paroxetine, Paxil
State markers of depression in sleep EEG: dependency on drug and gender in patients treated with tianeptine or paroxetine.

Murck H, Nickel T, Kunzel H, Antonijevic IA, Schill J, Zobel A, Steiger A, Sonntag A, Holsboer F.

Max Planck Institute of Psychiatry, Munich, Germany.

Tianeptine enhances while paroxetine inhibits serotonin reuptake into neurons; however, both show an antidepressive action. A subgroup of 38 depressed patients from a drug trial comparing the efficacy of tianeptine with that of paroxetine was studied with regard to their effects on sleep regulation, especially in relation to treatment response. We recorded sleep EEGs at day 7 and day 42 after the start of treatment with either compound, which allows measurement of changes due to the antidepressive medication in relation to the duration of treatment. Spectral analysis of the non-REM sleep EEG revealed a strong decline in the higher sigma frequency range (14-16 Hz) in male treatment responders independent of medication, whereas nonresponders did not show marked changes in this frequency range independent of gender. The patients receiving paroxetine showed less REM sleep and more intermittent wakefulness compared to the patients receiving tianeptine. REM density after 1 week of treatment was a predictor of treatment response in the whole sample. Psychopathological features with regard to the score in single items of the HAMD revealed predictive markers for response, some of which were opposite in the gender groups, especially those related to somatic anxiety. Changes in REM density were inversely correlated to the changes in HAMD in the paroxetine, but not the tianeptine, group. Our data suggest the importance of taking gender into account in the study of the biological effects of drugs. The study further points to the importance of the higher sigma frequency range in the sleep EEG of non-REM sleep and REM density as a marker of treatment response.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12589388&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers.

Skinner MH, Kuan HY, Pan A, Sathirakul K, Knadler MP, Gonzales CR, Yeo KP, Reddy S, Lim M, Ayan-Oshodi M, Wise SD.

Lilly Laboratory for Clinical Research, Indiana University Hospital and Outpatient Center, 550 N. University Road, Indianapolis, IN 46202-5250, USA. skinner lilly.com

BACKGROUND AND OBJECTIVES: Duloxetine, a potent dual reuptake inhibitor of serotonin and norepinephrine currently undergoing clinical investigation for treatment of depression and stress urinary incontinence, has the potential to act as both a substrate and an inhibitor of cytochrome P4502D6 (CYP2D6). Our objectives were to determine the effect of duloxetine on the pharmacokinetics of desipramine, a tricyclic antidepressant metabolized by CYP2D6 (study 1), and the effect of paroxetine, a potent CYP2D6 inhibitor, on duloxetine pharmacokinetics (study 2). METHODS: Subjects were healthy men and women between 21 and 63 years old. All subjects were genotypically CYP2D6 extensive metabolizers. In study 1, 50 mg of desipramine was administered as a single dose alone and in the presence of steady-state duloxetine 60 mg twice daily. In study 2, steady-state pharmacokinetics of duloxetine 40 mg once daily were determined in the presence and absence of steady-state paroxetine 20 mg once daily. RESULTS: Duloxetine increased the maximum plasma concentration of desipramine 1.7-fold and the area under the concentration-time curve 2.9-fold. Paroxetine increased the maximum plasma concentration of duloxetine and the area under the concentration-time curve at steady state 1.6-fold. Reports of adverse events were similar whether duloxetine was administered alone or in combination with desipramine or paroxetine. CONCLUSION: Duloxetine 60 mg twice daily is a moderately potent CYP2D6 inhibitor, intermediate between paroxetine and sertraline. The potent CYP2D6 inhibitor paroxetine has a moderate effect on duloxetine concentrations. The results of these 2 studies suggest that caution should be used when CYP2D6 substrates and inhibitors are coadministered with duloxetine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12621382&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Methodologic pitfalls in measurement of 5-hydroxytriptamine uptake transporters in human platelets by [3H]-paroxetine binding assay.

Jurado N, Torner C, Heinze G, Lopez G, Mendoza-Sotelo J, Lazo-Langner A, Moreno J.

Division de Servicios Clinicos, Instituto Nacional de Psiquiatria Ramon de la Fuente, Mexico City, DF, Mexico.

