Mg Of Paroxetine Research Articles

PAROXETINE OVERDOSE LEADING TO SEROTONIN SYNDROME

PAROXETINE OVERDOSE LEADING TO SEROTONIN SYNDROME

Effect of Paroxetine-Mediated G-Protein Receptor Kinase 2 Inhibition vs Placebo in Patients With Anterior Myocardial Infarction

Left ventricular remodeling following acute myocardial infarction results in progressive myocardial dysfunction and adversely affects prognosis. To investigate the efficacy of paroxetine-mediated G-protein-coupled receptor kinase 2 inhibition to mitigate adverse left ventricular remodeling in patients presenting with acute myocardial infarction. This double-blind, placebo-controlled randomized clinical trial was conducted at Bern University Hospital, Bern, Switzerland. Patients with acute anterior ST-segment elevation myocardial infarction with left ventricular ejection fraction (LVEF) of 45% or less were randomly allocated to 2 study arms between October 26, 2017, and September 21, 2020. Patients in the experimental arm received 20 mg of paroxetine daily; patients in the control group received a placebo daily. Both treatments were provided for 12 weeks. The primary end point was the difference in patient-level improvement of LVEF between baseline and 12 weeks as assessed by cardiac magnetic resonance tomography. Secondary end points were changes in left ventricular dimensions and late gadolinium enhancement between baseline and follow-up. Fifty patients (mean [SD] age, 62 [13] years; 41 men [82%]) with acute anterior myocardial infarction were randomly allocated to paroxetine or placebo, of whom 38 patients underwent cardiac magnetic resonance imaging both at baseline and 12 weeks. There was no difference in recovery of LVEF between the experimental group (mean [SD] change, 4.0% [7.0%]) and the control group (mean [SD] change, 6.3% [6.3%]; mean difference, -2.4% [95% CI, -6.8% to 2.1%]; P = .29) or changes in left ventricular end-diastolic volume (mean difference, 13.4 [95% CI, -12.3 to 39.0] mL; P = .30) and end-systolic volume (mean difference, 11.4 [95% CI, -3.6 to 26.4] mL; P = .13). Late gadolinium enhancement as a percentage of the total left ventricular mass decreased to a larger extent in the experimental group (mean [SD], -13.6% [12.9%]) compared with the control group (mean [SD], -4.5% [9.5%]; mean difference, -9.1% [95% CI, -16.6% to -1.6%]; P = .02). In this trial, treatment with paroxetine did not improve LVEF after myocardial infarction compared with placebo. ClinicalTrials.gov Identifier: NCT03274752.

Comparison of the effects of stellate ganglion block and paroxetine on hot flashes and sleep disturbance in breast cancer survivors.

BackgroundThe incidence of menopausal symptoms, including hot flashes and sleep disturbance, caused by drug treatment is a common problem in breast cancer survivors. Considering the limitations of hormone therapy in such patients, several studies have been conducted to find alternative methods. The aim of this study was to investigate and compare the effectiveness of stellate ganglion block (SGB) with that of paroxetine, which was approved by the US Food and Drug Administration (FDA) as a medicine for the treatment of hot flashes and ensuing sleep disturbance.Patients and methodsA total of 40 patients survived from breast cancer and complaining of these symptoms were equally assigned to two groups of 20 each. In the study group, SGB was performed successfully under sonography guidance using 10 mL of 0.5% bupivacaine, and in the control group (paroxetine), the daily administration of 7.5 mg of paroxetine was conducted for 6 weeks. The frequency and severity of hot flash attacks and sleep quality of patients were evaluated prior to the intervention and after 2, 4 and 6 weeks. The incidence of adverse events during treatment or follow-up was recorded.ResultsA significant decrease in hot flash score and sleep disturbance index (SDI) was observed in both groups. Comparison of the results showed no noticeable difference between the two groups. Two participants in the control group had discontinued medication due to gastrointestinal symptoms, and only one case of mild headache was reported in the study group.ConclusionSGB is as much effective as paroxetine in controlling hot flashes and sleep disturbances in breast cancer survivors and is associated with few complications.

