 mg/day). ATX and its metabolites were measured in oral fluid and plasma by liquid chromatography-mass spectrometry (LC-MS). Apparent pharmacokinetic parameters of ATX in oral fluid and plasma were estimated for each subject. All analytes under investigation were detected in plasma samples with concentrations from 0.6 to 1065.7 ng/ml for ATX, 0.7 to 17.1 ng/ml for 4-OH-ATX and 0.7 to 126.2 ng/ml for desmethyl-ATX. Only ATX and 4-OH-ATX were detected in oral fluid samples with concentrations from 0.5 to 36.0 ng/ml and 0.5 to 4.7 ng/ml, respectively. ATX concentrations in oral fluid were between one and two orders of magnitude lower than those in plasma. 4-OH-ATX was found in oral fluid at a peak concentration approximately one-fourth those in plasma with a mean t max of 2.3 in plasma and 3.0 h in oral fluid. The correlations between ATX and 4-OH-ATX concentrations in the two biological fluids indicate that oral fluid concentrations of this drug and its principal metabolite may be a predictor of plasma concentrations, even if values are too low and variable to be considered an alternative to plasma.
Effects of citalopram infusion on the serotonin transporter binding of [11C]DASB in healthy controls
Journal of Cerebral Blood Flow & Metabolism, 2008
The positron emission tomography (PET) ligand [11C]DASB is currently the most widely used imaging agent for quantitative studies of the serotonin transporter (SERT) in human brain. The aim of this work was to assess the effects of an intravenous infusion of 10 mg citalopram, a selective serotonin reuptake inhibitor (SSRI), before the PET scan on the kinetics of [11C]DASB in arterial plasma and in selected brain regions. Four healthy male volunteers underwent two PET scans with a mean of 523 MBq injected activity after either placebo or Citalopram infusion in a randomised design. The Citalopram infusion led to a substantial increase of the area under the curve of the metabolite-corrected arterial plasma input function. Total volumes of distribution VT were estimated applying the Logan plot to regional time—activity curves or by generating parametric maps with spectral analysis. A mean reduction of the cerebellar VT of 19% with Logan analysis and of 24% with spectral analysis was obse...
In vivo visualization of serotonin transporters in the human brain during fluoxetine treatment
European Neuropsychopharmacology, 1999
b-CIT can be used as a tracer for SPECT to visualize serotonin transporters in the human brain. We present a case of bulimia nervosa and major depressive disorder, who had been treated with up to 60 mg / d fluoxetine for several weeks. Four hours after injection of the tracer more than 40% of serotonin transporters were blocked. To our knowledge, this is the first direct documentation of the pharmacodynamic action of fluoxetine in the human brain in vivo.