BACKGROUND: Studies in platelet of 5-HT uptake transporters have been performed using binding assay methodology designed for ligand-receptor interactions; however, uptake transporters present requirements that may question the validity of these particular binding assays. METHODS: To explore methodologic aspects that may be crucial to the validity of these assays, we studied the binding of [3H]-paroxetine to platelet membranes of healthy subjects under different conditions of time, temperature, and protein concentrations. RESULTS: A correlation between protein concentration in incubation media and percentage of specific binding of [3H]-paroxetine was found: the lower the protein concentrations (10 and 20 microg/mL) in incubation media, the lower the percentage of specific [3H]-paroxetine binding. Moreover, low specificity in [3H]-paroxetine binding affected Bmax values obtained in saturation binding experiments. CONCLUSIONS: The use of low protein concentrations could affect Bmax values in binding assays of 5-HT uptake transporters. This may induce confusing interpretation of data in clinical experiments that use human platelets to explore the participation of serotonin in depressed patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14602510&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Effects of selective serotonin and serotonin/noradrenaline reuptake inhibitors on extracellular serotonin in rat diencephalon and frontal cortex.

Felton TM, Kang TB, Hjorth S, Auerbach SB.

Department of Cell Biology and Neuroscience, Nelson Biological Laboratories, Rutgers University, 604 Allison Road, Piscataway, NJ 08854, USA. matthews axon.rutgers.edu

Some clinical reports suggest that tricyclic antidepressants which block both noradrenaline and serotonin (5-HT) reuptake (SNRIs) are more effective than selective 5-HT reuptake inhibitors (SSRIs) in treating severe depression. Moreover, one neurochemical study reported larger increases in extracellular 5-HT in rat frontal cortex in response to the tricyclic antidepressant imipramine compared to the SSRI fluoxetine. However, imipramine, which blocks both 5-HT and noradrenaline reuptake, also binds with relatively high affinity to receptors for noradrenaline, histamine and acetylcholine. Thus, to test the hypothesis that compounds that inhibit both 5-HT and noradrenaline reuptake produce larger increases in 5-HT efflux, we compared the effects of acute systemic administration of several SNRIs and SSRIs. Extracellular 5-HT was measured using microdialysis probes implanted in the diencephalon and frontal cortex of unanesthetized rats. We tested the SSRIs paroxetine (0.3-10 mg/kg), citalopram (10-20 mg/kg) and fluoxetine (10 mg/kg), the nonselective tricyclic antidepressant imipramine (20 mg/kg) and the more selective SNRIs duloxetine (3-30 mg/kg) and venlafaxine (30-50 mg/kg). During the lights-off period, paroxetine and duloxetine increased 5-HT in the diencephalon approximately 300 and approximately 200%, respectively. During the lights-on period, paroxetine and duloxetine each increased 5-HT approximately 400% in the diencephalon. In the frontal cortex, both paroxetine and duloxetine increased 5-HT approximately 200%. Citalopram and venlafaxine each increased 5-HT in the diencephalon approximately 300%. Fluoxetine and imipramine increased 5-HT in the diencephalon by approximately 125 and approximately 80%, respectively. Thus, these results do not support the hypothesis that compared to SSRIs, compounds which inhibit both 5-HT and noradrenaline reuptake have a larger acute effect on extracellular 5-HT.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12644903&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Inhibition of P-glycoprotein by newer antidepressants.

Weiss J, Dormann SM, Martin-Facklam M, Kerpen CJ, Ketabi-Kiyanvash N, Haefeli WE.

