paroxetine, Paxil
Paroxetine-induced hyponatremia in older adults: a 12-week prospective study.

Fabian TJ, Amico JA, Kroboth PD, Mulsant BH, Corey SE, Begley AE, Bensasi SG, Weber E, Dew MA, Reynolds CF 3rd, Pollock BG.

Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA. fabiant msx.upmc.edu

BACKGROUND: Older depressed patients are at high risk for development of hyponatremia after initiation of the selective serotonin reuptake inhibitor paroxetine, despite clinical monitoring and preventive management. The purposes of this study were to determine the incidence and etiology of paroxetine-induced hyponatremia in older patients and to identify patient characteristics that may account for variability in susceptibility to this adverse event. METHODS: This prospective, longitudinal study was conducted in a university-based ambulatory psychiatric research clinic from August 1999 through September 2001. Patients included 75 men and women aged 63 through 90 years (mean +/- SD age, 75.3 +/- 6.0 years) who received a diagnosis of a current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, major depressive episode and were prescribed paroxetine. We monitored plasma sodium levels before initiating paroxetine therapy and after 1, 2, 4, 6, and 12 weeks of treatment. In a subset of individuals, we measured levels of antidiuretic hormone, glucose, serum urea nitrogen, and creatinine. Hyponatremia was defined as a plasma sodium level of less than 135 mEq/L after initiation of paroxetine therapy. RESULTS: Hyponatremia developed in 9 (12%) of the 75 patients after initiation of paroxetine treatment. Mean +/- SD time to development of hyponatremia was 9.3 +/- 4.7 days (median, 9 days; range, 1-14 days; n = 8). In the multivariate regression, lower body mass index and lower baseline plasma sodium level (<138 mEq/L) were significant risk factors for the development of hyponatremia in these patients. CONCLUSIONS: Hyponatremia is an under recognized and potentially serious complication of paroxetine treatment in older patients. Our results provide a foundation for understanding the etiology and risk factors associated with paroxetine-induced hyponatremia.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14769630&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
A desensitization of hypothalamic 5-HT1A receptors by repeated injections of paroxetine: reduction in the levels of G(i) and G(o) proteins and neuroendocrine responses, but not in the density of 5-HT1A receptors.

Li Q, Muma NA, Battaglia G, Van de Kar LD.

Department of Pharmacology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois 60153, USA.

The aim of the present study was to determine whether the previously observed desensitization of hypothalamic 5-hydroxytryptamine1A (5-HT1A) receptors, during daily injections of fluoxetine, is mediated by sustained blockade of 5-HT reuptake. In the present study, we examined the time course effects of another 5-HT uptake inhibitor, paroxetine. Paroxetine reduced the oxytocin, adrenal corticotropic hormone and corticosterone responses to a challenge with the 5-HT1A agonist 8-hydroxy-2-(dipropylamino)tetralin. These reductions in hormone responses were significant after 3 daily injections and reached a maximum after 7 daily paroxetine injections. These hormone responses remained maximally suppressed after 14 daily injections of paroxetine. A single day of paroxetine treatment did not alter the hormone responses to 8-hydroxy-2-(dipropylamino)tetralin. Repeated injections of paroxetine did not reduce the density of 5-HT1A receptors in any brain region but did produce a gradual reduction in the levels of G(i) and G(o) proteins in a region-specific manner. The time course of the paroxetine-induced reduction in the level of G(i1) and G(i3) proteins in the hypothalamus was similar to the effect previously observed with fluoxetine and was also similar to the time course of paroxetine-induced reductions in oxytocin and adrenal corticotropic hormone responses to 8-hydroxy-2-(dipropylamino)tetralin. In conclusion, these results suggest that blockade of 5-HT uptake sites produces a delayed and gradual desensitization of 5-HT1A receptors in the hypothalamus. This desensitization is not due to changes in the density of hypothalamic 5-HT1A receptors. Reduction in the hypothalamic level of G(i3) proteins may play a role in the desensitization of 5-HT1A receptor systems. However, reductions in G(i1) or G(o) proteins cannot be excluded as potential mediators of the desensitization of 5-HT1A receptor systems.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9316875&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Prescribing of selective serotonin reuptake inhibitors, anxiolytics, and sedative-hypnotics by general practitioners in The Netherlands: a multivariate analysis.

