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Purpose: The present study aimed to elucidate the transport properties of imipramine and paroxetine, which are the antidepressants, across the blood-brain barrier (BBB) in rats., Methods: In vivo influx and efflux transport of imipramine and paroxetine across the BBB were tested using integration plot analysis and a combination of brain efflux index and brain slice uptake studies, respectively. Conditionally immortalized rat brain capillary endothelial cells, TR-BBB13 cells, were utilized to characterize imipramine and paroxetine transport at the BBB in vitro., Results: The in vivo influx clearance of [ 3 H]imipramine and [ 3 H]paroxetine in rats was determined to be 0.322 mL/(min·g brain) and 0.313 mL/(min·g brain), respectively. The efflux clearance of [ 3 H]imipramine and [ 3 H]paroxetine was 0.380 mL/(min·g brain) and 0.126 mL/(min·g brain), respectively. These results suggest that the net flux of paroxetine, but not imipramine, at the BBB in vivo was dominated by transport to the brain from the circulating blood. The uptake of imipramine and paroxetine by TR-BBB13 cells exhibited time- and temperature-dependence and one-saturable kinetics with a K m of 37.6 μM and 89.2 μM, respectively. In vitro uptake analyses of extracellular ion dependency and the effect of substrates/inhibitors for organic cation transporters and transport systems revealed minor contributions to known transporters and transport systems and the difference in transport properties in the BBB between imipramine and paroxetine., Conclusions: Our study showed the comprehensive outcomes of imipramine and paroxetine transport at the BBB, implying that molecular mechanism(s) distinct from previously reported transporters and transport systems are involved in the transport., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

It is unclear whether anxiety increases or decreases suicidal risk. This may contribute to the lack of guidance on which antidepressant medications are best for suicidal depressed patients who present with high anxiety. This study explored whether anxiety predicts suicidal ideation in depressed individuals treated with paroxetine or bupropion. An 8-week double-blind trial comparing controlled-release paroxetine (N=36) versus extended-release bupropion (N=38) for effect on suicidal ideation and behavior in depressed patients with suicidal ideation, past attempt, or both found an advantage for paroxetine, but anxiety effects were not investigated. This secondary analysis explored the relationship, measured at baseline and weekly, of anxiety with suicidal ideation. Anxiety severity measured weekly correlated with suicidal ideation severity irrespective of treatment (P=0.012). Patients with high baseline anxiety showed a trend toward faster reduction of suicidal ideation with paroxetine compared with bupropion treatment (standard P=0.047; bootstrap P=0.077). The latter finding, if confirmed in larger samples, could enhance choice of antidepressant medication for suicidal, depressed patients presenting with high levels of anxiety.

Background: Depressive disorders are expected to be the second highest cause of morbidity in the world until few years. Moreover, patients with depression frequently show many side effects and low compliance to therapy. To find a more tolerated and more efficacy therapy is a growing need., Objective: This observational study investigates the efficacy, safety and tolerability of paroxetine hydrochloride comparing slow versus standard titration in a population affected by Depressive Disoders (according to DSM 5)., Methods: 186 outpatients were assessed throught the following scales: Hamilton Depression Rating Scale (HDRS) for depression and World Health Organization Quality of Life Scale Bref for the perceived quality of life (WHOQOL BREF). Treatment-emerged Adverse Events (TEAEs) were recorded throught self-reports. Statystical analysys was performed by GraphPad Prism Version 5.1., Results: The efficacy of paroxetine was confirmed in both titrations by the number of clinical remitters (HDRS ≤ 7 at 12 weeks for 53% of the standard titration group and 58% of the slow titration group), without differences. About safety and tolerability there were more frequent TEAEs among the standard titration group (p < 0.01). Comparing WHOQOL BREF between the two groups at the recruitment and at the twelth week emerged a statistically significant difference (p = 0.003), with highest scores reached in slow titration group., Conclusions: Although the short observation period is an evident limit, this study is consistent to the literature about the efficacy of both titrations of paroxetine to improve depression and shows promising results about the increased tolerability of paroxetine slow titration.

Repetitive transcranial magnetic stimulation (rTMS) has been introduced as a new and effective treatment option for major depression. This paper examined the effectiveness of rTMS on first episode depressed patients when combined with antidepressant drugs. A random sample of forty-three first-episode depressed patients received active or sham rTMS to the left dorsolateral prefrontal cortex, and concomitantly took paroxetine for 4 weeks, and paroxetine monotherapy for 4 weeks afterwards. Response was defined as a ≥50% decrease on the total Hamilton Depression Rating Scale (HDRS) from the baseline, and remission was defined as an HDRS total residual score <8. The dosage of paroxetine was the average dose per day in each week. Repeated-measures ANOVA revealed a significant improvement in the HDRS with active compared with sham rTMS from the end of the 1st week to the 4th week. At the end of the 4th week, response rate was 95.5% with active and 71.4% with sham rTMS, remission rate was 68.2% with active and 38.1% with sham rTMS, while these significant differences disappeared at the endpoint of the study. These findings indicate that rTMS at 10-Hz accelerated the onset of action and augmented the response to paroxetine for first-episode depressed patients., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Objectives: To evaluate the pharmacokinetics of paroxetine controlled-release (CR) tablets after single and multiple oral administrations and to evaluate its safety profile in healthy Chinese subjects., Methods: This was a phase 1, open-label, single- and multiple-dose combined study. All 12 healthy subjects received a single oral dose of 25-mg paroxetine CR, followed by a washout period of 5 days. Then, the subjects received multiple oral doses of 25-mg paroxetine CR for 14 consecutive days. Serial venous blood samples were collected 96 hours after single dosing and 24 hours after the last dose in multiple-dosing. Blood samples were analyzed using LC-MS/MS. Pharmacokinetic parameters of paroxetine were calculated via noncompartmental analysis using the WinNonlin software (Pharsight Corp., Mountain View, CA, USA)., Results: For both single- and multiple-dose regimens, a lag time of ~ 4 hours was observed before the absorption of paroxetine CR tablet with a t max of ~ 7 - 9 hours. From single- to multiple-dose regimens, the mean C max increased from 7.08 to 36.95 ng/mL, the mean AUC 0-24h increased from 100.91 to 706.75 h×ng/mL, and the mean t 1/2 increased from 12.3 to 83.6 hours (all p < 0.05). The point estimate and 90% confidence intervals of the C trough ratio indicated that the concentration of paroxetine reached steady state after 14 days of repeated dosing. The point estimate of the accumulation factor indicated that the extent of drug exposure at steady state was ~ 9 times that of single dosing. All reported adverse events were considered to be mild., Conclusions: Paroxetine CR tablet is absorbed with a delay of ~ 4 hours after oral administration, and the accumulation factor is ~ 9 at steady state. Paroxetine CR tablet is well tolerated by healthy Chinese subjects.
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Paroxetine is a selective serotonin reuptake inhibitor (SSRI) and is used for the treatment of depression and anxiety problems, but suffers from the drawback of poor oral bioavailability (less than 50%) due to its extensive first pass metabolism. The objective of the present study was to develop a paroxetine loaded nanoemulsion (o/w type) for direct nose-to-brain delivery. Nanoemulsions were prepared by the spontaneous emulsification technique using Capmul MCM, Solutol HS 15 and propylene glycol as oil phase, surfactant and co-surfactant, respectively, for delivery of drug directly to the brain through the nasal route for better management of depression. Formulations were studied for droplet size, polydispersity index (PDI), percentage transmittance, refractive index, viscosity, zeta potential, surface morphology and in vitro permeation study. TEM images of optimized formulation showed spherical droplets with a mean diameter of 58.47 ± 3.02 nm, PDI of 0.339 ± 0.007 and zeta potential values of -33 mV. The formulation showed good results for transmittance (100.60 ± 0.577%), refractive index (1.412 ± 0.003) and viscosity (40.85 ± 6.40 cP). Permeation studies revealed a 2.57-fold enhancement in permeation as compared to the paroxetine suspension. Behavioural studies such as the forced swimming test and locomotor activity test were done on Wistar rats to study the antidepressant effect of the optimized formulation. Treatment of depressed rats with paroxetine nanoemulsion (administered intranasally) significantly improved the behavioural activities in comparison to paroxetine suspension (orally administered). Biochemical estimation results revealed that the prepared nanoemulsion was effective in enhancing the depressed levels of glutathione and decreasing the elevated levels of TBARS.