Department of Internal Medicine VI, Clinical Pharmacology, and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany. Johanna_weiss med.uni-heidelberg.de

Pharmacokinetic drug-drug interactions often occur at the level of P-glycoprotein (Pgp). To study possible interactions caused by the newer antidepressants we investigated citalopram, fluoxetine, fluvoxamine, paroxetine, reboxetine, sertraline, and venlafaxine and their major metabolites desmethylcitalopram, norfluoxetine, paroxetine-metabolite (paroxetine-M), desmethylsertraline, N-desmethylvenlafaxine, and O-desmethylvenlafaxine for their ability to inhibit Pgp. Pgp inhibition was studied by a fluorometric assay using calcein-acetoxymethylester as Pgp substrate and two different cell systems: L-MDR1 cells (model for human Pgp) and primary porcine brain capillary endothelial cells (pBCECs, model for the blood-brain barrier). Both cell systems proved to be suitable for the evaluation of Pgp inhibitory potency of drugs. All antidepressants tested except O-desmethylvenlafaxine showed Pgp inhibitory activity with sertraline, desmethylsertraline, and paroxetine being the most potent, comparable with the well known Pgp inhibitor quinidine. In L-MDR1 cells fluoxetine, norfluoxetine, fluvoxamine, reboxetine, and paroxetine-M revealed intermediate Pgp inhibition and citalopram, desmethylcitalopram, venlafaxine, and N-desmethylvenlafaxine were only weak inhibitors. The ranking order was similar in pBCECs. The fact that some of the compounds tested exert Pgp inhibitor effects at similar concentrations as quinidine suggests that pharmacokinetic drug-drug interactions between the newer antidepressants and Pgp substrates should now be thoroughly studied in vivo.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12649369&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Relationship between platelet serotonin uptake sites and treatment outcome among African-American cocaine dependent individuals.

Patkar AA, Gottheil E, Berrettini WH, Thornton CC, Hill KP, Weinstein SP.

Department of Psychiatry and Human Behavior, Thomas Jefferson University, Philadelphia, PA 19107, USA. ashwin.patkar mail.tju.edu

We investigated whether platelet tritiated paroxetine binding, a measure of serotonin uptake sites differed between cocaine-dependent subjects and controls, and whether paroxetine binding was related to treatment-outcome for cocaine patients. One hundred twenty-five African-American cocaine-dependent individuals receiving outpatient treatment and 44 controls were studied. Tritiated paroxetine binding sites on platelets were assayed and standardized assessments of behavior were performed. The outcome measures were number of negative urine drug screens, days in treatment, dropout rates and number of treatment sessions attended. Cocaine patients had significantly lower Bmax values of paroxetine binding compared to controls. Furthermore, Bmax values showed a significant positive correlation with days in treatment and negative urines. A combination of Bmax and Addiction Severity Index (ASI) employment scores improved the prediction of days in treatment and a combination of Bmax and ASI drug scores enhanced the prediction of negative urines. The findings indicate that serotonergic mechanisms may be involved in cocaine dependence and may influence treatment-outcome among cocaine patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12661981&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Chronic paroxetine infusion influences macronutrient selection in male Sprague-Dawley rats.

Konkle AT, Sreter KB, Baker SL, Bielajew C.

School of Psychology, University of Ottawa, P.O. Box 450, Station A, 145 Jean-Jacques Lussier Street, Ottawa, Ontario, Canada K1N 6N5.

Decreased intake and weight loss are among the side effects frequently reported with chronic selective serotonin reuptake inhibitor (SSRI) use in both humans and animals. In an earlier study, we documented that paroxetine administered for several weeks induced a weight loss of greater than 10% in some male Sprague-Dawley rats (Pharmacol. Biochem. Behav. 63 (1999) 435). As a follow-up to that work, we investigated in this study whether such treatment influenced dietary macronutrient selection. Animals were first habituated to foods containing principally either proteins, fats, or carbohydrates in a self-selection paradigm, after which they were implanted intraperitoneally with osmotic minipumps that delivered either paroxetine (7.5 mg/kg/day) or vehicle (50:50 ethanol:water) for 28 days; food intake and weight changes were documented during this period. No acute effects of the drug were apparent. By the fifth day of treatment, significant differences in weight gain between groups were observed and thereafter generally maintained for the remainder of the study, with animals receiving paroxetine showing about an 8% decrease in weight gain overall. Carbohydrate and fat intakes were significantly reduced, whereas preference was unchanged in fats and proteins and initially decreased in carbohydrates; in the latter, this pattern reversed and exceeded vehicle animals for the second half of the study. Several hypotheses are discussed with respect to specific and nonspecific effects of paroxetine on feeding and macronutrient selection.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12667903&dopt=Abstract paroxetine, Paxil, Paxil CR