Sertraline - isolation methods and quantitation in biological material. / Sertralina ­ metody izolacji i analizy ilosciowej w materiale biologicznym.

Sertraline (SRT) is a modern and relatively safe selective serotonin reuptake inhibitor often used in the treatment of depression. Monitoring the body levels of this drug and its active metabolite, N-desmethylsertraline (DSRT), permits optimizing the dosage and personalizing the treatment, especially in the case of severe adverse reactions or lack of response to the applied therapy. The determination of SRT and DSRT in diagnostic material, i.e., blood, plasma, urine and saliva, and also in biological material from deceased persons, requires a variety of sensitive and reliable analytical methods to determine both the total drug level (blood) as well as the level of the unbound form (saliva and urine). This paper presents a detailed literature review of the methods of SRT and DSRT isolation from biological material and analytical techniques used for their determination. These include extractive procedures such as solid phase extraction and microextraction as well as liquid-liquid extraction. We pay particular attention to the parameters taken into account during optimization of extraction, i.e., the effect of pH, type of solvent and composition of the solvents mixture, on washing various types of sorbents (hydrophobic, hydrophilic-lipophilic and ion exchange) and elution of analytes. We show the advantages and disadvantages of the extraction techniques in terms of efficiency and precision of extraction. We also discuss protein precipitation as one of the more recent methods of sample purification. In our presentation of the final determination techniques, i.e., HPLC, LC and GC, we focus on the type of detector (UV, nitric-phosphate, MS) as the basic factor determining the sensitivity, expressed as the limits of detection and quantification achieved by a given method.

Inhibition of the Serotonin Transporter Is Altered by Metabolites of Selective Serotonin and Norepinephrine Reuptake Inhibitors and Represents a Caution to Acute or Chronic Treatment Paradigms.

Previous studies of transgenic mice carrying a single isoleucine to methionine substitution (I172M) in the serotonin transporter (SERT) demonstrated a loss of sensitivity to multiple antidepressants (ADs) at SERT. However, the ability of AD metabolites to antagonize SERT was not assessed. Here, we evaluated the selectivity and potency of these metabolites for inhibition of SERT in mouse brain-derived synaptosomes and blood platelets from wild-type (I172 mSERT) and the antidepressant-insensitive mouse M172 mSERT. The metabolites norfluoxetine and desmethylsertraline lost the selectivity demonstrated by the parent compounds for inhibition of wild-type mSERT over M172 mSERT, whereas desvenlafaxine and desmethylcitalopram retained selectivity. Furthermore, we show that the metabolite desmethylcitalopram accumulates in the brain and that the metabolites desmethylcitalopram, norfluoxetine, and desvenlafaxine inhibit serotonin uptake in wild-type mSERT at potencies similar to those of their parent compounds, suggesting that metabolites may play a role in effects observed following AD administration in wild-type and M172 mice.

Long term sertraline effects on neural structures in depressed and nondepressed adult female nonhuman primates.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for mood and other disorders. However, their neural effects are difficult to study due to patient compliance and drug history variability, and rarely studied in those prescribed SSRIs for non-mood disorders. Here we evaluated SSRI effects on neural volumetrics in depressed and nondepressed monkeys. METHODS: 42 socially-housed cynomolgus monkeys were randomized to treatment balanced on pretreatment depressive behavior and body weight. Monkeys were trained for oral administration of placebo or 20 mg/kg sertraline HCl daily for 18 months and depressive and anxious behavior recorded. Volumes of neural regions of interest in depression were measured in magnetic resonance images and analyzed by 2 (depressed, nondepressed)×2 (placebo, sertraline) ANOVA. RESULTS: Sertraline reduced anxiety (p=0.04) but not depressive behavior (p=0.43). Left Brodmann's Area (BA) 32 was smaller in depressed than nondepressed monkeys (main effect of depression: p<0.05). Sertraline and depression status interacted to affect volumes of left Anterior Cingulate Cortex (ACC), left BA24, right hippocampus (HC), and right anterior HC (sertraline×depression interactions: all p's<0.05). In the Placebo group, depressed monkeys had smaller right anterior HC and left ACC than nondepressed monkeys. In nondepressed monkeys, sertraline reduced right HC volume, especially right anterior HC volume. In depressed monkeys sertraline increased left ACC volume. In nondepressed monkeys, sertraline reduced left BA24 volumes resulting in smaller BA24 volumes in nondepressed than sertraline-treated depressed monkeys. CONCLUSIONS: These observations suggest that SSRIs may differentially affect neural structures in depressed and nondepressed individuals.

