Sertraline concentrations in pregnant women are steady and the drug transfer to their infants is low.

PURPOSE: Sertraline, a selective serotonin reuptake inhibitor (SSRI), is one of the most commonly used antidepressant during pregnancy. Plasma sertraline concentrations vary markedly between individuals, partly explained by variability in hepatic drug metabolizing cytochrome P450-enzyme activity. Our purpose was to study the variability in the plasma concentrations in pregnant women and the passage to their infants. METHOD: Pregnant women with moderate untreated depression were recruited in 2016-2019 in Stockholm Region and randomized to treatment with sertraline or placebo. All received Internet-based cognitive behavior therapy as non-medical treatment. Sertraline plasma concentrations were measured around pregnancy weeks 21 and 30, at delivery, 1-month postpartum, in cord blood and at 48 h of age in the infant. The clinical course of the infants was followed. RESULTS: Nine mothers and 7 infants were included in the analysis. Median dose-adjusted sertraline concentration in second trimester was 0.15(ng/mL) /(mg/day), in third trimester and at delivery 0.19 and 1-month postpartum 0.25, with a 67% relative difference between second trimester and postpartum. The interindividual variation was 10-fold. Median concentrations in the infants were 33% and 25% of their mothers', measured in cord blood, and infant plasma, respectively. Only mild and transient adverse effects were seen on the infants. CONCLUSION: Placental passage of sertraline to the infant is low. However, the interindividual variation in maternal concentrations during pregnancy is huge, why therapeutic drug monitoring might assist in finding the poor metabolizers at risk for adversity and increase the safety of the treatment. TRIAL REGISTRATION: The trial was registered at clinicaltrials.gov July 9, 2014 with TRN: NCT02185547.

The application of precision dosing in the use of sertraline throughout pregnancy for poor and ultrarapid metabolizer CYP 2C19 subjects: A virtual clinical trial pharmacokinetics study.

Sertraline is known to undergo changes in pharmacokinetics during pregnancy. CYP 2C19 has been implicated in the interindividual variation in clinical effect associated with sertraline activity. However, knowledge of suitable dose titrations during pregnancy and within CYP 2C19 phenotypes is lacking. A pharmacokinetic modeling virtual clinical trials approach was implemented to: (i) assess gestational changes in sertraline trough plasma concentrations for CYP 2C19 phenotypes, and (ii) identify appropriate dose titration strategies to stabilize sertraline levels within a defined therapeutic range throughout gestation. Sertraline trough plasma concentrations decreased throughout gestation, with maternal volume expansion and reduction in plasma albumin being identified as possible causative reasons. All CYP 2C19 phenotypes required a dose increase throughout gestation. For extensive metabolizer (EM) and ultrarapid metabolizer (UM) phenotypes, doses of 100-150 mg daily are required throughout gestation. For poor metabolizers (PM), 50 mg daily during trimester 1 followed by a dose of 100 mg daily in trimesters 2 and 3 are required.

Gelatin microsphere coated Fe3O4@graphene quantum dots nanoparticles as a novel magnetic sorbent for ultrasound-assisted dispersive magnetic solid-phase extraction of tricyclic antidepressants in biological samples.

Gelatin microsphere-coated Fe3O4@graphene quantum dots (Fe3O4@GQD@GM) were designed and synthesized as a novel sorbent via ultrasonic-assisted dispersive magnetic solid-phase extraction (UA-DMSPE) method. The synthesized sorbent was identified and confirmed by FT-IR, XRD, VSM, and SEM techniques. UA-DMSPE was combined with corona discharge ion mobility spectrometry for trace determination of desipramine, sertraline, and citalopram. Effective parameters were considered and optimized. The proposed method, under optimal conditions, showed excellent linearity in different concentration ranges (2-700 ng mL-1, R2 > 0.995), repeatability (RSD < 5.1%), good sensitivity (LODs in the range 0.6-1.5 ng mL-1), high preconcentration factor (PF = 207-218), and acceptable relative recoveries (93.5-101.8%). Eventually, this method was used to determine tricyclic antidepressants in various biological samples. Schematic presentation of the microextraction and monitoring of TCAs by ultrasonic-assisted dispersive magnetic solid phase microextraction-ion mobility spectrometry producer.

