paroxetine, Paxil
Functional consequences of perinatal exposure to 3,4-methylenedioxymethamphetamine in rat brain.

Kelly PA, Ritchie IM, Quate L, McBean DE, Olverman HJ.

Department of Clinical Neurosciences, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK. pk skull.dcn.ed.ac.uk

1. In this study we have examined methylenedioxymethamphetamine (MDMA)-induced toxicity in perinatal rat brain, related this to normal development of serotonin transporter sites (SERT), and determined whether early exposure to MDMA subsequently alters cerebral function in adults. 2. Perinatal development of SERT was visualized and quantified using [(3)H]-paroxetine binding autoradiography in embryonic and neonatal rat brain from embryonic day 15 (E15) to postnatal day p30 (p30). Cerebral glucose utilization (lCMR(glu)) was measured by 2-deoxyglucose autoradiography in adult rats. 3. [(3)H]-Paroxetine binding was observed in forebrain from E18. From birth (p0), binding was organized into neocortical columns (75% higher at p10 than in adult) which declined toward adult levels between p20 and p25. 4. MDMA treatment (20 mg x kg(-1) s.c. twice daily for four days) commencing at developmental stages from E15 (treatment given to dams) to p20, had no effect upon [(3)H]-paroxetine binding measured at p40. Treatments started on p25 or later resulted in significant decreases in [(3)H]-paroxetine binding (>or=46%). This was coincident with the development of adult patterns of binding in forebrain. 5. Despite the lack of MDMA-induced neurotoxicity, rats treated in utero (E15) showed increased lCMR(glu) in locus coeruleus (+37%), and in areas receiving ascending noradrenergic innervation, such as anterior thalamus (+44%) and septal nucleus (+24%). 6 These studies confirm that the susceptibility of serotonergic terminals to the neurotoxic properties of MDMA is absent in the immediate perinatal period, but also suggests that in utero MDMA exposure produces significant long-term effects on cerebral function by a mechanism as yet unknown.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12429568&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
A prospective study comparing paroxetine alone versus paroxetine plus sildenafil in patients with premature ejaculation.

Salonia A, Maga T, Colombo R, Scattoni V, Briganti A, Cestari A, Guazzoni G, Rigatti P, Montorsi F.

Department of Urology, University of Vita-Salute, School of Medicine, Scientific Institute H. San Raffaele, Milan, Italy.

PURPOSE: We compared the efficacy of paroxetine alone and combined with sildenafil in patients complaining of premature ejaculation. MATERIALS AND METHODS: Enrolled in this study were 80 consecutive potent men 19 to 47 years old (mean age 34) with premature ejaculation but without any obvious organic cause. Pretreatment evaluation included a history, self-administration of the International Index of Erectile Function (IIEF) questionnaire, physical examination and the Meares-Stamey test to exclude genital tract infection. The initial 40 patients received 10 mg. paroxetine daily for 21 days and then 20 mg. as needed, that is 3 to 4 hours before planned sexual activity, for 6 months (group 1). The other group of 40 men received 10 mg. paroxetine daily for 21 days and then 20 mg. as needed plus 50 mg. sildenafil as needed, that is 1 hour before planned sexual activity, for 6 months (group 2). Patients were followed 3 and 6 months after beginning therapy and were evaluated using several general assessment questions, IIEF and ejaculatory latency time. RESULTS: Mean ejaculatory latency time +/- SE in group 1 was 0.33 +/- 0.04, 3.7 +/- 0.10 (p <0.01) and 4.2 +/- 0.03 (p <0.01) minutes at baseline, 3 and 6-month followup, while in group 2 it was 0.35 +/- 0.03, 4.5 +/- 0.07 (p <0.01) and 5.3 +/- 0.02 (p <0.001) minutes, respectively. When improvement in ejaculatory latency time was compared in the 2 groups, group 2 results proved to be significantly greater (p <0.05). Baseline, and 3 and 6-month mean intercourse satisfaction domain values of the IIEF were 9, 11 and 11 (p = 0.09, not significant), and 9, 11 and 14 (p <0.05) in groups 1 and 2, respectively. Group 2 patients reported significantly greater intercourse satisfaction than those in group 1 (p <0.05). At baseline, 3 and 6 months there was a mean of 0.9 +/- 0.1, 1.7 +/- 0.3 (not significant) and 2.5 +/- 0.3 (p <0.01) coitus episodes weekly in group 1, and 1 +/- 0.2, 2.3 +/- 0.3 (p <0.01) and 3.2 +/- 0.1 (p <0.001) in group 2, respectively. Group 2 patients reported a significantly higher number of coitus episodes weekly (p <0.05). Side effects in the 40 group 1 cases included anejaculation in 1 (2.5%), gastrointestinal upset and/or nausea in 5 (12.5%), headache in 4 (10%) and decreased libido in 2 (5%). Side effects in the 40 group 2 cases included anejaculation in 1 (2.5%), headache in 8 (20%), gastrointestinal upset and/or nausea in 6 (15%) and flushing in 6 (15%). Group 2 patients reported significantly more headaches (p <0.01) and flushing episodes (p <0.001) than those in group 1. After 6 months of treatment 33 men (82.5%) in group 1 and 36 (90%) in group 2 were willing to continue therapy (not significant). CONCLUSIONS: Paroxetine combined with sildenafil appears to provide significantly better results in terms of ejaculatory latency time and intercourse satisfaction versus paroxetine alone in potent patients with premature ejaculation. However, combined treatment is associated with a mild increase in drug related side effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12441946&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Occupancy of brain serotonin transporters during treatment with paroxetine in patients with social phobia: a positron emission tomography study with 11C McN 5652.