Treatment of pruritus in a palliative care patient with low-dose paroxetine: a case report

BackgroundPruritus is a distressing symptom seen in palliative care. There is limited high-quality evidence of pharmaceutical treatments for pruritus in palliative care, including the use of paroxetine.Case presentationI present a case of a 70-year-old caucasian woman with metastatic ovarian cancer who presented with severe pruritus. She had been diagnosed with bile duct obstruction 1 month earlier. Antihistamines and over-the-counter skin creams were first trialed, to no effect. Paroxetine was started at 5 mg in the evening, with the intention of titrating up. However, 5 mg of paroxetine was effective, and the patient’s pruritus fully resolved after the second day.ConclusionsThis case supports the use of paroxetine as a therapy for pruritus in palliative care patients and suggests that paroxetine may be effective at a very low dose.

Impact of Functional Allelic Variations on Drug-Drug Interactions Involving CYP2D6

CYP2D6 genetically-predicted Extensive Metabolizers (gEMs) may carry one or two functional alleles. Currently phenotypes of carriers of two fully-functional alleles (genetic activity score 2, gAS2) and carriers of one fully-functional and one non-functional allele (genetic activity score 1, gAS1) are predicted EMs. However, drug-drug interactions (DDIs) might be underestimated among gAS1 patients. This study explores the impact of functional allelic variations on DDIs among gEMs. 34 healthy volunteers were allocated to two parallel study groups: gAS1 and gAS2. Dextromethorphan/dextrorphan metabolic ratio (UMR) in urine sampled for 10 hours after administration of 5 mg dextromethorphan was used to determined CYP2D6 phenotype in each of three study sessions. Volunteers additionally received 12 and 2 hours prior to dextromethorphan administration 60 mg of duloxetine in session 2 and 20 mg of paroxetine in session 3. Baseline phenotype distribution was not significantly different between the two genotypes. Higher proportion of IM was observed with the moderate inhibitor duloxetine: 71% of gAS1 and 25% of gAS2 subjects (p=0.009). With the strong inhibitor paroxetine, almost all gAS1 subjects were phenoconverted into PM (94%) whereas this proportion was lower in gAS2 subjects (56%, p=0.011). UMR values were significantly higher in gAS1 subjects than in gAS2 subjects in all conditions tested: 0.030 (CI95% 0.027–0.070) versus 0.009 (CI95% 0.007–0.022) (p=0.006) at baseline, 0.046 (CI95% 0.039–0.093) versus 0.017 (CI95% 0.012–0.038) with duloxetine (p=0.005) and 1.106 (CI95% 1.052–1.650) versus 0.344 (CI95% 0.249–0.745) with paroxetine (p<0.001). The proportion of PM phenoconversion with a strong inhibitor is higher in gEMs subjects carrying a non-functional CYP2D6 allele. Therefore, those individuals might be prone to adverse drug-drug interactions and might benefit from special attention when administered a CYP2D6 inhibitor.

Study of pharmacokinetic interaction of paroxetine and roxithromycin on bencycloquidium bromide in healthy subjects

PurposeThe aim of this study was to investigate the potential drug–drug interaction between Bencycloquidium bromide (BCQB) and paroxetine, and between BCQB and roxithromycin. MethodsTwo studies were conducted on healthy male Chinese volunteers. Study A was an open-label, two-period, one-sequence crossover study (n=21). Each participant received a single nasal spray dose of BCQB 180μg on day 1. After a 7-day wash-out period, subjects received 20mg of paroxetine from day 8 to 17, and were co-administered 20mg of paroxetine and BCQB 180μg on day 18. In study B, participants (n=12) were randomly assigned to two groups. In period I, group A received BCQB 180μg on day 1, followed by the same dose four times daily from day 4 to 10, then, on day 11 a single dose of 150mg roxithromycin with BCQB 180μg were co-administered. In parallel, group B received a single dose of roxithromycin 150mg on day 1, followed by 300mg of roxithromycin from day 4 to 10, then, on day 11 a single dose of BCQB 180μg with roxithromycin 300mg were co-administered. After a wash-out time of 7days the respective treatments of each group (A and B) were swapped in period II. Blood samples were collected for pharmacokinetic analysis. Statistical comparison of pharmacokinetic parameters was performed to identify a possible drug interaction between treatments. Tolerability was evaluated by recording adverse events. ResultsStudy A: Geometric mean AUC0–36 for BCQB alone and co-administered with paroxetine were 474.3 and 631.3pgh/ml, respectively. The geometric mean ratio (GMR) of AUC0–36 was 1.33 (1.13–1.46), 90% C.Is, and was out the predefined bioequivalence interval (90% C.Is, 0.80–1.25). Geometric mean Cmax were 187.0 and 181.2pg/ml. Study B: The GMR of AUC0–36 was 0.98 (0.90–1.07), 90% C.Is for BCQB, and the GMR of AUC0–72 was 0.98 (0.87–1.11), 90% C.Is for roxithromycin. Both GMRs were within the predefined bioequivalence interval (90% C.Is, 0.80–1.25). Other pharmacokinetic parameters were within the predefined interval. No serious adverse events were reported and no significant clinical changes were observed in laboratory test results, vital signs and ECGs in any of the studies. All treatments were well tolerated. ConclusionThe co-administration of BCQB with paroxetine showed a moderate increase in BCQB exposure, but was not clinically relevant. Also, no drug interaction was found between BCQB and roxithromycin.

