Dose Of Paroxetine Research Articles

Pindolol potentiates the panicolytic effect of paroxetine in the elevated T-maze

Aims The β-adrenergic and 5-HT 1A receptor antagonist pindolol has been used in combination with antidepressant drugs, to shorten the time of onset of clinical efficacy and/or increase the proportion of responders in depressive and anxiety disorders. The aim of this study was to examine the interaction between pindolol and the selective serotonin reuptake inhibitor (SSRI), paroxetine in rats submitted to the elevated T-maze (ETM). Main methods For assessing the drug combination effect, rats were administered with pindolol before paroxetine, using oral or intraperitoneal (i.p.) routes of acute administration, and were submitted to the ETM model. Key findings The highest dose of pindolol used (15.0 mg/kg, i.p.) increased both inhibitory avoidance and escape latencies in the ETM, probably due to nonspecific motor deficit, since locomotion in a circular arena was also significantly decreased. The highest dose of paroxetine (3.0 mg/kg, i.p.) selectively impaired escape, considered a panicolytic effect. Combination of pindolol (5.0 mg/kg, i.p.) with an ineffective dose of paroxetine (1.5 mg/kg, i.p.) impaired escape, indicating a potentiation of the panicolytic effect of paroxetine. By the oral route, neither paroxetine (3.0 mg/kg) nor pindolol (5.0 mg/kg) alone were effective, but the combination treatment had a marked panicolytic effect, again indicating drug potentiation. Significance The present results show that the combination of the ineffective doses of pindolol and paroxetine significantly increased escape latency, indicating a selective panicolytic effect. These findings give preclinical support for the use of this drug combination in the treatment of panic disorder (PD).

P.2.c.039 Noradrenergic uptake inhibition of higher doses of paroxetine in relation to clinical efficacy: the DELPHI-study

P.2.c.039 Noradrenergic uptake inhibition of higher doses of paroxetine in relation to clinical efficacy: the DELPHI-study

Antidepressant-like pharmacological profile of 3-(4-fluorophenylselenyl)-2,5-diphenylselenophene: Involvement of serotonergic system

This study evaluated the effect of 3-(4-fluorophenylselenyl)-2,5-diphenylselenophene (DPS) in the mouse forced swim test (FST) and tail suspension test (TST), two assays predictive of depressant activity. The involvement of serotonergic system in the effect caused by DPS was studied. The antidepressant-like effect of combined treatment with subeffetive doses of DPS and paroxetine, a selective serotonin reuptake inhibitor (SSRI) was investigated. Further, we verified the possible mechanism responsible for antidepressive-like effect of DPS. The results show that DPS (50 and 100 mg/kg, p.o.) significantly reduced the immobility time during the FST and TST, without accompanying changes in ambulation when assessed in the open-field test. The anti-immobility effect of DPS (50 mg/kg, p.o.) in the FST was prevented by pretreatment of mice with pCPA (100 mg/kg, i.p., once a day for 4 consecutive days, an inhibitor of 5-HT synthesis), WAY 100635 (0.1 mg/kg, s.c., a selective 5-HT1A receptor antagonist), ritanserin (1 mg/kg, i.p., a 5-HT2 receptor antagonist) or ondansetron (1 mg/kg, i.p., a 5-HT3 receptor antagonist). Combined treatment with paroxetine and DPS reduced the immobility time in the FST. DPS at the doses of 10-100 mg/kg did not produce any change in the cerebral activity of MAO-A or MAO-B. DPS at the dose of 50 mg/kg inhibited significantly 5-HT uptake in synaptosomes. These results suggest that DPS produced an antidepressant-like effect in the mouse FST and TST and this effect seems most likely to be mediated through an interaction with serotonergic system, particularly by 5-HT reuptake inhibition.

Paroxetine-induced increase in activity of locus coeruleus neurons in adolescent rats: implication of a countertherapeutic effect of an antidepressant.