Toxicity Profile, Pharmacokinetic, and Drug-Drug Interaction Study of Citalopram and Sertraline Following Oral Delivery in Rat: An LC-MS/MS Method for the Simultaneous Determination in Plasma.

The burden of depression and other mental disorders is on the rise globally, and successful treatment sometimes requires modifications of drugs and/or dose regimens. The development of novel analytical methods for the determination of antidepressant drugs in biological fluids is thus urgently required. Herein, a sensitive, robust, and rapid liquid chromatographic coupled tandem mass spectrometric method was developed and validated for the determination of citalopram (CIT) and sertraline (SER) in rat plasma after oral administration. The analytes of interest and internal standard (duloxetine (DUL)) were extracted from 100 µL of plasma with solid-phase extraction on an Oasis HLB cartridge followed by the separation with gradient elution with water containing 0.1% formic acid and acetonitrile on an Agilent Eclipse Plus ODS (4.6 × 100 mm, 3.5 µm) column at flow rate 0.2 mL min-1. The triple quadrupole mass spectrometry was applied via electrospray ionization source for detection. The fragmentation pattern of the protonated CIT, SER, and DUL was elucidated using multiple reaction monitoring of the transitions of m/z 325.2 to 109, 306.1 to 158.9, and 298.1 to 154.1 as [M + H]+ for CIT, SER, and DUL, respectively. The proposed method has been validated as per US-FDA bioanalytical guidelines in terms of linearity, accuracy, precision, matrix effects, stability, selectivity, and recovery. The method was linear over the concentration range of 1-2000 and 1-1000 ng mL-1 with the lower limit of detection of 0.12 and 0.19 ng mL-1 for CIT and SER, respectively. The interday and intraday precisions and accuracy expressed by the relative standard deviation and the relative standard error were both lower than 11.1% and 2.1%, respectively. The proposed method was successfully applied for the pharmacokinetics and drug monitoring studies of CIT and SER in rat plasma after a single oral dose of 120 mg kg-1 of CIT and SER. Coadministration of SER with CIT has affected the peak plasma concentrations, maximum plasma concentration time, area under the concentration-time curve, and oral clearance of CIT. Molecular modeling study showed that SER could competitively inhibit CYP2D6, the main enzyme involved in CIT metabolism. A possible drug-drug interaction in psychiatric patients undergoing chronic SER and CIT treatment is therefore worthy of more attention in an effort to avoid side effects and serotonin syndrome.

Association of platelet function with depression and its treatment with sertraline in patients with chronic kidney disease: analysis of a randomized trial.