Rationale: The SSRI antidepressant fluoxetine is one of the few drugs that is effective at treating depression in adolescent humans. In contrast, the SSRI paroxetine has limited efficacy and is more at risk for inducing suicidal behavior., Objective: The purpose of the present study was to more fully characterize the differential actions of paroxetine and fluoxetine., Methods: In experiment 1, male and female rats were injected with paroxetine (2.5 or 10 mg/kg), fluoxetine (10 mg/kg), or vehicle for 10 days starting on postnatal day (PD) 35, and affective behaviors were assessed using sucrose preference and elevated plus maze tasks. A separate set of rats were used to examine monoamine levels. In experiment 2, rats were injected with paroxetine (2.5, 5, or 10 mg/kg), fluoxetine (5, 10, or 20 mg/kg), or vehicle during the same time frame as experiment 1, and anxiety-like behaviors were measured using elevated plus maze, light/dark box, and acoustic startle., Results: Repeated SSRI treatment failed to alter sucrose preference, although both paroxetine and fluoxetine reduced time spent in the open arms of the elevated plus maze and light compartment of the light/dark box. Paroxetine, but not fluoxetine, enhanced acoustic startle and interfered with habituation. Serotonin turnover was decreased by both acute and repeated fluoxetine treatment but unaltered by paroxetine administration., Discussion: These results show that repeated treatment with paroxetine and fluoxetine has dissociable actions in adolescent rats. In particular, paroxetine, but not fluoxetine, increases acoustic startle at low doses and may increase sensitivity to environmental stressors.

Objectives: To reanalyse SmithKline Beecham's Study 329 (published by Keller and colleagues in 2001), the primary objective of which was to compare the efficacy and safety of paroxetine and imipramine with placebo in the treatment of adolescents with unipolar major depression. The reanalysis under the restoring invisible and abandoned trials (RIAT) initiative was done to see whether access to and reanalysis of a full dataset from a randomised controlled trial would have clinically relevant implications for evidence based medicine., Design: Double blind randomised placebo controlled trial., Setting: 12 North American academic psychiatry centres, from 20 April 1994 to 15 February 1998., Participants: 275 adolescents with major depression of at least eight weeks in duration. Exclusion criteria included a range of comorbid psychiatric and medical disorders and suicidality., Interventions: Participants were randomised to eight weeks double blind treatment with paroxetine (20-40 mg), imipramine (200-300 mg), or placebo., Main Outcome Measures: The prespecified primary efficacy variables were change from baseline to the end of the eight week acute treatment phase in total Hamilton depression scale (HAM-D) score and the proportion of responders (HAM-D score ≤8 or ≥50% reduction in baseline HAM-D) at acute endpoint. Prespecified secondary outcomes were changes from baseline to endpoint in depression items in K-SADS-L, clinical global impression, autonomous functioning checklist, self-perception profile, and sickness impact scale; predictors of response; and number of patients who relapse during the maintenance phase. Adverse experiences were to be compared primarily by using descriptive statistics. No coding dictionary was prespecified., Results: The efficacy of paroxetine and imipramine was not statistically or clinically significantly different from placebo for any prespecified primary or secondary efficacy outcome. HAM-D scores decreased by 10.7 (least squares mean) (95% confidence interval 9.1 to 12.3), 9.0 (7.4 to 10.5), and 9.1 (7.5 to 10.7) points, respectively, for the paroxetine, imipramine and placebo groups (P=0.20). There were clinically significant increases in harms, including suicidal ideation and behaviour and other serious adverse events in the paroxetine group and cardiovascular problems in the imipramine group., Conclusions: Neither paroxetine nor high dose imipramine showed efficacy for major depression in adolescents, and there was an increase in harms with both drugs. Access to primary data from trials has important implications for both clinical practice and research, including that published conclusions about efficacy and safety should not be read as authoritative. The reanalysis of Study 329 illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base., (© Le Noury et al 2015.)

Purpose: This study investigated population pharmacokinetics of paroxetine, and then performed an integrated analysis of exposure and clinical outcome using population pharmacokinetic parameter estimates in depressed patients treated with paroxetine., Patients and Methods: A total of 271 therapeutic drug monitoring (TDM) data were retrospectively collected from 127 psychiatric outpatients. A population nonlinear mixed-effects modeling approach was used to describe serum concentrations of paroxetine. For 83 patients with major depressive disorder, the treatment response rate and the incidence of adverse drug reaction (ADR) were characterized by logistic regression using daily dose or area under the concentration-time curve (AUC) estimated from the final model as a potential exposure predictor., Results: One compartment model was developed. The apparent clearance of paroxetine was affected by age as well as daily dose administered at steady-state. Overall treatment response rate was 72%, and the incidence of ADR was 30%. The logistic regression showed that exposure predictors were not associated with treatment response or ADR in the range of dose commonly used in routine practice. However, the incidence of ADR increased with the increase of daily dose or AUC for the patients with multiple concentrations., Conclusion: In depressed patients treated with paroxetine, TDM may be of limited value for individualization of treatment.

