paroxetine, Paxil
A comparison of fluvoxamine, fluoxetine, sertraline and paroxetine examined by observational cohort studies.

Mackay FJ, Dunn NR, Wilton LV, Pearce GL, Freemantle SN, Mann RD.

Drug Safety Research Unit, Bursledon Hall, Southampton, UK.

OBJECTIVE: To compare the safety and side-effect profiles of the four selective serotonin reuptake inhibitor antidepressants (SSRIs), fluvoxamine, fluoxetine, sertraline and paroxetine. METHODS: The results from four observational cohort studies of the four SSRIs were compared. Each of these studies was conducted by Prescription-Event Monitoring (PEM). The exposure data were derived from general practitioner (GP) prescriptions confidentially supplied by the Prescription Pricing Authority (PPA) in England. Outcome data were obtained from questionnaires (green forms) on which the prescribing doctor recorded event data. The main findings comprised demographic information, including patients' date of birth and sex; the indication for prescribing the monitored drug; the effectiveness of the drug as perceived by the GP; the reasons for stopping treatment and all events recorded during and after treatment. RESULTS: The final cohort for each of the four SSRIs exceeded 10,000 patients. The sex, age distributions and indications for prescribing the four SSRIs were very similar. Only 36% of the GPs expressing an opinion reported fluvoxamine as effective, compared with approximately 60% for fluoxetine, sertraline and paroxetine. Fluvoxamine was associated with a higher incidence of adverse events than the other three SSRIs. Nausea/vomiting was both the most frequent clinical reason for stopping all four SSRIs and the most frequently reported clinical event. Adverse events reported in patients aged 70 years and over were comparable with the events reported for the total cohorts. Differences were identified between the four SSRIs for less frequently reported adverse events. Withdrawal symptoms were significantly more frequent with paroxetine than the other three SSRIs. CONCLUSIONS: The data from the four studies were comparable in terms of age distribution, sex of patients and indication for prescribing the drugs. Fluvoxamine had a considerably higher incidence of side-effects associated with its use than the other three SSRIs. The side-effect profiles of the four SSRIs were comparable for frequently reported events. Important differences were identified between the four SSRIs in respect of less frequently reported events. This study suggests that fluvoxamine compares unfavourably with fluoxetine, sertraline and paroxetine, both in terms of reported effectiveness and the incidence of adverse events. Biases possibly affecting the comparisons involved in this study are unlikely to account for the observed differences between fluvoxamine and the other three SSRIs. Copyright 1997 John Wiley & Sons, Ltd.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15073774&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Desensitization of the neuronal 5-HT carrier following its long-term blockade.

Pineyro G, Blier P, Dennis T, de Montigny C.

McGill University, Department of Psychiatry, Montreal, Quebec, Canada.

In vivo extracellular unitary recordings, in vitro 3H-5-hydroxy-tryptamine (5-HT) uptake, and 3H-paroxetine binding assays were used to assess the effect of acute and long-term administration of the 5-HT reuptake inhibitor paroxetine on the neuronal 5-HT transporter in the rat dorsal hippocampus. Recovery time of the firing activity of CA3 hippocampus pyramidal neurons following microiontophoretic application of 5-HT was used as an index of in vivo reuptake activity. In a first series of experiments, the acute intravenous administration of paroxetine and 5-HT denervation with the neurotoxin 5,7-dihydroxytryptamine produced a marked prolongation of the suppressant effect of 5-HT, indicating that reuptake into 5-HT terminals plays a significant role in terminating the action of microiontophoretically applied 5-HT. In a second series of experiments, rats were treated with paroxetine (10 mg/kg/d, s.c.) for 2 or 21 d. In both treatment groups, there was a marked prolongation of the effect of microiontophoretically applied 5-HT; however, in rats treated for 2 d, the prolongation was significantly greater than that observed in rats treated for 21 d. After the 21 d treatment with paroxetine and a 48 hr washout, the prolongation of the effect of microiontophoretically applied 5-HT by acute intravenous paroxetine was significantly reduced, suggesting a decrease in the number of 5-HT carriers. In keeping with this interpretation, following the same treatment regimen, there was a 50% and 60% reduction of the in vitro 3H-5-HT uptake in hippocampal and dorsal raphe slices, respectively, and a reduced effectiveness of paroxetine in blocking 3H-5-HT uptake in both regions. The determination of the binding parameters of 3H-paroxetine revealed that, in rats treated for 21 d with paroxetine (10 mg/kg/d, s.c.), following a 48 hr washout Kd values were unchanged but Bmax values were reduced by 70% and 60% in hippocampal and cortical membranes, respectively.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8182457&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Prenatal cocaine exposure potentiates paroxetine-induced desensitization of 5-HT2A receptor function in adult male rat offspring.