Kent JM, Coplan JD, Lombardo I, Hwang DR, Huang Y, Mawlawi O, Van Heertum RL, Slifstein M, Abi-Dargham A, Gorman JM, Laruelle M.

New York State Psychiatry Institute, New York, NY 10032, USA. JMK14 columbia.edu

RATIONALE: Although selective serotonin reuptake inhibitors (SSRIs) are widely used in the treatment of anxiety and depressive disorders, the occupancy of the serotonin reuptake transporter (SERT) achieved in humans at typical clinical doses by these agents remains poorly characterized. OBJECTIVE: The purpose of this study was to determine the occupancy of the SERT achieved in vivo by the SSRI paroxetine in social phobia patients at typical antianxiety doses. METHODS: Measures of SERT availability were obtained with positron emission tomography and the SERT radiotracer [(11)C](+)-McN 5652 in five patients with social phobia before and during treatment with paroxetine at usual therapeutic doses (20-40 mg per day). RESULTS: Occupancy of the SERT by paroxetine was high in all subjects and in all regions measured after 3-6 months of continuous treatment. CONCLUSIONS: The results of this study in an anxiety disorder sample are consistent with previously reported results in a depressed sample and suggest that paroxetine at therapeutic doses achieves very high occupancy levels of the SERT.

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paroxetine, Paxil
Comparison of the effects of antidepressants on norepinephrine and serotonin concentrations in the rat frontal cortex: an in-vivo microdialysis study.

Beyer CE, Boikess S, Luo B, Dawson LA.

Neuroscience Discovery Research, Wyeth Research, Princeton, New Jersey 08543-8000, USA. beyerc1 wyeth.com

The present study employed in-vivo microdialysis techniques in the freely moving rat to systematically compare the neurochemical effects of various antidepressant agents on extracellular concentrations of norepinephrine (NE) and serotonin (5-HT) in the frontal cortex. We found that acute administration of the tricyclic antidepressant, desipramine (3-30 mg/kg, s.c.) and the dual serotonin/norepinephrine reuptake inhibitor, venlafaxine (3-30 mg/kg, s.c.), produced dose-dependent and robust increases in cortical NE concentrations (498% and 403%, respectively). Conversely, acute injection of the selective serotonin reuptake inhibitors, fluoxetine (30 mg/kg, s.c.) and paroxetine (1-10 mg/kg, s.c.), did not alter forebrain NE concentrations. However, paroxetine did produce a significant increase in cortical NE concentrations (164%) when administered at 30 mg/kg. These changes in NE were not paralleled by 5-HT, which showed no increase following administration of desipramine, venlafaxine, paroxetine or fluoxetine. Combination treatment with the 5-HT1A receptor antagonist, WAY-100635 (0.3 mg/kg, s.c.), significantly enhanced extracellular 5-HT concentrations following venlafaxine (10 and 30 mg/kg), fluoxetine (30 mg/kg) and paroxetine (3-30 mg/kg). Alternatively, WAY-100635 produced no augmentation of the antidepressant-induced changes in extracellular NE. Collectively, these studies show that paroxetine, at low to intermediate doses, and fluoxetine are selective for 5-HT versus NE systems, whereas venlafaxine produces similar effects on both 5-HT and NE levels at the effective doses tested.

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paroxetine, Paxil
Efficacy of sildenafil as adjuvant therapy to selective serotonin reuptake inhibitor in alleviating premature ejaculation.

Chen J, Mabjeesh NJ, Matzkin H, Greenstein A.

