sertraline, Zoloft
Evidence of the dual mechanisms of action of venlafaxine.

Harvey AT, Rudolph RL, Preskorn SH.

Psychiatric Research Institute and the Department of Psychiatry, University of Kansas School of Medicine, Wichita 67214-2878, USA. aharvey kumc.edu

BACKGROUND: Indirect evidence suggests that the antidepressant venlafaxine hydrochloride selectively inhibits serotonin (5-HT) uptake at low doses, whereas at high doses, it inhibits both 5-HT and norepinephrine (NE) uptake. We hypothesized that, in vivo, both high and low doses would inhibit the 5-HT uptake of platelets but that the higher dose would differentially blunt the pressor response to tyramine, a marker for NE uptake. METHODS: Healthy male volunteers aged 18 to 45 years received either 75 mg or 375 mg of venlafaxine hydrochloride per day, the 5-HT uptake inhibitor sertraline hydrochloride (50 mg/d), or the NE uptake inhibitor maprotiline hydrochloride (150 mg/d) (n = 8 for each of 4 treatment groups). Changes in platelet 5-HT uptake and the pressor response to intravenous tyramine were assessed following the initial dose and after 1 and 2 weeks of drug administration. RESULTS: Platelet 5-HT uptake was inhibited by venlafaxine across the dose range and by sertraline but not maprotiline. Inhibition was competitive, related to increases in affinity and not related to capacity. Steady-state drug levels were associated with a 5-HT uptake inhibition of 87% or more in subjects taking venlafaxine or sertraline. The pressor response to tyramine differentially distinguished maprotiline from sertraline and the low dose of venlafaxine but not from the high dose of venlafaxine. CONCLUSION: This study provides the first in vivo evidence in healthy humans that both 5-HT uptake and NE uptake inhibition are mechanisms of action sequentially engaged by venlafaxine over its clinically relevant dose range.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10807491&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Sertraline in the treatment of mixed anxiety and depression disorder.

Carrasco JL, Diaz-Marsa M, Saiz-Ruiz J.

Department of Psychiatry, Hospital Fundacion Jimenez Diaz, Universidad Autonoma, Av. Reyes Catolicos, 2, 28040, Madrid, Spain. jlcarrasco fjd.es

BACKGROUND: Mixed anxiety and depression disorder (MAD) has been recognized in ICD-10 as a diagnostic group including those anxious and depressed patients which do not fit sufficient criteria for any major axis I disorders. MAD is usually treated as a combination of anxiety and depression, although there are data indicating that selective serotonin reuptake inhibitors (SSRIs) might be active on both anxiety and depression. METHOD: 38 patients diagnosed of MAD according to ICD-10 criteria were treated with flexible doses of sertraline for 8 weeks. Benzodiazepines were not allowed during the trial. Efficacy was evaluated with the Clinical Global Impression (CGI) improvement scale and with Hamilton's depression and anxiety Scales. Personality scales, including the Cloninger's TCI and Eysenck's EPQ, were used to test the predictive value of personality traits in the response to treatment. RESULTS: Anxiety was reduced by 55% and depression by 60% in Hamilton scales. At week 8, 29 patients were considered responders (CGI 1 o 2). Two patients discontinued the trial, only one of them due to adverse events. The mean dose of sertraline was 83.4 mg/day. CONCLUSION: Sertraline showed an excellent tolerability in patients with mixed anxiety-depression disorder despite high levels of baseline anxiety. The response level was high and similar to that reported for patients with major depression. These results warrant further controlled trials to assess the efficacy of SSRIs in MAD.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10814773&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Synergistic effect of pramipexole and sertraline in the forced swimming test.

Maj J, Rogoz Z.

Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow.

The authors studied the effect of sertraline, one of selective serotonin reuptake inhibitors (SSRIs), and pramipexole, administered jointly, to male Wistar rats in the forced swimming test. Both those drugs were injected three times (24, 5 and 1 h before the test): sertraline at doses of 5 and 10 mg/kg ip, pramipexole at doses of 0.05, 0.1 and 0.3 mg/kg sc. Sertraline given separately was inactive in the test used. Pramipexole reduced the immobility time only at a dose of 0.3 mg/kg. Joint administation of both those drugs distinctly shorted the immobility time, that effect.being particularly strong at pramipexole, 0.3 mg/kg, and sertraline, 5 or 10 mg/kg. The obtained results indicate that sertraline--like the previously tested citalopram and fluoxetine--shows a synergistic effect when given with pramipexole in the forced swimming test.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10817524&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Antidepressant-induced sexual dysfunction during treatment with moclobemide, paroxetine, sertraline, and venlafaxine.

Kennedy SH, Eisfeld BS, Dickens SE, Bacchiochi JR, Bagby RM.

Department of Psychiatry, University of Toronto, Centre for Addiction and Mental Health, Ontario, Canada. sidney_kennedy camh.net

