Single- and multiple-dose pharmacokinetics and tolerability of a paroxetine controlled-release tablet in healthy Chinese subjects
.

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 tmax of ~ 7 - 9 hours. From single- to multiple-dose regimens, the mean Cmax increased from 7.08 to 36.95 ng/mL, the mean AUC0-24h increased from 100.91 to 706.75 h×ng/mL, and the mean t1/2 increased from 12.3 to 83.6 hours (all p < 0.05). The point estimate and 90% confidence intervals of the Ctrough 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.
.

Therapeutic Drug Monitoring of Selective Serotonin Reuptake Inhibitors in Elderly Patients.

BACKGROUND: Elderly patients are at increased risk for elevated serum concentrations from treatment with selective serotonin reuptake inhibitors (SSRIs). The aim of this study was to examine the use of therapeutic drug monitoring (TDM) of SSRIs in elderly compared with younger patients. METHODS: All serum concentration measurements of SSRIs (escitalopram, citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) performed at our laboratory in 2011 were included. The use of TDM (relative frequency) in older versus younger patients was examined by comparing the use of TDM in patients aged 60 years or older with that in patients younger than 60 years and by evaluating the use of TDM relative to age (age groups in decennials). The number of patients with an SSRI dispensed by prescription in the same region and period (the Norwegian Prescription Database) was used as reference. Additionally, the number of samples above the upper limit of the recommended reference range in patients aged 60 years or older and patients younger than 60 years was evaluated. RESULTS: TDM of an SSRI had been performed in 6333 patients. For all SSRIs, the use of TDM was significantly lower (8.2% versus 10.6% for citalopram, 10.0% versus 13.8% for escitalopram, 8.6% versus 17.0% for fluoxetine, 5.6% versus 10.3% for paroxetine, and 8.1% versus 15.0% for sertraline) in patients aged 60 years or older compared with those younger than 60 years (P < 0.001). There was a gradual decline in the use of TDM with increasing age, with a 3-fold difference between the youngest (10-19) and oldest (90+) patients (P < 0.0001). The percentage of samples above the upper limit of the recommended reference range was 2-fold higher in patients aged 60 years or older (6.7%) compared with patients younger than 60 (3.4%) years (P < 0.0001). CONCLUSIONS: Clinical follow-up of patients with TDM of SSRIs is less frequent in older patients compared with younger patients. This is in contrast to the general guidelines for TDM where patients of advanced age are considered of particular importance to monitor closely.

Cytochrome P450 2D6 genotype affects the pharmacokinetics of controlled-release paroxetine in healthy Chinese subjects: comparison of traditional phenotype and activity score systems.

PURPOSE: This study evaluated the effects of cytochrome P450 (CYP) 2D6 polymorphisms on the pharmacokinetics of controlled-release paroxetine in healthy Chinese subjects and used paroxetine as a tool drug to compare the performance of traditional phenotype and activity score systems. METHODS: Pharmacokinetic data were evaluated in 24 subjects who received a single oral dose of 25 mg controlled-release paroxetine. Plasma paroxetine concentrations were measured by LC-MS/MS. CYP2D6 genotypes were tested by PCR and direct DNA sequencing. Subjects were classified by two systems of phenotype prediction. In the traditional phenotype system, subjects were classified as extensive metabolizers or intermediate metabolizers; in the activity score system, subjects were divided into four activity groups. Analysis of variance testing was applied to estimate the effects of CYP2D6 polymorphisms on the pharmacokinetics of paroxetine. RESULTS: With the traditional phenotype system, significant differences were observed in the following pharmacokinetic parameters of paroxetine: t 1/2, C max, AUC0-t, AUC0-inf, Vz/F, and CL/F (all P < 0.05). The AUC or exposure of paroxetine was about 3.5-fold higher in the intermediate metabolizer group than in the extensive metabolizer group. With the activity score system, significant differences were observed in the t 1/2, C max, AUC0-t, AUC0-inf, Vz/F, and CL/F among the four different activity score groups (all P < 0.05). We found that the AUC of paroxetine decreased by around one half as the activity score increased by 0.5. CONCLUSION: The pharmacokinetics of controlled-release paroxetine after a single administration was affected by CYP2D6 polymorphisms. Both the traditional phenotype and the activity score systems performed well and distinguished subjects with different drug exposures. The activity score system provided a more detailed classification for the subjects.