The concern that antidepressant (AD) drugs, especially selective serotonin reuptake inhibitors and paroxetine (PAR) in particular, can increase suicidality during the early treatment of juvenile patients (children and adolescents) has created a dilemma for clinicians treating depressives. Although preclinical research cannot resolve controversy in this area, our present findings may provide insight into how AD drugs might, under certain conditions, exacerbate rather than ameliorate the depressive state. Both clinical and preclinical evidences indicate that the principal noradrenergic cell group in the brain, the locus coeruleus (LC), is overactive in depressives and that, conversely, effective AD treatments decrease the activity of LC neurons. We report here that short-term (2 and 4 days) administration of PAR produces an increase in the activity of LC neurons (spontaneous firing rate and sensory-evoked responses) in young rats, contrary to the 'therapeutic' decrease in activity typically observed in adult rats. Blood levels of PAR were lower in young rats than in adult rats, although similar low blood levels produced by a lower dose of PAR in adult rats failed to produce an increase in LC activity. In addition, activity of young rats in the swim test was determined to assess depressive-like responses. The same dose/durations of PAR, which produced the largest increases in LC activity in young rats, produced decreases in swim-test activity, indicating that brief administration of PAR in young rats can promote, rather than reduce, the depressive state. These results offer a model that may help screen potential adjunctive treatments to avoid early adverse effects of ADs.

Paroxetine increases brain-derived neurotrophic factor in postmenopausal women

Menopause is marked by a decline in ovarian function resulting in one or more climacteric symptoms. In the last few years, attention has been focused on the use of selective serotonin reuptake inhibitors (SSRIs) in the treatment of vasomotor symptoms associated with the menopausal transition. Thanks to the recent findings on the interaction between the serotoninergic system and neurotrophins, it has been suggested that brain-derived neurotrophic factor (BDNF) could contribute to the activity of SSRIs. Moreover, because endogenous gonadal hormones modulate both BDNF expression and serotonin biosynthesis and bioavailability and regulate brain functions like affective and cognitive functions, we proposed to evaluate the effects of a treatment with paroxetine, an SSRI, in a group of postmenopausal women and to clarify the possible relationship between paroxetine, plasma BDNF levels, and climacteric symptoms. A total of 119 postmenopausal women (age, 46-60 y; menopause age, 1-20 y) were included; 89 took paroxetine 10 mg/day for 6 months and 30 took estrogen + progestogen therapy (EPT) for 6 months. Blood samples were taken before the beginning of the therapy and at 3 and 6 months. The Green Climacteric Scale questionnaire was used to follow up women's clinical conditions. Plasma BDNF levels significantly increased after 3 and 6 months of therapy (P < 0.001), although a negative correlation between plasma BDNF level and both age and menopause age persisted throughout the treatment. Moreover, a significant reduction in the Greene Climacteric Scale score was observed. In the EPT group, the plasma BDNF level significantly increased after 6 months of therapy. The plasma BDNF levels after 6 months of paroxetine were significantly lower than those after 6 months of EPT. The present data suggest that a low dose of paroxetine is effective in enhancing plasma BDNF levels, and this increase might have a role in improving climacteric symptoms, highlighting the possible role of BDNF in endocrinological and cognitive functions.

SEROTONIN SYNDROME AFTER ADMINISTRATION OF MILNACIPRAN FOR FIBROMYALGIA

We report a patient who presented with classic serotonin syndrome (SS) after being started on milnacipran for fibromyalgia. To our knowledge, this is the first case of serotonin toxicity reported since milnacipran was approved by the Food and Drug Administration (FDA) for the treatment of fibromyalgia. ### Level of evidence. This is a case report describing a single patient treated for classic symptoms of serotonin toxicity with milnacipran, while on a chronic dose of paroxetine, and is therefore a Class IV study. ### Case report. A 76-year-old man with a history of chronic pain presented to the emergency room with progressive worsening of lethargy and confusion. The patient was initially noted by the family to be confused and asking the same questions repeatedly. Throughout the following 2 days, the patient became more confused and eventually severely dysarthric. He was ultimately brought to the emergency room after he was found on the floor lethargic with incomprehensible speech. The patient had a history of depression and had been on paroxetine, 25 mg daily, for 5 years. Eight days prior to this presentation, the patient had been diagnosed with fibromyalgia and started on milnacipran 50 mg twice daily, a newly approved medication for the treatment of fibromyalgia. On physical examination, the patient was found to have a temperature ranging from 100.5 …