The aim of this study is to evaluate whether an adjunct antidepressant therapy at a higher dose to a mood stabilizer would make a difference in the treatment of bipolar depression. This is a post-hoc analysis of the data from the randomized treatment for acute depression of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), in which patients with bipolar depression were randomly assigned to treatment with a mood stabilizer plus adjunctive antidepressant drugs or placebo. According to the highest dose received in the course of treatment, the subjects were divided into one of the following three groups: high-dose, low-dose and placebo groups. The primary and secondary outcomes were durable recovery (which was operationally defined as eight consecutive weeks with

Neuropsychological dysfunction is associated with risk for suicidal behavior, but it is unknown if antidepressant medication treatment is effective in reducing this dysfunction, or if specific medications might be more beneficial. A comprehensive neuropsychological battery was administered at baseline and after 8 weeks of treatment within a randomized, double-blind clinical trial comparing paroxetine and bupropion in patients with DSM-IV Major Depressive Disorder and either past suicide attempt or current suicidal thoughts. Change in neurocognitive performance was compared between assessments and between medication groups. Treatment effects on the Hamilton Depression Rating Scale and Scale for Suicide Ideation were compared with neurocognitive improvement. Neurocognitive functioning improved after treatment in all patients, without clear advantage for either medication. Improvement in memory performance was associated with a reduction in suicidal ideation independent of the improvement of depression severity. Overall, antidepressant medication improved neurocognitive performance in patients with major depression and suicide risk. Reduced suicidal ideation was best predicted by a combination of the independent improvements in both depression symptomatology and verbal memory. Targeted treatment of neurocognitive dysfunction in these patients may augment standard medication treatment for reducing suicidal behavior risk., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: Paroxetine is commonly used to treat depression in the elderly; however, titration issues have been raised. Rapid titration may lead to increased anxiety and early dropout. The aim of this cost-utility analysis was to compare the potential benefit of standard (10 mg the first day) versus slow titration (2.5 mg gradually increased)., Methods: Clinical analysis was based on a naturalistic trial integrated with a decision-analytic model representing second treatments for those who initially did not respond and for dropout cases. Treatment setting was a public outpatient center for mental disorders in Italy. Service use data were estimated from best practice guidelines, whereas costs (Euros; 2012) were retrieved from Italian official sources., Results: Slow titration approach produced 0.031 more quality-adjusted life years (remission rate: 57% vs 44% in standard titration group) at an incremental cost of €5.53 (generic paroxetine) and €54.54 (brand paroxetine syrup). Incremental cost-effectiveness ratio (ICER) values were €159 and €1768, respectively, in favor of slow titration approach. Cost-effectiveness threshold, defined as ICER < 1 GDP per capita according to World Health Organization criteria, is about €25 000 in Italy., Conclusions: Our results are consistent with a superiority of slow titration of paroxetine in older depressed patients. However, these findings, in part based on simulated data, need to be replicated in clinical trials., (Copyright © 2014 John Wiley & Sons, Ltd.)

Aim: Clinical evidence shows that co-administration of pravastatin and paroxetine deregulates glucose homeostasis in diabetic patients. The aim of this study was to verify this phenomenon in diabetic rats and to elucidate the underlying mechanisms., Methods: Diabetes mellitus was induced in male SD rats by a high-fat diet combined with a low-dose streptozotocin injection. The rats were orally administered paroxetine (10 mg/kg) and pravastatin (10 mg/d) or both the drugs daily for 28 d. The pharmacokinetics of paroxetine and pravastatin were examined on d 1 and d 28. Biochemical parameters including serum insulin, glucose and lipids were monitored during the treatments. An insulin-secreting cell line (INS-1) was used for measuring insulin secretion., Results: In diabetic rats, co-administration of paroxetine and pravastatin markedly increased the concentrations of both the drugs compared with administration of each drug alone. Furthermore, co-administration severely impaired glucose homeostasis in diabetic rats, as demonstrated by significantly increased serum glucose level, decreased serum and pancreatic insulin levels, and decreased pancreatic Insulin-2 mRNA and tryptophan hydroxylase-1 (Tph-1) mRNA levels. Treatment of INS-1 cells with paroxetine (5 and 10 μmol/L) significantly inhibited insulin secretion, decreased the intracellular insulin, 5-HT, Insulin-2 mRNA and Tph-1 mRNA levels. Treatment of the cells with pravastatin (10 μmol/L) significantly stimulated insulin secretion, which was weakened by co-treatment with paroxetine., Conclusion: Paroxetine inhibits insulin secretion at least via decreasing intracellular 5-HT and insulin biosynthesis. The deregulation of glucose homeostasis by co-administration of paroxetine and pravastatin in diabetic rats can be attributed to enhanced paroxetine exposure.

Purpose: Re-examine association of fluoxetine and paroxetine with risk of testicular cancer noted in drug screening, with 4 years more follow-up and expanded study of these and other antidepressant drugs., Methods: In the Kaiser Permanente Medical Care Program in Northern California, 906 men with testicular cancer diagnosed August 1996-December 2010 were compared with 38,253 matched controls with race/ethnicity recorded regarding receipt of antidepressant drugs at least 2 years before diagnosis or control index date. Analyses emphasized duration of use and histological subgroups., Results: With control for race/ethnicity and use of other antidepressant drugs, odds ratios (OR) and 95 % confidence intervals (CI) for associations with testicular cancer were as follows: fluoxetine 1.22 (0.88-1.71), paroxetine 1.19 (0.78-1.83), and 1.21 (0.92-1.58) for all serotonin reuptake inhibitors. There was no statistically significant association with risk of all testicular cancers or their histological subtypes for any individual drug or for tricyclics or all antidepressants combined except for citalopram with all testicular cancers 2.55 (1.43-4.52) and those of mixed histology 4.36 (1.50-12.68) and nefazodone with embryonal cancers 9.79 (1.85-51.81). These could readily be chance findings in the context of the many analyses that were performed. Duration of use was not associated with risk of the drugs and drug groups with sufficient numbers of exposed cases for analysis., Conclusions: We found little evidence to support a testicular carcinogenic effect of fluoxetine, paroxetine, or other antidepressant drugs, but a weakly positive association is not ruled out. The signals in prior screening may have been due to chance and/or uncontrolled confounding.

