paroxetine, Paxil
Simultaneous measurement of serotonin and paroxetine in rat brain microdialysate by a single-pump column-switching technique.

Ramaiya A, Karnes HT.

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

Simultaneous quantitation of paroxetine and serotonin in rat brain microdialysate is presented as a means to study the neuropharmacokinetics and neuropharmacodynamics of paroxetine, a selective serotonin reuptake inhibitor. In order to achieve this objective, a single-pump column-switching technique was developed. Optimization of the mobile phase in terms of the concentration of ion-pairing agent, pH of mobile phase, temperature of the stationary phase and concentration of organic modifier was investigated and a single mobile phase was developed for both separations. The design was such that the switching valve employed column I (50 mm length) and column II (250 mm length) in series in position A. At 15.3 min, the valve was switched to position B, in which the flow of the mobile phase was directed only through the short column (column I). A flow gradient program was used to increase the flow-rate from 0.125 ml/min to 0.4 ml/min, which enabled a reduction in total analysis time to less than 20 min. The limits of detection for serotonin and paroxetine were 6 fmol and 300 fmol, respectively. The accuracy of the method demonstrated percent differences from spiked samples that were within 12.5% and the precision was found to be within 10% R.S.D.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9140765&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Long-term food restriction down-regulates the density of serotonin transporters in the rat frontal cortex.

Huether G, Zhou D, Schmidt S, Wiltfang J, Ruther E.

Department of Psychiatry, University of Gottingen, Germany.

The influence of feeding rats only half the amount of their normal daily intake of a complete rat chow on the affinity and the density of serotonin (5-HT) transporters was measured in membrane preparations of the frontal cortex and the midbrain by a [3H]paroxetine binding assay. In young rats (10 weeks), a significant reduction of about 30% of the Bmax values of [3H]paroxetine binding occurred in the frontal cortex after 1 and 2 weeks of restricted food intake. No starvation-induced decline of the density of 5-HT transporters was seen in the midbrain. When older rats (50 weeks) were subjected to the same 50% reduction of daily food intake for 2 weeks, no such down-regulation of the density of cortical 5-HT transporters was observed. The affinity of the 5-HT transporters, as indicated by the unchanged Kd values of [3H]paroxetine binding, was not affected by semistarvation in both regions and at both ages. The observed decline of [3H]paroxetine binding sites in the frontal cortex of young adult rats is the first demonstration of long-term regulatory phenomena of brain 5-HT transporters triggered by a physiologic stimulus.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9171908&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Time to antidepressant discontinuation: a comparison of controlled-release paroxetine and immediate-release selective serotonin-reuptake inhibitors.

Eaddy M, Bramley T, Regan T.

Applied Health Outcomes, Palm Harbor, Florida, USA.

Despite advances in depression therapy, early treatment discontinuation with antidepressants remains high and contributes to poor clinical outcomes. In clinical trials, treatment discontinuation with controlled-release paroxetine was similar to placebo and significantly better than immediate-release paroxetine. To examine whether this benefit noted in clinical trials translated into longer therapy duration in practice settings, survival-analysis models were constructed to compare the time to treatment discontinuation of controlled-release paroxetine with that of immediate-release selective serotonin-reuptake inhibitors (SSRIs). Survival analysis indicated that patients receiving controlled-release paroxetine were 28% less likely to discontinue therapy during a 180-day period when compared with patients receiving immediate-release SSRIs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14750459&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Platelet [3H]imipramine and [3H]paroxetine binding in depressed patients.

Rosel P, Menchon JM, Vallejo J, Arranz B, Navarro MA, Liron F, Alvarez P.

Hormone Unit, Hospital Princeps d'Espanya, Barcelona, Spain.

[3H]Paroxetine and [3H]imipramine binding to blood platelet membranes was simultaneously measured in 63 control subjects and 18 patients with DSM-III-R criteria for major depression with melancholia. Both binding sites showed significantly different (p < 0.001) maximum binding (Bmax) and equilibrium dissociation constant (Kd) values. Age was not correlated with either [3H]imipramine Bmax or Kd values, but a negative correlation was found between [3H]paroxetine Bmax and age in healthy controls. Furthermore, depressed patients showed significantly lower [3H]imipramine Bmax values (p < 0.001) and higher Kd values (p < 0.001) in comparison to the control group. No differences were observed in [3H]paroxetine Bmax and Kd values between the two groups.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9186805&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Paroxetine in depressed adolescents with intellectual disability: an open label study.

Masi G, Marcheschi M, Pfanner P.

Institute of Developmental Neurology, Psychiatry and Educational Psychology, University of Pisa, Italy.

The aim of this study was to evaluate the efficacy and side-effects of paroxetine treatment in adolescents with mild intellectual disability and major depressive disorder (MDD). Seven adolescents (14.7-18.4 years of age) were treated with paroxetine (dosage 20-40 mg day-1). Clinical changes were assessed at the beginning of the pharmacological treatment and after 9 weeks utilizing the DSM-IV diagnostic criteria and the Montgomery-Asberg Depression rating Scale (MADRS). Four out of the seven subjects did not fulfil the DSM-IV diagnostic criteria after the 9-week treatment. The mean decrease in the total score on the MADRS was significant (41%). Some items of the MADRS showed significant improvement: inner tension (66%); lassitude (55%); apparent sadness (53%); inability to feel (44%); and reported sadness (43%). Three subjects showed sedation, two subjects gastrointestinal complaints and one subject insomnia; all these symptoms were transitory and not severe. No behavioural activation was evident. This preliminary, uncontrolled study of a few cases suggests that adolescents with intellectual disability and MDD may respond to paroxetine, and that adverse side-effects are mild.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9219077&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Effect of a selective 5-HT reuptake inhibitor in combination with 5-HT1A and 5-HT1B receptor antagonists on extracellular 5-HT in rat frontal cortex in vivo.