Chen Z, Waimey K, Van de Kar LD, Carrasco GA, Landry M, Battaglia G.

Department of Pharmacology and Center for Serotonin Disorders Research, Loyola University of Chicago, Stritch School of Medicine, 2160 South First Avenue, Maywood, IL 60153, USA.

This study investigated the ability of prenatal exposure to cocaine to alter serotonin(2A) (5-HT(2A)) receptor function and paroxetine-induced desensitization of 5-HT(2A) receptor function in rat offspring. Following exposure to saline or (-)cocaine (15 mg/kg, s.c., b.i.d.), during gestational days 13-20, adult male offspring were treated with either saline or paroxetine (10 mg/kg/day, i.p. 14 days). Eighteen hours post-treatment, changes in the stimulation of oxytocin, adrenocorticotropic hormone (ACTH) and corticosterone by (-)4-iodo-2,5-dimethoxyphenylisopropylamine (DOI, 0.5 or 2.0 mg/kg, s.c.) and in 5-HT(2A) receptor densities were determined. Prenatal cocaine exposure did not alter 5-HT(2A) receptor-mediated neuroendocrine responses or 5-HT(2A) receptor densities. In contrast, paroxetine treatment reduced cortical 5-HT(2A) receptors (18-25%) and desensitized 5-HT(2A) receptor-mediated oxytocin responses in both offspring groups. Furthermore, in cocaine offspring, paroxetine produced an inhibition of 5-HT(2A) receptor-mediated increase in plasma ACTH levels and a greater attenuation of the oxytocin responses to (-)DOI. Paroxetine-induced reductions in body weight gain (-8.8%) were comparable in both offspring groups. These data, demonstrating that prenatal exposure to cocaine potentiates paroxetine-induced desensitization of 5-HT(2A) receptor function, may be clinically relevant with respect to treating mood disorders in adults exposed in utero to cocaine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15081791&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Characterization of serotonin transporter in goldfish retina by the binding of [3H]paroxetine and the uptake of [3H]serotonin: modulation by light.

Lima L, Schmeer C.

Laboratorio de Neuroquimica, Instituto Venezolano de Investigaciones Cientificas, Caracas.

The serotonin (5-HT) uptake system of goldfish retina was evaluated by the binding of [3H]paroxetine to membrane preparations and the uptake of [3H]5-HT into isolated cells from goldfish retina. The order of potency of inhibitors of [3H]paroxetine binding was imipramine > 5-methoxy-N,N- dimethyltryptamine > desipramine > fluoxetine > citalopram > 5-HT. The saturation experiments indicated a high-affinity binding site, and positive cooperativity with Hill coefficient higher than unity. The association reached equilibrium at about one hour of incubation and was efficiently displaced by imipramine. The equilibrium dissociation constants calculated by the antilog of the log concentration of ligand giving 50% of occupation, and by the ratio of dissociation/association constants, were similar: 5.84 and 2.34 nM, respectively. The binding was not significantly reduced by decreasing the temperature of incubation and was sodium dependent. The lesion with 5,7-dihydroxytryptamine reduced the binding to 60%. The uptake of [3H]5-HT into isolated cells also showed positive cooperativity. The order of potency of inhibitors was similar to the one obtained for the binding of [3H]paroxetine. Darkness increased the uptake of 5-HT. The allosteric regulation of the 5-HT transporter and the modulation by light could be related to the physiological role of the monoamine, as a neurotransmitter and as a precursor of melatonin synthesis in the retina.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8294915&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Brain neurosteroid changes after paroxetine administration in mice.

Nechmad A, Maayan R, Spivak B, Ramadan E, Poyurovsky M, Weizman A.

Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Petah Tikva, Israel.