Development and validation of an EI-GC/MS method for the determination of sertraline and its major metabolite desmethyl-sertraline in blood.

A sensitive and specific GC/MS method for the determination of sertraline and its main metabolite desmethyl-sertraline in whole blood has been developed, optimized and validated. Sample preparation included solid-phase extraction of both analytes and their derivatization with heptafluorobutyric anhydride (HFBA). Protriptyline was used as internal standard for the determination of both analytes. Limits of detection and quantification for both sertraline and desmethyl-sertraline were 0.30 and 1.00 µg/L, respectively. The calibration curves were linear within the dynamic range of each analyte (1.00-500.0 µg/L) with a correlation coefficient (R(2)) exceeding 0.991. Extraction efficiency ranged from 90.1(± 5.8)% to 95.4(± 3.0)% for sertraline, and from 84.9(± 8.2)% to 107.7(± 4.4)% for desmethyl-sertraline. The precision for sertraline and desmethyl-sertraline was between 3.6-5.5% and 4.7-7.2%, respectively, while the accuracy was in the range of -6.67% to 2.20% and -6.33% to 2.88% for sertraline and desmethyl-sertraline, respectively. The method was applied to real blood samples obtained from patients that follow sertraline treatment and also in cases of forensic interest. The developed method can be used in routine every day analysis by clinical and forensic laboratories, for pharmacokinetic studies, for therapeutic sertraline monitoring or for the investigation of forensic cases where sertraline is involved.

Development and validation of a HPLC method for the determination of sertraline and three non-chiral related impurities.

In this study, a screening on reversed-phase stationary phases (including C(8), C(18), CN, PEG and amide) was carried out in order to obtain an efficient HPLC method for the determination of sertraline and three of its more closely related synthetical and non-chiral impurities, without using ion-pair reagents. The best results in terms of both retention time and resolution of the target analytes were obtained with a Zorbax Bonus-RP column, which contains a polar amide group embedded in a C(14) alkyl chain. Once the most suitable stationary phase was chosen, the HPLC method was optimized by using a factorial design, evaluating three quantitative factors (column temperature, buffer pH and buffer concentration) in order to find the best conditions which maximize the resolution between impurities A and B (positional isomers) and minimize the total run time. The final HPLC conditions were set by means of a second experimental design, which allowed optimizing the effects of the buffer pH and the proportion of methanol in the mobile phase. The optimal conditions for simultaneously determining sertraline and its impurities, being baseline separated in less than 10 min, were finally obtained with Zorbax Bonus-RP column (150 mmx4.6mm, 5 microm), under isocratic conditions with phosphate buffer (pH 2.8; 10mM)-methanol (63:37, v/v) at 50 degrees C, at the flow-rate of 1.0 mL/min. UV detection was set at 220 nm. This method was successfully validated following ICH guidelines and it proved to be reliable for the determination of sertraline and related impurities in tablets as pharmaceutical forms.

A chemoenzymatic approach to enantiomerically pure amines using dynamic kinetic resolution: application to the synthesis of norsertraline.

Racemization catalyst 5 c and the enzyme Candida antarctica lipase B were combined in a one-pot dynamic kinetic resolution (DKR) of primary amines in which a wide range of amines were transformed to their corresponding amides in up to 95 % isolated yield and >99 % ee. The DKR protocol was applicable with either isopropyl acetate or dibenzyl carbonate as the acyl donor. In the latter case, release of the free amine from the carbamate products was carried out under very mild conditions. The racemization of (S)-1-phenylethylamine with several different Ru catalysts was also evaluated. Catalyst 5 c, of the Shvo type, was able to selectively racemize amines and was also compatible with the reaction conditions used for DKR. A racemization study of three different amines with varying electronic properties was also performed. Competitive racemization of a 1:1 mixture of the deuterated and non-deuterated amine was carried out with 5 c and a primary kinetic isotope effect was observed for all three amines, providing support that the rate-determining step is beta-hydride elimination. The chemoenzymatic DKR protocol was applied to the synthesis of norsertraline (16) by using a novel route starting from readily available 1,2,3,4-tetrahydro-1-naphthylamine (1 o).