Pathiyal A, Hylan TR, Jones JK, Davtian D, Sverdlov L, Keyser M.

Degge Group, Ltd., Arlington, Virginia, USA.

A study of the prescribing of anxiolytics and sedative-hypnotics and the occurrence of anxiety or sleep disorders before and after the initiation of selective serotonin reuptake inhibitor (SSRI) therapy may provide insight into differences in individual SSRIs. The purpose of our study was to evaluate whether and in what way the likelihood of being prescribed an anxiolytic or sedative-hypnotic or receiving a diagnosis of an anxiety or sleep disorder differed in patients prescribed either fluoxetine or paroxetine by a general practitioner (GP) in the Netherlands, where these two agents are the most commonly prescribed SSRIs. Episodes of SSRI treatment were constructed from a recently available GP database in the Netherlands. Logistic regression analysis was used to determine whether, after controlling for other observable factors, the receipt of paroxetine or fluoxetine was a statistically significant determinant for receipt of an anxiolytic or sedative-hypnotic or a diagnosis of an anxiety or sleep disorder. We found that patients who were prescribed fluoxetine as their index drug were less likely to receive a concomitant sedative-hypnotic on their index date compared with patients receiving paroxetine. After controlling for other observable factors, such as use of anxiolytics and sedative-hypnotics before SSRI therapy or on the index date or the existence of comorbid anxiety or sleep disorders, patients starting fluoxetine therapy were no more likely than patients starting paroxetine therapy to receive an anxiolytic or sedative-hypnotic or a diagnosis of an anxiety or sleep disorder during the 60-day post period. The likelihood of a patient's being diagnosed with or receiving a prescription for an anxiety or sleep disorder does not appear to be a differentiating factor between the prescribing of fluoxetine or paroxetine by GPs in the Netherlands.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9377622&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Evaluation of the neuropharmacodynamics of paroxetine in vivo utilizing microdialysis.

Ramaiya A, Johnson JH, Karnes HT.

Department of Pharmacy & Pharmaceutics, Medical College of Virginia/Virginia Commonwealth University, Richmond 23298-980533, USA.

The effect of paroxetine, a selective serotonin reuptake inhibitor used in the treatment of depression, on extracellular serotonin levels was evaluated in freely moving conscious rats. Microdialysis, a powerful in vivo technique to monitor the extracellular levels of neurotransmitters, was used to monitor the baseline changes in the levels of serotonin in rat brain anterior lateral striatum post paroxetine administration, which is a measure of the neuropharmacodynamic effect of the drug. Microdialysis sampling was performed for 210 min prior to and for 240 min after intraperitoneal administration of paroxetine (10 mg/kg). Paroxetine caused a statistically significant increase in the extracellular levels of serotonin in the anterior lateral striatum sampled by microdialysis. The present study demonstrates the utility of microdialysis for studying the in vivo neuropharmacodynamics of paroxetine in conscious rats.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9423168&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Changes in plasma prolactin during SSRI treatment: evidence for a delayed increase in 5-HT neurotransmission.

Cowen PJ, Sargent PA.