Sharp T, Umbers V, Gartside SE.

University of Oxford Department of Clinical Pharmacology, Radcliffe Infirmary.

1. Selective 5-hydroxytryptamine (5-HT; serotonin) reuptake inhibitors (SSRIs) cause a greater increase in extracellular 5-HT in the forebrain when the somatodendritic 5-HT1A autoreceptor is blocked. Here, we investigated whether blockade of the terminal 5-HT1B autoreceptor influences a selective 5-HT reuptake inhibitor in the same way, and whether there is an additional effect of blocking both the 5-HT1A and 5-HT1B autoreceptors. 2. Extracellular 5-HT was measured in frontal cortex of the anaesthetized rat by use of brain microdialysis. In vivo extracellular recordings of 5-HT neuronal activity in the dorsal raphe nucleus (DRN) were also carried out. 3. The selective 5-HT reuptake inhibitor, paroxetine (0.8 mg kg-1, i.v.), increased extracellular 5-HT about 2 fold in rats pretreated with the 5-HT1A receptor antagonist, WAY100635. When administered alone neither paroxetine (0.8 mg kg-1, i.v.) nor WAY100635 (0.1 mg kg-1, i.v.) altered extracellular 5-HT levels. 4. Paroxetine (0.8 mg kg-1, i.v.) did not increase 5-HT in rats pretreated with the 5-HT1B/D receptor antagonist, GR127935 (1 mg kg-1, i.v.). GR127935 (1 and 5 mg kg-1, i.v.) had no effect on extracellular 5-HT when administered alone. 5. Interestingly, paroxetine (0.8 mg kg-1, i.v.) caused the greatest increase in 5-HT (up to 5 fold) when GR127935 (1 or 5 mg kg-1, i.v.) was administered in combination with WAY100635 (0.1 mg kg-1, i.v.). Administration of GR127935 (5 mg kg-1, i.v.) plus WAY100635 (0.1 mg kg-1, i.v.) without paroxetine, had no effect on extracellular 5-HT in the frontal cortex. 6. Despite the lack of effect of GR127935 on 5-HT under basal conditions, when 5-HT output was elevated about 3 fold (by adding 1 microM paroxetine to the perfusion medium), the drug caused a dose-related (1 and 5 mg kg-1, i.v.) increase in 5-HT. 7. By itself, GR127935 slightly but significantly decreased 5-HT cell firing in the DRN at higher doses (2.0-5.0 mg kg-1, i.v.), but did not prevent the inhibition of 5-HT cell firing induced by paroxetine. 8. In summary, our results suggest that selective 5-HT reuptake inhibitors may cause a large increase in 5-HT in the frontal cortex when 5-HT autoreceptors on both the somatodendrites (5-HT1A) and nerve terminals (5-HT1B) are blocked. This increase is greater than when either set of autoreceptors are blocked separately. The failure of a 5-HT1B receptor antagonist alone to enhance the effect of the selective 5-HT reuptake inhibitor in our experiments may be related to a lack of tone on the terminal 5-HT1B autoreceptor due to a continued inhibition of 5-HT cell firing. These results are discussed in relation to the use of 5-HT autoreceptor antagonists to augment the antidepressant effect of selective 5-HT reuptake inhibitors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9222551&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Chronic paroxetine desensitises 5-HT1D but not 5-HT1B autoreceptors in rat lateral geniculate nucleus.

Davidson C, Stamford JA.

Anaesthetics Unit (Neurotransmission Laboratory), St. Bartholomew's and the Royal London School of Medicine and Dentistry, Royal London Hospital, Whitechapel, UK.

The present study examined the effect of chronic paroxetine (10 mg/kg p.o., 21 days) on the 5-HT1B and 5-HT1D autoreceptors controlling 5-HT efflux in slices of rat ventrolateral geniculate nucleus. Electrically stimulated 5-HT efflux (10 pulses, 200 Hz, 0.1 ms, 10 mA) was measured using fast cyclic voltammetry. Peak 5-HT efflux was greater (P < 0.01) after chronic paroxetine (22.2 +/- 1.4 nM, mean +/- S.E.M.) than water (15.8 +/- 1.4 nM). 5-HT efflux was inhibited by CP 93129 (1 nM-10 microM) and sumatriptan (1 nM-1 microM), agonists at 5-HT1B and 5-HT1D receptors, respectively. Chronic paroxetine did not affect the sensitivity of the 5-HT1B autoreceptor but shifted the sumatriptan concentration-response curve to the right (P < 0.05). These data suggest that chronic paroxetine increases evoked 5-HT efflux. This may be the result of desensitisation of 5-HT1D but not 5-HT1B autoreceptors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9237540&dopt=Abstract paroxetine, Paxil, Paxil CR