paroxetine, Paxil
Antidepressants and the risk of suicidal behaviors.

Jick H, Kaye JA, Jick SS.

Boston Collaborative Drug Surveillance Program, Boston University School of Medicine, Lexington, Mass 02421, USA. hjick bu.edu

CONTEXT: The relation between use of antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), and suicidal ideation and behaviors has received considerable public attention recently. The use of such drugs among teenagers has been of particular concern. OBJECTIVE: To estimate the relative risks (RRs) of nonfatal suicidal behavior in patients starting treatment with 1 of 3 antidepressant drugs compared with patients starting treatment with dothiepin. DESIGN AND SETTING: Matched case-control study of patients treated in UK general practices using the UK General Practice Research Database for 1993-1999. PARTICIPANTS: The base population included 159,810 users of the 4 antidepressant drugs. Participants could have used only 1 of these antidepressants and had to have received at least 1 prescription for the study antidepressant within 90 days before their index date (the date of suicidal behavior or ideation for cases and the same date for matched controls). MAIN OUTCOME MEASURES: Frequency of first-time exposure to amitriptyline, fluoxetine, paroxetine, and dothiepin of patients with a recorded diagnosis of first-time nonfatal suicidal behavior or suicide compared with comparable patients who did not exhibit suicidal behavior. RESULTS: After controlling for age, sex, calendar time, and time from first antidepressant prescription to the onset of suicidal behavior, the relative risks for newly diagnosed nonfatal suicidal behavior in 555 cases and 2062 controls were 0.83 (95% confidence interval, [CI] 0.61-1.13) for amitriptyline, 1.16 (95% CI, 0.90-1.50) for fluoxetine, and 1.29 (95% CI, 0.97-1.70) for paroxetine compared with those using dothiepin. The RR for suicidal behavior among patients first prescribed an antidepressant within 1 to 9 days before their index date was 4.07 (95% CI, 2.89-5.74) compared with patients who were first prescribed an antidepressant 90 days or more before their index date. Time since first antidepressant prescription was not, however, a confounder of the relation between specific antidepressants and suicidal behavior since its relation to suicidal behavior was not materially different among users of the 4 study drugs. Similarly for fatal suicide, the RR among patients who were first prescribed an antidepressant within 1 to 9 days before their index date was 38.0 (95% CI, 6.2-231) compared with those who were first prescribed an antidepressant 90 days or more before their index date. There were no significant associations between the use of a particular study antidepressant and the risk of suicide. CONCLUSIONS: The risk of suicidal behavior after starting antidepressant treatment is similar among users of amitriptyline, fluoxetine, and paroxetine compared with the risk among users of dothiepin. The risk of suicidal behavior is increased in the first month after starting antidepressants, especially during the first 1 to 9 days. A possible small increase in risk (bordering statistical significance) among those starting the newest antidepressant, paroxetine, is of a magnitude that could readily be due to uncontrolled confounding by severity of depression. Based on limited information, we also conclude that there is no substantial difference in effect of the 4 drugs on people aged 10 to 19 years.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15265848&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Paroxetine, other antidepressants, and youth suicide in New York City: 1993 through 1998.

Leon AC, Marzuk PM, Tardiff K, Teres JJ.

Department of Psychiatry, Weill Medical College of Cornell University, New York, NY10021, USA. acleon med.cornell.edu

BACKGROUND: Regulatory agencies in the United Kingdom and the United States have recently issued warnings about a possible link between suicidal ideation and attempts and the use of paroxetine in a pediatric patient population. The objective of this study was to determine the proportion of youth suicides that tested positive for paroxetine or other antidepressants in medical examiner toxicologic testing in New York City from 1993 through 1998, the first 6 years that paroxetine was available in the United States. METHOD: Subjects in this medical examiner surveillance study were suicides less than 18 years of age. Serum toxicology was examined for paroxetine and other antidepressants. RESULTS: There were 66 suicides among persons under 18 years of age in the years 1993 through 1998. Toxicology was tested in 58 (87.9%) of the 66 suicides, and 54 (81.8%) had injury-death intervals of 3 days or less. None of the victims had paroxetine detected in their blood obtained at the time of autopsy. Imipramine was detected in 2 victims and fluoxetine in another 2. CONCLUSION: Despite regulatory concerns, none of the autopsies of youth suicides in New York City detected paroxetine in the victims, although other antidepressants were detected in 4 victims. However, in the vast majority of the youth suicides, there was no evidence of anti-depressant use immediately prior to death.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15291679&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
FDA-preapproved drugs targeted to the translational regulation and processing of the amyloid precursor protein.