University Department of Psychiatry, Littlemore Hospital, Oxford, UK. phil.cowen psychiatry.ox.ac.uk

We studied the effect of the selective serotonin reuptake inhibitor (SSRI), paroxetine, on basal plasma prolactin concentrations in 11 healthy subjects. Subjects were tested before paroxetine, and after 1 and 3 weeks of treatment (20 mg daily). On each test occasion prolactin levels were sampled before and following administration of a placebo capsule, for a total of 4 h. After 3 weeks paroxetine treatment plasma prolactin levels were significantly higher than those seen either pre-treatment or after 1 week of treatment. In contrast, 1 week of paroxetine treatment did not significantly increase prolactin concentrations over pre-treatment values. Plasma concentrations of paroxetine did not differ between 1 and 3 weeks of treatment. The secretion of plasma prolactin is, in part, under the tonic regulation of serotonergic pathways and the present results therefore support animal experimental data suggesting that SSRIs produce a delayed increase in some aspects of brain serotonin neurotransmission.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9443523&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
High affinity [3H]imipramine and [3H]paroxetine binding sites in suicide brains.

Rosel P, Arranz B, Vallejo J, Oros M, Menchon JM, Alvarez P, Navarro MA.

Hormone Unit (Biochemistry Department), Hospital Princeps D'Espanya, Barcelona, Spain.

Specific binding of [3H]imipramine and [3H]paroxetine was simultaneously examined in human brains (frontal cortex, temporal cortex, cingulate cortex, hypothalamus, hippocampus and amygdala) from 11 controls and 11 depressed suicide victims. A single saturable high affinity site was obtained for both radioligands. Age was not related to significant changes in [3H]imipramine and [3H]paroxetine binding parameters, which indicates the stability of the brain serotonergic system with increasing age. A major finding of the present study concerns the existence of a significant decrease in the maximum number (Bmax) of [3H]imipramine binding sites in hippocampus from depressed suicides as compared with the control group, without changes in the binding affinity (Kd). In contrast, when [3H]paroxetine was used as radioligand, no changes in either Bmax or Kd were detected in any of the brain regions studied. These findings suggest that [3H]imipramine may be a better marker than [3H]paroxetine when alterations in the presynaptic serotonergic uptake site are to be detected.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9451724&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Synthesis and ligand binding of tropane ring analogues of paroxetine.

Keverline-Frantz KI, Boja JW, Kuhar MJ, Abraham P, Burgess JP, Lewin AH, Carroll FI.

Research Triangle Institute, North Carolina 27709, USA.

(3S,4R)-4-(4-Fluorophenyl)-3-[[3,4-(methylenedioxy)phenoxy]methyl] piperidine [(3S,9R)-3, paroxetine] is a selective serotonin reuptake inhibitor (SSRI) used as an antidepressant in humans. In previous studies, we reported that certain (1R)-3 beta-(substituted phenyl)nortropane-2 beta-carboxylic acid methyl esters (2a) exhibited high affinity and reasonable selectivity for the serotonin transporter (5-HTT). The major structural differences between 2a and (3S,4R)-3 are that 2a possesses a different absolute stereochemistry and has an ethylene bridge not present in 3. In addition, 2a possesses a carbomethoxy substituent adjacent to the aryl ring, whereas (3S,4R)-3 contains a [3,4-(methylenedioxy)phenoxy]methyl group. In this study, we present the synthesis and biological evaluations of six of the possible eight isomers of 3-(4-fluorophenyl)-2-[[3,4-(methylenedioxy)phenoxy]methyl]nortropane+ ++ (4). The data for inhibition of [3H]paroxetine binding show that (1R)-2 beta, 3 alpha-4c, which has the same stereochemistry as paroxetine, has the highest affinity at the 5-HTT. Strikingly, the most potent compounds for inhibition of [3H]WIN-35,428 binding were not the (1R)-2 beta, 3 beta-isomers but rather (1R)-2 beta, 3 alpha-4c and (1S)-2 beta, 3 alpha-4f. Conformational analyses show that these isomers exist in a flattened boat conformation with pseudoequatorial substituents. Thus, the binding data show that this conformation is recognized by the DAT-associated binding site and also suggest that this conformation of paroxetine is recognized by the 5-HTT-associated binding site.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9457247&dopt=Abstract paroxetine, Paxil, Paxil CR