The aim of this study was to determine whether a tapered dosage regimen of paroxetine in pregnant women might be useful to avoid withdrawal syndromes in neonates after delivery. We characterized the transplacental transfer of paroxetine in perfused human placenta, fitting a pharmacokinetic model to the results and applying the model and parameters to evaluate a tapered dosage regimen. Paroxetine was perfused from the maternal or fetal side of an isolated human placental preparation with various perfusion protocols, and paroxetine concentrations in the effluent and placental tissue were determined. The transplacental pharmacokinetic parameters of paroxetine were estimated by simultaneous fitting of a five-compartment transplacental pharmacokinetic model to the set of paroxetine concentration profiles. The developed model and parameters were used to simulate the maternal and fetal concentrations of paroxetine, and the results were compared with reported data. Paroxetine showed a larger distribution volume in placental tissue and a smaller transplacental transfer as compared with antipyrine, a passive diffusion marker. A five-compartment model could well describe the transplacental transfer of paroxetine and could well simulate the maternal and umbilical venous concentrations of paroxetine at delivery. Transplacental transfer kinetic parameters of paroxetine were estimated by fitting a pharmacokinetic model to perfusion study data. The model and parameters appeared to be suitable for simulation of paroxetine kinetics in fetus. The model was also applicable to design a dosage regimen to avoid an abrupt decrease of paroxetine concentration in fetal plasma.

Background: Late-life depression, often in association with anxiety, affects approximately 15% of individuals older than 65 years. Selective serotonin reuptake inhibitors are the first-line treatment but could be responsible of an early exacerbation of anxiety, possibly reduced by a very gradual titration of drugs. The main aim of this study is to compare gradual and rapid (standard) titration of paroxetine in an elderly population., Methods: In a naturalistic setting, 50 elderly (≥60 years old) outpatients with unipolar mood disorder or anxiety disorder were naturalistically assigned to abrupt initiation of 10 mg of paroxetine or to a gradual increase with 2.5 mg on alternate days up to 10 mg in 7 days. Then dosage could be maintained at 10 mg or increased according to clinical response. Primary outcome was efficacy as assessed by the Hamilton Depression Rating Scale (HAM-D) 21, HAM-D symptom subscales (core, psychic anxiety, somatic anxiety cluster), and Hamilton Anxiety Rating Scale changes. Secondary outcome was evaluation of overall dropouts at eighth week and evaluation of most common adverse effects through the global judgment of the Dosage Record and Treatment Emergent Symptom Scale. All data were recorded weekly for the first 8 weeks of treatment (with 1 more evaluation after 3 days from the baseline)., Results: Samples were comparable at baseline, with patients in gradual titration showing a higher level of psychic anxiety. During the first 3 days of treatment, a significant worsening in psychic anxiety was observed in patients treated abruptly with 10 mg of paroxetine (difference in HAM-D psychic anxiety subscale from baseline: 110.61% vs 89.38% with rapid and slow titration, respectively; t test P = 0.03). Overall, a significantly greater improvement in depressive and anxious symptoms favored gradual titration (HAM-D core cluster and HAM-D psychic anxiety cluster, respectively, P = 0.014 and P < 0.001, also when controlling for confounders). At the eighth week, significant higher dropouts in patients administered with abrupt dosage was observed (12.00% vs 40.91%, P = 0.02, respectively for slow and rapid titration)., Conclusions: Our results suggest that a gradual titration of paroxetine could avoid the initial treatment anxiety worsening and dropout at the beginning of the treatment.

Aims: Literature data show that one third of patients discontinue antidepressant therapy within the first month of treatment. The aim of this study was to evaluate whether paroxetine liquid solution 10 mg/ml may influence adherence inpatients receiving long-term treatment., Methods: 71 subjects affected by mood disorders or panic disorder were monitored for six months. The study sample was divided into two groups: controls (n=33) maintained their own therapy with paroxetine tablets; 38 patients maintained the same dosage of paroxetine, but shifted to liquid formulation 10 mg/ml. Compliance and general wellness were evaluated with the Medication Adherence Rating Scale (MARS) and the World Health Organization Quality of Life questionnaire (WhoQol). Data were analyzed using analysis of variance (ANOVA) and multivariate analysis of covariance (MANCOVA)., Results: Significant differences were found in MARS scores: patients on oral solution 10 mg/ml showed an improvement of compliance month by month. In addition, age, formulation and quality of life had a significant impacton patient compliance. Significant correlations were found between MARS and quality of life. A specific paroxetine formulation could be a variable able to influence adherence to psychopharmacological treatment. The same consideration can be made for quality of life, sex and age that showed a trend towards improved adherence when compared with controls. Inparticular, the WhoQol subscale analysis of delta scores showed a significant difference in self-perception of quality of life inpatients treated with paroxetine either in tablet or drop formulation., Discussion: Formulation in drops 10 mg/ml is equally effective to tablets, but it may allow patients having a higher cognition and control on drug assumption.

Granuloma annulare (GA) is a benign granulomatous skin disease with several clinical manifestations and characteristic histological findings. GA located in photoexposed areas is a rare finding and its association to a drug-induced systemic photosensitivity is even less common. To the best of our knowledge, only one case of systemic drug photosensitivity manifesting as a GA has been reported. We describe a patient with systemic photosensitivity to paroxetine with clinical and histological manifestations of GA, which was confirmed by the photobiological study. The phototest revealed a reduction of the minimal erythematous dose for UVB while taking the paroxetine and its normalization after its withdrawal, which was accompanied by the clinical resolution of the skin eruption. The manifestation of systemic drug photosensitivity as a GA like in our case is exceptional., (© 2012 John Wiley & Sons A/S.)

Aims: Prominent anxiety symptoms are related to poor clinical course and outcome in major depressive disorder (MDD). The aim of this randomised, open-label, controlled study is to compare the efficacy and tolerability of mirtazapine in the form of orally disintegrating tablets against paroxetine in treating MDD patients with anxiety symptoms., Methods: A total of 60 MDD patients with a score above 18 on the Hamilton Anxiety Rating Scale (HARS) were randomly assigned to 8 weeks of fixed dosing treatment with mirtazapine (15-30 mg/day) and paroxetine (10-20 mg/day). Efficacy was primarily assessed with the HARS and with the 17-item Hamilton Depression Rating Scale (HDRS) at weeks 1, 2, 4 and 8 after treatment. Tolerability was assessed from adverse events., Results: The generalised estimating equations (GEE) models showed that the rates of improvement in HDRS scores from baseline to week 8 were similar between mirtazapine and paroxetine groups. However, patients with mirtazapine exhibited earlier improvement in HARS scores at weeks 1 and 2. Week-by-week GEE models showed that these significant differences in improvement of HARS scores between the two treatment groups were detectable from the first evaluation after the treatment (week 1) and maintained through week 2. There was no difference in the overall frequency of adverse events experienced between the two treatment groups. The most common adverse event in the mirtazapine group was somnolence (n = 8), whereas that in the paroxetine group was gastrointestinal discomfort (n = 9)., Conclusions: Mirtazapine and paroxetine were equally effective and well tolerated for the depressive symptoms in MDD patients with the high level of anxiety symptoms. Mirtazapine was, however, more effective in reducing the anxiety symptoms than paroxetine in the early weeks of treatment, suggesting that mirtazapine may have an earlier-onset action for the anxiety symptoms in MDD patients., (© 2011 Blackwell Publishing Ltd.)

