NDLI: A Mathematical Model for Paroxetine Antidepressant Effect Time Course and Its Interaction with Pindolol

Content Provider	Springer Nature Link
Author	Gruwez, Berangere Dauphin, Alain Tod, Michel
Copyright Year	2005
Abstract	Although selective 5-HT reuptake inhibitors (SSRIs) block monoamine uptake within hours of administration to patients, their full clinical effect does not appear until 2–4 weeks after treatment onset. Pindolol, a betablocker with weak partial 5-HT$_{1A}$ receptor agonist activity has been shown to produce a more rapid onset of antidepressant action of SSRIs. Howewer, the optimal dosing schedule of pindolol remains controversial. Building on a set-point model described previously for the hypothermic effect of 5-HT agonists, we have developed a model based on the concept of homeostatic control mechanisms, in which SSRIs exert their antidepressant effect by increasing the transduction set-point of the postsynaptic 5-HT$_{1A}$ receptor, and pindolol exerts its effect by increasing the rate of feedback mechanisms. The predictive distribution of the proportion of responders at each day of measurement (based on population simulation from the model) was not significantly different from the proportions observed in two published clinical trials, one with fluoxetine, the other with paroxetine alone or combined with pindolol. The model was applied to the simulation of paroxetine response (clinical score) time course with or without pindolol, after administration of different doses of each drug. The simulated total scores on the MADR scale obtained after treatment with paroxetine alone (20 mg/day) or paroxetine (20 mg/day) with different doses of pindolol (1.5, 7.5 and 37.5 mg/day) support that the reason for inconstant pindolol efficacy is that the 7.5 mg dose is too low. The model might be useful as a basis for clinical trial simulation
Starting Page	663
Ending Page	683
Page Count	21
File Format	PDF
ISSN	1567567X
Journal	Journal of Pharmacokinetics and Pharmacodynamics
Volume Number	32
Issue Number	5-6
e-ISSN	15738744
Language	English
Publisher	Kluwer Academic Publishers-Plenum Publishers
Publisher Date	2005-01-01
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	SSRI pindolol pharmacokinetic pharmacodynamic modeling clinical trial simulation set-point Pharmacology/Toxicology Pharmacy Veterinary Medicine Biochemistry Biomedical Engineering
Content Type	Text
Resource Type	Article
Subject	Pharmacology

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