Therapeutic reference range for plasma concentrations of paroxetine in patients with major depressive disorders.

BACKGROUND: We investigated the relationship between plasma concentrations of paroxetine and the therapeutic effect of the drug, and we evaluated the therapeutic reference range for plasma concentration of paroxetine in patients with major depressive disorders (MDD). METHODS: In this study, 120 patients with MDD were treated with 10-40 mg/d of paroxetine for 6 weeks, and 89 patients completed the protocol. The Montgomery-Asberg Depression Rating Scale (MADRS) was used to evaluate the patients at 0, 1, 2, 4, and 6 weeks. At the 6-week treatment time point, the patients were divided into 7 groups according to their paroxetine plasma concentrations in increments of 20 ng/mL. We used an analysis of variance and a χ test to define the therapeutic reference range for plasma paroxetine concentrations. RESULTS: We used 50% as the cutoff values for the percentage of MADRS improvement to determine the responder rates, and we defined remitters as patients with MADRS scores <10 at the 6-week treatment time point. We analyzed the responder and remitter rates of the patients according to their plasma paroxetine concentrations: 20 ng/mL, 40 ng/mL, and 60 ng/mL using the χ test. According to the results of the χ test in the responder rates, the 20-60 ng/mL plasma paroxetine group showed the highest effect size. CONCLUSIONS: The results of this study suggested that a range of 20-60 ng/mL is the therapeutic reference range for concentrations of paroxetine in plasma in patients with MDD.

Association of 2 neurotrophic factor polymorphisms with efficacy of paroxetine in patients with major depressive disorder in a Chinese population.

BACKGROUND: To evaluate the influence of the single nucleotide polymorphism (SNP) rs 6265 in the brain-derived neurotrophic factor (BDNF) gene and 21 SNPs of the glial cell line-derived neurotrophic factor (GDNF) gene on the efficacy of paroxetine in patients with major depressive disorder (MDD). METHODS: Genotyping for BDNF and GDNF polymorphisms was performed in 298 patients with MDD who started 20 mg paroxetine per day and had their plasma concentrations measured after 6 weeks. The SNPs were selected from the HapMap Chinese ethnic group and literature reports. Changes in the severity of MDD were assessed with the Hamilton Depression Rating Scale (HAM-D) at baseline and at a 6-week follow-up. Paroxetine plasma concentration was measured using high-performance liquid chromatography with fluorescence detection. The Sequenom MassArray system was used for genotyping. RESULTS: At the 6-week follow-up, 219 of the 298 patients (73.5%) were responders and 79 patients (26.5%) were nonresponders to paroxetine treatment. The lower threshold concentration of paroxetine for response was 50 ng/mL, and a linear relationship was found between paroxetine plasma concentration and clinical response. The allele types for the SNPs rs 6265 (P < 0.001), rs 2973049 (P = 0.005), and rs 2216711 (P = 0.006) demonstrated significant associations with paroxetine treatment remission at week 6. CONCLUSIONS: Genetic variants in the BDNF and GDNF regions may be indicators of treatment response to paroxetine in patients with MDD.

Effects of escitalopram on plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, in Japanese patients.

INTRODUCTION: The effects of escitalopram (10 mg/d) coadministration on plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, were studied in 13 Japanese psychiatric patients and compared with those of paroxetine (10 mg/d) coadministration. METHODS: The patients had received 6-24 mg/d of aripiprazole for at least 2 weeks. Patients were randomly allocated to one of 2 treatment sequences: paroxetine-escitalopram (n=6) or escitalopram-paroxetine (n=7). Each sequence consisted of two 2-week phases. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass spectrometric detection. RESULTS: Plasma concentrations of aripiprazole and the sum of aripiprazole and dehydroaripiprazole during paroxetine coadministration were 1.7-fold (95% confidence intervals [CI], 1.3-2.1, p<0.001) and 1.5-fold (95% CI 1.2-1.9, p<0.01) higher than those values before the coadministration. These values were not influenced by escitalopram coadministration (1.3-fold, 95% CI 1.1-1.5 and 1.3-fold, 95% CI 1.0-1.5). Plasma dehydroaripiprazole concentrations remained constant during the study. CONCLUSION: The present study suggests that low doses of escitalopram can be safely coadministered with aripiprazole, at least from a pharmacokinetic point of view.