Aim: Paroxetine is a drug of choice in the treatment of major depressive disorder (MDD). Its metabolism has recently been reported to be mediated through the CYP enzymes 1A2 and 2D6. In our current study, we tested whether genetic polymorphisms in CYP1A2 are associated with the treatment efficacy and side effects of paroxetine., Materials & Methods: A total of 241 MDD patients who had taken paroxetine continually for 8 weeks were recruited, and their steady state paroxetine concentrations were measured at weeks 2, 4 and 8. The genotypes of these patients were then assessed for the presence of nine SNPs, which were selected from either the HapMap Chinese ethnic group, the literature report or through their functional role in the CYP1A2 gene., Results: The allele types for SNPs rs4646425 (permutation p = 0.03), rs2472304 (permutation p = 0.01) and rs2470890 (permutation p = 0.004) demonstrated significant associations with paroxetine treatment remission at week 8. Response rates in the Hamilton Rating Scale for Depression (HAM-D) and for The Hamilton Rating Scale for Anxiety (HAM-A) were significantly associated with the SNPs rs4646425 (p = 0.0126 and 0.0088 for HAM-D and HAM-A, respectively) and rs4646427 (p = 0.0067 and 0.0196 for HAM-D and HAM-A, respectively). The inducible SNP rs762551 had a significant association with paroxetine dose at week 4 (permutation p = 0.012). We did not find an association between these SNPs and the side effects or serum concentrations of paroxetine., Conclusion: Genetic variants in the CYP1A2 region may be indicators of treatment response in MDD patients to paroxetine.

Objective: To compare the efficacy and safety of adjunctive treatment with paroxetine or amitriptyline in patients with bipolar disorder who relapsed into a depressive episode during lithium maintenance therapy., Methods: Data from a randomized, double-blind trial comparing paroxetine (N=18) or amitriptyline (N=22) as adjunctive treatment for an episode of depression during lithium maintenance therapy were reanalyzed. Only patients with a diagnosis of bipolar disorder were included. The primary endpoint was the change in Hamilton Rating Scale for Depression (HAM-D21) from randomization to study end (week 6)., Results: There was a significant reduction of HAM-D21 total score from randomization to study end in both treatment groups. The mean change in HAM-D21 score in the paroxetine and amitriptyline groups at study end was -14.9 and -15.5 (p=0.798), and the mean HAM-D21 at study end was 8.2 vs. 9.9 (p=0.420), respectively. The patients treated with paroxetine showed a more rapid improvement with lower HAM-D21 scores between weeks 3 and 5. Tolerability was similar in both groups., Limitations: No placebo comparator group and relatively small study sample size., Conclusions: Adjunctive treatment with either paroxetine or amitriptyline is a viable option for breakthrough depression during lithium maintenance therapy., (Copyright © 2010. Published by Elsevier B.V.)

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 (15.0mg/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 (3.0mg/kg, i.p.) selectively impaired escape, considered a panicolytic effect. Combination of pindolol (5.0mg/kg, i.p.) with an ineffective dose of paroxetine (1.5mg/kg, i.p.) impaired escape, indicating a potentiation of the panicolytic effect of paroxetine. By the oral route, neither paroxetine (3.0mg/kg) nor pindolol (5.0mg/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)., (2010 Elsevier Inc. All rights reserved.)

Background: Serotonin syndrome is a condition resulting from an overabundance of serotonin at postsynaptic receptors. The syndrome usually responds to cyproheptadine and benzodiazepines. However, some patients do not respond to conventional treatment., Objective: The authors report on the history and management of a patient, a 55-year-old man, who had taken a massive overdose of paroxetine, controlled-release., Method: The authors present a case report of history and treatment. Paroxetine levels were measured on Days 3 and 7 after admission, with rising values of the drug. The patient received a course of cyproheptadine and lorazepam, to which he was unresponsive, and he was transferred to the Medical Intensive Care Unit for heavy sedation., Results: The patient had initially presented with minor symptoms of serotonin syndrome, but these quickly progressed in severity, and he eventually died from resulting complications: a pulmonary embolism 9 days after admission, despite appropriate prophylaxis with enoxaparin., Conclusion: The authors are the first to report on a paroxetine overdose of this magnitude, and they provide one of the few reports on a prolonged course of serotonin syndrome that was unresponsive to standard treatment.

Purpose: To investigate paroxetine's putative dose-dependent impact on pupil reaction and inhibition of the O-demethylation of tramadol., Methods: Twelve healthy CYP2D6 extensive metabolizers participated in this double-blinded randomized five-way placebo controlled cross-over study; they received placebo, 10, 20, 30, and 50 mg paroxetine as single oral doses at bedtime. Next morning the pupil was measured followed by oral intake of 50 mg of tramadol, and urine was collected for 8 h. Three hours after ingestion of tramadol a second measurement of the pupil was performed. Enantioselective urine concentrations of (+/-)-tramadol and (+/-)-O-desmethyltramadol (M1) were determined., Results: With placebo, the median maximum pupil diameter was 6.43 mm (range 5.45-7.75 mm) before tramadol and 6.22 mm (4.35-7.65 mm) after 50 mg of tramadol (P = 0.4935). Paroxetine resulted in a statistically significant, dose-dependent dilatation of the pupil with a geometric mean difference of 1.17 (95% CI 1.10-1.24) after ingestion of 50 mg paroxetine (P < 0.001). Likewise, a reduction in the relative constriction amplitude with a geometric mean difference of 0.81 (95% CI 0.71-0.92) (P < 0.001) was seen. A dose-dependent inhibition of the metabolism of tramadol by an increase in the two urinary metabolic ratios (+)-tramadol / (+)-M1 [geometric mean difference 9.09, 95% CI 5.60-14.73 (P < 0.001)] and (-)-M1 / (+)-M1 [geometric mean difference 2.84, 95% CI 2.15-3.77 (P < 0.001)] was also observed., Conclusions: Paroxetine is a dose-dependent dilator of the pupil and as expected a dose-dependent inhibitor of (+)-tramadol's O-demethylation.