Morse LJ, Payton SM, Cuny GD, Rogers JT.

Laboratory for Functional Genomics, Brigham and Women's Hospital, Harvard Medical School, USA.

The 5' untranslated region (5'UTR) of the transcript encoding the Alzheimer's amyloid precursor protein (APP) is a key regulatory sequence that determines the amount of intracellular APP holoprotein present in brain derived cells. Using neuroblastoma cells (SY5Y) we developed a transfection based screen of a library of FDA drugs to identify compounds that limited APP luciferase reporter expression translated from the APP 5'UTR. Paroxetine (Paxil trade mark ), dimercaptopropanol, phenserine, desferrioxamine, tetrathiolmobdylate, and azithromycin were six leads that were subsequently found to also suppress APP holoprotein levels or to alter APP cleavage (azithromycin). Since APP holoprotein levels are proportionate to Abeta peptide output in many systems we tested the efficacy of paroxetine and dimercaptopropanol to limit Abeta secretion as measured by ELISA assays. Paroxetine and dimercaptopropanol limited Abeta peptide secretion from lens epithelial cells (B3 cells). Interestingly, paroxetine changed the steady-state levels of transferrin receptor mRNAs. These data suggested that this serotonin reuptake inhibitor (SSRI) provided extra pharmacological action to chelate interacellular iron or change the intracellular iron distribution. An altered iron distribution would be predicted to indirectly limit APP holoprotein expression and Abeta peptide secretion. Copyright 2004 Humana Press Inc.

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paroxetine, Paxil
Paroxetine administration to influence human exercise capacity, perceived effort or hormone responses during prolonged exercise in a warm environment.

Strachan AT, Leiper JB, Maughan RJ.

Department of Clinical Biochemistry, Grampian University Hospital NHS Trust, Foresterhill, Aberdeen, AB25 2ZD, UK. a.t.strachan arh.grampian.scot.nhs.uk

The purpose of the experiment was to examine whether selective serotonin (5-HT) re-uptake transporter blockade by paroxetine has any effect on perceived effort (RPE) during exercise or the time to reach volitional fatigue and on the prolactin and cortisol responses during prolonged exercise performed in a warm environment. Eight healthy males performed two cycle rides to exhaustion in a warm (32 degrees C) environment at 60% of maximum oxygen uptake. Paroxetine (20 mg) or placebo was administered 5 h before exercise trials in a randomised double blind fashion. Time to exhaustion was not significantly influenced by administration of paroxetine: median (range) time to exhaustion was 93.3 (76.2-175.0) min on the placebo trial and 92.5 (66.0-151.0) min on the paroxetine trial. Rectal temperature was higher at rest and throughout exercise on the paroxetine trial. The serum concentrations of prolactin and cortisol were determined throughout exercise as peripheral markers of central 5-HT activity. RPE increased over time but was not influenced by paroxetine administration. Prolactin and cortisol levels increased over time but paroxetine administration did not influence the hormone responses during exercise. In conclusion, acute administration of paroxetine failed to alter RPE, exercise capacity or the response of the determined peripheral hormone markers of central 5-HT activity during prolonged exercise in a warm environment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15328306&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Evaluating the economic consequences of early antidepressant treatment discontinuation: a comparison between controlled-release and immediate-release paroxetine.

Sheehan DV, Eaddy M, Sarnes M, Vishalpura T, Regan T.

University of South Florida College of Medicine, Tampa, FL, USA.

INTRODUCTION: Early antidepressant discontinuation has been linked to significant clinical and economic consequences. Clinical practice guidelines suggest that treatment should last for at least 3 to 9 months into the continuation phase; however, 30% of patients discontinue therapy within 30 days, and over 40% discontinue therapy within 90 days of initiation, primarily due to adverse events. Clinical trials have shown that controlled-release (CR) paroxetine has a favorable tolerability profile when compared to immediate-release (IR) paroxetine, which may result in lower discontinuation rates and improved economic outcomes. This is the first study to directly compare treatment discontinuation rates and health care expenditures of a CR selective serotonin reuptake inhibitors with its IR counterpart. METHODS: This matched retrospective study used claims from a national managed care database to assess differences in discontinuation rates and health care expenditures between paroxetine CR and IR for treating depression and/or anxiety. Discontinuation was assessed by survival analysis, and health care expenditure was assessed using average monthly medical and pharmacy charges. RESULTS: There were 1275 paroxetine CR patients and 2550 paroxetine IR patients matched in the analysis. At 90 days, 62% of paroxetine CR patients continued therapy versus 56% of paroxetine IR patients. At 180 days, 51% of paroxetine CR patients continued therapy versus 42% of paroxetine IR patients. When evaluating all medical charges, paroxetine CR patients incurred US 119 dollars less per month than paroxetine IR patients (P = 0.054). CONCLUSIONS: Patients receiving paroxetine CR remained on therapy longer than patients on paroxetine IR, which resulted in lower total monthly medical costs for patients receiving paroxetine CR. Differences in costs were primarily driven by reduction in hospitalization expenditures.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15349013&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Effects of dosage and CYP2D6-mutated allele on plasma concentration of paroxetine.