BACKGROUND: Major Depressive Disorder (MDD) can lead to adverse cardiovascular outcomes in patients with chronic kidney disease (CKD). Although one of the proposed mechanisms is heightened platelet activation, effects of MDD and its treatment with a selective serotonin reuptake inhibitor (SSRI) on platelet function in patients with CKD remain unclear. METHODS: In a pre-specified analysis, changes from baseline to 12 weeks in whole blood platelet aggregation (WBPA) and plasma levels of E-selectin and P-selectin on treatment with sertraline vs. placebo were investigated in 175 patients with CKD (estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73m2) and MDD (MDD+/CKD+) in a randomized, double-blind trial. Correlations between severity of depressive symptoms and platelet function were also analyzed. In order to investigate whether differences in platelet function were due to presence of CKD or MDD, we compared a subgroup of 49 MDD+/CKD+ patients with eGFR < 30 ml/min/1.73m2 to 43 non-depressed CKD controls (28 CKD with eGFR < 30 ml/min/1.73m2 [MDD-/CKD+] and 15 individuals with eGFR ≥90 ml/min/1.73m2 [MDD-/CKD-]. RESULTS: In MDD+/CKD+ individuals, there were no significant correlations between severity of depressive symptoms and platelet function, and no significant changes in platelet function after 12 weeks of treatment with sertraline vs. placebo. There were no significant differences in platelet function among MDD+/CKD+ patients and controls without MDD except in WBPA to 10 µM ADP (P = 0.03). WBPA to ADP was lower in the MDD-/CKD- group (8.0 Ω [5.0 Ω, 11.0 Ω]) as compared to the MDD-/CKD+ group (12.5 Ω [8.0 Ω, 14.5 Ω]), P = 0.01, and the MDD+/CKD+ group (11.0 Ω [8.0 Ω, 15.0 Ω]), P < 0.01. CONCLUSIONS: Heightened ADP-induced platelet aggregability was observed in CKD patients compared to controls with normal kidney function, regardless of presence of comorbid MDD, and treatment with sertraline did not affect platelet function. These findings suggest that increased platelet activation may not be a major contributory underlying mechanism by which depression may lead to worse cardiovascular outcomes in patients with CKD. Future studies should include positive MDD controls without CKD to confirm our findings. TRIAL REGISTRATION: ClinicalTrials.gov identifier numbers: CAST Study: NCT00946998 (Recruitment Status: Completed. First Posted: July 27, 2009. Results First Posted: January 30, 2018). WiCKDonASA Study: NCT01768637 (Recruitment Status: Completed. First Posted: January 15, 2013. Results First Posted: April 19, 2019).

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.

Effect of proton pump inhibitors on the serum concentrations of the selective serotonin reuptake inhibitors citalopram, escitalopram, and sertraline.

BACKGROUND: The selective serotonin reuptake inhibitors (SSRIs) citalopram, escitalopram, and sertraline are all metabolized by the cytochrome P-450 isoenzyme CYP2C19, which is inhibited by the proton pump inhibitors (PPIs) omeprazole, esomeprazole, lansoprazole, and pantoprazole. The aim of the present study was to evaluate the effect of these PPIs on the serum concentrations of citalopram, escitalopram, and sertraline. METHODS: Serum concentrations from patients treated with citalopram, escitalopram, or sertraline were obtained from a routine therapeutic drug monitoring database, and samples from subjects concomitantly using PPIs were identified. Dose-adjusted SSRI serum concentrations were calculated to compare data from those treated and those not treated with PPIs. RESULTS: Citalopram concentrations were significantly higher in patients treated with omeprazole (+35.3%; P < 0.001), esomeprazole (+32.8%; P < 0.001), and lansoprazole (+14.7%; P = 0.043). Escitalopram concentrations were significantly higher in patients treated with omeprazole (+93.9%; P < 0.001), esomeprazole (+81.8%; P < 0.001), lansoprazole (+20.1%; P = 0.008), and pantoprazole (+21.6%; P = 0.002). Sertraline concentrations were significantly higher in patients treated with esomeprazole (+38.5%; P = 0.0014). CONCLUSIONS: The effect of comedication with PPIs on the serum concentration of SSRIs is more pronounced for omeprazole and esomeprazole than for lansoprazole and pantoprazole, and escitalopram is affected to a greater extent than are citalopram and sertraline. When omeprazole or esomeprazole are used in combination with escitalopram, a 50% dose reduction of the latter should be considered.

Sertraline and breastfeeding: review and meta-analysis.