A fatal case of desvenlafaxine and paroxetine poisoning.

Desvenlafaxine (O-desmethylvenlafaxine) and paroxetine are antidepressants that inhibit serotonin reuptake. Despite their relatively safe profiles, several serious side effects, including serotonin syndrome, bleeding, mania, and high blood pressure, are observed. We report the confirmation of the death of a 41-year-old female, with an overdose of desvenlafaxine and paroxetine suspected as the main cause of death. To quantify the level of desvenlafaxine and paroxetine in whole blood and urine, solid phase extraction combined with liquid chromatography-tandem mass spectrometry was developed and validated. Calibration curves were linear with coefficients of determination (r2) >0.999 for desvenlafaxine and paroxetine. The limits of detection and the limits of quantification for both desvenlafaxine and paroxetine were 0.001 µg/mL and 0.02 µg/mL, respectively. Desvenlafaxine and paroxetine were detected in the postmortem samples, along with various psychiatric drugs, and the blood alcohol content level was below 0.010%. The concentrations of desvenlafaxine and paroxetine in the heart blood were 11.0 µg/mL and 2.1 µg/mL, respectively, indicating lethal concentrations. In the urine, the concentrations of desvenlafaxine and paroxetine were 87.7 µg/mL and 3.5 µg/mL, respectively. This is the first report to determine the blood concentration of desvenlafaxine in a fatal intoxication caused by an overdose of desvenlafaxine single formulation.

Effect of paroxetine on physiological response to stress and smoking.

OBJECTIVE: Smokers often smoke during stressful events, which leads to large increases in cardiovascular measures such as blood pressure (BP) and heart rate (HR). Because exaggerated cardiovascular response to stress is associated with cardiovascular disease risk, this study examined paroxetine's effect on the physiological response to combining stress and smoking. METHODS: Sixty-two participants completed this randomized, double-blind, crossover study in which BP, HR, plasma epinephrine, norepinephrine, and cortisol concentrations were measured at rest, while smoking, and during a speech and math task. Laboratory sessions occurred after 1 month of paroxetine and after 1 month of placebo. RESULTS: Significant increases occurred for all measures (except cortisol) during smoking, with further increases occurring during the speech task (time effect, p < .001). After 1 month of paroxetine, norepinephrine and HR values were lower and cortisol values were higher (versus placebo) throughout the laboratory session (treatment effect, p < .001). Treatment × time effects were observed for BP and HR (all, p < .01). For systolic and diastolic BP, a smaller increase (from baseline to measures during speech) was observed after paroxetine compared with placebo (both, p < .006). In both measures, the increase in response to smoking was similar for both treatments; however, the further increase during the speech was smaller when taking paroxetine (versus placebo). CONCLUSIONS: This study suggests that paroxetine affects physiological response to stress in smokers. Further research is needed to determine the impact of these results on cardiovascular health. Trial Registration clinicaltrials.gov Identifier: NCT00218439.

Pharmacokinetic model incorporating mechanism-based inactivation of CYP2D6 can explain both non-linear kinetics and drug interactions of paroxetine.

OBJECTIVE: To develop a pharmacokinetic model able to describe the nonlinear pharmacokinetics of paroxetine (PRX) and to predict the drug-drug interaction between PRX and metoprolol under various dosage regimens. METHODS: A pharmacokinetic model of PRX incorporating mechanism-based inhibition was developed. This model was fitted to the drug concentration profiles obtained after single and repeated administrations of PRX to estimate the pharmacokinetic parameters of PRX and degradation rate constant of cytochrome P450 (CYP) 2D6. It was also fitted to the time profile of S-metoprolol after coadministration of metoprolol and PRX, and the fractional contribution of CYP2D6 to overall clearance of S-metoprolol was estimated. Using the developed model and estimated parameters, an optimal dosage regimen for metoprolol during withdrawal of PRX was simulated. RESULTS: The developed model well described the time profiles of both PRX and metoprolol concentration during concomitant administration. The estimated parameters were consistent with reported values. The nonlinear and accumulation properties of PRX could be explained by mechanism-based inhibition of CYP2D6 by PRX. Upon tapering PRX from 20 mg/ day to 10 mg/day for 14 days then 5 mg/day for 14 days until cessation, the optimal dosage regimen to resume 120 mg/day of metoprolol based on the developed model was as follows: 30 mg/day during concomitant administration, 40 mg/day for the next 14 days, 60 mg/day for the next 14 days, and finally 120 mg/day. CONCLUSIONS: The developed model enabled us to quantitatively estimate drug-drug interactions of PRX and CYP2D6 substrate drugs, and to predict optimal dosage regimens.