Potential Benefits of Slow Titration of Paroxetine Treatment in an Elderly Population

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. 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). 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). Our results suggest that a gradual titration of paroxetine could avoid the initial treatment anxiety worsening and dropout at the beginning of the treatment.

Pleuropulmonary complications related to pulmonary instillation of activated charcoal

described the interesting case of a 20-year-old female patient who attempted suicide by ingesting lead shot. She was treated with atropine and received 50 g of activated charcoal (AC) diluted in 400 mL of mannitol administered through a gastric tube. A few hours later, the patient vomited, as well as experiencing a decreased level of consciousness and agonal respiration. At bronchoscopy, blackish material mixed with food debris was obtained, characterizing the occurrence of aspiration of the material. Imaging studies revealed bilateral alveolar opacities.We would like to report our experience of a case of attempted suicide in which the pulmonary and pleural complications were due not to aspiration, but to direct instillation of AC into the airways. The patient was a 23-year-old female who was admitted to the hospital approximately one hour and a half after the ingestion of 200 mg of paroxetine. Upon her arrival, she was in a coma and underwent gastric lavage with a solution of 1.5 L of AC. The patient immediately developed dry cough and dyspnea. A chest X-ray showed right pleural effusion, and, during thoracentesis, there was discharge of black fluid, identified as AC (Figure 1). A CT scan showed pleural effusion and consolidation in the right lower lobe, both of which exhibited high density (attenuation values of approximately 130 HU), as well as pneumothorax (Figure 2). These findings raised the suspicion of direct instillation of AC into the lungs due to placement of the nasogastric tube within the patient’s airway. At bronchoscopy, there was discharge of black material from the right lower lobe. An air leak was noted from the chest tube, suggesting bronchopleural fistula. The patient underwent thoracoscopy and pleural lavage. Fifteen days later, the fistula closed, and the patient was discharged from the hospital. Some of the data on this case have been reported in a previous publication.

Transdermal drug delivery of paroxetine through lipid-vesicular formulation to augment its bioavailability

Paroxetine (PAX) is the most potent serotonin reuptake blocker antidepressant clinically available. This study is aimed to reduce the side effects accompanied with the initial high plasma concentration after oral administration of PAX and fluctuations in plasma levels and also to decrease the broad metabolism of the drug in the liver by developing and optimizing liposomal transdermal formulation of PAX in order to improve its bioavailability. PAX liposomes were prepared by reverse phase evaporation technique using lecithin phosphatidylcholine (LPC), cholesterol (CHOL) and drug in different molar ratios. The prepared liposomes were characterized for size, shape, entrapment efficiency and in vitro drug release. The studies demonstrated successful preparation of PAX liposomes. The effect of using different molar ratios of (LPC:CHOL) on entrapment efficiency and on drug release was studied. Liposomes showed percentage entrapment efficiency (%EE) of 81.22 ± 3.08% for optimized formula (F5) which composed of (LPC:CHOL, 7:7) and 20mg of PAX, with average vesicle size of 220.53 ± 0.757 nm. The selected formula F5 (7:7) was incorporated in gel bases of HPMC-E4M (2%, 4%, and 6%). The selected formula of PAX liposomal gel of HPMC-E4M (2% and 4%) were fabricated in the reservoir type of transdermal patches and evaluated through in vitro release. After that the selected formula of PAX liposomal gel transdermal patch was applied to rabbits for in vivo bioavailability study in comparison with oral administration of the marketed PAX tablet. An HPLC method was developed for the determination of PAX in plasma of rabbits after transdermal patch application and oral administration of the marketed PAX tablets of 20mg dose. The intra- and inter-day accuracy and precision were determined as relative error and relative standard deviation, respectively. The linearity was assessed in the range of 5-200 ng/ml. Pharmacokinetic parameters were determined as the C(max) of PAX liposomal transdermal patch was found to be 92.53 ng/ml at t(max) of 12h and AUC(0-48) was 2305.656 ngh/ml and AUC(0-∞) was 3852.726 ngh/ml, compared to the C(max) of 172.35 ng/ml after oral administration of the marketed PAX tablet with t(max) of 6h and AUC(0-24) was 1206.63 ngh/ml and AUC(0-∞) was 1322.878 ngh/ml. These results indicate improvement of bioavailability of the PAX after liposomal transdermal patch application and sustaining of the therapeutic effects compared to oral administration.

Impact of paroxetine on sleep problems in 426 cancer patients receiving chemotherapy: A trial from the University of Rochester Cancer Center Community Clinical Oncology Program

Sleep problems are a frequent distressing symptom in cancer patients, yet little is known about their treatment. Sleep problems and depression frequently co-occur, leading healthcare professionals to treat depression with the expectation that sleep problems will also improve. The purpose of this study was to compare the effect of paroxetine to placebo on sleep problems via a secondary data analysis of a RCT designed to compare the effects of paroxetine to placebo on fatigue in cancer patients undergoing chemotherapy. A previously published report found a significant effect of paroxetine on depression in this cohort. A total of 426 patients were randomized following Cycle 2 of chemotherapy to receive either 20mg of paroxetine or placebo. Sleep problems were assessed using questions from the Hamilton Depression Inventory three times during chemotherapy. A total of 217 patients received paroxetine and 209 received placebo. Significantly fewer patients taking paroxetine reported sleep problems compared to patients on placebo (Paroxetine 79% versus Placebo 88%; p<0.05). These differences remained significant even after controlling for baseline sleep problems and depression (p<0.05). Paroxetine had a significant benefit on sleep problems in both depressed and non-depressed cancer patients. However, rates of sleep problems remained high even among those effectively treated for depression with paroxetine. There is a need to develop and deliver sleep-specific interventions to effectively treat sleep-related side effects of cancer treatments. These findings suggest that sleep problems and depression are prevalent and co-morbid. Cancer progression, its response to treatment, and overall patient survival are intricately linked to host factors, such as inflammatory response and circadian rhythms, including sleep/wake cycles. Sleep problems and depression are modifiable host factors that can influence inflammation and impact cancer progression and quality of life. Future research should focus on discovering the pathogenesis of sleep dysregulation and depression in cancer so that better treatment approaches can be developed to ameliorate these symptoms.

Abstract 763: A phase 1 open-label study to investigate the potential drug-drug interaction (DDI) between single-dose (SD) dacomitinib (PF-00299804; DC) and steady-state (SS) paroxetine (PX) in healthy volunteers (HVs)

Abstract Introduction: DC, a small molecule, pan-HER inhibitor, is partly metabolized by cytochrome P450 (CYP) 2D6. Concomitant administration with therapeutic agents that are inhibitors of CYP2D6 could potentially cause DDIs. This study evaluated the effect of PX, a potent CYP2D6 inhibitor, on the pharmacokinetics (PK) of DC in HVs who were extensive CYP2D6 metabolizers. The safety and tolerability of SD DC was also assessed when given alone and co-administered with PX. Methods: In this Phase 1, single fixed-sequence, 2-period study, 14 HVs received a 45 mg SD of DC alone (Period 1). After a 21-day washout, 30 mg of PX was given daily for 10 days (Period 2) and on Day 4, a 45 mg SD of DC was co-administered with PX. Blood samples were collected up to 240 h post DC dose in both periods and analyzed for DC, its CYP2D6 metabolite PF-05199265, and PX using validated high performance liquid chromatographic tandem mass spectrometric methods. PK parameters were calculated using noncompartmental methods. Analysis of variance was performed on natural log transformed AUC and Cmax to estimate adjusted mean treatment differences and 90% confidence intervals (CI) which were exponentiated to produce the adjusted geometric mean ratio (GMR) and 90% CI of the ratios. Results: 14 males (median age 41 [23-54] yrs; 9 black, 5 Caucasian) were evaluated for PK and safety. The GMR and 90% CI of AUCinf and Cmax for DC when given as DC + PX vs DC alone was 137.2% (109.1%, 172.6%) and 110% (82.9%, 145.1%), respectively. Median Tmax of DC was 8 and 10 h post dose, and its half-life was 96 and 90 h, in the presence and absence of PX, respectively. Total exposure (AUC240) to PF-05199265 was decreased in the presence of SS PX (33.5 vs 322 ng.hr/mL). There were no serious adverse events (AEs), severe AEs, or deaths during the study. The majority of AEs were mild (including all 14 events reported during DC treatment alone) and resolved. Conclusions: PX inhibited DC metabolism resulting in 90% reduction in exposure (AUC240) of the CYP2D6 metabolite, PF-05199265. No meaningful change in absorption was observed when DC was given with SS concentrations of PX. DC seems to present a low extraction profile and high variability during the absorption phase, the latter probably due to its physicochemical characteristics (BCS Class II). In the presence of PX, there was an approximate 37% increase in DC exposure (AUCinf) with a wide CI, reflecting large intra-subject variability. The DC change in exposure reported in this study is likely to be less in the clinical setting (45 mg QD). As the exposure of DC reported in the presence of PX is within the range shown to be tolerated and efficacious, no dose adjustment is recommended for DC when administered concomitantly with a CYP2D6 inhibitor, such as PX. SD DC administered alone and in combination with PX was well tolerated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 763. doi:1538-7445.AM2012-763

Determination of Paroxetine in Plasma by Liquid Chromatography Coupled to Tandem Mass Spectrometry for Pharmacokinetic and Bio equivalence Studies

A rapid and validated liquid chromatography coupled to tandem mass spectrometric method (LC-MS-MS) has been developed and applied to pharmacokinetic and bioequivalence studies in 24 healthy male Korean volunteers. The procedure involves a liquid-liquid extraction of paroxetine (CAS 61869-08-7) and fluoxetine (internal standard, CAS 54910-89-3) with ether/methyl chloride (7:3, v/v) and separated by LC equipped with C18 column using acetonitrile: 5 mmol/L ammonium formate (4:3, v/v) as mobile phase. Detection is carried out on an API 2000 MS system by multiple reactions monitoring mode. The ionization was optimized using ESI(+) and selectivity was achieved by MS-MS analysis, mlz 330.0-->192.0 and m/ z 310-->148 for paroxetine and fluoxetine, respectively. The method has a total run time of 1.5 min and was linear over a working range of 0.05-20 ng/mL and the lower limit of quantification was 0.05 ng/ mL. No endogenous compounds were found to interfere with the analysis. The inter-day and intra-day accuracy was in the ranges of 102.69-107.79% and 102.07-109.57%, respectively and precision of inter-day and intra-day expressed as relative standard deviation were 1.86-9.99% and 1.52-6.28%, respectively. The validation of this method on linearity, specificity, accuracy, precision as well as applicability to pharmacokinetic and bioequivalence studies by analysis of blood samples taken up to 72 h after oral administration of 20 mg of paroxetine in 24 healthy volunteers were found to be good performance.

Neural Correlates of Antidepressant-Related Sexual Dysfunction: A Placebo-Controlled fMRI Study on Healthy Males Under Subchronic Paroxetine and Bupropion

Sexual dysfunction is a common side effect of selective serotonin reuptake inhibitors (SSRIs) like paroxetine in the treatment of depression, imposing a considerable risk on medication adherence and hence therapeutic success. Bupropion, a norepinephrine and dopamine reuptake inhibitor, is recommended as an alternative treatment without adverse effects concerning sexual arousal and libido. We investigated the neural bases of paroxetine-related subjective sexual dysfunction when compared with bupropion and placebo. We scanned 18 healthy, heterosexual males in a randomized, double-blind, within-subject design while watching video clips of erotic and nonerotic content under steady-state conditions after taking 20 mg of paroxetine, 150 mg of bupropion, and placebo for 7 days each. Under paroxetine, ratings of subjective sexual dysfunction increased compared with placebo or bupropion. Activation along the anterior cingulate cortex (ACC), including subgenual, pregenual, and midcingulate cortices, in the ventral striatum and midbrain was decreased when compared with placebo. In contrast, bupropion let subjective ratings and ACC activations unchanged and increased activity of brain regions including posterior midcingulate cortex, mediodorsal thalamus, and extended amygdala relative to placebo and paroxetine. Brain regions that have been related to the processing of motivational (ventral striatum), emotional, and autonomic components of erotic stimulation (anterior cingulate) in previous studies showed reduced responsiveness under paroxetine in our study. Drug effects on these regions may be part of the mechanism underlying SSRI-related sexual dysfunction. Increased activation under bupropion may point to an opposite effect that may relate to the lack of impaired sexual functioning.