We examined the risk-benefit profile of sertraline treatment during breastfeeding, summarized the available literature on sertraline use, presented previously unpublished data, and performed a correlation-based meta-analysis of sertraline serum levels in mother-infant pairs. We conducted a search of PubMed and the National Library of Medicine LactMed database. We performed a meta-analysis to examine correlations between maternal and infant serum sertraline levels in the existing literature and in previously unpublished data. Of 167 available infant sertraline levels, 146 (87.4 %) were below the limit of detection, and the meta-analysis found no significant relationship between maternal and infant sertraline concentrations. Of 150 infant desmethylsertraline levels, 105 (70.0 %) were below the limit of detection. The correlation analysis revealed a significant relationship between maternal and infant desmethylsertraline concentrations, but this metabolite has only a fraction of the activity of sertraline. A significant relationship was also found for the sum of sertraline and desmethylsertraline, which stems primarily from the contribution of desmethylsertraline. Sertraline is a first-line drug for breastfeeding women due to documented low levels of exposure in breastfeeding infants and very few adverse events described in case reports. Based on the current literature, neither routine serum sampling nor genotyping is warranted for breastfeeding mothers taking sertraline and/or their infants. Routine pediatric care is appropriate monitoring for breastfed infants of women who take sertraline monotherapy.

A study of sertraline in dialysis (ASSertID): a protocol for a pilot randomised controlled trial of drug treatment for depression in patients undergoing haemodialysis.

BACKGROUND: The prevalence of depression in people receiving haemodialysis is high with estimates varying between 20 and 40 %. There is little research on the effectiveness of antidepressants in dialysis patients with the few clinical trials suffering significant methodological issues. We plan to carry out a study to evaluate the feasibility of conducting a randomised controlled trial in patients on haemodialysis who have diagnosed Major Depressive Disorder. METHODS/DESIGN: The study has two phases, a screening phase and the randomised controlled trial. Patients will be screened initially with the Beck Depression Inventory to estimate the number of patients who score 16 or above. These patients will be invited to an interview with a psychiatrist who will invite those with a diagnosis of Major Depressive Disorder to take part in the trial. Consenting patients will be randomised to either Sertraline or placebo. Patients will be followed-up for 6 months. Demographic and clinical data will be collected at screening interview, baseline interview and 2 weeks, and every month (up to 6 months) after baseline. The primary outcome is to evaluate the feasibility of conducting a randomised, double blind, placebo pilot trial in haemodialysis patients with depression. Secondary outcomes include estimation of the variability in the outcome measures for the treatment and placebo arms, which will allow for a future adequately powered definitive trial. Analysis will primarily be descriptive, including the number of patients eligible for the trial, drug exposure of Sertraline in haemodialysis patients and the patient experience of participating in this trial. DISCUSSION: There is an urgent need for this research in the dialysis population because of the dearth of good quality and adequately powered studies. Research with renal patients is particularly difficult as they often have complex medical needs. This research will therefore not only assess the outcome of anti-depressants in haemodialysis patients with depression but also the process of running a randomised controlled trial in this population. Hence, the outputs of this feasibility study will be used to inform the design and methodology of a definitive study, adequately powered to determine the efficacy of anti-depressants in patient on haemodialysis with depression. TRIAL REGISTRATION: ISRCTN registry ISRCTN06146268 and EudraCT reference: 2012-000547-27.

Parallel electromembrane extraction in a multiwell plate.

This paper describes the concept of parallel electromembrane extraction (Pa-EME) with flat membranes in a multiwell format for the first time. The setup is based on a multiwell plate and provided simultaneous and selective isolation, cleanup, and enrichment of several human plasma samples as well as LC-MS-compatible extracts within 8 min of extraction. Undiluted human plasma samples spiked with four antidepressant drugs were added to separate wells in the donor plate. Subsequently, the samples were extracted with Pa-EME. The four drugs migrated electrokinetically from undiluted human plasma through a flat polypropylene membrane impregnated with 2-nitrophenyl octyl ether, and were isolated into formic acid. Extraction time, extraction voltage, agitation rate, sample volume, and acceptor solution volume were all optimized with an experimental design. The optimal conditions were as follows: The agitation rate was 1,040 rpm, and an extraction voltage of 200 V was applied. The sample volume and acceptor solution volume was 240 and 70 µL, respectively. The extraction was continued for 8 min. Eventually, the extracts were analyzed by LC-MS/MS. The combination of Pa-EME with LC-MS/MS provided quantitation limits below the therapeutic level and reported relative standard deviations in the range 5-13 %. Linear calibration curves were obtained for all analytes, and the correlation coefficients were above 0.9974 in the range 1-400 ng mL(-1). The drug concentrations from two subjects treated with quetiapine and sertraline were successfully determined with Pa-EME combined with LC-MS/MS. Post-column infusion experiments demonstrated that Pa-EME provided extracts free from interfering matrix components.

