paroxetine, Paxil
The behavioral effects of sertraline, fluoxetine, and paroxetine differ on the differential-reinforcement-of-low-rate 72-second operant schedule in the rat.

Sokolowski JD, Seiden LS.

Department of Neurobiology, Pharmacology and Physiology, University of Chicago, 947E. 58th St., Chicago, IL 60637, USA.

RATIONALE: Recent evidence indicates that specific serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) are not a clinically or experimentally homogeneous class of drugs. Because the differential- reinforcement-of-low-rates 72-second (DRL 72-s) operant schedule has been extensively used as a screen for antidepressant effects of drugs, different SSRIs were compared on the task to further examine their behavioral effects. OBJECTIVES: These experiments were designed with two main purposes in mind: first, to determine whether all three SSRIs tested would produce antidepressant-like effects on the DRL 72-s (as measured primarily by an increase in reinforcement rate) and, second, to identify differences between the drugs using peak-deviation analysis of inter-response times (IRTs). METHODS: Different groups of rats were injected with one of three SSRIs: fluoxetine, sertraline, or paroxetine. Following drug administration, rats were tested on the DRL 72-s operant schedule. RESULTS: All three SSRIs produced significant increases in reinforcement rate, but only sertraline and fluoxetine significantly decreased response rate. Additionally, paroxetine was observed to disrupt the pattern of responding as indicated by decreases in peak area (PkA). Sertraline and paroxetine, but not fluoxetine, produced increases in peak location (PkL). CONCLUSIONS: These results indicate that, although SSRIs are correctly identified as antidepressants by the DRL 72-s operant schedule, they may exert their effects in subtly different ways, as indicated by the differences observed to exist between the drugs. It appears unlikely that the behavioral effects of the SSRIs are attributable solely to 5-HT transporter binding. Instead, the differential behavioral effects may be the result of a combination of factors, including 5-HT transporter binding, 5-HT(1A) autoreceptor activation, and binding to other receptors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10591882&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Simultaneous determination of citalopram, fluoxetine, paroxetine and their metabolites in plasma and whole blood by high-performance liquid chromatography with ultraviolet and fluorescence detection.

Kristoffersen L, Bugge A, Lundanes E, Slordal L.

National Institute of Forensic Toxicology, Oslo, Norway. lena.kristoffersen labmed.uio.no

A method for the simultaneous determination of the three selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine, paroxetine and their metabolites in whole blood and plasma was developed. Sample clean-up and separation were achieved using a solid-phase extraction method with C8 non-endcapped columns followed by reversed-phase high-performance liquid chromatography with fluorescence and ultraviolet detection. The robustness of the solid-phase extraction method was tested for citalopram, fluoxetine, paroxetine, Cl-citalopram and the internal standard, protriptyline, using a fractional factorial design with nine factors at two levels. The fractional factorial design showed two significant effects for paroxetine in whole blood. The robustness testing for citalopram, fluoxetine, Cl-citalopram and the internal standard revealed no significant main effects in whole blood and plasma. The optimization and the robustness of the high-performance liquid chromatographic separation were investigated with regard to pH and relative amount of acetonitrile in the mobile phase by a central composite design circumscribed. No alteration in the elution order and no significant change in resolution for a deviation of +/-1% acetonitrile and +/-0.3 pH units from the specified conditions were observed. The method was validated for the concentration range 0.050-5.0 micromol/l with fluorescence detection and 0.12-5.0 micromol/l with ultraviolet detection. The limits of quantitation were 0.025 micromol/l for citalopram and paroxetine, 0.050 micromol/l for desmethyl citalopram, di-desmethyl citalopram and citalopram-N-oxide, 0.12 micromol/l for the paroxetine metabolites by fluorescence detection, and 0.10 micromol/l for fluoxetine and norfluoxetine by ultraviolet detection. Relative standard deviations for the within-day and between-day precision were in the ranges 1.4-10.6% and 3.1-20.3%, respectively. Recoveries were in the 63-114% range for citalopram, fluoxetine and paroxetine, and in the 38-95% range for the metabolites. The method has been used for the analysis of whole blood and plasma samples from SSRI-exposed patients and forensic cases.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10595721&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Localized orbitofrontal and subcortical metabolic changes and predictors of response to paroxetine treatment in obsessive-compulsive disorder.

Saxena S, Brody AL, Maidment KM, Dunkin JJ, Colgan M, Alborzian S, Phelps ME, Baxter LR Jr.

University of California Los Angeles, Department of Psychiatry and Biobehavioral Sciences, USA.

Previous positron emission tomography (PET) studies of patients with obsessive-compulsive disorder (OCD) have found elevated glucose metabolic rates in the orbitofrontal cortex (OFC) and caudate nuclei that normalize with response to treatment. Furthermore, OCD symptom provocation differentially activates specific subregions of the OFC, which have distinct patterns of connectivity and serve different functions. Therefore, we sought to determine the role of specific subregions of the OFC and associated subcortical structures in mediating OCD symptoms, by determining how glucose metabolism in these structures changed with paroxetine treatment of OCD patients. We also sought to determine whether pretreatment OFC metabolism would predict response to paroxetine, as it has for other OCD treatments. Twenty subjects with OCD received [18F]-fluorodeoxyglucose (FDG)-PET scans before and after 8 to 12 weeks of treatment with paroxetine, 40 mg/day. In patients who responded to paroxetine, glucose metabolism decreased significantly in right anterolateral OFC and right caudate nucleus. Lower pretreatment metabolism in both left and right OFC predicted greater improvement in OCD severity with treatment. These results add to evidence indicating that orbitofrontal-subcortical circuit function mediates the symptomatic expression of OCD. Specific subregions of the OFC may be differentially involved in the pathophysiology of OCD and/or its response to pharmacotherapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10633474&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Effects of repeated selective serotonin reuptake inhibitor paroxetine treatments on mouse forced swimming.