Serotonin Toxicity Caused by Moclobemide Too Soon After Paroxetine-Selegiline

Serotonin toxicity is an iatrogenic complication of serotonergic drug therapy. It is due to an overstimulation of central and peripheral serotonin receptors that lead to neuromuscular, mental and autonomic changes. Moclobemide is a reversible inhibitor of monoamine oxidase (MAO)-A, selegiline is an irreversible selective inhibitor of MAO-B, and paroxetine is a selective serotonin reuptake inhibitor. Combined use of these agents is known to cause serotonin toxicity. A 53-year-old woman had been treated with paroxetine and selegiline. After moclobemide was prescribed in place of paroxetine without a washout period, she quickly developed confusion, agitation, ataxia, diaphoresis, tremor, mydriasis, ocular clonus, hyperreflexia, tachycardia, moderately elevated blood pressure and high fever, symptoms that were consistent with serotonin toxicity. Discontinuation of the drugs, hydration and supportive care were followed by remarkable improvement of baseline status within 3 days. This case demonstrates that serotonin toxicity may occur even with small doses of paroxetine, selegiline and moclobemide in combination. Physicians managing patients with depression must be aware of the potential for serotonin toxicity and should be able to recognize and treat or, ideally, anticipate and avoid this pharmacodynamically-mediated interaction that may occur between prescribed drugs.

NMDA receptor/nitrergic system blockage augments antidepressant-like effects of paroxetine in the mouse forced swimming test

In this study, we evaluated the involvement of N-methyl-D-aspartate receptor (NMDAR)/nitric oxide (NO) system on the antidepressant-like effects of paroxetine in the mouse forced swimming test. Swim sessions were conducted by placing mice in individual glass cylinders filled with water for 6 min. The duration of behavioral immobility during the last 4 min of the test was evaluated. Paroxetine (8 and 16 mg/kg, intraperitoneal [i.p.]) significantly reduced the immobility times of mice, whereas lower doses (2 and 4 mg/kg) had no effect. NMDA antagonists MK-801 (0.1 and 0.25 mg/kg, i.p.) and ifenprodil (1 and 3 mg/kg, i.p.) and the NO synthase inhibitor NG-L-arginine methyl ester (L-NAME; 30 and 100 mg/kg, i.p.) significantly decreased the immobility time. Lower doses of MK-801 (0.01 and 0.05 mg/kg), ifenprodil (0.1 and 0.5 mg/kg), and L-NAME (10 mg/kg) had no effect. Combined treatment of subeffective doses of paroxetine (4 mg/kg) and MK-801 (0.05 mg/kg), ifenprodil (0.5 mg/kg), and L-NAME (10 mg/kg) robustly exerted an antidepressant-like effect. The noneffective dose of a NO precursor L: -arginine (750 mg/kg, i.p.) prevented the antidepressant-like effect of paroxetine (30 mg/kg). We suggested, for the first time, a possible role for NMDAR/NO signaling in the antidepressant-like effects of paroxetine, providing a new approach for the treatment of depression.

Role of nitric oxide in obsessive–compulsive behavior and its involvement in the anti-compulsive effect of paroxetine in mice

In view of the reports that nitric oxide modulates the neurotransmitters implicated in obsessive–compulsive disorder, patients with obsessive–compulsive disorder exhibit higher plasma nitrate levels, and drugs useful in obsessive–compulsive disorder influence nitric oxide, we hypothesized that nitric oxide may have some role in obsessive–compulsive behavior. We used marble-burying behavior of mice as the animal model of obsessive–compulsive disorder, and nitric oxide levels in brain homogenate were measured using amperometric nitric oxide-selective sensor method. Intraperitoneal administration of nitric oxide enhancers viz. nitric oxide precursor—l-arginine (800mg/kg), nitric oxide donor—sodium nitroprusside (3mg/kg) or phosphodiesterase type 5 inhibitor—sildenafil (3mg/kg) significantly increased marble-burying behavior as well as brain nitrites levels, whereas treatment with 7-nitroindazole—neuronal nitric oxide synthase inhibitor (20–40mg/kg, i.p.) or paroxetine—selective serotonin reuptake inhibitor (5–10mg/kg, i.p.) dose dependently attenuated marble-burying behavior and nitrites levels in brain. Further, co-administration of sub-effective doses of 7-nitroindazole (10mg/kg) and paroxetine (2.5mg/kg) significantly attenuated marble-burying behavior. Moreover, pretreatment with l-arginine (400mg/kg, i.p.), sodium nitroprusside (2.0mg/kg, i.p.) or sildenafil (2.0mg/kg, i.p.) significantly attenuated the inhibitory influence of 7-nitroindazole (40mg/kg) or paroxetine (10mg/kg) on marble-burying behavior as well as on brain nitrites levels. None of the above treatment had any significant influence on locomotor activity. In conclusion, obsessive compulsive behavior in mice appears related to nitric oxide in brain, and anti-compulsive effect of paroxetine appears to be related to decrease central levels of nitric oxide.

