paroxetine, Paxil
A comparison of the direct costs and cost effectiveness of serotonin reuptake inhibitors and associated adverse drug reactions.

Sullivan PW, Valuck R, Saseen J, MacFall HM.

Pharmaceutical Outcomes Research Program, Department of Clinical Pharmacy, School of Pharmacy, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. Patrick.Sullivan UCHSC.edu

BACKGROUND: The economic burden of depression is known to be high and was estimated to be USD 83.1 billion in 2000. Serotonin reuptake inhibitors (SRIs), including both selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), have a superior adverse effect and safety profile relative to traditional agents (e.g. TCAs), and as a result have demonstrated superior cost effectiveness. Although efficacy across the SRIs is similar, the incidence of adverse drug reactions (ADRs) within SRIs remains significant and varies by agent. Patients who experience ADRs from SRIs may seek medical care, require additional treatment, and even discontinue treatment altogether, leading to increased utilisation and cost of therapy. OBJECTIVE: This study estimates the direct cost and cost effectiveness, taking into account the impact of treatment-related ADRs, of eight currently marketed SRIs (citalopram, escitalopram, generic fluoxetine, paroxetine, paroxetine controlled release [CR], sertraline, venlafaxine and venlafaxine extended release [XR]) used as initial treatment for depression. METHODS: A decision analytic model with a 6-month treatment goal was used to estimate the direct cost and cost effectiveness of treatment from the managed care/payer perspective. Estimates of SRI-related ADRs, associated treatments and costs were derived from the US FDA-approved prescribing information and published literature. Efficacy was assumed to be similar across all SRIs. Effectiveness was measured using quality-adjusted life years (QALY) based on EuroQol EQ-5D scores derived from the 2000 Medical Expenditure Panel Survey (MEPS). Censored least absolute deviations (CLAD) regression analysis was used to derive age-adjusted estimates of utility for all health states. Univariate and Bayesian second-order multivariate probabilistic sensitivity analyses were conducted to examine the impact of uncertainty in the parameter estimates. RESULTS: The expected direct cost and cost effectiveness of treatment from least to most expensive were: escitalopram (USD 3891; 0.341), citalopram (USD 3938; 0.340), generic fluoxetine (USD 4034; 0.335), venlafaxine XR (USD 4226; 0.336), sertraline (USD 4250; 0.335), generic paroxetine (USD 4385; 0.332), paroxetine CR (USD 4440; 0.332) and venlafaxine (USD 4613; 0.326). Monte Carlo simulation results suggested that escitalopram was the most likely (77%) to be cost effective for a willingness to pay < or = USD 50,000 per QALY, followed by citalopram (22%), generic fluoxetine (0.3%) and all other SRIs (0%). Sensitivity analyses indicated that the results of the study were robust to the assumptions underpinning the model. CONCLUSIONS: SRI-related ADRs have a significant impact on the direct cost and cost effectiveness of treatment. Escitalopram, with the lowest ADR rate of the SRIs, had the lowest expected treatment cost and greatest effectiveness when compared with citalopram, generic fluoxetine, generic paroxetine, paroxetine CR, sertraline, venlafaxine and venlafaxine XR.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15521793&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Implication of 5-HT(2) receptor subtypes in the mechanism of action of antidepressants in the four plates test.

Nic Dhonnchadha BA, Ripoll N, Clenet F, Hascoet M, Bourin M.

EA 3256, Neurobiologie de l'anxiete et de la depression, Faculte de Medecine, 1 rue Gaston Veil, BP 53508, 44035, Nantes Cedex 01, France.