Although it is known that selective serotonin reuptake inhibitors (SSRIs), as other antidepressants, elevate mood only after 3-4 weeks of treatment, the mechanism responsible for this delay is not understood. SSRIs have been demonstrated to alter the levels of neurosteroids such as allopregnanolone (THP) which possess anxiolytic and mood-elevating properties. We compared the effect of 9 and 21 days i.p. administration of paroxetine, a potent SSRI, on the synthesis of THP and its precursor, 5alpha-dihydroprogesterone (DHP), in the mouse cortex, hypothalamus and olfactory bulb. Cortex, olfactory bulb and hypothalamus synthesized levels of DHP were significantly raised after 9 days of paroxetine administration, whereas a significant rise in the THP synthesized level was observed only after 21 days of treatment. Peripheral synthesis of DHP, measured by the level in serum, significantly increased after 9 days, but reverted to normal values after 21 days. No increase was detected in serum THP levels either after 9 or 21 days treatment. Differences in peripheral and brain synthesis indicates independence in brain synthesis. The data indicate that paroxetine administration differentially increases [3H]DHP and [3H]THP content, depending on the duration of the treatment. Our results suggest that brain THP may be involved in the antidepressive and anxiolytic activity of paroxetine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12957330&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Comparison of [3H]paroxetine and [3H]cyanoimipramine for quantitative measurement of serotonin transporter sites in human brain.

Gurevich EV, Joyce JN.

Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, USA.

Previous studies have demonstrated that [3H]paroxetine and [3H]cyanoimipramine ([3H]CN-IMI) are highly selective ligands for the serotonin (5-HT) transporter. Using membrane preparation from the putamen, we confirmed that in human brain [3H]paroxetine labeled with high affinity one class of site associated with the 5-HT transporter. [3H]CN-IMI labeled two classes of sites in human brain. The one displaceable by 5-HT and with high affinity to 5-HT uptake inhibitors accounts for about 60% of the [3H]CN-IMI binding and, presumably, is associated with the 5-HT transporter. From the competition experiments, citalopram was selected to define [3H]CN-IMI binding to the 5-HT transporter in tissue sections because of its high selectivity to 5-HT transporter sites. A good correlation of the regional distribution patterns for [3H]CN-IMI and [3H]paroxetine was found using quantitative autoradiography. However, [3H]paroxetine underestimated high concentrations of the 5-HT transporter comparing to [3H]CN-IMI. This is likely to be due to the higher specific activity of [3H]CN-IMI. There is a good correlation between the regional distribution of 5-HT transporter sites labeled with either [3H]paroxetine or [3H]CN-IMI and the density of serotonergic innervation. This suggests that the brain areas that receive numerous serotonergic afferents, such as the hypothalamus and basal forebrain, might be common targets of these antidepressant drugs. Pharmacologic similarity of the sites labeled by both ligands as well as their similar distribution in the brain suggests that both antidepressant drugs interact with the same protein, thereby eliciting a similar neurochemical response.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8703300&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Paroxetine in the treatment of premature ejaculation.

Ludovico GM, Corvasce A, Pagliarulo G, Cirillo-Marucco E, Marano A, Pagliarulo A.

Divisione e Cattedra di Urologia, Universita degli Studi di Bari, Italy.

OBJECTIVE: To test the efficacy and the adverse effects of a new anti-depressant drug (paroxetine) in the treatment of premature ejaculation. PATIENTS AND METHODS: The study comprised 32 men (mean age 28 years) with premature ejaculation (14 of whom ejaculated before penetration) who were treated with paroxetine (20 mg orally each evening for 2 months). The study group excluded those with neurological and psychiatric disorders, urinary tract infections and drug or alcohol abuse. RESULTS: After about 14 days, the patients' symptoms improved and all patients reported a longer interval before ejaculation. The adverse effects were sleepiness in 19 patients (61%) and mild sensory confusion in 21 (68%), but only one had to withdraw from therapy. Three weeks after the end of therapy, the premature ejaculation recurred in 28 (90%) of the patients. CONCLUSIONS: These results indicate that paroxetine is an effective therapy for premature ejaculation. Further studies with different dosages are necessary to decrease the adverse effects and to prolong the efficacy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8705226&dopt=Abstract paroxetine, Paxil, Paxil CR