BACKGROUND: Recent reports suggest that adverse effects on sexual function occur in up to 50% of patients who are treated with selective serotonin reuptake inhibitor (SSRI) antidepressants. Previously cited low rates were more likely a function of underreporting than underoccurrence. There is less evidence about rates of dysfunction with serotonin-norepinephrine reuptake inhibitor (SNRI) and reversible inhibitor of monoamine oxidase A (RIMA) antidepressants. The purpose of this report is to evaluate disturbances in sexual drive/desire and arousal/orgasm in 107 patients who met criteria for major depressive disorder and received treatment with either moclobemide, paroxetine, sertraline, or venlafaxine. METHOD: All consenting eligible patients who met DSM-IV criteria for major depressive disorder completed the Sexual Functioning Questionnaire, version 1 (SFQ) and were assessed using the 17-item Hamilton Rating Scale for Depression (HAM-D) prior to and after 8 or 14 weeks of antidepressant therapy. Analyses were carried out to examine the effect of gender, drug type, pretreatment level of sexual dysfunction, and drug response on reported sexual dysfunction. RESULTS: Compared with women, men experienced a significantly greater level of drug-related impairment in drive/desire (p < .05), whereas there were no statistically significant differences in levels of arousal/orgasm impairment between men and women. The reported impairment in drive/desire items for men ranged from 38% to 50% and from 26% to 32% for women. No differences were found across the 4 antidepressants in men, whereas in women, rates of dysfunction were generally higher with sertraline and paroxetine, but only significantly so in comparison with moclobemide on some measures (p < .03). Rates of sexual dysfunction with venlafaxine tended to fall between those of SSRIs and the RIMA agent. An unexpected relationship was found between favorable drug response and a decreased level of drug-induced sexual dysfunction. CONCLUSION: Antidepressant-induced sexual dysfunction occurs in approximately 30% to 70% of patients who are treated with sertraline or paroxetine. Lower rates are reported with moclobemide and venlafaxine. Clinicians should evaluate the various aspects of sexual dysfunction before and during antidepressant therapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10830148&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Simultaneous determination of human plasma levels of four selective serotonin reuptake inhibitors by high-performance liquid chromatography.

Lucca A, Gentilini G, Lopez-Silva S, Soldarini A.

Istituto Scientifico Ospedale San Raffaele, Department of Neuropsychiatric Sciences, Milan, Italy.

A reversed-phase high-performance liquid chromatography (HPLC) method with fluorimetric detection, which allows the simultaneous determination of plasma concentrations of four selective serotonin reuptake inhibitors (SSRIs) is presented. Fluvoxamine, paroxetine, sertraline, and fluoxetine were extracted from plasma with ethyl acetate and then derivatized with dansyl chloride. The analytes were separated using Hypersyl ODS C18 (5 microm) 250 x 4.6 mm column (ThermoQuest, Runcorn, UK). For continuous gradient separation, the mobile phase consists of two eluents, acetonitrile and potassium phosphate buffer (10 mmol/L, pH 7.2) at total flow rate of 1.5 mL/min. Detection was carried out at lambda exc = 366 nm and lambda em = 490 nm. The authors found recoveries of 90% to 95% for fluvoxamine, 94% to 100% for paroxetine, 88% to 95% for sertraline, 93% to 100% for fluoxetine, and 97% to 100% for internal standard (nortriptyline). Imprecision of the method ranged from 2.5% to 8.9%. The assay was linear from 10 to 1500 ng/mL for sertraline, and from 5 to 1500 ng/mL for the other drugs. The authors conclude that this method is suitable for monitoring antidepressant therapy. In addition, the authors report the effects of adding paroxetine to fluvoxamine on plasma levels in a group of patients in combined drug therapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10850393&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Terfenadine-antidepressant interactions: an in vitro inhibition study using human liver microsomes.

Jurima-Romet M, Wright M, Neigh S.

Bureau of Drug Research, Therapeutic Products Directorate, Health Canada, Ottawa, Canada.

AIMS: Inhibition of the metabolism of terfenadine has been associated with torsades de pointes ventricular arrhythmias. The aim of this study was to assess in vitro the potency of the antidepressants nefazodone, sertraline and fluoxetine in inhibiting terfenadine biotransformation. METHODS: Human liver microsomes were incubated with terfenadine and the antidepressants at various concentrations. Formation of the two major metabolites of terfenadine was determined by h.p.l.c. RESULTS: The apparent Km for microsomes from four human livers was 11+/-5 and 18+/-3 microM (mean +/-s.e.mean) for the N-dealkylation and C-hydroxylation pathways, respectively. Nefazodone, sertraline and fluoxetine inhibited terfenadine N-dealkylation with K(i) values of 10+/-4, 10+/-3 and 68+/-15 microM respectively. Inhibition of the C-hydroxylation pathway yielded noncompetitive K(i) values of 41+/-4, 67+/-13 and 310+/-40 microM respectively. CONCLUSIONS: Nefazodone and sertraline were moderately weak in vitro inhibitors of terfenadine metabolism while fluoxetine was a very weak inhibitor. Clinically significant interaction of terfenadine is more likely with nefazodone than sertraline or fluoxetine since therapeutic plasma levels of nefazodone are comparatively higher.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10896409&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Therapeutic drug monitoring of sertraline: variability factors as displayed in a clinical setting.

Lundmark J, Reis M, Bengtsson F.

Department of Neuroscience and Locomotion, Linkoping University Hospital, Sweden.

This report describes sertraline pharmacokinetics derived from routine therapeutic drug monitoring (TDM) data. A high-performance liquid chromatographic method with ultraviolet detection was established for routine sertraline TDM, and 924 analyses were performed from April 1995 to May 1997. Extensive predefined inclusion/exclusion criteria were applied to increase the validity of scientifically evaluated data. Subsequently, 605 samples (65.5%) were excluded. The remaining 319 samples from 319 patients, representative of steady state trough specimens and accompanied by essential clinical information provided on request forms, were scrutinized. A pronounced interindividual variability was observed. Smokers had significantly lower concentration-to-dose (C/D) mean ratios of serum sertraline (s-sert) and its main metabolite desmethylsertraline (s-dsert) than nonsmokers. Higher s-sert and s-dsert C/D mean ratios were found in elderly patients than in adults aged less than 65 years. In a subset of 20 patients in whom repeated TDM analyses were performed, observed intraindividual sertraline TDM outcome variability was low. The results highlight sertraline TDM as a tool for individual dose optimization and evaluation of patient drug compliance as well as drug-drug interactions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10942186&dopt=Abstract sertraline Zoloft