Department of Urology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

OBJECTIVES: To evaluate the efficacy of sildenafil and selective serotonin reuptake inhibitor in alleviating premature ejaculation (PE) in patients in whom other treatments had failed. METHODS: Healthy men evaluated for primary PE graded their ejaculation on a scale of 0 to 8 (0 = almost never, 8 = almost always). The intravaginal ejaculatory latency time (IVELT) was graded on a scale of 0 to 3 (0 = longer than 5 minutes, 3 = shorter than 1 minute). The 138 men who scored their PE as 4 or greater and IVELT as 2 or greater comprised the study group. Psychological and behavioral counseling was provided during the study. PE was graded using the same scales 3 months after the initiation of each treatment. Topical 5% lidocaine ointment comprised the initial treatment: dissatisfied patients (PE grade 4 or greater, IVELT 2 or greater), took one tablet of paroxetine 20 mg for 30 days and then one tablet 7 hours before intercourse. Sildenafil was added to the treatment of patients dissatisfied with paroxetine alone. RESULTS: The mean initial PE grade was 5.67 +/- 0.13 and that for IVELT was 2.9 +/- 0.19 for all participants (mean age 28.7 years). Thirty-eight reported improvement (PE grade 2.0 +/- 0.8, P <0.01; IVELT 0.13 +/- 0.34, P <0.001) after local lidocaine application. Of the 100 treated with paroxetine, 42 reported improvement (PE grade 2.5 +/- 0.1, P <0.01; IVELT 0.28 +/- 0.46, P <0.001), and 56 of the remaining 58 who were treated with a combination of paroxetine and sildenafil reported improvement (PE grade 1.78 +/- 0.23, P <0.001; IVELT 0.16 +/- 0.37, P <0.001). Two patients remained dissatisfied with all treatment modalities. CONCLUSIONS: Sildenafil combined with paroxetine and psychological and behavioral counseling alleviated PE in patients in whom other treatments failed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12559295&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Apparent mechanism-based inhibition of human CYP2D6 in vitro by paroxetine: comparison with fluoxetine and quinidine.

Bertelsen KM, Venkatakrishnan K, Von Moltke LL, Obach RS, Greenblatt DJ.

Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.

Paroxetine, a selective serotonin reuptake inhibitor, is a potent inhibitor of cytochrome P450 2D6 (CYP2D6) activity, but the mechanism of inhibition is not established. To determine whether preincubation affects the inhibition of human liver microsomal dextromethorphan demethylation activity by paroxetine, we used a two-step incubation scheme in which all of the enzyme assay components, minus substrate, are preincubated with paroxetine. The kinetic parameters of inhibition were also estimated by varying the time of preincubation as well as the concentration of inhibitor. From these data, a Kitz-Wilson plot was constructed, allowing the estimation of both an apparent inactivator concentration required for half-maximal inactivation (K(I)) and the maximal rate constant of inactivation (k(INACT)) value for this interaction. Preincubation of paroxetine with human liver microsomes caused an approximately 8-fold reduction in the IC(50) value (0.34 versus 2.54 microM). Time-dependent inhibition was demonstrated with an apparent K(I) of 4.85 microM and an apparent k(INACT) value of 0.17 min(-1). Spectral scanning of CYP2D6 with paroxetine yielded an increase in absorbance at 456 nm suggesting paroxetine inactivation of CYP2D6 via the formation of a metabolite intermediate complex. This pattern is consistent with the metabolism of the methylenedioxy substituent in paroxetine; such substituents may produce mechanism-based inactivation of cytochrome P450 enzymes. In contrast, quinidine and fluoxetine, both of which are inhibitors of CYP2D6 activity, did not exhibit a preincubation-dependent increase in inhibitory potency. These data are consistent with mechanism-based inhibition of CYP2D6 by paroxetine but not by quinidine or fluoxetine.

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paroxetine, Paxil
Reduction of hypothalamic vasopressinergic hyperdrive contributes to clinically relevant behavioral and neuroendocrine effects of chronic paroxetine treatment in a psychopathological rat model.

Keck ME, Welt T, Muller MB, Uhr M, Ohl F, Wigger A, Toschi N, Holsboer F, Landgraf R.

Max Planck Institute of Psychiatry, Munich, Germany. keck mpipsykl.mpg.de

The neuroendocrine and behavioral effects of chronic paroxetine treatment were investigated in two rat lines selectively bred for high anxiety-related behavior (HAB) or low anxiety-related behavior (LAB) emotionality. In addition to a characteristic behavioral phenotype with markedly passive stress-coping strategies, HAB rats show a hypothalamic vasopressinergic hyperdrive that is causally related to hypothalamic-pituitary-adrenocortical dysregulation as demonstrated in the combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test. A total of 8 weeks of chronic paroxetine treatment induced a more active coping strategy in the forced swim test in HAB rats only. In contrast, paroxetine-treated LAB rats did not change their swimming behavior. To investigate the neuroendocrine alterations linked to these behavioral changes, a combined DEX/CRH test was performed. In HAB rats, the paroxetine-induced behavioral changes towards more active coping strategies were accompanied by a normalization of the CRH-stimulated increase in corticotropin (ACTH) and corticosterone secretion. Concomitantly, the hypothalamic vasopressinergic hyperdrive was found to be reduced in HAB but not LAB rats, as indicated by a decrease in vasopressin mRNA expression, whereas vasopressin 1a receptor binding was unaffected. These findings provide the first evidence that the vasopressinergic system is likely to be critically involved in the behavioral and neuroendocrine effects of antidepressant drugs. This novel mechanism of action of paroxetine on vasopressin gene regulation renders vasopressinergic neuronal circuits a promising target for the development of more causal antidepressant treatment strategies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12589376&dopt=Abstract paroxetine, Paxil, Paxil CR