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

[A comparative study of efficacy and safety of torin and zoloft].

Zoloft (sertraline) is an original antidepressant of "Pfizer", torin is a generic form of sertraline of Veropharm. An aim of the study was to compare clinical effectiveness and tolerability of original and generic drugs. Forty patients with moderate and severe depression without psychotic symptoms have been studied: 20 of them were treated with torin and 20 with zoloft. Patient's state has been assessed during 7 weeks (1 week--wash out and 6 week--active therapy) clinically and using the Hamilton and CGI scales on 7th, 14th, 21st, 28th and 42nd days. The clinical equivalence of torin and the original drug demonstrated. Torin had a distinct thymoanaleptic effect, the primary action of which addresses anxious affect. This drug was soft as well as zoloft.

Addition of risperidone to sertraline improves sertraline-resistant refractory depression without influencing plasma concentrations of sertraline and desmethylsertraline.

In the present study, we examined the efficacy of risperidone addition on sertraline-resistant depressed patients and the effects of risperidone on the metabolism of sertraline. Ten patients (M/F: 4/6, age: 54 +/- 10 years) met the DSM-IV criteria for major depressive disorder enrolled the study. Hamilton Dating Scale for Depression (HAM-D) scores (mean +/- SD) in all 10 patients significantly decreased from 19 +/- 4 (before risperidone addition) to 11 +/- 3 (4 weeks after risperidone addition). Plasma levels of sertraline and desmethylsertraline did not change after risperidone addition. Serum BDNF levels in responders to risperidone addition were changed from 8.1 +/- 2.7 ng/ml (before risperidone addition) to 11.5 +/- 0.9 ng/ml (4 weeks after risperidone addition); in contrast, those in nonresponders changed from 7.8 +/- 2.2 ng/ml (before risperidone addition) to 7.9 +/- 2.4 ng/ml (4 weeks after risperidone addition). These results suggest that the addition of risperidone to sertraline is effective and well tolerated for sertraline-resistant depressive patients, which is accompanied with the increase in serum BDNF levels in responders to the risperidone addition, and the addition of risperidone to sertraline does not seem to influence sertraline metabolism.

Serum concentrations of sertraline and N-desmethyl sertraline in relation to CYP2C19 genotype in psychiatric patients.

OBJECTIVE: To investigate the impact of CYP2C19 genotype on serum concentrations of sertraline and N-desmethyl sertraline in psychiatric patients. METHODS: Patients treated with sertraline (n = 121) were divided into six subgroups according to CYP2C19 genotype: CYP2C19*17/*17, CYP2C19*1/*17, CYP2C19*1/*1, CYP2C19*17/def, CYP2C19*1/def and CYP2C19def/def (def = allele encoding defective CYP2C19 metabolism, i.e. *2 and *3). Dose-adjusted serum concentrations were compared by linear mixed model analyses using the CYP2C19*1/*1 subgroup as reference. RESULTS: Subgroups carrying one or two alleles encoding defective CYP2C19 metabolism achieved significantly higher mean dose-adjusted serum concentrations of sertraline and N-desmethyl sertraline compared to the CYP2C19*1/*1 subgroup (P < 0.05). The effect of CYP2C19 genotype was expressed as 3.2-fold (sertraline) and 4.5-fold (N-desmethyl sertraline) higher dose-adjusted serum concentrations in the CYP2C19def/def subgroup compared to the CYP2C19*1/*1 subgroup (P < 0.01). The CYP2C19*17 allele had no influence on the dose-adjusted serum concentrations of sertraline and N-desmethyl sertraline. CONCLUSION: The significantly higher serum concentrations associated with alleles encoding defective CYP2C19 metabolism might be of relevance for the clinical outcome of sertraline treatment.

Changes in antidepressant metabolism and dosing across pregnancy and early postpartum.