The relation between dosage, serum concentrations, and clinical outcome in children and adolescents treated with sertraline: a naturalistic study.

OBJECTIVE: This naturalistic therapeutic drug monitoring (TDM) study aimed to evaluate the relationship between dosage, serum concentration, and clinical outcome in children and adolescents treated with the serotonin reuptake inhibitor sertraline for different indications. METHODS: Steady-state trough serum concentrations were analyzed in 90 subjects, treated with 25-200 mg sertraline per day. Therapeutic efficacy was assessed by the Clinical Global Impression Improvement subscale and side effects by the Udvalg for Kliniske Undersogelser-Side Effect Rating Scale. RESULTS: In the study population, children were administered higher body weight normalized daily doses than adolescents. The relationships between sertraline daily dosage and serum concentrations (rs = 0.67, P < 0.0001) as well as between body weight normalized daily doses and serum concentrations (r = 0.62, P < 0.0001) were linear. In the whole patient group, no correlation between serum concentrations and either the therapeutic effect or side effects could be observed, neither significant effects of gender, age, concomitant medications, or smoking habits. When analyzing just the patients with depression, those with side effects had significantly higher sertraline serum concentrations than those without (44.8 ng/mL versus 22.3 ng/mL, P = 0.01). In general, occurrence of side effects was significantly more frequent in patients with psychiatric comedication (37.9%) than those without (11.5%, P = 0.002). DISCUSSION: As this study has the typical limitations of naturalistic studies, the results should be interpreted cautiously. From the data, it is not possible to suggest an age-specific therapeutic window for children and adolescents. However, as the intraindividual variability of sertraline serum concentrations is known to be low, TDM may certainly help to predict serum concentrations after dose adjustment, to assess pharmacokinetic drug-drug interactions influencing serum concentrations and the patient's compliance, finally allowing for personalizing dose through TDM.

Human therapeutic plasma levels of the selective serotonin reuptake inhibitor (SSRI) sertraline decrease serotonin reuptake transporter binding and shelter-seeking behavior in adult male fathead minnows.

Selective serotonin reuptake inhibitors (SSRIs) represent a class of pharmaceuticals previously reported in aquatic ecosystems. SSRIs are designed to treat depression and other disorders in humans, but are recognized to elicit a variety of effects on aquatic organisms, ranging from neuroendocrine disruption to behavioral perturbations. However, an understanding of the relationships among mechanistic responses associated with SSRI targets and ecologically important behavioral responses of fish remains elusive. Herein, linking Adverse Outcomes Pathways (AOP) models with internal dosimetry represent potential approaches for developing an understanding of pharmaceutical risks to aquatic life. We selected sertraline as a model SSRI for a 28-d study with adult male fathead minnows. Binding activity of the serotonin reuptake transporter (SERT), previously demonstrated in mammals and fish models to respond to sertraline exposure, was selected as an endpoint associated with therapeutic activity. Shelter-seeking behavior was monitored using digital tracking software to diagnose behavioral abnormalities. Fish plasma levels of sertraline exceeding human therapeutic doses were accurately modeled from external exposure concentrations when pH influences on ionization and log D were considered. We observed statistically significant decreases in binding at the therapeutic target (SERT) and shelter-seeking behavior when fish plasma levels exceeded human therapeutic thresholds. Such observations highlights the strengths of coupling physiologically based pharmacokinetic modeling and AOP approaches and suggest that internal dosimetry should be monitored to advance an understanding of the ecological consequences of SSRI exposure to aquatic vertebrates.