Antidepressant-like effects of paroxetine are produced by lower doses than those which produce nausea

Paroxetine is prescribed to treat depression, but it also produces nausea. The potential of animal models to detect nauseating, antidepressant-like, and rewarding/aversive effects of paroxetine were assessed. In Experiments 1 (spaced conditioning trials) and 3 (massed conditioning trials), a dose of 30 mg/kg, but not lower doses (3 and 10 mg/kg) of paroxetine produced conditioned gaping reactions (reflective of nausea) in the Taste Reactivity (TR) test. In Experiment 2, when administered 23.5, 5 and 1 h prior to a 5 min forced swim test (FST) a dose as low as 3 mg/kg of paroxetine increased swimming and decreased immobility (reflective of antidepression) compared to controls. In Experiment 3, neither 10 nor 30 mg/kg of paroxetine produced a conditioned floor preference/aversion, but both doses decreased activity during conditioning trials. These results suggest that paroxetine produced an antidepressant-like effect at a lower dose (3 mg/kg) than that necessary to produce nausea (30 mg/kg). The TR test may be beneficial for assessing the side effect of nausea in preclinical tests of new compounds.

Erratum: Evidence Why Paroxetine Dose Escalation is Not Effective in Major Depressive Disorder: A Randomized Controlled Trial with Assessment of Serotonin Transporter Occupancy

Erratum: Evidence Why Paroxetine Dose Escalation is Not Effective in Major Depressive Disorder: A Randomized Controlled Trial with Assessment of Serotonin Transporter Occupancy

Evaluation of risk factors for elevated tricyclic antidepressant plasma concentrations

To quantify the effect of clinical and demographic factors on the risk of elevated and toxic tricyclic antidepressant (TCA) plasma concentrations (Cp) and to describe the rates of elevated and toxic TCA Cp. This matched, case-control study was conducted among adult patients enrolled in a group model HMO who had a TCA Cp laboratory measurement and purchased at least one TCA prescription for either amitriptyline or nortriptyline during the 70 days preceding the TCA Cp measurement. Predictive models of experiencing an elevated or toxic Cp were created using multivariate conditional logistic regression. At least one Cp was drawn in 1057 unique patients with a TCA purchase. Of these, 18.4% (194/1057) patients (cases) had an elevated TCA Cp and were matched to 716 non-elevated Cp patients. Additionally, 27.3% (53/194) of the cases (matched to 196 controls) experienced a toxic TCA Cp. The best fitting model of an elevated TCA Cp included TCA dose category (daily doses >or=150 mg, OR = 4.08; doses of 50 to <100 mg, OR = 0.36; and doses <50 mg, OR = 0.18, p < 0.05 for all comparisons), female gender (OR = 1.78, p < 0.05) and concurrent use of fluoxetine or paroxetine (OR = 1.75, p < 0.05). The best fitting predictive model of a toxic TCA Cp included the same factors as for the predictive model of an elevated TCA Cp. Recognizing and monitoring predictors of elevated or toxic TCA Cps, including increasing TCA dose, female gender, and concurrent use of fluoxetine or paroxetine, may reduce serious adverse drug reactions and deaths in the TCA-receiving patient population.

