paroxetine, Paxil
Breastfeeding during maternal antidepressant treatment with serotonin reuptake inhibitors: infant exposure, clinical symptoms, and cytochrome p450 genotypes.

Berle JO, Steen VM, Aamo TO, Breilid H, Zahlsen K, Spigset O.

Centre for Child and Adolescent Mental Health, University of Bergen, Bergen, Norway. jean.berle psyk.uib.no

BACKGROUND: The aims of the study were to quantify the drug exposure in breastfed infants of antidepressant-treated mothers, to identify possible adverse events, and to correlate these variables to maternal and infant drug metabolism-relevant genotypes and milk triglyceride content. METHOD: The study included 25 lactating women treated with citalopram (N = 9), sertraline (N = 6), paroxetine (N = 6), fluoxetine (N = 1), or venlafaxine (N = 3) and their 26 breastfed infants. Drug concentrations in maternal and infant serum and milk were analyzed using liquid chromotography mass spectrometry methods; milk triglyceride levels were measured with a commercial kit. Cytochrome P450 (CYP) 2D6 and CYP2C19 activity was determined by polymerase chain reaction-based genotyping of the mothers and infants. An infant adverse event questionnaire was completed by the medication-treated mothers as well as by a control group of medication-free breastfeeding mothers of 68 infants. RESULTS: Sertraline and paroxetine were not detected in any of the drug-exposed infants. The infant serum level of citalopram was either undetectable (N = 4) or low (N = 6). All venlafaxine-exposed infants had measurable drug concentrations. We identified a paroxetine-treated mother and her infant who were both CYP2D6 poor metabolizers, as well as a citalopram-treated mother with CYP2C19 poor metabolizer status, but the serum drug levels of their infants were still either undetectable (paroxetine) or low (citalopram). There was no evidence of adverse events in the drug-exposed infants. CONCLUSION: Serum drug levels in breastfed infants of antidepressant-treated mothers were undetectable or low. This study adds further evidence to previously published data indicating that breastfeeding should not be generally discouraged in women using serotonin reuptake inhibitor anti-depressants.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15367050&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Tolerance and side-effects of paroxetine in elderly depressed patients.

Ghose K.

Cardiff Royal Infirmary, Cardiff, UK.

Paroxetine, a selective serotonin reuptake inhibitor (SSRI) antidepressant, is considered to have fewer side-effects than a typical tricyclic antidepressant. As the elderly frequently suffer from adverse effects of psychotropic drugs, safeties and tolerance of paroxetine and their relationship with dose were studied in a double-blind study. Sixteen nondashhospitalised depressed patients, aged 72-86 years, were recruited but 12 patients completed the study. Patients were randomly selected to receive either 15 mg or 30 mg paroxetine daily for 42 days in a double-blind study. A trained nurse made weekly home visits to monitor their medication and general conditions. Patients were assessed at the hospital on days 1, 7, 14, 28 and 42. There were four drop-outs during the first week of study due to lack of motivation, skin rash and upper gastrointestinal symptoms ( [Formula: see text] ). Plasma levels of paroxetine showed a dose-related increase in concentrations and indicated a good compliance. At the dosages used, no changes in blood pressure, heart rate, salivary volume, visual choice reaction time, critical flicker fusion threshold and short-term memory were observed in these patients. However, there was a significant improvement in their subjective symptoms (as assessed by a symptom check list and Hamilton Rating Scale) in the 30 mg group, indicating a feeling of well-being.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15374134&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Hydrolysis and photolysis of paroxetine, a selective serotonin reuptake inhibitor, in aqueous solutions.

Kwon JW, Armbrust KL.

Mississippi State Chemical Laboratory, Mississippi State University, PO Box CR, Mississippi State, Mississippi 39762, USA.