Determination of paroxetine in serum treated with simple pretreatment by pre-column high-performance liquid chromatography using 4-(5,6-dimethoxy-2-phthalimidinyl)-2-methoxyphenylsulfonyl chloride as a fluorescent labeling reagent.

The therapeutic drug monitoring of paroxetine could be used to optimize the pharmacological treatment of depressed patients. A simple and sensitive high-performance liquid chromatography procedure was developed for the determination of paroxetine in serum. After simple pretreatment of serum (50 µL) with acetonitrile and o-phthalaldehyde, paroxetine was derivatized with 4-(5,6-dimethoxy-2-phthalimidinyl)-2-methoxyphenylsulfonyl chloride at 70°C for 20 min in borate buffer (0.1 mol/L, pH 8.0) to produce a fluorescent product. The derivative was separated on a reversed-phase column at 40°C for stepwise elution with (A) acetic acid (10 mmol/L) and (B) acetonitrile. The flow rate was 1.0 mL/min. The fluorescence intensity was monitored at excitation and emission wavelengths of 320 and 400 nm, respectively. The within-day and day-to-day relative standard deviations were 3.0-3.4 and 2.7-8.3%, respectively. The detection limit of paroxetine was 8.3 fmol at a signal-to-noise ratio of 3. As the proposed method that only requires a small quantity of serum (50 µL) is simple, sensitive and reproducible, it would be useful for clinical and biochemical research as well as drug monitoring.

Platelet serotonin transporter and 5-HT2A receptor binding in adolescents with eating disorders.

The pathogenetic involvement of the serotonergic system in eating disorders is an established finding. Conclusions from platelet studies are based on results from investigations of subjects with a mean age of 20 years or more. The aim was to investigate whether previous findings in adults are valid also for adolescents who are examined within a relatively short interval after the onset of the eating disorder. [(3)H]paroxetine binding to the platelet serotonin transporter and [(3)H]lysergic acid diethylamide ([(3)H]LSD) binding to the 5-HT2A receptor was studied in 15 female adolescents with eating disorders (11 with anorexia nervosa and 4 with clearly anorectic eating behaviour not fulfilling the criteria for anorexia nervosa) and 32 controls. The patients revealed a higher density of serotonin transporters and a lower density of 5-HT2A receptors compared with healthy controls of the same age (775 ± 165 vs. 614 ± 111 fmol/mg protein (p = 0.003) for [(3)H]paroxetine binding and 215 ± 59 vs. 314 ± 151 fmol/mg protein (p = 0.005) for [(3)H]LSD binding). The findings of increased density of platelet serotonin transporters and reduced density of 5-HT2A receptors differ from previous results in older patients. The lower patient age and the short duration of disease in the present study, possibly in conjunction with variations in stress-related psychological and biological factors, may have caused these differences. Although the present findings contradict prevailing evidence, they add further information concerning the nature of serotonergic involvement in eating disorders and indicate that demographic and course-related factors might influence the regulation of the serotonin system in these disorders.

Pharmacokinetics of paroxetine, a selective serotonin reuptake inhibitor, in Grey parrots (Psittacus erithacus erithacus): influence of pharmaceutical formulation and length of dosing.