RATIONALE. The selective serotonin reuptake inhibitors (SSRIs) and the serotonin and noradrenaline reuptake inhibitors (SNRIs) increase synaptic levels of serotonin, leading to an increased activation of a multitude of specific postsynaptic 5-HT receptors. However, it is not yet known which 5-HT receptor subtypes mediate the therapeutic effects of antidepressants. METHODS. The effects of the SSRI, paroxetine and the SNRI, venlafaxine were evaluated in the mouse four plates test (FPT). RESULTS. Paroxetine administered intraperitoneally (IP) (0.5, 2-8 mg/kg) potently augmented the number of punished passages accepted by mice in this paradigm. The effects of paroxetine (8 mg/kg) were not reversed by the selective 5-HT(2C) receptor antagonist, RS 10-2221 (0.1 mg/kg and 1 mg/kg) or the selective 5-HT(2B/2C) receptor antagonist SB 206553 (0.1 mg/kg and 1 mg/kg), at doses which lack an effect when administered alone. In contrast, the selective 5-HT(2A) receptor antagonist, SR 46349B (0.1 mg/kg and 1 mg/kg) completely abolished the paroxetine-induced increase in punished passages. The acute administration of venlafaxine induced an anxiolytic-like effect in the FPT at the doses of 2-16 mg/kg. This effect was reversed by the 5-HT(2B/2C) receptor antagonist as did SR 46349B, for both doses administered. Our results strongly suggest that activation of 5-HT(2A) receptors is critically involved in the anxiolytic activity of paroxetine, whereas the 5-HT(2A) and 5-HT(2B) receptors are involved in the anti-punishment action of venlafaxine in the FPT. The co-administration of selective 5-HT(2A, 2B, 2C) receptor agonists (DOI, 0.06 mg/kg and 0.25 mg/kg; BW 723C86, 0.5 mg/kg and 2 mg/kg and RO 60-0175, 0.06 mg/kg and 0.25 mg/kg), respectively, was subsequently investigated. The effects of sub-active doses of paroxetine (0.25 mg/kg and 1 mg/kg) were augmented by BW 723C86 and RO 60-0175 receptor agonist challenge. The anti-punishment effects of venlafaxine (0.25 mg/kg and 1 mg/kg) were potentialised only by DOI co-administration. CONCLUSION. These results indicate that the co-administration of 5-HT(2) receptor agonists with paroxetine and venlafaxine may provide a powerful tool for enhancing the clinical efficacy of these antidepressants.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15551125&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
A comparative study of milnacipran and paroxetine in outpatients with major depression.

Sechter D, Vandel P, Weiller E, Pezous N, Cabanac F, Tournoux A; study co-coordinators.

Service de Psychiatrie de l'Adulte, Centre Hospitalier Universitaire St Jacques, Besancon, Cedex F-25030, France. daniel.sechter ufc-chu.univ-fcomte.fr

BACKGROUND: Milnacipran is a dual-action antidepressant which inhibits both serotonin and noradrenaline reuptake with no affinity for any neurotransmitter receptor studied. METHODS: A 6-week double-blind multicentre study compared milnacipran (100 mg/day) with paroxetine (20 mg/day) in 300 outpatients with major depression. Efficacy was evaluated using HAMD17, MADRS and CGI for severity of illness and global improvement. Data were analysed on an intention to treat, last observation carried forward, basis. RESULTS: Milnacipran and paroxetine were both effective and well tolerated with no significant difference in their effects. After treatment discontinuation, milnacipran was associated with significantly less emergent symptoms. Responders, at endpoint, to milnacipran had significantly greater levels of psychomotor retardation at baseline than non-responders. LIMITATIONS: The study did not include a placebo group so that it is impossible to determine absolute levels of efficacy. CONCLUSIONS: Both milnacipran and paroxetine were effective and well tolerated by outpatients with major depression treated for 6 weeks. After treatment discontinuation milnacipran was associated with less emergent symptoms. Psychomotor retardation at baseline may be a predictive factor of a favourable response to milnacipran.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15555719&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Effects of oral administration of extracts of Hypericum perforatum (St John's wort) on brain serotonin transporter, serotonin uptake and behaviour in mice.

Hirano K, Kato Y, Uchida S, Sugimoto Y, Yamada J, Umegaki K, Yamada S.

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

The pharmacological effects of extracts of Hypericum perforatum (St John's wort) were characterized in-vitro and ex-vivo, in relation to its behavioural effects. In in-vitro experiments, St John's wort inhibited brain synaptosomal [(3)H]serotonin uptake in mice with little effect on specific [(3)H]paroxetine binding. For selective serotonin-reuptake inhibitors (SSRIs), the IC50 value for [(3)H]serotonin uptake (molar concentration of unlabelled drug necessary to displace 50% of specific uptake) correlated well with the inhibition constant K(i) value for [(3)H]paroxetine binding in mouse brain. Oral administration of St John's wort (900 mg kg(-1)), paroxetine (1 mg kg(-1)) and sertraline (10 mg kg(-1)) brought about significant increases in the K(m) value for [(3)H]serotonin uptake into brain synaptosomes 4 h later, and only SSRIs suppressed specific [(3)H]paroxetine binding in mouse brain. St John's wort and SSRIs significantly inhibited marble-burying behaviour in mice and the time-course of attenuation of this behaviour by St John's wort was similar to that of [(3)H]serotonin uptake inhibition. In the forced swimming test, St John's wort, but not SSRIs, suppressed the immobility time of mice after oral administration. These results provide the first in-vivo evidence to suggest that the mode of antidepressant action of St John's wort differs from that of SSRIs. Thus, this study may have a significant impact on phytotherapy with St John's wort.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15563766&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
[Paroxetine versus clomipramine in female adolescents suffering from anorexia nervosa and depressive episode--a retrospective study on tolerability, reasons for discontinuing the antidepressive treatment and different outcome measurements]

[Article in German]

Strobel M, Warnke A, Roth M, Schulze U.