OBJECTIVE: Little information about the disposition of individual antidepressant drugs during pregnancy has been published. We examined the dose requirements and level-to-dose (L/D) ratios of citalopram, escitalopram, and sertraline during pregnancy and after birth. METHOD: Women aged from 32 to 43 years with major depressive disorder according to the Structured Clinical Interview for DSM-IV Axis I Disorders participated in the study. Doses were charted across each week of gestation and post-partum. Samples were collected at 20, 30, and 36 weeks' gestation; delivery; and at 2 and 12 weeks postpartum. Plasma trough levels were obtained 8 to 15 hours after dose intake. Across pregnancy and postpartum, the mean dose-corrected plasma concentrations (L/D ratios) of S- and R-citalopram and S-sertraline, and the corresponding primary chiral metabolites S- and R-desmethylcitalopram and N-desmethylsertra-line were assessed. The samples were analyzed for concentrations of stereospecific parent drug and metabolites. The study was conducted from 2003 to 2006. RESULTS: Three women received citalopram, 2 women were treated with escitalopram, and 6 women received sertraline. In 4 of 5 subjects who received citalopram or escitalopram and 5 of 6 subjects who received sertraline, the L/D ratios for the stereoisomers of the parent compound and primary metabolite decreased between 20 weeks gestation and delivery, which reflects increased drug metabolism. By 12 weeks postpartum the L/D ratios were similar to those detected at 20 weeks gestation. CONCLUSIONS: Our cases illustrate that dose requirements frequently increase during the second half of pregnancy to offset increased drug turnover and maintain optimal pharmacotherapy. These findings replicate and extend earlier published data with other antidepressants. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00279370.

Sertraline and its metabolite desmethylsertraline, but not bupropion or its three major metabolites, have high affinity for P-glycoprotein.

The ATP-binding cassette (ABC) transporter protein subfamily B1 line (ABCB1) transporter P-glycoprotein (P-gp) plays an important role in the blood-brain barrier limiting a broad spectrum of substrates from entering the central nervous system. In the present study, the transport activity of P-gp for sertraline, desmethylsertraline, bupropion, and the major metabolites of bupropion, threo-amino alcohol (TB), erythro-amino alcohol (EB), and hydroxy metabolite (HB) was studied using an ATPase assay in expressed human P-gp membranes by measuring concentrations of inorganic P(i) in expressed human P-gp membranes. Verapamil was included as a positive control. The Michaelis-Menten equation was used for characterizing the kinetic data. Sertraline and desmethylsertraline showed high affinity for P-gp. The V(max)/K(m) values of sertraline (1.6 min(-1) x 10(-3)) and desmethylsertraline (1.4 min(-1) x 10(-3)) were comparable with that of verapamil (1.7 min(-1) x 10(-3)). Bupropion and its three metabolites showed very weak affinity for P-gp, with V(max)/K(m) values lower than 0.01 min(-1) x 10(-3). The results of the present study indicate that sertraline and desmethylsertraline have high affinity for P-gp, whereas bupropion and its three major metabolites TB, EB, and HB have very weak affinity for P-gp. These findings may help to explain observed drug-drug interactions among antidepressants.

Determination of sertraline and N-desmethylsertraline in human plasma by CE with LIF detection.

A method has been developed for the analysis of the antidepressant drug sertraline together with its main metabolite N-desmethylsertraline (DMS) in human plasma. It is based on CE with LIF detection (lambda = 488 nm). A SPE procedure is employed for biological sample pretreatment, followed by a derivatization step with FITC; reboxetine was the internal standard. The effect of CD, acetone and N-methyl-D-glucamine (GLC) as constituents of the BGE for analyte separation was investigated. The final BGE consisted of 20 mM carbonate buffer, pH 9.0, with 2.5 mM heptakis(2,6-di-O-methyl)-beta-CD, 50 mM GLC and 20% v/v acetone. With 30 kV applied voltage, the electrophoretic run is completed in 7.5 min. Linearity was observed in the plasma concentration range from 3.0 to 500 ng/mL for sertraline and 4.0 to 500 ng/mL for DMS. Extraction yield was >97.1%, precision - expressed as RSD% - was <3.7, accuracy (recovery) was >95.6%. Due to its sensitivity and selectivity, the method was suited for the analysis of plasma samples from patients undergoing therapy with sertraline.

Structure investigation of sertraline drug and its iodine product using mass spectrometry, thermal analyses and MO-calculations.