Paroxetine-induced increase in LDL cholesterol levels

Paroxetine is widely prescribed because it has the indication for multiple psychiatric disorders. Our objective was to assess the effect of short-term administration of paroxetine on low-density lipoprotein cholesterol (LDL-C) levels in both healthy controls (HCs) and in patients with panic disorder (PD). Blood samples for measurement of LDL-C were collected atbaseline, after 8 weeks of paroxetine administration and post-discontinuation in 24 male HCs and nine male patients suffering from PD, for a total of 33 subjects. Paroxetine treatment, both in HCs and PD patients, induced a mean 9% increase per subject in LDL-C that normalized post-discontinuation, suggesting causality. The National Cholesterol Education Program (NCEP) guidelines suggest that this paroxetine-induced increase in LDL-C is clinically significant but would not warrant therapeutic intervention in this population selected to be at low cardiovascular risk. However, the increase in LDL-C levels raised above the threshold of 2.7 mmol/L (100 mg/dL) in 36% of our low-risk subjects. The LDL-C increase in this subgroup would be associated with a minor increase in coronary heart disease (CHD) risk. A similar 9% paroxetine-induced increase in LDL-C observed in the large number of psychiatric patients suffering from comorbid established CHD would be detrimental from a cardiovascular perspective and would oppose the new NCEP therapeutic goals of decreasing LDL-C levels by 30-40% in high and moderately high-risk patients. It is possible that longer treatment duration and use of higher doses of paroxetine would lead to a greater increase in LDL-C.

Low Doses of Controlled-Release Paroxetine in the Treatment of Late-Life Depression

To evaluate the efficacy and tolerability of low daily doses of controlled-release (CR) paroxetine in patients with late-life depression. This was a 10-week, multicenter, placebo-controlled, double-blind, fixed-dose trial randomly assigning patients >or= 60 years old to daily doses of paroxetine CR 12.5 mg (N = 168), paroxetine CR 25 mg (N = 177), or placebo (N = 180). Patients had major depressive disorder (DSM-IV criteria) and 17-item Hamilton Rating Scale for Depression (HAM-D) total scores of >or= 18. The primary efficacy variable was the change from baseline to study endpoint in total HAM-D scores. The study was conducted from June 2003 to October 2004. The drug/placebo difference in HAM-D change from baseline at study endpoint was -1.8 (95% CI = -3.41 to -0.19, p = .029) for paroxetine CR 12.5 mg, and -3.3 (95% CI = -4.84 to -1.68, p < .001) for paroxetine CR 25 mg. A significantly larger percentage of patients achieved remission (HAM-D total score <or= 7 at endpoint) with paroxetine CR 25 mg (41%), but not with 12.5 mg (31%), as compared with placebo (28%) (p = .008). Both doses of paroxetine CR also achieved statistical significance compared to placebo for the Clinical Global Impressions-Severity of Illness scale (p < .01) and the patient-rated measures of depression severity (p < .05) and quality of life (p <or= .001). Both active treatments were generally well tolerated, with adverse event withdrawal rates of 6%, 8%, and 7% for paroxetine CR 12.5 mg, paroxetine CR 25 mg, and placebo, respectively. These data demonstrate that paroxetine CR 12.5 mg and 25 mg daily are efficacious and well tolerated in the treatment of major depressive disorder in patients >or= 60 years of age, although effect sizes are relatively smaller with the 12.5 mg/day dose.

Evidence Why Paroxetine Dose Escalation is Not Effective in Major Depressive Disorder: A Randomized Controlled Trial With Assessment of Serotonin Transporter Occupancy