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.

The 5-hydroxytryptamine (5-HT(4)) receptor may be implicated in depression and is a new potential target for antidepressant treatment. We have investigated the brain 5-HT(4) receptor [(3)H]SB207145 binding in the Flinders Sensitive Line rat depression model by quantitative receptor autoradiography, and related this to 5-HT transporter (S)-[N-methyl-(3)H]citalopram binding. We also determined the regulation of 5-HT(4) receptor binding by 1, 14, and 21 days of paroxetine administration and subchronic 5-HT depletion, and compared this with changes in 5-HT(2A) receptor [(3)H]MDL100907 binding. In the Flinders Sensitive Line, the 5-HT(4) receptor and 5-HT transporter binding were decreased in the dorsal and ventral hippocampus, and the changes in binding were directly correlated within the dorsal hippocampus. Chronic but not acute paroxetine administration caused a 16-47% down-regulation of 5-HT(4) receptor binding in all regions evaluated including the basal ganglia and hippocampus, while 5-HT depletion increased the 5-HT(4) receptor binding in the dorsal hippocampus, hypothalamus, and lateral globus pallidus. In comparison, the 5-HT(2A) receptor binding was decreased in the frontal and cingulate cortices after chronic paroxetine administration, and markedly reduced in several regions after 5-HT depletion. Thus, the 5-HT(4) receptor binding was decreased in the Flinders Sensitive Line depression model and in response to chronic paroxetine administration.

Purpose: 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., Methods: 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., Results: 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., Conclusions: 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., ((c) 2009 John Wiley & Sons, Ltd.)

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).

Objective: To evaluate the efficacy and tolerability of low daily doses of controlled-release (CR) paroxetine in patients with late-life depression., Method: 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., Results: 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= 60 years of age, although effect sizes are relatively smaller with the 12.5 mg/day dose., (Copyright 2009 Physicians Postgraduate Press, Inc.)

Aims: Several trials have proved the efficacy of selective serotonin re-uptake inhibitors (SSRI) in the treatment of premenstrual dysphoric disorder (PMDD) in Western society. The SSRI can be administered continuously throughout the entire cycle or intermittently from ovulation to the onset of menstruation (luteal phase). The purpose of the present study was to compare continuous and intermittent paroxetine treatment in oriental PMDD women during 6 months follow up., Methods: Thirty-six subjects were evaluated and drug free for two menstrual cycles, and they received daily paroxetine (20 mg) for two further full cycles. They were then randomly divided into continuous or intermittent treatment groups (n = 16, 14) over the next four cycles. Responses were assessed every 2 weeks. Outcome measures included scores on the Prospective Record of the Impact and Severity of Menstrual Symptomatology (PRISM) calendar, Hamilton Rating Scale for Depression/Anxiety (HAMD/HAMA), and the Clinical Global Impression scale (CGI)., Results: All these women had significant improvements in the HAMA, HAMD, CGI, and PRISM calendar. The rate of response to paroxetine treatment lay between 50% and 78.6% in the continuous-treatment group, and 37.5-93.8% in the intermittent-treatment group, as determined at the study end-point. Limitations of the present study included the open-label design and the incorporation of a limited sample size., Conclusions: The present results indicate that paroxetine is effective in both continuous and intermittent treatment of oriental PMDD women, and that the effects of active treatment lasted for six consecutive treatment menstrual cycles.

Objective: The objective of this study was to evaluate the efficacy of paroxetine in treating major depressive disorder (MDD) in persons with multiple sclerosis (MS)., Method: In this double-blind trial, 42 participants with MS and MDD were randomly assigned to one of two parallel 12-week treatment arms: paroxetine or placebo. The participants started at an initial dose of 10 mg/day paroxetine or placebo, titrated up to 40 mg daily based on symptoms response and side effects. The primary outcome measure was the Hamilton Rating Scale for Depression (HAM-D). Secondary outcomes included fatigue, anxiety and self-reported quality of life., Results: Intent-to-treat analyses revealed that both groups improved from pretreatment to posttreatment. Although the treatment group improved more than the control group on most measures, few differences were statistically significant. For the primary outcome, 57.1% of participants in the treatment arm had at least a 50% reduction in HAM-D score, compared with 40% in the control group (nonsignificant). Treatment effects were greater among the participants who completed the study; 78.6% of completers had a treatment response compared with 42.1% of controls (P=.073)., Conclusion: Although paroxetine may not be efficacious for all persons with MS and MDD, it appears to benefit some individuals.

The present study was designed to assess the effect of dexamethasone, a synthetic glucocorticoid receptor agonist, in the sucrose preference test in rats. Rats treated acutely with dexamethasone (5-10 mg/kg) showed a significant decrease in sucrose preference (anhedonia) in comparison to vehicle treated rats, although 1 mg/kg dexamethasone did not alter the sucrose preference. Daily paroxetine treatment (10 g/kg, i.p., 14 days) reversed the anhedonic effect of acute dexamethasone (5 mg/kg), while causing no increased sucrose preference in rats that received dexamethasone vehicle. The paroxetine vehicle treated rats showed anhedonia even 14 days after acute dexamethasone administration. Paroxetine (10 mk/kg, i.p. for 28 days) also reversed anhedonia induced by chronic mild stress (8 weeks). In conclusion, acute dexamethasone induced an enduring anhedonic state that was reversed by repeated paroxetine treatment. Thus, the present study adds new data to the evidence supporting an important role for glucocorticoid in depression.

Background: Many older patients who recover from an episode of major depression continue to suffer from depressed mood, anxiety, and sleep problems. Our study assesses the impact of these residual symptoms on the risk of recurrence during maintenance treatment of late-life depression., Method: We analyzed data from a randomized clinical trial of maintenance treatment in patients with unipolar depression aged > or =70, 116 of whom remitted and remained stable during open pharmacotherapy and interpersonal psychotherapy (IPT) and were randomized to clinical management/pharmacotherapy; clinical management/placebo; monthly maintenance IPT/ pharmacotherapy; or monthly maintenance IPT/placebo. We assessed the impact of overall residual symptoms (based on the Hamilton Depression Rating Scale (HAM-D) total score) and of specific residual symptom clusters - mood symptoms (depressed mood, guilt, suicidality, energy/interests), sleep disturbance (early, middle, late insomnia), and anxiety (agitation, psychic and somatic anxiety, hypochondriasis) measured at randomization. Sleep disturbance was also assessed with the Pittsburgh Sleep Quality Index (PSQI). We used Cox proportional hazards regression models controlling for assignment to antidepressant medication versus placebo to identify predictors of recurrence., Results: Residual anxiety and residual sleep disturbance (as measured by the PSQI but not the HAM-D) independently predicted early recurrence., Limitations: Use of HAM-D clusters to define residual symptoms; analysis limited to completers of acute and continuation treatment., Conclusions: In patients with late-life depression who have remitted with pharmacotherapy and psychotherapy, the deleterious effect of residual symptoms is due to persisting anxiety and, possibly, residual sleep disturbance.