Akagawa Y, Masuda Y, Maruyama A, Shimizu T, Hishikawa Y.

Department of Neuropsychiatry, Akita University School of Medicine, Japan.

Studies were performed in the mouse forced swimming model, a well known experimental depression model, in order to detect the mechanism of the antidepressive effects induced by repeated serotonin reuptake inhibitor (SSRI) dosing. Five-day repeat dosing of a typical SSRI, paroxetine, increased climbing, a distinctive antidepressive behavior, 1 h after but not 1 h before treatment. The coinjection of paroxetine and serum in mice treated with four repeated doses of paroxetine distinctively increased the behavior, but the coinjection of paroxetine and serum in mice without paroxetine did not. These results indicate that repeated dosing of paroxetine produces a serum substance related to the antidepressive effects induced by serotonin neuron activities. Furthermore, the behavior induced by 5-day repeated dosing of paroxetine was decreased by 100 and 10 micrograms/kg of ketanserin (5-HT2 antagonist) and 100 micrograms/kg of LY-278584 (5-HT3 antagonist). The present findings strongly suggest that repeated dosing of paroxetine produces a serum substance stimulating the antidepressive neuronal pathway sensitively mediated by 5-HT2 and 5-HT3 receptor activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10669904&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Paroxetine in human breast milk and nursing infants.

Stowe ZN, Cohen LS, Hostetter A, Ritchie JC, Owens MJ, Nemeroff CB.

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA.

OBJECTIVE: The purpose of this study was to determine the extent of infant medication exposure through breast-feeding during maternal treatment with paroxetine. METHOD: Breast milk and paired maternal and infant sera were collected after 10 days of maternal treatment with paroxetine at a stable daily dose (10-50 mg/day). All samples were analyzed by means of high-performance liquid chromatography with ultraviolet detection and a limit of detection of 2 ng/ml. RESULTS: Breast milk paroxetine concentrations were highly variable (2-101 ng/ml) and were present in all breast milk samples (N=108). A significant gradient effect was observed, with greater paroxetine concentrations found in later portions of breast milk (hind milk) than in early portions (fore milk). No clear time course of paroxetine excretion into breast milk was demonstrated, although maternal paroxetine daily dose reliably predicted both trough and peak breast milk concentrations over a 24-hour period. In 16 mother and infant serum pairs, no detectable concentrations of paroxetine were found in the serum of the nursing infants. CONCLUSIONS: This study extends previous data by demonstrating the presence of paroxetine in the breast milk of nursing women treated with this medication. The low concentrations of paroxetine in infant serum and lack of any observable adverse effects after maternal use of this medication while breast-feeding parallels the available data on other selective serotonin reuptake inhibitors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10671385&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Effect of chronic paroxetine treatment on 5-HT1B and 5-HT1D autoreceptors in rat dorsal raphe nucleus.

Davidson C, Stamford JA.

Academic Department of Anaesthesia and Intensive Care, St Bartholomew's and the Royal London School of Medicine and Dentistry, Royal London Hospital, Whitechapel, London, UK.

This study reports the effect of chronic paroxetine (10 mg/kg p.o., 21 days) on 5-HT1B and 5-HT1D autoreceptors controlling stimulated 5-HT efflux in slices of rat dorsal raphe nucleus. Electrically evoked 5-HT (10 pulses, 200 Hz, 0.1 ms, 10 mA) was measured using fast cyclic voltammetry. 5-HT efflux was inhibited by CP 93129 (10 nM-10 microM) and by sumatriptan (1 nM-1 microM) agonists at 5-HT1B and 5-HT1D receptors, respectively. Chronic paroxetine did not, initially, appear to alter the sensitivity of the 5-HT1B autoreceptors to CP 93129. However, when constructed in the presence of WAY 100635 (10 nM) the selective and silent 5-HT1A antagonist, there was a significant (P < 0.001) rightward shift of the CP 93129 concentration-response curve in the paroxetine-treated rats but not in the controls, implying a desensitisation of the 5-HT1B autoreceptor by paroxetine. Chronic paroxetine did not affect the sumatriptan concentration-response curve, even with WAY 100635 present, implying that there was no (de)sensitisation of the 5-HT1D autoreceptor. These data suggest that chronic paroxetine treatment may desensitise 5-HT1B autoreceptors in the dorsal raphe nucleus but that this effect is unmasked only when the dominant 5-HT1A autoreceptor control is antagonised.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10676872&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Method development and validation for the HPLC assay (potency and related substances) for 20 mg paroxetine tablets.

Lambropoulos J, Spanos GA, Lazaridis NV.

Analytical Method Development and Validation, AAI, Inc., Wilmington, NC 28405, USA.

A reversed phase high performance liquid chromatographic (HPLC) method was developed and validated for use as a stability indicating assay (potency and related substances) of paroxetine in paroxetine hydrochloride 20 mg tablets. Assay samples were extracted at a paroxetine concentration of 0.4 mg ml(-1) utilizing mobile phase as the extraction solvent. The chromatographic conditions employed a C18 column (Inertsil, 5 microm, 15 cm x 4.6 mm), isocratic elution with 10 mM 1-decane sulfonic acid sodium salt containing 10 mM sodium phosphate monobasic (pH 3.0)-ACN (60:40, v/v) and ultraviolet (UV) detection at 235 nm.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10698543&dopt=Abstract paroxetine, Paxil, Paxil CR