Dose escalation is often used in depressed patients who fail to respond to standard doses of selective serotonin reuptake inhibitors, but clinical efficacy is equivocal. We aimed to reassess the efficacy of paroxetine dose escalation and quantify whether paroxetine dose escalation increases occupancy of the serotonin transporter (SERT) more than placebo dose escalation in a randomized controlled trial. We recruited 107 nonpsychotic, unipolar depressed outpatients (18-70 years; Hamilton Depression Rating Scale (HDRS(17)) >18) from primary care and psychiatric outpatient departments. After 6 weeks, open-label paroxetine 20 mg per day (T0), nonresponding patients (HDRS(17) decrease <50%; n=60) were randomized to double-blind paroxetine (30-50 mg per day as tolerable) or placebo dose escalation (paroxetine 20 mg per day+placebo). Patients were followed until 6 weeks after randomization (T1). Forty-nine patients, drug free at study entry, underwent single-photon emission-computed tomography (SPECT) scanning before treatment and were scanned repeatedly at T0 and T1. Paroxetine serum concentrations and SERT occupancy were determined at T0 and T1 (n=32). We terminated the dose-escalation trial after an interim analysis. Thirty nonresponding patients were randomized to paroxetine (46.7+/-5.5 mg per day), 27 to placebo dose escalation. Response rates were 10/30 (33.3%) and 10/27 (37.0%), respectively. Repeated measurement analyses showed no significant effect for treatment (p=0.88, exceeding a priori stopping rules for futility (p>0.5)). Overall dropout was higher for placebo (26.7%) than paroxetine (3.3%; p=0.03). Paroxetine dose escalation increased paroxetine serum concentrations (p<0.001). SPECT measurements (12 patients randomized to paroxetine (46.9+/-4.8 mg) and 14 to placebo dose escalation) showed no significant increase of midbrain SERT occupancy (2.5+/-26.4%, paroxetine; 3.1+/-25.8% placebo; p=0.687) nor in diencephalon (p=0.529). Paroxetine dose escalation in depressed patients has no clinical benefit over placebo dose escalation. This is explained by the absence of significant increases of SERT occupancy by paroxetine dose escalation, despite increased paroxetine serum concentrations (ISRCTN44111488).

Interaction of zinc with antidepressants in the tail suspension test

The antidepressant-like effect of zinc has been shown in several animal models of depression. In this study, zinc chloride (ZnCl 2) was given alone or in combination with different classes of antidepressants by oral route (p.o.) to mice and the behavioral response in the tail suspension test (TST), a predictive test of antidepressant action, was investigated. ZnCl 2 at a dose of 10 and 30 mg/kg, p.o., reduced the immobility time in the TST, without affecting the locomotor activity in open-field test. The antidepressants fluoxetine, paroxetine, imipramine, desipramine and bupropion produced a significant reduction in the immobility time in TST at the doses of 10, 1, 1, 1 and 10 mg/kg, p.o., respectively. The combined treatment of sub-effective doses of ZnCl 2 (1 mg/kg) with sub-effective doses of fluoxetine (5 mg/kg), paroxetine (0.1 mg/kg), desipramine (0.1 mg/kg), imipramine (0.1 mg/kg) or bupropion (1 mg/kg) induced a significant reduction in the immobility time in the TST when compared with the groups treated with ZnCl 2 or with antidepressants alone. The treatment with sub-effective doses of ZnCl 2 and antidepressants alone or in combination did not affect the locomotion in open-field test, except that desipramine alone reduced the ambulation. The results first indicate that ZnCl 2 administered by p.o. route produces an antidepressant-like effect in the TST. Moreover, synergistic effects of zinc with antidepressants were shown in the TST, suggesting that an improvement in the response to the antidepressant therapy occurs when zinc is combined with different classes of antidepressants.

Luteal Phase Administration of Paroxetine for the Treatment of Premenstrual Dysphoric Disorder

To evaluate the efficacy and safety of intermittent, luteal phase-only administration of paroxetine (10 mg and 20 mg) in the treatment of premenstrual dysphoric disorder (PMDD). In this multicenter trial, female outpatients (aged 18-45 years) from 4 Canadian health centers meeting DSM-IV criteria for PMDD were asked to perform daily ratings of their premenstrual symptoms for 2 consecutive menstrual cycles. Those displaying the symptoms of irritability and/or depressed mood in the luteal phases but not in the follicular phases of their menstrual cycles were randomly assigned to intermittent, luteal phase-only treatment with paroxetine 10 mg or 20 mg or placebo for 4 additional cycles. The primary efficacy endpoint was the percent change from baseline at study endpoint on the visual analog scale irritability score. Treatment differences were tested using analysis of covariance ad hoc. Estimated treatment mean differences and their associated 95% confidence intervals were also calculated. Data were collected from May 1999 to November 2002. Ninety-nine patients were included in the intention-to-treat population. When compared with placebo, patients treated with paroxetine 20 mg attained a significant reduction in irritability (difference in median percent change: -23.9, 95% CI = -51.3 to -6.2, p = .014; difference in mean absolute change: -18.6, 95% CI = -32.5 to -4.6, p = .007). A statistically significant difference was not observed when the patients treated with the lower dose of paroxetine (10 mg) were compared with placebo. Treatment was well tolerated with no unexpected side effects. Intermittent administration of paroxetine 20 mg significantly reduced irritability symptoms in patients with PMDD. These results are consistent with previous studies suggesting that PMDD may be treated effectively by luteal phase-only administration of a selective serotonin reuptake inhibitor. clinicaltrials.gov Identifier: NCT00620581.