Sertraline (C(17)H(17)Cl(2)N) as an antidepressant drug was investigated using thermal analysis (TA) measurements (TG/DTG and DTA) in comparison with electron impact (EI) mass spectral (MS) fragmentation at 70eV. Semi-empirical MO-calculations, using PM3 procedure, has been carried out on neutral molecule and positively charged species. These calculations included bond length, bond order, bond strain, partial charge distribution and heats of formation (DeltaH(f)). Also, in the present work sertraline-iodine product was prepared and its structure was investigated using elemental analyses, IR, (1)H NMR, (13)C NMR, MS and TA. It was also subjected to molecular orbital calculations (MOC) in order to confirm its fragmentation behavior by both MS and TA in comparison with the sertraline parent drug. In MS of sertraline the initial rupture occurred was CH(3)NH(2)(+) fragment ion via H-rearrangement while in sertraline-iodine product the initial rupture was due to the loss of I(+) and/or HI(+) fragment ions followed by CH(2)NH(+) fragment ion loss. In thermal analyses (TA) the initial rupture in sertraline is due to the loss of C(6)H(3)Cl(2) followed by the loss of CH(3)-NH forming tetraline molecule which thermally decomposed to give C(4)H(8), C(6)H(6) or the loss of H(2) forming naphthalene molecule which thermally sublimated. In sertraline-iodine product as a daughter the initial thermal rupture is due to successive loss of HI and CH(3)NH followed by the loss of C(6)H(5)HI and HCl. Sertraline biological activity increases with the introduction of iodine into its skeleton. The activities of the drug and its daughter are mainly depend upon their fragmentation to give their metabolites in vivo systems, which are very similar to the identified fragments in both MS and TA. The importance of the present work is also due to the decision of the possible mechanism of fragmentation of the drug and its daughter and its confirmation by MOC.

Postpartum depression: a randomized trial of sertraline versus nortriptyline.

Symptom reduction and improvement in functioning in women with postpartum major depression treated with a tricyclic antidepressant versus a serotonin reuptake inhibitor were compared. The design was a double-blind, 8-week comparative trial of nortriptyline (NTP) versus sertraline (SERT) with a 16-week continuation phase. Women aged 18 to 45 years with postpartum major depression and a 17-item Hamilton Rating Scale for Depression score of 18 or more were eligible. Subjects were randomized to NTP or SERT and treated with a fixed-dosing strategy. Of 420 women interviewed, 109 eligible women received medication, and 95 provided follow-up data. The proportion of women who responded and remitted did not differ between drugs at 4, 8, or 24 weeks. Times to response and remission also did not differ. Psychosocial functioning improved similarly in both drug-treated groups of mothers. The total side effect burden of each drug was similar, although side effect profiles differed between agents. No clinical or demographic variables differentiated responders by drug. Women who were responders and remitters at week 8 could be identified earlier if they were treated with SERT than with NTP. Breast-fed infant serum levels were near or below the level of quantifiability for both agents.

Conversion of sertraline to N-methyl sertraline in embalming fluid: a forensic implication.

Zoloft (sertraline hydrochloride) is one of the antidepressant medications used to treat depression, obsessive-compulsive disorder, and social anxiety disorder. The practice of embalming a cadaver is common, yet it may create problems for forensic toxicologists if the case was not previously suspected to involve drug overdose. According to the Eschweiler-Clarke reaction, drugs containing a secondary amine group react with formaldehyde to give N-methyl derivatives. Sertraline has a secondary amine group; therefore, we predicted that it may react with formalin to give N-methyl derivatives. The stability of sertraline in formalin solution was studied at three different concentrations (5%, 10%, and 20%) and at three different pHs (3.0, 7.0, and 9.5) for a period of 30 days. Setraline and its degraded products were extracted by liquid-liquid extraction using chloroform, and the concentrated extracts were analyzed by gas chromatography-mass spectrometry using electron impact ionization mode. The rate of conversion is rapid at higher pH. Sertraline was totally converted to the N-methyl derivative after 30 days in 10% and 20% formalin solutions at neutral and basic conditions. Therefore, forensic toxicologists should be cautious when performing a death investigation if formalin solution is the only sample available for analysis. This work shows that analysis for parent drug or its N-methyl derivative may provide data that will reduce the likelihood of false negatives.

HPLC analysis of the second-generation antidepressant sertraline and its main metabolite N-desmethylsertraline in human plasma.