Paroxetine, a selective serotonin reuptake inhibitor, may be beneficial in the treatment of behavioural disorders in pet birds. The lack of pharmacokinetic data and clinical trials currently limits the use of this drug in clinical avian practice. This paper evaluates the pharmacokinetic properties and potential side effects of single and repeated dosing of paroxetine in Grey parrots (Psittacus erithacus erithacus). Paroxetine pharmacokinetics were studied after single i.v. and single oral dosing, and after repeated oral administration during 1 month. Plasma paroxetine concentrations were determined by liquid chromatography-tandem mass spectrometry. No undesirable side effects were observed during the study. Pharmacokinetic analysis revealed a quick distribution and rapid elimination after i.v. administration. Oral administration of paroxetine HCl dissolved in water resulted in a relatively slow absorption (T(max)=5.9±2.6 h) and a low bioavailability (31±15%). Repeated administration resulted in higher rate of absorption, most likely due to a saturation of the cytochrome P450-mediated first-pass metabolism. This study shows that oral administration of paroxetine HCl (4 mg/kg twice daily) in parrots results in plasma concentrations within the therapeutic range recommended for the treatment of depressions in humans. Further studies are needed to demonstrate the clinical efficacy of this dosage regimen in parrots with behavioural disorders.

The relationship between clinical pharmacokinetics of aripiprazole and CYP2D6 genetic polymorphism: effects of CYP enzyme inhibition by coadministration of paroxetine or fluvoxamine.

PURPOSE: To investigate the effects of coadministration of paroxetine or fluvoxamine on the pharmacokinetics of aripiprazole in healthy adult Japanese with different CYP2D6 genotypes. METHODS: Fourteen CYP2D6 extensive metabolizer (EM) and 14 CYP2D6 intermediate metabolizer (IM) subjects were coadministered a single oral dose of aripiprazole 3 mg after steady-state plasma concentrations of the SSRIs paroxetine (20 mg/day) or fluvoxamine (100 mg/day) were reached by repeated oral doses for 6-7 days. The pharmacokinetics of aripiprazole with and without coadministration of SSRIs were compared according to CYP2D6 genotypes. RESULTS: Coadministration of paroxetine, a potent CYP2D6 inhibitor, decreased systemic clearance (CL/F) of aripiprazole by 58 and 23% in CYP2D6 EMs and IMs, respectively, demonstrating that the percentage inhibition of CYP2D6 activity by coadministration of paroxetine was apparently greater in CYP2D6 EMs than in IMs. Coadministration of fluvoxamine, a less potent CYP3A4 inhibitor, decreased the CL/F of aripiprazole by 39% in CYP2D6 EMs and 40% in IMs, indicating the same inhibitory effect on CYP enzymes, regardless of the CYP2D6 genotype. Percent contribution of CYP2D6 to total CL/F (CYP2D6 plus CYP3A4) of aripiprazole estimated as a reduced percentage of CL/F by CYP enzyme inhibition was 62% for CYP2D6 EMs and 24% for IMs in paroxetine coadministration, and 40% for CYP2D6 EMs and 18% for IMs in fluvoxamine coadministration. CONCLUSIONS: There were marked differences in the degree of influence of paroxetine coadministration on the pharmacokinetics of aripiprazole between CYP2D6 EMs and IMs, but no apparent differences were found between two CYP2D6 genotypes in fluvoxamine coadministration. Aripiprazole can be used safely in combination with SSRIs that have a CYP enzyme-inhibitory action.

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).

Differential behavioural and neurochemical outcomes from chronic paroxetine treatment in adolescent and adult rats: a model of adverse antidepressant effects in human adolescents?

Selective serotonin reuptake inhibitor use is associated with increased risk of suicidal ideation in adolescent humans, yet the neuropharmacological basis of this phenomenon is unknown. Consequently, we examined the behavioural and neurochemical effects of chronic paroxetine (PRX) treatment in adult and adolescent rats. Rats received PRX in their drinking water (target dose 10 mg/kg) for 22 d, during which time they were assessed for depression- and anxiety-like behaviours. Subsequent ex-vivo analyses examined serum PRX concentrations, striatal neurotransmitter content, and regional serotonin and dopamine transporter (SERT, DAT) binding density. After 11-12 d treatment, PRX-treated adolescent rats showed a significant inhibition of social interaction while adults were unaffected. After 19-20 d treatment, adolescents failed to show an antidepressant-like effect of PRX treatment on the forced swim test (FST), while PRX-treated adults showed a typical decrease in immobility and increase in swimming. Two PRX-treated adolescents died unexpectedly after the FST suggesting a compromised response to physical stress. Despite their greater apparent adverse reaction to the drug, adolescents had significantly lower plasma PRX than adults at day 22 of treatment. Chronic PRX treatment had similar effects in adults and adolescents on striatal 5-HT (unchanged relative to controls) and 5-HIAA levels (decreased), while markers of dopaminergic function (DOPAC, HVA, DA turnover) were increased in adults only. SERT density was up-regulated in the amygdala in PRX-treated adolescents only while DAT density in the nucleus accumbens was down-regulated only in PRX-treated adults. These data suggest that the immature rat brain responds differently to PRX and that this might be of use in modelling the atypical response of human adolescents to antidepressants. The age-specific PRX-induced changes in dopaminergic markers and SERT and DAT binding provide clues as to the neural mechanisms underlying adverse PRX effects in adolescent humans.