The aim of the study was to compare the distribution of therapeutic efficacy and sexual dysfunction during maintenance paroxetine treatment in 17 males and 38 females genotyped and phenotyped to determine their CYP2D6 metabolic status. Clinical results were monitored on scales Clinical Global Impression-Severity of Illness Scale (CGIS) and Arizona Sexual Experience Scale (ASEX). The phenotype procedure showed 7 males and 12 females with extensive metabolic status (EM) and 10 males and 26 females with poor metabolic status (PM). No variation in therapeutic efficacy between male and female subjects classified as PM and those marked as EM was found. A significantly higher rate of sexual dysfunction (p = 0.01) was recorded among females with a PM phenotype.

Background: Depression is frequently observed in patients with heart failure and is associated with poor quality of life and adverse prognosis. However, the prevalence of depression in heart failure could be overestimated because symptoms of depression overlap with those of heart failure. Similarly, the importance of depression may be overestimated if depression merely reflects worse heart failure. Because the response to depression treatment has not been evaluated in this patient population, we evaluated the efficacy of controlled-release paroxetine (paroxetine CR), a selective serotonin reuptake inhibitor, on depression and quality of life in chronic heart failure., Methods: A double-blind, randomized, placebo-controlled design was used to evaluate reductions in depression following 12 weeks of treatment with paroxetine CR (n = 14, age 62.1 +/- 12.3 years) or placebo (n = 14, age = 61.9 +/- 9.0 years). Patients with symptomatic congestive heart failure and a score of at least 10 on the Beck Depression Inventory (BDI) were eligible. Beck Depression Inventory was obtained at baseline and 4, 8, and 12 weeks of follow-up. Quality of life was assessed using the Medical Outcomes Study Short Form and the Minnesota Living with Heart Failure Questionnaire., Results: Controlled-release paroxetine resulted in significantly more recovery from depression (BDI <10) than placebo (69% vs 23%, P = .018) and resulted in lower continuous BDI scores throughout the intervention (P = .024). Controlled-release paroxetine was associated with higher general health levels compared with placebo on the Medical Outcomes Study 36-Item Short Form survey (38 +/- 10 vs 30 +/- 6, P = .016) at 12 weeks of follow-up. Reductions in depression were correlated with improvements in psychological aspects of quality of life (P < .05) but not with physical quality of life measures (P > .10)., Conclusion: Antidepressant therapy with paroxetine CR results in significant reductions in depression among patients with heart failure. The reductions in depression with paroxetine CR are accompanied by improvements in psychological aspects of quality of life. Larger controlled trials are needed to further document the effectiveness of paroxetine CR and other selective serotonin reuptake inhibitors in patients with heart failure and to determine patient subgroups that are most likely to benefit from antidepressive interventions.

Rationale: The cognitive impairments apparent in many depressed patients appear to be alleviated by chronic treatments with antidepressants. However, evaluation of antidepressant treatments in rodents rarely includes investigation of their effects on cognitive performance., Objectives: The aim of this study was to investigate in rat the effects of paroxetine, a selective serotonin reuptake inhibitor antidepressant, and imipramine, a tricyclic antidepressant, on learning and memory in spatial and non-spatial tasks., Materials and Methods: Adult male Sprague-Dawley rats weighing 230-250 g were used in two sets of experiments., Results: Spatial working memory was first tested in a radial-arm maze using the delayed spatial win-shift task. During the course of a 10-day treatment, paroxetine-treated rats (10 mg/kg) did not show any deficit in memory performance. Conversely, imipramine-treated rats (10 mg/kg) made significantly more errors than controls. Secondly, we tested temporal order memory for objects. Rats received one injection or chronic injections (28 days) of imipramine (10 mg/kg), paroxetine (10 mg/kg) or saline. In contrast to controls, on the day after the acute injection, both imipramine- and paroxetine-treated rats were unable to discriminate the old from the recent objects. After chronic treatment, the imipramine-treated rats were unable to differentiate between the two objects, whereas paroxetine-treated rats, as controls, spent more time exploring the old one. When the delay before the test phase was increased to 4 h, controls could not discriminate the objects, whereas rats treated for 28 days with paroxetine were able to distinguish the old from the recent object., Conclusions: In contrast to the persistent harmful effects of imipramine, chronic treatment with paroxetine does not alter spatial working memory performance and appears to improve temporal order memory performance.

Venlafaxine is generally considered to be a dual 5-HT and NE reuptake inhibitor when it is used at doses above 75 mg/d in humans. While its 5-HT reuptake-inhibiting property has been demonstrated, some controversy still exists regarding the doses of venlafaxine required to inhibit NE reuptake. Healthy male volunteers received, on a double-blind basis, paroxetine (20 mg/d), desipramine (100 mg/d), nefazodone (300 mg/d), or venlafaxine (150 or 300 mg/d) in the last 5 d of a 7-d period of administration. Inhibition of 5-HT reuptake was estimated by determining the degree of depletion of whole-blood 5-HT, while that of NE was assessed by measuring the attenuation of the systolic blood pressure increases produced by intravenous injections of tyramine. Paroxetine, both regimens of venlafaxine, and to a lesser extent desipramine significantly decreased whole-blood 5-HT content. Nefazodone failed to produce any significant change. Desipramine abolished the tyramine pressor response, whereas all other drug regimens left this parameter unaltered. Venlafaxine and paroxetine acted as potent 5-HT reuptake inhibitors in the present study. In contrast, neither the moderate nor the high dose of venlafaxine displayed any significant inhibiting activity in this model assessing NE reuptake in peripheral NE terminals. The validity of the model was confirmed by the potent inhibitory action of desipramine on NE reuptake. While the reasons for this unexpected lack of action remain unclear, venlafaxine appeared to be an effective NE reuptake agent in depressed patients using the same approach.