The hydrolysis and photolysis of paroxetine HCI, a selective serotonin reuptake inhibitor, in aqueous buffer solutions (pH 5, 7, and 9), in synthetic humic water, and in lake water were investigated at 25 degrees C in the dark and in a growth chamber outfitted with fluorescent lamps simulating the ultraviolet (UV) output of sunlight. Paroxetine was degraded completely within 4 d by simulated sunlight in all aqueous media. Photolysis of paroxetine HCI was accelerated by increasing pH. The t1/2 values at pH 5, 7, and 9 were 15.79, 13.11, and 11.35 h, respectively. The half-lives of paroxetine in synthetic humic water and two lake waters were slightly longer than in pH 7 buffer. Two photoproducts were detected and their structures were identified by liquid chromatography-mass spectrometry in positive mode. Photoproduct I was found to be photolytically unstable, being gradually degraded after 12 to 18 h of irradiation. However, photoproduct II was photolytically very stable throughout the experiment period, indicating that it was persistent to further photodegradation. In the dark, paroxetine in all aqueous solutions was found to be stable over a 30-d period. In conclusion, paroxetine is a relatively photolabile drug that has a possibility of photodegradation by sunlight in surface water.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15376524&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Paroxetine controlled release for premenstrual dysphoric disorder: a double-blind, placebo-controlled trial.

Cohen LS, Soares CN, Yonkers KA, Bellew KM, Bridges IM, Steiner M.

Perinatal and Reproductive Psychiatry Program, Massachusetts General Hospital, 15 Parkman Street, WACC 812, Boston, MA 02114, USA. Lcohen2 partners.org

BACKGROUND: Better characterization of safety and efficacy of multiple doses of selective serotonin reuptake inhibitors for the treatment of a wider range of symptoms of premenstrual dysphoric disorder (PMDD) will provide clinicians with flexibility to provide symptom relief along with acceptable tolerability. This study was designed to assess the efficacy and tolerability of multiple doses of paroxetine controlled release (CR) in PMDD. METHODS: In a multicenter (43 outpatient U.S. sites), placebo-controlled trial, 327 females aged 18 to 45 years, with regular menstrual cycles, meeting DSM-IV criteria for PMDD, were randomly assigned to receive paroxetine CR 12.5 mg; paroxetine CR 25 mg; or placebo, once daily, for up to three treatment cycles. The primary efficacy outcome was change from baseline to end point in mean luteal phase Visual Analogue Scale-Mood (irritability, tension, affective lability, depressed mood) score. RESULTS: At end point, subjects treated with paroxetine CR (12.5 mg and 25 mg) demonstrated significant improvement in VAS-Mood scores compared with those who received placebo (paroxetine CR 12.5 mg mean treatment difference vs. placebo, -8.7 mm; 95% CI, -15.7, -1.7; p =.015; paroxetine CR 25 mg mean treatment difference vs. placebo, -12.1 mm; 95% CI, -18.9, -5.3; p <.001). Results were also significant across measures of physical symptoms and social functioning. Paroxetine CR was well tolerated; 9.5% of subjects treated with 12.5 mg and 13.5% of subjects treated with 25 mg withdrew from the trial due to adverse events, compared with 6.5% of subjects in the placebo group. CONCLUSIONS: Both doses of paroxetine CR 12.5 mg and 25 mg daily are effective and well tolerated in patients who suffer from PMDD. Efficacy with both doses affords greater flexibility to the prescribing physician.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15385695&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Paroxetine combined with a 5-HT(1A) receptor antagonist reversed reward deficits observed during amphetamine withdrawal in rats.

Markou A, Harrison AA, Chevrette J, Hoyer D.

Department of Neuropharmacology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA, amarkou scripps.

RATIONALE: "Diminished interest or pleasure" in rewarding stimuli is an affective symptom of amphetamine withdrawal and a core symptom of depression. An operational measure of this symptom is elevation of brain stimulation reward thresholds during drug withdrawal. Data indicated that increasing serotonin neurotransmission by co-administration of the selective serotonin reuptake inhibitor (SSRI) fluoxetine and the serotonin-1A receptor antagonist p-MPPI reversed reward deficits observed during drug withdrawal (Harrison et al. 2001).OBJECTIVES: We tested the hypothesis that increased serotonergic and noradrenergic neurotransmission, using the SSRI paroxetine which also inhibits noradrenaline reuptake, would alleviate affective aspects of amphetamine withdrawal.METHODS: A discrete-trial, current-threshold, self-stimulation procedure was used to assess brain reward function. The effects of paroxetine and p-MPPI alone and in combination were assessed in non-drug-withdrawing animals. We assessed also the effects of paroxetine and p-MPPI alone and in combination on reward deficits associated with amphetamine withdrawal.RESULTS: Paroxetine or p-MPPI alone had no effect on thresholds, while the co-administration of p-MPPI (3 mg/kg) and paroxetine (1.25 mg/kg) elevated thresholds in non-withdrawing rats. Amphetamine withdrawal resulted in threshold elevations. The co-administration of p-MPPI and paroxetine reduced the duration of amphetamine-withdrawal-induced reward deficits.CONCLUSIONS: Increased serotonergic and noradrenergic neurotransmission decreased reward function in non-withdrawing rats, while the same treatment reversed reward deficits associated with amphetamine withdrawal. Considering that paroxetine acts on both the serotonin and noradrenaline transporter, these results indicate that the affective symptoms of amphetamine withdrawal, similar to non-drug-induced depressions, may be, in part, mediated through reduced serotonergic and noradrenergic neurotransmission.