Lack of interaction between sertraline and lamotrigine in psychiatric patients: a retrospective study.

INTRODUCTION: This study evaluates the pharmacokinetic interaction between sertraline and lamotrigine in psychiatric patients. METHODS: We identifi ed patients with at least 1 measurement of trough lamotrigine plasma concentration (at steady-state) during lamotrigine therapy and compared dose and plasma concentrations between patients who received lamotrigine with sertraline and patients who received lamotrigine without sertraline. RESULTS: The dose corrected concentration of lamotrigine in patients receiving lamotrigine in combination with sertraline was 60.4 µmol/L × 1,000/mg/day (SD: 31.1) (N = 7) compared to 51.1 µmol/L × 1 000/mg/day (SD: 27.6) (N = 44) in patients using lamotrigine without sertraline (p = 0.42). DISCUSSION: The slightly slower metabolism of lamotrigine in patients receiving lamotrigine with sertraline compared with those receiving lamotrigine alone is not believed to be of clinical signifi cance. However, due to the limited power, we may have overlooked a diff erence that could be clinically relevant.

Determination of sertraline in rat plasma by HPLC and fluorescence detection and its application to in vivo pharmacokinetic studies.

A simple, rapid, and sensitive HPLC method based on 9H-fluoren-9-ylmethyl chloroformate derivatization for the quantification of sertraline in rat plasma has been developed, requiring a plasma sample of only 0.1 mL, which was deproteinized and derivatized for 5 min in two single steps. The obtained derivative was stable at room temperature and was determined by HPLC using a fluorescence detector. The analytical column was a C(18) column and the mobile phase was acetonitrile and water (80:20, v/v). Calibration curves were linear in the range of 10-500 ng/mL. The limit of detection was approximately 3 ng/mL, and the lower limit of quantification was established at 10 ng/mL. The bias of the method was lower than 10%, and the within day as well as between day, relative standard deviations were lower than 12%. This analytical method was successfully applied to characterize sertraline pharmacokinetics in rats following intravenous (t(1/2) = 213 ± 48 min, Cl = 43.1 ± 8.7 mL/min, V(d) = 11560 ± 1861 mL) and oral (C(max) = 156 ± 76 ng/mL, t(max) = 63.8 ± 16.3 min) administration of 2 and 5 mg, respectively.

Population Pharmacokinetics of Sertraline in Healthy Subjects: a Model-Based Meta-analysis.

Sertraline pharmacokinetics is poorly understood and highly variable due to large between-subject variability with inconsistent reports for oral bioavailability. The study objective was to characterize sertraline pharmacokinetics by developing and validating a sertraline population pharmacokinetic (PK) model in healthy subjects using published clinical PK data. We carried a systematic literature search in PubMed in October 2015 and identified 27 pharmacokinetic studies of sertraline conducted in healthy adult subjects and reported in the English language. Sixty mean plasma concentration-time profiles made of 748 plasma concentrations following IV, single, and multiple oral doses ranging from 5 to 400 mg were extracted and analyzed for dose proportionality by a log-linear model and fitted to a 2-compartment pharmacokinetic model in NONMEM using a model-based meta-analysis (MBMA) approach. After a single oral dose, sertraline Cmax and AUC∞ increased with dose proportionally between 50 and 200 mg, and bioavailability increased nonlinearly with dose from 5 to 50 mg and plateaued afterwards while Tmax and t1/2 did not change with dose. Following multiple oral doses, Cmax and AUC∞ increased proportionally with dose across the entire dose range (5-200 mg) while bioavailability, Tmax, and t1/2 remained constant with dose. Sertraline absorption was time-dependent and best described by a sigmoidal Emax function of time after dose. Study findings indicate that sertraline PK is linear in healthy adult subjects at doses ≥ 50 mg, and exposures were nonlinear only after single oral doses < 50 mg likely due to reduced bioavailability.

