Serotonin transporter occupancy induced by paroxetine in patients with major depression disorder: a 123I-ADAM SPECT study.
BACKGROUND
To assess the paroxetine-induced serotonin transporter (SERT) occupancy (SERTocc) using in vivo (123)I-ADAM SPECT.


OBJECTIVE
(123)I-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.


METHODS
Measures of SERT availability by means of (123)I-ADAM SPECT were obtained in ten MDD patients before and after 4- to 6-week treatment with paroxetine 20 mg/day. (123)I-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 SERTocc(max) = 70.5% and a Cp(50) = 2.7 ng/ml.


CONCLUSIONS
Using (123)I-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 (123)I-ADAM SPECT-measured SERTocc. This approach may be useful for pharmacokinetic-pharmacodynamic relationships in drug development.
Catafau
Ana M
AM
Experimental Medicine, Clinical Pharmacology Discovery Medicine, Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, 08005, Barcelona, Spain. ana.m.catafau@gsk.om
Perez
Victor
V
Plaza
Pedro
P
Pascual
Juan-Carlos
JC
Bullich
Santiago
S
Suarez
Marina
M
Penengo
Maria M
MM
Corripio
Iluminada
I
Puigdemont
Dolors
D
Danus
Monica
M
Perich
Javier
J
Alvarez
Enric
E
D000328:Adult; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002928:Cinanserin / Q000031:analogs & derivatives / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D017374:Paroxetine / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D011869:Radioligand Assay / Q000379:methods; D012702:Serotonin Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D013788:Thalamus / Q000187:drug effects / Q000378:metabolism; D015899:Tomography, Emission-Computed, Single-Photon; D016896:Treatment Outcome
D002928:Cinanserin; D007457:Iodine Radioisotopes; D017374:Paroxetine; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C413491:2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine