paroxetine, Paxil
Feeding and reward interactions from chronic paroxetine treatment.

Konkle AT, Bielajew C.

School of Psychology, University of Ottawa, Ontario, Canada.

The self-stimulation paradigm was used to evaluate threshold changes following acute and chronic administration of the selective serotonergic reuptake inhibitor paroxetine; stimulation sites were located in medial forebrain bundle structures. Rats received daily systemic injections of one of three doses of paroxetine (2.5, 5, or 7.5 mg/kg), either with or without stimulation, while the last group received the same number of vehicle injections with stimulation. Frequency thresholds were collected over a period of 6 h on day 1 (acute phase); no marked difference in the values were observed over this time span. Thereafter, the animals were tested every third day (chronic phase), for a total of 11 sessions or roughly 31 days. Commencing around day 10 of the drug treatment, the higher dose of paroxetine produced a significant and persistent facilitation in self-stimulation thresholds, mimicking the delay in clinical response in humans that is well documented. We also monitored on a daily basis the animals' weights and food intake. A large difference in the percent efficiency of food utilization, measured by calculating the ratio of weight change to food intake, was observed between the animals receiving stimulation and those that were not, exclusive to the higher dose of paroxetine. The percent efficiency of food utilization remained low in the animals only receiving the drug treatment, whereas they returned to baseline levels and above in subjects receiving both paroxetine and stimulation. Two findings emerge from these data: 1) the paradigm appears to model the human response to this class of antidepressants, and 2) rewarding stimulation seems to counteract the drug-induced weight loss.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10418785&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Paroxetine pharmacokinetics in depressed children and adolescents.

Findling RL, Reed MD, Myers C, O'Riordan MA, Fiala S, Branicky L, Waldorf B, Blumer JL.

Department of Psychiatry, Case Western Reserve University School of Medicine, University Hospitals of Cleveland, OH 44106-5080, USA.

OBJECTIVE: To describe the pharmacokinetics and safety of paroxetine in children and adolescents and to explore the role of genetic polymorphisms in paroxetine pharmacokinetics. METHOD: Thirty depressed youths were enrolled. Samples for phenotyping with respect to cytochrome P450 2D6 (CYP2D6) and catechol-O-methyltransferase were collected. A single 10-mg dose of paroxetine was then administered followed by 5 days of blood and urine collection for pharmacokinetic analyses. Subjects subsequently received open treatment for 8 weeks, and weekly blood samples were obtained for plasma concentration measurements. RESULTS: There was tremendous interindividual variability in paroxetine disposition. The mean half-life of paroxetine was 11.1 +/- 5.2 (SD) hours. The average clearance was 88.7 +/- 66.4 mL/min/kg. The mean area under the plasma drug concentration curve was 0.09 +/- 0.10 microgram/mL.hr. Within-subject variability of plasma paroxetine concentrations was generally not significant. Clearance and fractional urinary excretion of paroxetine were found to correlate with CYP2D6 activity. Two subjects developed hypomania necessitating drug discontinuation. No clinically significant changes in any safety assessments were noted. CONCLUSIONS: Paroxetine is more rapidly cleared in youths than adults and may be given once daily in this population. Short-term treatment with paroxetine appears safe and well tolerated in this relatively small sample of pediatric patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10434486&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
The effects of single dose nefazodone and paroxetine upon 5-HT2A binding potential in humans using [18F]-setoperone PET.

Meyer JH, Cho R, Kennedy S, Kapur S.

The Mood and Anxiety Division and PET Centre, The Clarke Division of the Centre for Addictions and Mental Health, Toronto, Ontario, Canada.

RATIONALE: Alterations in 5-HT2A receptor binding are implicated in suicidality and depression. 5-HT2A receptors may also be involved in the therapeutic effects of antidepressants. OBJECTIVES: The purpose of this study was to assess the effect of paroxetine and nefazodone on 5-HT2A receptors after a single dose. METHODS: Seven subjects received a single dose of nefazodone 200 mg and five subjects received a single dose of paroxetine 20 mg. Before and after the dose, 5-HT2A binding potentials (Bmax/Kd) were determined in each subject using [18F]-setoperone PET. RESULTS: Nefazodone induced a significant change in 5-HT2A binding potential (-39+/-17%,, P = 0.003) while paroxetine showed no significant alteration of 5-HT2A binding potential (+3+/-13%, P = 0.73). CONCLUSIONS: The change in 5-HT2A binding potential seen with nefazodone represents blockade of 5-HT2A receptors by the drug. We do not find evidence for acute downregulation of 5-HT2A receptors with paroxetine within 9 h.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10435395&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Paroxetine during breast-feeding: infant weight gain and maternal adherence to counsel.

Merlob P, Stahl B, Sulkes J.

Department of Neonatology, Rabin Medical Centre, Beilinson Campus, 49100, Petah Tiqwa, Israel. merlobp post.tau.ac.il

The aims of the present study were to examine the weight gain in infants breast fed by mothers taking paroxetine and to assess the clinical implementation of the recommendations of the teratology service in our centre. A prospective cohort study design was used. The study group included 27 mothers who had taken paroxetine for at least 2 weeks while breast-feeding, 19 mothers who did not taken paroxetine and did not breast-feed their infants, and 27 mothers who breast fed their infants but did not take any drugs. Participants completed a detailed outcome questionnaire at 3 months to 1 year after the birth of their child. Additional infant data were obtained from specific follow-up forms routinely completed by the paediatricians and nurses at well baby clinics and paediatric services in Israel. Infant weight and developmental milestones at ages 3, 6, and 12 months were recorded. There were no statistically significant differences between the paroxetine group and control groups in mean infant weight at ages 6 and 12 months. The usual developmental milestones were reached in all groups. There were no reported adverse effects of paroxetine during lactation except for irritability in one infant. Mothers expressed satisfaction with the treatment. CONCLUSION: paroxetine use during breast-feeding does not affect infant weight gain and rarely has adverse effects on the infant. Paroxetine may be an acceptable solution for depression in lactating women provided that they adhere to four important restrictions: use lowest dose (20 mg/day), preferable single bed-time dose, avoid combinations of drugs, and ensure close medical follow-up of the infant.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14745552&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Paroxetine (Paxil) overdose: a pediatric focus.

Myers LB, Krenzelok EP.

Pittsburgh Poison Center, Children's Hospital of Pittsburg, PA 15213, USA.

The antidepressant paroxetine (PAXIL) was approved for use in 1993. Thus far, this selective serotonin reuptake inhibitor (SSRI) has shown a high threshold for the development of toxic manifestations in adult overdoses. However, the toxic threshold doses and profile of toxic manifestations for pediatric exposures has not been well-established. All pediatric paroxetine exposures reported at a certified regional poison information center over a 24-mo period were reviewed. The parameters evaluated included age, amount, co-ingestants, symptoms, treatment and outcome. Thirty-five pediatric paroxetine exposures were documented. Ages ranged from 10.5 mo to 17 y. Paroxetine alone accounted for 28 cases and 7 were with concomitant medications. Of the paroxetine-alone ingestants, 16 cases were in children < or = 5 y (mean age 2.4 y) with ingestant amounts ranging from 10-120 mg. All patients remained asymptomatic with or without gastrointestinal decontamination. The remainder of sole ingestant cases included 12 patients > or = 12 y (mean age 17.2 y) who ingested 100-800 mg (mean 292 mg). Most remained asymptomatic. There were 7 patients in the co-ingestant group > or = 13 y. Only 2 remained asymptomatic, but the symptoms reported were also consistent with the co-ingestants taken. Paroxetine is less sedating and has fewer cardiovascular effects than the tricyclic antidepressants, even in the pediatric population. The high therapeutic index is consistent with other SSRI's. In contrast to more toxic antidepressants in the pediatric group, paroxetine overdose patients are less likely to develop toxic manifestations. Ingestions of 120 mg or less in children < or = 5 y led to favorable outcomes following gastrointestinal decontamination and minimal supportive care. However, continued evaluation of paroxetine is essential to determine more specific toxic thresholds.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9080633&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
An autoradiographic study of dextromethorphan high-affinity binding sites in rat brain: sodium-dependency and colocalization with paroxetine.

Meoni P, Tortella FC, Bowery NG.

Department of Pharmacology, School of Pharmacy, University of London.

1. The distribution and some pharmacological properties of centrally located dextromethorphan high-affinity binding sites were investigated by in vitro autoradiography. 2. Sodium chloride (50 mM) induced a 7 to 12 fold increase in dextromethorphan binding to rat brain in all areas tested. The effect of sodium was concentration-dependent with a higher dose (120 mM) exerting a smaller effect on binding. 3. [3H]-dextromethorphan binding in the presence of sodium was inhibited in the presence of the anticonvulsant phenytoin at a concentration of 100 microM, while the sigma ligand (+)-3-(-3-hydroxyphenyl)-N-(1-propyl)pipendine ((+)-PPP) had no effect on the binding, suggesting an interaction with the DM2 site. 4. The distribution of the sodium-dependent binding identified in this study correlated significantly with the distribution of the selective 5-HT uptake inhibitor [3H]-paroxetine, and paroxetine and dextromethorphan mutually displaced their binding at concentrations in the low nanomolar range. 5. These data show that dextromethorphan and paroxetine share a sodium-dependent high affinity binding site in rat brain, and suggest that dextromethorphan might interact, in the presence of sodium, with the 5-HT uptake mechanism in rat brain.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9105700&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Efficacy of paroxetine for the treatment of depression in the context of HIV infection.

Grassi B, Gambini O, Garghentini G, Lazzarin A, Scarone S.

Department of Neuropsychiatric Sciences, University of Milan Medical School, Italy.

Recent studies in the literature point out that HIV-infected subjects are affected by depression with a relatively high frequency. The aim of this study was to assess the efficacy and tolerability of paroxetine for the treatment of depression in the context of HIV infection. 15 HIV-infected subjects (10 patients with a major depressive episode and 5 patients with an adjustment disorder with depressed mood, according to the DSM IV diagnostic criteria) were administered paroxetine at a daily dosage of 20 mg. Depressive symptomatology was monitored by means of the Hamilton Rating Scale for Depression (HAM-D) at the time of enrollment and 2 weeks, 4 weeks, and 6 weeks later; at the same times adverse effects were recorded. 14 patients completed the study, and all of these recovered from depression; HAM-D mean scores significantly improved from baseline to final assessment, both when all subjects were considered (ANOVA for repeated measurements: p < or = 0.0001) and when only patients with a major depressive episode were included in the statistical analysis (ANOVA for repeated measurements: p < 0.0001). No significant adverse effects were recorded. Because of its efficacy and good tolerability paroxetine seems to be suitable for the treatment of depression in the context of HIV infection.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9131727&dopt=Abstract paroxetine, Paxil, Paxil CR