Use of Dried Plasma Spots in the Determination of Pharmacokinetics in Clinical Studies: Validation of a Quantitative Bioanalytical Method

A novel approach has been developed for the quantitative determination of circulating drug concentrations in clinical studies using dried plasma spots (DPS) on paper substrates, rather than conventional plasma samples. A quantitative bioanalytical high-pressure liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) assay has been validated using paroxetine as a tool compound (range 0.2-200 ng/mL human plasma). The assay employed simple solvent extraction of a punched disk taken from the DPS sample, followed by reversed phase HPLC separation, combined with multiple reaction monitoring mass spectrometric detection. In addition to performing routine experiments to establish the validity of the assay to internationally accepted criteria (precision, accuracy, linearity, sensitivity, selectivity), experiments are included to assess the effect of the volume of plasma spotted and the use of an indicating paper. The validated DPS approach was successfully applied to a clinical study utilizing pooled samples and a direct comparison of DPS and plasma was made (single oral dose of 37.5 mg of paroxetine).

Serotonin Augmentation Reduces Response to Attack in Aggressive Individuals

We tested the theory that central serotonin (5-hydroxytryptamine, or 5-HT) activity regulates aggression by modulating response to provocation. Eighty men and women (40 with and 40 without a history of aggression) were randomly assigned to receive either 40 mg of paroxetine (to acutely augment serotonergic activity) or a placebo, administered using double-blind procedures. Aggression was assessed during a competitive reaction time game with a fictitious opponent. Shocks were selected by the participant and opponent before each trial, with the loser on each trial receiving the shock set by the other player. Provocation was manipulated by having the opponent select increasingly intense shocks for the participant and eventually an ostensibly severe shock toward the end of the trials. Aggression was measured by the number of severe shocks set by the participant for the opponent. As predicted, aggressive responding after provocation was attenuated by augmentation of serotonin in individuals with a pronounced history of aggression.

Effects of Acute Alcohol Intoxication and Paroxetine on Aggression in Men

The purpose of this study was to examine the role of the serotonin (5-HT) system in alcohol-related aggression. Specifically, we experimentally examined the effects of 5-HT augmentation on alcohol-related aggression in men (n = 56). After consuming either alcohol (mean blood alcohol concentration of 0.10%) or a placebo (no alcohol) drink, and taking either 20 mg of paroxetine (Paxil) or a placebo pill, participants were provided the opportunity to administer electric shock to a (faux) opponent during a task disguised as a reaction-time game. Aggression was defined as the intensity of shock chosen and the frequency with which an extreme (clearly painful) shock was chosen. We predicted that 5-HT augmentation would be associated with lower aggressive behavior overall, and also reduce the aggression facilitating effects of acute alcohol intoxication. The results indicated that alcohol intoxication increased aggression, particularly under low provocation. Paroxetine decreased aggression, particularly during high provocation. These effects, however, occurred independently of each other. The effect of alcohol on extreme aggression was moderated by previous aggression history, with more aggressive individuals showing greater alcohol-related increases in extreme aggression.

Pharmacokinetic interaction of flecainide and paroxetine in relation to the CYP2D6*10 allele in healthy Korean subjects

The objectives were to evaluate the effect of CYP2D6 genetic polymorphism on the pharmacokinetics of flecainide, and also on the extent of drug interaction with paroxetine as a CYP2D6 inhibitor after a single oral administration in healthy subjects. An open-label, two-period, single-sequence, cross-over study was performed in 21 healthy Korean male volunteers (seven for CYP2D6*1/*1 or *1/*2, group 1; seven for CYP2D6*1/*10, group 2; seven for CYP2D6*10/*10 or *10/*36, group 3). Subjects were administered 200 mg of flecainide on day 1. After a 7-day wash-out period, subjects were administered 20 mg of paroxetine from day 8 to 14, and 200 mg of flecainide on day 15. Blood sampling was performed up to 72 h after flecainide administration. Terminal elimination half-life and mean residence time (MRT) were significantly different among three genotype groups after a single oral administration of flecainide (P = 0.021, 0.011, respectively). Area under the concentration-time curve, terminal elimination half-life and MRT increased significantly after paroxetine co-administration only in groups 1 and 2. This study reports that the extent of drug interaction between flecainide and paroxetine is influenced by the CYP2D6*10 allele in healthy subjects, which is frequent in Asians.

