sertraline, Zoloft
The effect of selective serotonin reuptake inhibitors (SSRIs) on the pharmacokinetics and metabolism of perazine in the rat.

Daniel WA, Syrek M, Haduch A, Wojcikowski J.

Polish Academy of Sciences, Institute of Pharmacology, Krakow. nfdaniel cyf-kr.edu.pl

The aim of this study was to investigate the effect of three selective serotonin reuptake inhibitors (SSRIs), fluoxetine, fluvoxamine and sertraline, on the pharmacokinetics and metabolism of perazine in a steady state in rats. Perazine (10 mg kg(-1), i.p.) was administered twice daily for two weeks, alone or jointly with one of the SSRIs. Concentrations of perazine and its two main metabolites (N-desmethylperazine and 5-sulfoxide) in the plasma and brain were measured 30 min and 6 and 12 h after the last dose of the drugs. Of the investigated SSRIs, fluoxetine and fluvoxamine significantly increased plasma and brain concentrations of perazine (up to 900% and 760% of the control value, respectively), their effect being most pronounced after 30 min and 6 h. Moreover, simultaneous increases in perazine metabolites concentrations and in the perazine/metabolite concentration ratios were observed. Sertraline elevated plasma and brain concentrations of perazine after 30 min. In-vitro studies with liver microsomes of rats treated chronically with perazine, SSRIs ortheir combinations showed decreased concentrations of cytochrome P-450 after perazine and a combination of perazine and fluvoxamine (vs control), and increased concentration after a combination of perazine and fluoxetine (vs perazine-treated group). Prolonged treatment with perazine did not significantly change the rate of its own metabolism. Chronic administration of fluoxetine or sertraline, alone or in a combination with perazine, accelerated perazine N-demethylation (vs control or perazine group, respectively). Fluvoxamine had a similar effect. The 5-sulfoxidation of perazine was accelerated by fluvoxamine and sertraline treatment, but the process was inhibited by administration of a combination of perazine and fluoxetine or fluvoxamine (vs control). Kinetic studies using control liver microsomes, in the absence or presence of SSRIs added in-vitro, demonstrated competitive inhibition of both N-demethylation and sulfoxidation by the investigated SSRIs. Sertraline was the most potent inhibitor of perazine N-demethylation but the weakest inhibitor of sulfoxidation. Results of in-vivo and in-vitro studies indicate that the observed interaction between perazine and SSRIs mainly involves competition for an active site of perazine N-demethylase and sulfoxidase. Moreover, increases in the concentrations of both perazine and metabolites measured, produced by the investigated drug combinations in-vivo, suggest simultaneous inhibition of another, yet to be investigated, metabolic pathway of perazine (e.g. aromatic hydroxylation).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11341361&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
A double-blind, placebo-controlled trial of sertraline in depressed adolescent alcoholics: a pilot study.

Deas D, Randall CL, Roberts JS, Anton RF.

Medical University of South Carolina, Center for Drug and Alcohol Programs, 67 President Street, PO Box 250861, Charleston, SC 29425, USA.

In order to preliminarily evaluate the efficacy, safety and tolerability of the serotonin reuptake inhibitor, sertraline, in the treatment of adolescents with a primary depressive disorder and a comorbid alcohol use disorder, a 12-week double-blind, placebo-controlled trial of sertraline plus cognitive behavior group therapy was conducted. Subjects were 10 outpatient treatment-seeking adolescents. Baseline assessment included the K-SADS, HAM-D, SCID, and the Time-Line Follow-Back. The HAM-D and the Time-Line Follow-Back were performed weekly thereafter. Both groups showed a significant reduction in depression scores with an average reduction between baseline and endpoint HAM-D score of -9.8 (F(1,8)=26.14, p</=0.001), although there were no significant group differences. There was an overall reduction in Percent Days Drinking (PDD); (F(1,8)=8.90, p<0.02) and in Drinks Per Drinking Day (DDD); (F(1,8)=20.48, p<0.002), however, there were no group differences. Depression responders tended to have higher baseline PDD than non-responders (F(1,8)=3.9, p=0.08) and change in HAM-D scores tended to correlate with change in PDD (r=0.57, p=0.09). Our data support that sertraline is safe and well tolerated in the treatment of adolescents with depression and alcohol dependence. Small sample size and cognitive behavior group therapy given to all subjects may limit the lack of group differences. Copyright 2000 John Wiley & Sons, Ltd.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12404308&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
The antidepressant effect of sertraline is not enhanced by dose titration: results from an outpatient clinical trial.

Schweizer E, Rynn M, Mandos LA, Demartinis N, Garcia-Espana F, Rickels K.

Department of Psychiatry, University of Pennsylvania, Philadelphia 19104-3309, USA.