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paroxetine, Paxil
In vivo identification and characterization of binding sites for selective serotonin reuptake inhibitors in mouse brain.

Hirano K, Maruyama S, Kimura R, Kagawa Y, Yamada S.

Department of Biopharmaceutical Sciences and Center of Excellence (COE) Program in the 21st Century, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.

The present study was undertaken to identify and characterize in vivo binding sites of selective serotonin reuptake inhibitors (SSRIs) in the mouse brain by using [3H]paroxetine as radioligand. Relatively higher concentration of [3H]paroxetine was detected in the whole brain (minus cerebellum) than in the plasma of mice after the i.v. injection of the radioligand, and the half-life (t1/2) of elimination was much slower. The in vivo specific [3H]paroxetine binding in the mouse brain after the i.v. injection was defined as the difference of particulate-bound radioactivity between the whole brain and cerebellum, and it was dose-dependently attenuated by oral or intraperitoneal administration of fluoxetine (8.68-116 micromol/kg). Furthermore, oral administration of fluvoxamine, fluoxetine, paroxetine and sertraline at the pharmacologically relevant doses reduced significantly (25-94%) in vivo specific [3H]paroxetine binding in the cerebral cortex, striatum, hippocampus, thalamus and midbrain of mice, and their significant decreases were observed up to at least 8 h (fluvoxamine), 24 h (fluoxetine), and 12 h (paroxetine and sertraline) later. The value of area under the curve (AUC) for decrease in [3H]paroxetine binding vs. time in each brain region was largest for fluoxetine among these SSRIs, due to the relatively longer-lasting occupation of brain serotonin transporter. The AUC value in mouse brain after oral administration of each SSRI was 1.2-3.2 times greater in the thalamus and midbrain than in the cerebral cortex, striatum and hippocampus. Thus, the present study has revealed that [3H]paroxetine may be a suitable radioligand for in vivo characterization of brain binding sites and pharmacological effects of SSRIs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15454344&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
The catechol-O-methyltransferase Val108/158Met polymorphism affects short-term treatment response to mirtazapine, but not to paroxetine in major depression.

Szegedi A, Rujescu D, Tadic A, Muller MJ, Kohnen R, Stassen HH, Dahmen N.

Department of Psychiatry, Charite-University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany. armin.szegedi charite.de

The catechol-O-methyltransferase (COMT) is a major degrading enzyme in the metabolic pathways of catecholaminergic neurotransmitters such as dopamine and norepinephrine. This study investigated whether the functionally relevant Val(108/158)Met gene variant is associated with differential antidepressant response to mirtazapine and/or paroxetine in 102 patients with major depression (DSM-IV criteria) participating in a randomized clinical trial with both drugs. In patients treated with mirtazapine, but not paroxetine, allelic variations in the COMT gene were associated with differential response. COMT(VAL/VAL) and COMT(VAL/MET) genotype carriers showed a better response than COMT(MET/MET)-bearing patients in the mirtazapine group. Moreover, carriers of the COMT(VAL/VAL) or COMT(VAL/MET) genotype had significantly greater HAMD-17 (Hamilton Rating Scale for Depression 17 item version) score reductions than COMT(MET/MET) homozygotes from week 2 to 6, respectively, in the mirtazapine group. Time course of response and antidepressant efficacy of mirtazapine, but not paroxetine, seem to be influenced in a clinically relevant manner by this allelic variation within the COMT gene.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15520843&dopt=Abstract paroxetine, Paxil, Paxil CR