Sawamura K, Suzuki Y, Someya T.

Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachidori-ichibancho, 951-8510 Niigata, Japan.

OBJECTIVE: We investigated the effect of dosages of paroxetine and cytochrome P450 (CYP) 2D6 genotypes on the plasma concentration of paroxetine in Japanese patients being treated with paroxetine. METHODS: Blood samples were collected from 73 individuals after at least 2 weeks of the same daily dose of paroxetine. The plasma paroxetine concentration was measured using HPLC, and the CYP2D6 genotypes were identified by PCR. Genotype groups were compared by one-way analysis of variance at different paroxetine doses. RESULTS: The mean plasma paroxetine concentrations at daily doses of 10, 20, 30, and 40 ng/ml were 6.6+/-7.4, 34.9+/-26.8, 74.8+/-37.2, and 130.5+/-96.8 ng/ml, respectively, showing a disproportionate and nonlinear increase in plasma drug levels of paroxetine upon increasing doses. Plasma paroxetine concentrations in patients with CYP2D6*10 alleles were significantly higher than those without *10 allele at 10 mg/day (7.3+/-6.11 vs. 2.99+/-3.52 ng/ml), but there was no significant difference between *1/ *1, *1/ *10 and *10/ *10 genotypes at the higher doses. Similarly, patients with CYP2D6*5 alleles showed higher plasma paroxetine concentrations than those without *5 allele, although differences in the plasma paroxetine concentration did not reach statistical significance level because of the small number of subjects with *5 alleles. CONCLUSIONS: Our results indicate the possibility of saturation in paroxetine metabolism with an increase in paroxetine dose, and that CYP2D6*10 allele(s) have significant impact on plasma paroxetine concentration at low doses in Japanese population.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15349705&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
On-demand treatment of premature ejaculation with clomipramine and paroxetine: a randomized, double-blind fixed-dose study with stopwatch assessment.

Waldinger MD, Zwinderman AH, Olivier B.

Department of Psychiatry and Neurosexology, Leyenburg Hospital, Leyweg 275, 2545 CH The Hague, The Netherlands. md waldinger.demon.nl

OBJECTIVE: To investigate the degree of ejaculation delay induced by on-demand treatment with 20 mg paroxetine and 25 mg clomipramine and to assess the type and severity of non-sexual side-effects of treatment at the day of and the day after treatment with these drugs. METHOD: A randomized, double-blind, fixed-dose, on-demand study in 30 men with lifelong premature ejaculation was performed. During a 1-month baseline period and a 4-week drug treatment period patients assessed the intravaginal ejaculation latency time (IELT) at home with a stopwatch. Only men with an IELT <1 min were randomly assigned to drug treatment. Patients assessed the drug coitus interval time (DCIT) and used the UKU side effect scale questionnaire at baseline, the day of and the day after intercourse. RESULTS: On-demand treatment with 25 mg clomipramine, with a mean DCIT of 5.14 h, led to a 4.05 (95%CI: 3.26-5.02) fold-increase of the IELT. On-demand treatment with 20 mg paroxetine, with a mean DCIT of 5.39 h, led to a 1.41 (95%CI: 1.22-1.63) fold-increase of the IELT. Both drugs had a high incidence of non-sexual side effects at the coitus day and the next day. At the day of coitus paroxetine led to significant sleepiness and yawning compared to clomipramine. At the day after coitus clomipramine induced significant nausea compared to paroxetine. CONCLUSION: On-demand treatment with 25 mg clomipramine led to a clinical relevant ejaculation delay. In contrast, 20 mg paroxetine had no clinical relevant ejaculation delay in men with lifelong premature ejaculation with an IELT of less than 1 minute. Both drugs exert mostly mild yet annoying non-sexual side effects both at the coitus day and the next day.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15363569&dopt=Abstract paroxetine, Paxil, Paxil CR