A previous report suggested that 5 weeks of continued treatment with 20 mg of fluoxetine was approximately as effective as double-blind titration to a dose of 60 mg in patients who had failed to respond to 3 weeks of initial treatment at 20 mg. The current study was undertaken to evaluate whether 150 mg of sertraline was any more effective than 50 mg in treating depressed patients who were non-responders at 3 weeks. Ninety-one outpatients with DSM-IV major depressive disorder who had a 17-item Hamilton Depression Rating Scale (HAM-D) score > or = 18 were treated with open label sertraline for 3 weeks. Patients who did not achieve remission (defined as 17-item HAM-D total score < or = 8 by week 3) were then randomized to 5 more weeks of double-blind treatment with either 50 mg of sertraline or immediate titration to 150 mg of sertraline. Efficacy was assessed at each visit with the HAM-D, Clinical Global Impressions (CGI)-severity and improvement scale, and the Hopkins Symptom Checklist. There were no significant between-group differences in clinical or demographic features at baseline for the three treatment groups. After 3 weeks of open-label treatment, 16 patients were not randomized, of whom 11 (69%) met responder criteria. The remaining patients were randomized, double-blind, to 50 mg of sertraline (n = 37; HAM-D = 19.2 +/- 5.0) or 150 mg of sertraline (n = 38; HAM-D = 18.4 +/- 5.0). PROC-Mixed analyses found no significant difference in slopes for any outcome measure when comparing 50 mg and 150 mg sertraline treatment groups. At week 8 (LOCF), the overall remission rate (HAM-D < or = 8) for 3-week non-responders was 40%, with no statistically significant between-group difference for the 50 mg versus 150 mg doses of sertraline (P > 0.10). A completer analysis yielded similar results. Adverse events were mostly mild on both doses of sertraline and led to few treatment discontinuations. The results suggest that for most patients continued treatment with 50 mg dose of sertraline yields a rate of antidepressant response that is comparable to what is achieved by dose escalation from 50 mg to 150 mg of sertraline after 3 weeks of treatment. While some patients clearly benefit from higher doses, the results of the current study are consistent with the lack of any evidence for a dose-response curve with sertraline in the treatment of depression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11354108&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Electrochemical behaviour of sertraline at a hanging mercury drop electrode and its determination in pharmaceutical products.

Vela MH, Quinaz Garcia MB, Montenegro MC.

CEQUP/Departamento de Quimica-Fisica, Faculdade de Farmacia, Universidade do Porto, Portugal.

The electrochemical behaviour of sertraline at a hanging mercury drop electrode (HMDE) was described. Different voltammetric techniques, such as cyclic, linear sweep, differential pulse and square wave voltammetry, were used. Voltammograms were obtained at different pH values with a Britton-Robinson buffer solution used as supporting electrolyte. The best results were found by square wave voltammetry with electrodeposition at alkaline pH using a borate buffer with a pH = 8.2 for the samples, containing 12% (v/v) methanol. Under optimised conditions, a linear relationship between 2.33 x 10(-7) and 3.15 x 10(-6) M of sertraline with a limit of detection of 1.98 x 10(-7) M was obtained. The electrochemical method developed was applied to the determination of sertraline in pharmaceutical formulations. Recoveries were close to 100%, thus proving efficacy of the proposed method for the quantification of sertraline in commercial samples.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11371048&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Comparison of peripheral inhibitory effects of clomipramine with selective serotonin re-uptake inhibitors on contraction of vas deferens: in vitro and in vivo studies.

Seo KK, Kim SC, Lee MY.

Department of Urology and Physiology, College of Medicine, Chung-Ang University, Seoul, Korea.

PURPOSE: We compared the peripheral inhibitory effects of the tricyclic antidepressant clomipramine with those of various selective serotonin re-uptake inhibitors on the contractile response of the vas deferens. MATERIALS AND METHODS: The contractile responses of 17 circular smooth muscle strips of human vas deferens to 10-4 M. norepinephrine were observed in the absence and presence of clomipramine, and the selective serotonin re-uptake inhibitors fluoxetine, sertraline and paroxetine. The intraluminal pressure response of rat vas deferens to electrical stimulation of the hypogastric nerve was measured in 5 rats in the central plus peripheral effect group before and after the intravenous injection of 4.2 mg./kg. clomipramine or 8.3 mg./kg. sertraline. The pressure response to each agent was also observed after the transection of all proximal sympathetic input to the hypogastric nerve in 5 animals in the peripheral effect group. RESULTS: Clomipramine was about 100-fold more potent than sertraline, fluoxetine or paroxetine for inhibiting the norepinephrine induced contraction of human vasal muscle strips. The inhibitory effect of sertraline on rat intravasal pressure in the peripheral effect group was significantly lower than in the central plus peripheral effect group (p <0.05), while no significant difference was noted in the 2 groups regarding clomipramine. The effect of clomipramine was significantly higher than that of sertraline in the central plus peripheral and peripheral effect groups (p <0.01). CONCLUSIONS: Differences in potency of the peripheral inhibitory effects of the selective serotonin re-uptake inhibitors and clomipramine may contribute to their differential effects on delaying ejaculatory latency in patients with premature ejaculation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11371937&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Platelet inhibition by sertraline and N-desmethylsertraline: a possible missing link between depression, coronary events, and mortality benefits of selective serotonin reuptake inhibitors.