Objective: Paroxetine is believed to be a substrate of CYP2D6. However, no information was available indicating drug interaction between paroxetine and inhibitors of CYP2D6. The aim of this study was to examine the effects of terbinafine, a potent inhibitor of CYP2D6, on pharmacokinetics of paroxetine., Methods: Two 6-day courses of either a daily 150-mg of terbinafine or a placebo, with at least a 4-week washout period, were conducted. Twelve volunteers took a single oral 20-mg dose of paroxetine on day 6 of both courses. Plasma concentrations of paroxetine were monitored up to 48 h after dosing., Results: Compared with the placebo, terbinafine treatment significantly increased the peak plasma concentration (C(max)) of paroxetine, by 1.9-fold (6.4 +/- 2.4 versus 12.1 +/- 2.9 ng/ml, p < 0.001), and the area under the plasma concentration-time curve from zero to 48 h [AUC (0-48)] of paroxetine by 2.5-fold (127 +/- 67 vs 318 +/- 102 ng/ml, p < 0.001). Elimination half-life differed significantly (15.3 +/- 2.4 vs 22.7 +/- 8.8 h, p < 0.05), although the magnitude of alteration (1.4-fold) was smaller than C(max )or AUC., Conclusion: The present study demonstrated that the metabolism of paroxetine after a single oral dose was inhibited by terbinafine, suggesting that inhibition of CYP2D6 activity may lead to a change in the pharmacokinetics of paroxetine. However, further study is required to confirm this phenomenon at steady state.

Aims: Two studies were conduced to assess the effects of ketoconazole, a CYP3A4/5 inhibitor; fluconazole, a CYP2C9 inhibitor; and paroxetine, a CYP2D6 inhibitor, on lasofoxifene pharmacokinetics., Methods: The first parallel group study was conducted in 45 healthy postmenopausal women (15 per group) to compare the pharmacokinetics of a single dose of lasofoxifene (0.25 mg) administered alone and in combination with ketoconazole (400 mg daily x 20 days) or fluconazole (400 mg daily x 20 days). Lasofoxifene was administered on day 2 and blood samples were collected serially for up to 456 h postdose (20 days). The second study enrolled 20 healthy postmenopausal women (10 per group) to compare the pharmacokinetics of a single dose of lasofoxifene (0.25 mg) alone and in combination with paroxetine (30 mg qd x 21 days). Lasofoxifene was given on day 8 of paroxetine treatment and blood samples were collected serially for up to 336 h postdose., Results: All subjects completed the study and the treatments were well tolerated. Lasofoxifene C(max) and AUC ratios [90% confidence interval (CI)] with/without ketoconazole were 111% (98.4, 127) and 120% (105, 136), respectively, and were 91.3% (80.3, 104) and 104% (91.4, 118), respectively, with/without fluconazole. Lasofoxifene C(max) and AUC ratios (90% CI) with/without paroxetine were 118% (95.4, 146) and 135% (120, 152), respectively., Conclusions: Coadministration of potent inhibitors of CYP3A4/5 and CYP2D6, but not CYP2C9, resulted in a moderate increase in lasofoxifene exposure. No dosage adjustment should be required when lasofoxifene is coadministered with ketoconazole, fluconazole, paroxetine or other agents that inhibit these CYP enzymes.

To date, no large-scale, controlled trial comparing a serotonin-norepinephrine reuptake inhibitor and selective serotonin reuptake inhibitor with placebo for the treatment of panic disorder has been reported. This double-blind study compares the efficacy of venlafaxine extended-release (ER) and paroxetine with placebo. A total of 664 nondepressed adult outpatients who met DSM-IV criteria for panic disorder (with or without agoraphobia) were randomly assigned to 12 weeks of treatment with placebo or fixed-dose venlafaxine ER (75 mg/day or 150 mg/day), or paroxetine 40 mg/day. The primary measure was the percentage of patients free from full-symptom panic attacks, assessed with the Panic and Anticipatory Anxiety Scale (PAAS). Secondary measures included the Panic Disorder Severity Scale, Clinical Global Impressions--Severity (CGI-S) and--Improvement (CGI-I) scales; response (CGI-I rating of very much improved or much improved), remission (CGI-S rating of not at all ill or borderline ill and no PAAS full-symptom panic attacks); and measures of depression, anxiety, phobic fear and avoidance, anticipatory anxiety, functioning, and quality of life. Intent-to-treat, last observation carried forward analysis showed that mean improvement on most measures was greater with venlafaxine ER or paroxetine than with placebo. No significant differences were observed between active treatment groups. Panic-free rates at end point with active treatment ranged from 54% to 61%, compared with 35% for placebo. Approximately 75% of patients given active treatment were responders, and nearly 45% achieved remission. The placebo response rate was slightly above 55%, with remission near 25%. Adverse events were mild or moderate and similar between active treatment groups. Venlafaxine ER and paroxetine were effective and well tolerated in the treatment of panic disorder.

(1) Between 20% and 30% of newborns exposed to selective serotonin reuptake inhibitor antidepressants (SSRIs) towards the end of gestation have disorders such as agitation, abnormal muscle tone and suction, seizures and hyponatraemia. (2) Worrisome data concerning a possible teratogenic effect were published in late 2005. (3) In a Danish cohort including 1054 pregnant women, the estimated relative risk of all congenital malformations, compared with the general population, among the offspring of women who received a prescription for an SSRI was 1.4 (95% CI 1.1-1.9), and the relative risk of cardiac malformations was 1.6 (95% CI 1.0-2.6). (4) An American retrospective study compared the newborns of women who were prescribed paroxetine during the first trimester of pregnancy with all newborns exposed to other antidepressants: 4% of newborns exposed to paroxetine had malformations (2% had cardiac malformations). The estimated relative risk for all congenital malformations was 2.20 (95% CI 1.34-3.63), and the estimated relative risk of cardiovascular malformations was 2.08 (95% CI 1.03-4.23). (5) Analysis of a Swedish birth register provided an estimated relative risk of cardiac malformations associated with paroxetine of 2.22 (95% CI 1.39-3.55) compared with the general population. (6) Another American study showed a global increase in the risk of malformations with paroxetine compared with all antidepressants. The risk of cardiovascular malformations was not significantly increased. (7) In a case-control study based on an American register of birth defects, the estimated relative risk of omphalocele was 3.0 with all SSRIs (95% CI 1.4 to 6.1), and the estimated relative risk of craniosynostosis was 1.8 (95% CI 1.0-3.2). (8) In practice, all SSRIs have been implicated in a possible increase in the risk of congenital malformations, but the most worrisome evidence concerns paroxetine. This potential risk implies that the justification for paroxetine treatment in pregnant women should be carefully weighed; this means double-checking the diagnosis, the potential benefits and adverse effects, and possible alternatives.