Complete Atrioventricular Block Associated With Concomitant Use of Metoprolol and Paroxetine

A 63-year-old woman, who had been treated with 20 mg of paroxetine and 0.5 mg of alprazolam daily for 1 year and with 50 mg of metoprolol daily for 15 days, presented to a facility elsewhere with presyncope and complete atrioventricular block. Three days after her initial presentation and cessation of metoprolol treatment, she was transferred to our clinic to be considered for permanent pacemaker implantation. Paroxetine treatment was discontinued on day 1 and atrioventricular block resolved on day 5, which was confirmed with a 24-hour Holter recording. No bradyarrhythmia was induced with similar doses of either metoprolol or paroxetine alone. At 2- and 3-year follow-up, the patient was still free of bradyarrhythmia documented with electrocardiography and 24-hour Holter recordings. To our knowledge, we report the first case of complete atrioventricular block associated with coadministration of paroxetine and metoprolol. Increasing physicians' awareness of drug-induced severe bradyarrhythmia might prevent unnecessary implantation of permanent pacemakers.

The effect of paroxetine on the pharmacokinetics, safety, and tolerability of ramosetron in healthy subjects

The aim of our study was to investigate the effects of multiple doses of paroxetine on the pharmacokinetics, safety, and tolerability of a single oral 10-microg dose of ramosetron. METHODS This was an open, one-sequence crossover design study. On day 1, healthy male and female subjects were administered a single dose of 10 microg ramosetron. On the morning of day 3, the subjects were administered paroxetine to reach steady state, which consisted of morning doses of 20 mg on days 3-12. The dose on day 11 was administered in combination with a single dose of 10 microg ramosetron. In subjects genotyped as extensive CYP2D6 metabolizers, coadministration of paroxetine with ramosetron resulted in an increase in area under the curve from 0 to infinity (AUC(0-inf)) and the peak concentration (Cmax) of ramosetron by 1.14-fold (90% confidence interval (CI): 1.07-1.22) and by 1.06-fold (90% CI: 1.00-1.11), respectively. It can be concluded that the single-dose pharmacokinetic profile of ramosetron 10 microg is not affected to a clinically relevant degree by paroxetine 20 mg once daily administered for 10 days.

Concentrações plasmáticas de paroxetina em pacientes adultos e idosos com depressão

INTRODUÇÃO: O efeito do envelhecimento nas concentrações plasmáticas em estado de equilíbrio da paroxetina foi investigado em 136 pacientes com depressão, tratados com doses variando entre 10 e 120 mg/dia de paroxetina. MÉTODOS: Os pacientes foram separados em três grupos: com idade até 64 anos (idade média ± desvio padrão: 41,7±12,6 anos; n = 44), entre 65 e 79 anos (72,8±4,7 anos; n = 64), e com mais de 80 anos (82,8±3,3 anos; n = 28). As doses de paroxetina foram normalizadas para 20 mg/dia. Amostras de sangue foram coletadas em condições de estado de equilíbrio. Os níveis plasmáticos de paroxetina foram medidos por cromatografia gasosa - espectrometria de massa. As funções hepática e renal foram medidas por testes laboratoriais clínicos estandardizados. RESULTADOS: Uma grande variabilidade interindividual dos níveis plasmáticos de paroxetina (37 vezes) foi medida para uma mesma dose. A média dos níveis plasmáticos de paroxetina corrigida para uma dose diária de 20 mg foi 87% maior no grupo com mais de 80 anos (56,4±64,1 ng/mL; p &lt; 0,05) e 57% maior no grupo com idades entre 65 e 79 anos (46,7±33,4 ng/mL; p &lt; 0,001) quando comparada com a média dos pacientes com menos de 64 anos (29,9±11,9 ng/mL). A idade foi correlacionada significativamente com os níveis plasmáticos de paroxetina (r = 0,21, p &lt; 0,05) CONCLUSÃO: A redução de doses da paroxetina em pacientes idosos parece justificada.