Effect of paroxetine on depression and insomnia in 547 fatigued cancer patients undergoing 9501 chemotherapy

9501 Background: Little is known about insomnia in cancer patients during chemotherapy. Insomnia and depression frequently co- occur suggesting a common etiology that leads healthcare professionals to treat depression and expect insomnia will improve with reductions in depression. Methods: The purpose of this study is to compare the impact of paroxetine to placebo on insomnia symptoms via secondary analysis of a RCT designed to compare the effects of medication on depression and fatigue in cancer patients undergoing chemotherapy. Patients were asked about insomnia via the Hamilton Depression Inventory. 547 Patients were randomized at Cycle 2 of chemotherapy to receive either 20mg of paroxetine or placebo. Insomnia was assessed at Cycles 1, 2, 3 and 4. Results: During Cycle 1 of chemotherapy, 84.6% reported insomnia problems and 52.1% met diagnostic criteria for clinical insomnia (defined as difficulty falling asleep, staying asleep and/or early awakenings 3–5 nights a week lasting ½ hour per night or more). These rates of insomnia were 3 times higher than rates found in the general population. 76% Of patients reported Initial Insomnia symptoms, 59% reported Middle Insomnia, 45% reported Late Insomnia and 26.4% met criteria for depression (Center for Epidemiologic Studies Depression Scale ≥19) at Cycle 1. Paroxetine had no significant impact on insomnia at Cycle 3 or 4 controlling for insomnia and fatigue at Cycle 2. Insomnia symptoms significantly decreased from Cycle 1 to 2, 3 and 4 suggesting that patients might be adapting to their chemotherapy regime. Insomnia symptoms remained high at Cycle 4. 87% Of patients who experienced insomnia symptoms at Cycle 1 continued to experience insomnia symptoms at Cycle 4 (42% met criteria for clinical insomnia). Although the published results demonstrate that depression was significantly reduced at Cycle 4 by paroxetine, insomnia symptoms were not. Conclusions: These findings suggest that using SSRIs to treat depression and expecting that insomnia will also improve is ineffective. Future research is needed to develop effective pharmaceutical, behavioral/cognitive-behavioral treatments for cancer patients that specifically target insomnia rather than expecting insomnia to improve if depression is effectively managed. No significant financial relationships to disclose.

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.

Clinical application of paroxetine for tapering benzodiazepine use in non‐major‐depressive outpatients visiting an internal medicine clinic

Chronic benzodiazepine (BDZ) users often have difficulty with BDZ withdrawal. To examine clinical effects of selective serotonin reuptake inhibitor (SSRI) on tapering BDZ use in non-depressive patients, 97 outpatients with a history of BDZ use for at least 3 months were recruited at an internal medicine clinic of a university hospital. After the 4th edition of the Diagnostic and Statistical Manual (DSM-IV) clinical interviews for screening major depression, 66 outpatients (68%) without the DSM-IV major depression were randomly assigned to one of three groups: SSRI-assisted BDZ-reduction group (10-20 mg of paroxetine, n = 22), simple BDZ-reduction group (no paroxetine, n = 23), and reference group (no BDZ-reduction, n = 21). A standardized 8-week program involving gradual BDZ discontinuation was performed in the two BDZ-reduction groups. The Hamilton Rating Scales for Depression (HAM-D) and Anxiety (HAM-A) and the BDZ Withdrawal Symptom Questionnaire were assessed during the intervention period. Those with major depression were excluded from the BDZ-reduction intervention and treated with a different protocol of medication. In total, 10 (45.5%) in the SSRI-assisted BDZ-reduction group (n = 22) succeeded in becoming BDZ-free after completing the program, whereas only four (17.4%) in the simple BDZ-reduction group (n = 23) succeeded. The assistance of the SSRI significantly predicted the success of becoming BDZ-free (P = 0.023), controlling for the effects of age, gender, period of BDZ use, and baseline HAM-D and HAM-A scores. The score changes on the three questionnaires were comparable (all P > 0.05) among the three groups during the intervention period. The use of SSRI may have beneficial effects on BDZ withdrawal without the worsening of mood states in cases without major depression.