Serebruany VL, Gurbel PA, O'Connor CM.

Sinai Center for Thrombosis Research, Johns Hopkins University, Baltimore, MD, USA. Heartdrug aol.com

Recently, clinical depression has been identified as an independent risk factor for increased mortality in patients following acute coronary events. Although the underlying mechanisms of this link remain uncertain, increased platelet activity has been suggested but never proven as the mechanism responsible for this association. Sertraline hydrochloride is a selective serotonin reuptake inhibitor (SSRI), and is an effective antidepressant agent. Its major liver metabolite, N-desmethylsertraline (NDMS), is known to be neurologically inactive. We assessed the in vitro effects of escalating concentrations of sertraline and NDMS on human platelets by aggregometry in plasma and whole blood, by expression of major surface receptors with flow cytometry in washed cells and in the whole blood, and quantitatively by various platelet function analysers in healthy volunteers and patients with coronary artery disease. Pretreatment of blood samples with sertraline and NDMS resulted in a dose-dependent inhibition of platelet-rich plasma aggregation induced by 5 microM ADP (P =, 0.002), by 10 microM ADP (P = 0.0017), by collagen (P = 0.008), and by thrombin (P = 0.026). Whole blood platelet aggregability was also significantly reduced when induced by 20 microM ADP (P = 0.006), and by collagen (P = 0.01). Surface expression of CD9 (P = 0.004), GP Ib (P = 0.0001), GP IIb/IIIa (P = 0.007), VLA-2 (P = 0.01), P-selectin (P = 0.02), and PECAM-1 (P = 0.01), but not the vitronectin receptor, was also reduced in sertraline and NDMS pretreated washed platelets. Whole blood flow cytometry revealed significant inhibition of GP IIb/IIIa (P = 0.008), and P-selectin expression (P = 0.0001) in NDMS treated samples. Closure time was delayed for the collagen-ADP cartridge (P = 0.009), and for the collagen-epinephrin cartridge (P = 0.01), indicating platelet inhibition in whole blood under high shear conditions. Rapid platelet-function assay revealed a decreased (P = 0.002) ability of platelets to agglutinate fibrinogen-coated beads, suggesting GP IIb/IIIa inhibition. Both sertraline, and its neurologically inactive metabolite NDMS, exhibited significant dose-dependent inhibition of human platelets. The documented anti-platelet effects of sertraline and NDMS may be directly related to the mortality benefits of SSRIs after ischemic events including myocardial infarction and stroke. Copyright 2001 Academic Press.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11394937&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Effects of sertraline on regional neuropeptide concentrations in olfactory bulbectomized rats.

Bissette G.

Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4505, USA. gbissette psychiatry.umsmed.edu

Corticotropin-releasing factor (CRF) and thyrotropin-releasing hormone (TRH) are two neuropeptides that exhibit increased cerebrospinal fluid (CSF) concentrations during major depressive episodes while somatostatin (somatotropin-release inhibiting factor, SRIF) is decreased. Clinical and basic research findings indicate that clinically effective antidepressant therapies often normalize the indicators of CRF and TRH hypersecretion as well as SRIF hyposecretion. The olfactory bulbectomized (OBX) rat is used to screen potential antidepressant drugs for clinical efficacy. This model requires chronic administration of the antidepressant drug to normalize OBX-induced behaviors such as increased locomotion in a novel environment. This report describes the regional brain concentration changes in CRF, TRH and SRIF produced by OBX and demonstrates the ability of the selective serotonin re-uptake inhibitor and antidepressant drug, sertraline (10 mg/kg), to normalize certain of these alterations in regional neuropeptide concentrations as well as normalizing OBX-induced increases in locomotor activity. OBX-induced increases in CRF concentrations in the hypothalamus and bed nucleus of the stria terminalis were specifically and significantly decreased by sertraline. OBX-induced increases in TRH concentrations in the hypothalamus were reversed by sertraline. The concentration of SRIF was significantly reduced by OBX in the anterior caudate and the piriform cortex, but sertraline reversed these changes only in the anterior caudate.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11420095&dopt=Abstract sertraline Zoloft