A liquid chromatographic method with ultraviolet detection was developed for the analysis of the recent antidepressant sertraline and its main metabolite N-desmethylsertraline in human plasma. The analytes were separated on a C8 reversed phase column, using a mobile phase composed of acetonitrile and a 12.3 mM, pH 3.0 phosphate buffer containing 0.1% triethylamine (35:65, v/v). Clomipramine was used as the Internal Standard. Using a solid phase extraction procedure with C2 cartridges high extraction yields (>94%) and good purification from matrix interference were obtained. Good linearity was obtained in the 7.5-250.0 ng mL(-1) range for sertraline and in the 10-500 ng mL(-1) range for N-desmethylsertraline. The analytical method was validated in terms of precision, extraction yield and accuracy. These assays gave R.S.D.% values for precision always lower than 3.9% and mean accuracy higher than 90%. Thanks to its good selectivity, the method proved to be suitable for the analysis of plasma samples from patients treated with sertraline as either monotherapy or polypharmacy.

Development of a solid phase extraction for 13 'new' generation antidepressants and their active metabolites for gas chromatographic-mass spectrometric analysis.

A solid phase extraction procedure (SPE) for 13 'new' antidepressants (venlafaxine, fluoxetine, viloxazine, fluvoxamine, mianserin, mirtazapine, melitracen, reboxetine, citalopram, maprotiline, sertraline, paroxetine and trazodone) together with eight of their metabolites (O-desmethylvenlafaxine, norfluoxetine, desmethylmianserine, desmethylmirtazapine, desmethylcitalopram, didesmethylcitalopram, desmethylsertraline and m-chlorophenylpiperazine) from plasma is optimized using HPLC-DAD as monitoring system. Special attention has been paid to the choice of washing and eluting solvent, resulting in a highly concentrated, clean and moisture free extract, also suitable for GC-MS. A total number of 10 sorbents (apolar, polymeric, ion-exchange and mixed mode) was evaluated. Based on recovery, reproducibility and absence of interfering substances the strong cation exchanger gave the best results. Recoveries were determined at low and high therapeutic and toxic levels and ranged between 70 and 109% for all compounds, except for trazodone (39%).

Relationship between release of platelet/endothelial biomarkers and plasma levels of sertraline and N-desmethylsertraline in acute coronary syndrome patients receiving SSRI treatment for depression.

OBJECTIVE: In a platelet/endothelial biomarker substudy of the Sertraline AntiDepressant Heart Attack Randomized Trial (SADHART), the authors sought to determine whether plasma levels of sertraline and its primary metabolite N-desmethylsertraline affect the release of platelet/endothelial biomarkers. METHOD: Fifty-five acute coronary syndrome patients with depression were randomly assigned to receive sertraline (N=23) or placebo (N=32). Twenty-six serial plasma samples collected at week 6 (N=12) and week 16 (N=14) were analyzed. Platelet factor 4 (PF4), beta-thromboglobulin (beta-TG), platelet/endothelial cell adhesion molecule 1 (PECAM-1), P-selectin, thromboxane B(2) (TxB(2)), prostacyclin (6-keto-PGF1alpha), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin were measured by enzyme-linked immunosorbent assay. Concentrations of sertraline and N-desmethylsertraline were determined by liquid chromatography with fluorescence detection in autologous samples. RESULTS: Strong, mostly time-dependent negative correlations were found for the plasma levels of sertraline and N-desmethylsertraline with PF4 (week 6: r=-0.69 and -0.33, respectively; week 16: r=-0.63 for both), beta-TG (week 6: r=-0.43 and -0.29; week 16: r=-0.66 and -0.57), PECAM-1 (week 6: r=-0.82 and -0.49; week 16: r=-0.60 for both), P-selectin (week 6: r=-0.82 and -0.49; week 16: r=-0.73 and -0.43), and TxB(2) (week 6: r=-0.66 and -0.59; and week 16: r=-0.64 and -0.41). Regression analysis revealed some borderline correlations for endothelial markers such as 6-keto- PGF1alpha and E-selectin and a positive correlation for VCAM-1. CONCLUSIONS: This is the first documented evidence that plasma release of platelet/endothelial biomarkers is directly related to the levels of sertraline and N-desmethylsertraline in acute coronary syndrome patients receiving SSRI treatment for depression. The clinical significance of these findings should be assessed in the setting of a randomized clinical trial.