Impact of CYP2C19 genotype on sertraline exposure in 1200 Scandinavian patients.

Sertraline is an (SSRI-)antidepressant metabolized by the polymorphic CYP2C19 enzyme. The aim of this study was to investigate the impact of CYP2C19 genotype on the serum concentrations of sertraline in a large patient population. Second, the proportions of patients in the various CYP2C19 genotype-defined subgroups obtaining serum concentrations outside the therapeutic range of sertraline were assessed. A total of 2190 sertraline serum concentration measurements from 1202 patients were included retrospectively from the drug monitoring database at Diakonhjemmet Hospital in Oslo. The patients were divided into CYP2C19 genotype-predicted phenotype subgroups, i.e. normal (NMs), ultra rapid (UMs), intermediate (IMs), and poor metabolisers (PMs). The differences in dose-harmonized serum concentrations of sertraline and N-desmethylsertraline-to-sertraline metabolic ratio were compared between the subgroups, with CYP2C19 NMs set as reference. The patient proportions outside the therapeutic concentration range were also compared between the subgroups with NMs defined as reference. Compared with the CYP2C19 NMs, the sertraline serum concentration was increased 1.38-fold (95% CI 1.26-1.50) and 2.68-fold (95% CI 2.16-3.31) in CYP2C19 IMs and PMs, respectively (p < 0.001), while only a marginally lower serum concentration (-10%) was observed in CYP2C19 UMs (p = 0.012). The odds ratio for having a sertraline concentration above the therapeutic reference range was 1.97 (95% CI 1.21-3.21, p = 0.064) and 8.69 (95% CI 3.88-19.19, p < 0.001) higher for IMs and PMs vs. NMs, respectively. CYP2C19 IMs and PMs obtain significantly higher serum concentrations of sertraline than NMs. Based on the relative differences in serum concentrations compared to NMs, dose reductions of 60% and 25% should be considered in PMs and IMs, respectively, to reduce the risk of sertraline overexposure in these patients.

Pharmacokinetic interactions between clozapine and sertraline in smokers and non-smokers.

Clozapine is an effective antipsychotic drug for treatment-resistant schizophrenia. Sertraline is a widely prescribed antidepressant and often concomitantly applied to address negative symptoms or depression. However, data on interactions between clozapine and sertraline are inconsistent. The aim of our study was to evaluate pharmacokinetic interactions between clozapine and sertraline analysing a therapeutic drug monitoring database of 1644 clozapine-medicated patients. We compared four groups: non-smokers (n = 250) and smokers (n = 326) with co-medication without known effects on cytochrome P450 and without sertraline, and non-smokers (n = 18) and smokers (n = 17) with sertraline co-medication. Measured and dose-corrected concentrations (C/D) of clozapine were compared between the groups using non-parametrical tests with a significance level of 0.05. Post hoc analyses included pairwise comparisons to account for smoking status. Although we detected significant differences for clozapine levels and C/D values between study groups (P < .001 for Kruskal-Wallis test in both cases), post hoc analyses revealed no differences for concentrations and C/D values of clozapine (P > .05 for Mann-Whitney U test in both cases). A negative correlation between the sertraline dose and the clozapine concentration was found in non-smokers (Spearman's rank correlation, rs = -0.535, P = .048). A potential pharmacokinetic interaction between clozapine and a standard therapeutic sertraline dose seems to be of minor clinical importance.

Magnetic solid-phase extraction coupled with UHPLC-MS/MS for four antidepressants and one metabolite in clinical plasma and urine samples.