Klinik und Poliklinik fur Kinder- und Jugendpsychiatrie und Psychotherapie der Julius-Maximilian-Universitat Wurzburg.

OBJECTIVES: So far, there have only been few studies concerning the question of indication and efficacy of antidepressive medication in children and adolescents with anorexia nervosa and depressive episode in the course of an inpatient treatment. In addition, there is a lack of studies comparing the tolerability and efficacy of different antidepressants given to anorectic patients of this particular age group. This study compares paroxetine, a specific SRI, with clomipramine, a TCA with SRI activity, concerning the frequency and quality of adverse side effects, the frequency and the reasons for discontinuating the antidepressive treatment and different outcome measurements. METHODS: 83 female patients, aged 10.9 to 18.1 years, who underwent an inpatient treatment at the Departement of Child and Adolescent Psychiatry and Psychotherapy at the University of Wuerzburg, Germany, were enrolled in this retrospective study. All of them met the ICD-10 criteria for anorexia nervosa and depressive episode and received an antidepressant medication with clomipramine or paroxetine. We collected data from basic documentation, treatment reports, and the multiaxial classification (MAS). Outcome measurements were the duration of treatment (days) and the increase of body weight (kg/m2). RESULTS: The discontinuation of the antidepressive treatment due to adverse side effects or a lack of efficacy was significantly more frequent with clomipramine than paroxetine (33.3 vs. 15.4%). The increase of body weight (2.8 vs. 2.6 kg/m2) was similar in both groups, but the duration of treatment was significantly shorter under paroxetine (71.9 vs. 96.5 days). CONCLUSIONS: A shorter duration of treatment, faster increase of body weight, lower percentage of dicontinuating the antidepressive medication and last but not least economic reasons lead to the conclusion, that paroxetine should be preferred in female adolescents with anorexia nervosa and depressive episode. However, prospective studies are needed to confirm our findings.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15565897&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Long-term treatment with paroxetine increases verbal declarative memory and hippocampal volume in posttraumatic stress disorder.

Vermetten E, Vythilingam M, Southwick SM, Charney DS, Bremner JD.

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

BACKGROUND: Animal studies have shown that stress is associated with damage to the hippocampus, inhibition of neurogenesis, and deficits in hippocampal-based memory dysfunction. Studies in patients with posttraumatic stress disorder (PTSD) found deficits in hippocampal-based declarative verbal memory and smaller hippocampal volume, as measured with magnetic resonance imaging (MRI). Recent preclinical evidence has shown that selective serotonin reuptake inhibitors promote neurogenesis and reverse the effects of stress on hippocampal atrophy. This study assessed the effects of long-term treatment with paroxetine on hippocampal volume and declarative memory performance in PTSD. METHODS: Declarative memory was assessed with the Wechsler Memory Scale-Revised and Selective Reminding Test before and after 9-12 months of treatment with paroxetine in PTSD. Hippocampal volume was measured with MRI. Of the 28 patients who started the protocol, 23 completed the full course of treatment and neuropsychological testing. Twenty patients were able to complete MRI imaging. RESULTS: Patients with PTSD showed a significant improvement in PTSD symptoms with treatment. Treatment resulted in significant improvements in verbal declarative memory and a 4.6% increase in mean hippocampal volume. CONCLUSIONS: These findings suggest that long-term treatment with paroxetine is associated with improvement of verbal declarative memory deficits and an increase in hippocampal volume in PTSD.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14512209&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Severe adverse effects in a newborn with two defective CYP2D6 alleles after exposure to paroxetine during late pregnancy.

Laine K, Kytola J, Bertilsson L.

Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland. karlai utu.fi

Paroxetine, like other SSRIs, is reported not to increase the number of malformations in infants exposed to these drugs in utero. However, late pregnancy exposure to SSRIs sometimes leads to perinatal complications resembling the symptoms seen in serotonergic overstimulation. We report here a case of third trimester paroxetine exposure with adverse birth outcome in a newborn. The clinical symptoms in the infant included severe tremor and rigidity as well as loose stools during the first 4 days of life. Plasma paroxetine concentrations in infant plasma were quite low after birth, but she was genotyped to be a poor metabolizer of CYP2D6, the enzyme catalyzing the metabolism of paroxetine. In accordance with an earlier report, we suggest that even low plasma concentrations of paroxetine may be related to perinatal complications in infants exposed to paroxetine during late pregnancy and that the poor metabolizer genotype of CYP2D6 may be a risk factor for these complications.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15570195&dopt=Abstract paroxetine, Paxil, Paxil CR