Determinants of pharmacodynamic trajectory of the therapeutic response to paroxetine in Japanese patients with panic disorder.

PURPOSE: The objective of this study was to evaluate genetic and pharmacokinetic factors to establish the pharmacotherapeutic effect of paroxetine (PAX) in patients with panic disorder (PD). METHOD: Subjects were 65 drug-naïve patients who fulfilled the DSM-IV-TR criteria for PD diagnosis. All subjects were administered PAX (10 mg/day) for 4 weeks, and PD severity was assessed using the Panic and Agoraphobia Scale (PAS) at baseline and at 2 and 4 weeks after initiation of treatment. Plasma PAX concentration was determined by high-performance liquid chromatography. Serotonin transporter gene-linked polymorphic region (5-HTTLPR) variants and the -1019C/G promoter polymorphism of the serotonin 1A receptor (5-HT(1A)) gene were determined by PCR analysis. RESULTS: Multiple regression analysis revealed that the plasma concentrations of PAX, 5-HTTLPR genotype, and -1019C/G 5-HT(1A) gene polymorphism were significant factors affecting clinical response to PAX (reduction ratio of PAS score) at 2 weeks after the initiation of pharmacotherapy. The -1019C/G 5-HT(1A) gene promoter polymorphism, PAS score at baseline, and adverse effects were found to be the significant factors affecting clinical response to PAX at 4 weeks after initiation of pharmacotherapy. CONCLUSION: The present study revealed that plasma concentration of PAX, 5-HTTLPR genotype, -1019C/G 5-HT(1A) genotype, PAS score at baseline, and adverse effects may influence the therapeutic response to PAX in patients with PD.

Platelet [³H] paroxetine binding in female patients with borderline personality disorder and their sisters.

Paroxetine binding could be a vulnerability marker for traits associated with borderline personality disorder (BPD). To study this relationship, we examined [³H] paroxetine binding in female patients with BPD and their sisters. The sample consisted of 54 sibling pairs in which a proband met criteria for BPD. All subjects were given the Diagnostic Interview for Borderlines, revised (DIB-R), the Diagnostic Assessment for Personality Pathology: Brief Questionnaire (DAPP-BQ), the Barratt Impulsivity Scale (BIS), the Affective Lability Scale (ALS), the Hamilton Rating Scale for Anxiety (HAM-A), the Hamilton Rating Scale for Depression (HAM-D), and the Symptom Checklist-90, revised (SCL-90-R). All subjects had platelets assayed for [³H] paroxetine binding. There were no significant differences between probands and sisters, but both groups scored significantly lower than a previously studied control group on B(max). There were no differences on Kd. Neither B(max) nor K(d) was related to most trait or symptomatic measures. Paroxetine binding could reflect endophenotypes common to BPD probands and their first-degree relatives.

Association between plasma paroxetine concentration and changes in plasma brain­derived neurotrophic factor levels in patients with major depressive disorder.