Aim: Routine therapeutic drug monitoring is highly recommended since common antidepressant combinations increase the risk of drug-drug interactions or overlapping toxicity. Materials & methods: A magnetic solid-phase extraction by using C18-functionalized magnetic silica nanoparticles (C18-Fe3O4@SiO2 NPs) as sorbent was proposed for rapid extraction of venlafaxine, paroxetine, fluoxetine, norfluoxetine and sertraline from clinical plasma and urine samples followed by ultra-HPLC-MS/MS assay. Results: The synthesized C18-Fe3O4@SiO2 NPs showed high magnetization and efficient extraction for the analytes. After cleanup by magnetic solid-phase extraction, no matrix effects were found in plasma and urine matrices. The analytes showed LODs among 0.15-0.75 ng ml-1, appropriate linearity (R ≥ 0.9990) from 2.5 to 1000 ng ml-1, acceptable accuracies 89.1-110.9% with precisions ≤11.0%. The protocol was successfully applied for the analysis of patients' plasma and urine samples. Conclusion: It shows high potential in routine therapeutic drug monitoring of clinical biological samples.

Analysis of second-generation antidepressant drug, sertraline and its active metabolite, N-desmethyl sertraline in human plasma by a sensitive and selective liquid chromatography-tandem mass spectrometry method.

A precise, sensitive and high throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of sertraline (SER) and its primary metabolite, N-desmethyl sertraline (NDS) in human plasma is developed and validated. The analytes and the internal standard-fluoxetine were extracted from 300 microL aliquots of human plasma via liquid-liquid extraction in methyl tert-butyl ether. Chromatographic separation was achieved in a run time of 2.5 min on a Betasil C8 column (100 mm x 2 .1 mm, 5 microm) under isocratic conditions. Detection of analytes and IS was done by tandem mass spectrometry, operating in positive ion and multiple reaction monitoring (MRM) acquisition mode. The protonated precursor to product ion transitions monitored for SER, NDS and IS were m/z 306.2-->159.0, 292.1-->159.0 and 310.6-->148.4, respectively. The method was fully validated for its sensitivity, selectivity, linearity, accuracy and precision, matrix effect, stability study and dilution integrity. A linear dynamic range of 0.5-150 ng/mL was established for both the analytes with mean correlation coefficient (r) of 0.9993 and 0.9980, respectively. The intra-batch and inter-batch precision (%CV) across five quality control levels was

Pharmacokinetics of sertraline across pregnancy and postpartum.

Insufficient data inform dosing of antidepressants and clinical monitoring for major depressive disorder (MDD) during the perinatal period. The objectives were to assess the pharmacokinetics of sertraline (SER) across pregnancy and postpartum. Participants treated with SER for MDD underwent serial sampling to measure steady-state concentrations of SER and norsertraline during the second and third trimesters and postpartum (total of 3 assessments). Blood was drawn before observed SER administration and 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours after administration. A sensitive high-performance liquid chromatography/mass spectrometric method for simultaneous determination of serum concentrations of SER and norsertraline was developed and validated. For each sampling period for SER, area under the serum concentration versus time curve, maximal serum concentration (Cmax), and the time at which Cmax occurred (Tmax) were determined. Of 11 women initially enrolled, 6 completed second- and third-trimester assessments, and 3 completed all 3 assessments (including the postpartum assessment). Mean changes on all pharmacokinetic parameters were nonsignificant between assessments, although there was a marked heterogeneity among individuals. Results were not significantly altered by incorporation of body weights into the analyses. The range of pharmacokinetic changes between individuals was broad, indicating heterogeneity regarding the impact of pregnancy on SER metabolism. Overall, lowest observed SER area under the curve and Cmax occurred in the third trimester (observed in 5 of 6 participants). Despite nonsignificant mean pharmacokinetic changes, the range of pharmacokinetic changes across pregnancy warrants careful monitoring of depressive symptoms in women with MDD in late pregnancy and further study.