Recent studies have implicated brain­derived neurotrophic factor (BDNF) in the pathophysiology of depression and in the activities of antidepressant drugs. Serum BDNF levels are lower in depressed patients and increase in response to antidepressant medications; however, no studies have examined the association between plasma concentrations of antidepressant drugs and plasma BDNF levels. We assessed plasma BDNF levels and paroxetine concentrations in 45 patients with major depression who were being treated with paroxetine. Plasma samples were collected between 10:00 h and 12:00 h at baseline and after 1, 2 and 6 weeks of treatment. The BDNF level and paroxetine concentration of each sample were measured via enzyme immunoassay and high­performance liquid chromatography, respectively. Plasma BDNF levels increased after 2 and 6 weeks of paroxetine treatment. Plasma BDNF levels were significantly lower in men than in women. Changes in plasma BDNF level were correlated with plasma drug concentration after 2 (r = 0.309, p < 0.05) and 6 weeks (r = 0.329, p < 0.05) but not correlated with plasma drug concentration after 1 week (r = 0.284, ns). Multiple regression analysis confirmed that this change was only significantly correlated with plasma paroxetine concentration after 2 (standardised beta = 0.343, p < 0.05) and 6 weeks (standardised beta = 0.375, p < 0.05). These results suggest that paroxetine treatment increases plasma BDNF levels and that plasma paroxetine levels play an important role in changes in plasma BDNF levels.

Inverse correlation between clinical response to paroxetine and plasma drug concentration in patients with major depressive disorders.

OBJECTIVE: There are few data concerning a clear relationship between the clinical effect of paroxetine and plasma drug concentrations, although therapeutic ranges have been established for some tricyclic antidepressants. METHODS: In this study, 120 patients with major depressive disorders were treated with 10-40 mg/day of paroxetine for 6 weeks, and a total of 89 patients completed the protocol. A clinical evaluation using the Montgomery-Asberg Depression Rating Scale (MADRS) was performed at 0, 1, 2, 4 and 6 weeks. RESULTS: Significant correlations were found between the plasma concentrations of paroxetine and the percentage improvement in the total MADRS scores (r = -0.282, p < 0.01) and the final MADRS scores at 6 weeks (r = 0.268, p < 0.05). The conventional receiver-operating-characteristic curve showed the fraction of true positive results and false negative results for various cut-off levels of paroxetine concentration for response and remission. The thresholds for both response and remission that gave the maximal sensitivity and specificity for paroxetine concentrations were 64.2 ng/ml. CONCLUSIONS: These results suggest that plasma paroxetine concentrations are negatively associated with improvement and that response occurs at the upper threshold of 64.2 ng/ml of paroxetine. These findings should be replicated with a larger patient sample.

Pitfalls and challenges associated with phenoconversion in forensic toxcicology.

PURPOSE: In recent years, several publications have demonstrated the interest and the usefulness of pharmacogenetics in forensic toxicology. However, this approach remains namely focused on DNA-based phenotype, which may potentially lead to misinterpretation. Other determinants such as co-medication or physiological parameters may also impact the phenotype. This article aims to highlight the importance of considering such determinants in forensic toxicology, through the original case of a heroin-related fatality. METHOD: Ethanol concentration determination and toxicological screening were performed using gas chromatography with flame ionization detection, liquid chromatography with diode array detection and gas chromatography with mass spectrometry detection. CYP2C19 and CYP2D6 genotypes were determined by Taqman® real-time PCR analyses. RESULTS: Femoral blood analyses revealed the presence of ethanol, morphine, codeine, venlafaxine (VEN), O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV), paroxetine, and risperidone. 6-acetylmorphine was also identified in urine. VEN, paroxetine and risperidone were quantified at supra-therapeutic or toxic blood concentrations. NDV was not quantified. The metabolic ratio of VEN (ODV to VEN) was exceptionally low (about 0.7). Pharmacogenetics testing showed that the patient was heterozygous for the CYP2C19*2 loss-of-function allele, which predict an intermediate metabolism for CYP2C19. None of the deficient CYP2D6 alleles investigated were identified. Those results suggest an extensive CYP2D6-metabolism phenotype. CONCLUSION: A discrepancy was seen between the results of the genomic evaluation and the observed metabolic ratio of VEN. This tends to exclude a genetic origin and lead us to formulate other hypotheses, such as phenoconversion that may have been induced by drug interaction involving patients' regular medications. Phenoconversion is as a complex phenomenon that leads to genotype-phenotype mismatch without any genetic abnormality particularly described for cytochromes P450 2D6 and 2C19. Although transient, phenoconversion can have a significant impact on the analysis and interpretation of genotype-focused clinical outcomes correlation and in forensic toxicology conclusions.