sertraline, Zoloft
Venlafaxine: in vitro inhibition of CYP2D6 dependent imipramine and desipramine metabolism; comparative studies with selected SSRIs, and effects on human hepatic CYP3A4, CYP2C9 and CYP1A2.

Ball SE, Ahern D, Scatina J, Kao J.

Drug Safety and Metabolism, Wyeth-Ayerst Research, Princeton, NJ 08543-8000, USA.

AIMS: In order to anticipate drug-interactions of potential clinical significance the ability of the novel antidepressant, venlafaxine, to inhibit CYP2D6 dependent imipramine and desipramine 2-hydroxylation was investigated in human liver microsomes. The data obtained were compared with the selective serotonin re-uptake inhibitors, fluoxetine, sertraline, fluvoxamine and paroxetine. Venlafaxine's potential to inhibit several other major P450 s was also studied (CYP3A4, CYP2D6, CYP1A2). METHODS: Ki values for venlafaxine, paroxetine, fluoxetine, fluvoxamine and sertraline as inhibitors of imipramine and desipramine 2-hydroxylation were determined from Dixon plots of control and inhibited rate data in human hepatic microsomal incubations. The inhibitory effect of imipramine and desipramine on liver microsomal CYP2D6 dependent venlafaxine O-demethylation was determined similarly. Venlafaxine's IC50 values for CYP3A4, CYP1A2 CYP2C9 were determined based on inhibition of probe substrate activities (testosterone 6 beta-hydroxylation, ethoxyresorufin O-dealkylase and tolbutamide 4-hydroxylation, respectively). RESULTS: Fluoxetine, paroxetine, and fluvoxamine were potent inhibitors of imipramine 2-hydroxylase activity (Ki values of 1.6 +/- 0.8, 3.2 +/- 0.8 and 8.0 +/- 4.3 microM, respectively; mean +/- s.d., n = 3), while sertraline was less inhibitory (Ki of 24.7 +/- 8.9 microM). Fluoxetine also markedly inhibited desipramine 2-hydroxylation with a Ki of 1.3 +/- 0.5 microM. Venlafaxine was less potent an inhibitor of imipramine 2-hydroxylation (Ki of 41.0 +/- 9.5 microM) than the SSRIs that were studied. Imipramine and desipramine gave marked inhibition of CYP2D6 dependent venlafaxine O-demethylase activity (Ki values of 3.9 +/- 1.7 and 1.7 +/- 0.9 microM, respectively). Venlafaxine did not inhibit ethoxyresorufin O-dealkylase (CYP1A2), tolbutamide 4-hydroxylase (CYP2C9) or testosterone 6 beta-hydroxylase (CYP3A4) activities at concentrations of up to 1 mM. CONCLUSIONS: It is concluded that venlafaxine has a low potential to inhibit the metabolism of substrates for CYP2D6 such as imipramine and desipramine compared with several of the most widely used SSRIs, as well as the metabolism of substrates for several of the other major human hepatic P450s.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9205822&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
The degree of inhibition of dopaminergic neurons in the ventral tegmental area induced by selective serotonin reuptake inhibitors is a function of the density-power-spectrum of the interspike interval.

Di Mascio M, Esposito E.

Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri, Sud, Santa Maria Imbaro (Chieti), Italy.

Electrophysiological techniques and computational methods were used to study the effect of the selective serotonin reuptake inhibitors fluvoxamine, paroxetine and sertraline on the basal activity of dopamine neurons in the ventral tegmental area. Acute injection of fluvoxamine, paroxetine and sertraline (20-1280 microg/ kg, i.v.) caused a dose-dependent inhibition of some ventral tegmental area DA neurons but it did not affect the basal firing rate of other DA cells. A Fast-Fourier-Transformation based analysis of the basal activity of 32 ventral tegmental area DA neurons showed a positive correlation between the value of a functional operator (psi) equivalent to the density-power-spectrum of the signals and the degree of selective serotonin reuptake inhibitor-induced inhibition of ventral tegmental area DA cells. All ventral tegmental area DA neurons sampled were subdivided into two subclasses: (A) neurons with no changes in their basal firing rate and (B) neurons showing an approximately linear inhibitory effect in response to selective serotonin reuptake inhibitors. The neurons belonging to subclass A showed a more regular behavior of the interspike interval functions corresponding to lower values detected by the functional operator psi, whereas the neurons belonging to subclass B showed a less regular behavior of interspike interval functions corresponding to higher psi values detected by the same functional operator. Fluvoxamine, paroxetine and sertraline also caused a dose-dependent increase of the percentage of spikes occurring in bursts in neurons belonging to subclass A (low values of psi), whereas the mean basal firing rate of these cells was not affected. It is suggested that this difference in density-power-spectrum could reflect the asymmetry of serotonergic input to the ventral tegmental area DA neurons, and the differential effects of selective serotonin reuptake inhibitors on these neurons might depend on the characteristics of their basal firing mode.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9219958&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
An open study of the effects of sertraline on adolescent major depression.

McConville BJ, Minnery KL, Sorter MT, West SA, Friedman LM, Christian K.

Department of Psychiatry, University of Cincinnati Medical Center, Ohio, USA.

This open study investigated the effects of sertraline in treating 13 adolescents, ages 12 to 18, who were hospitalized for treatment of a major depressive episode. The sample included 7 adolescents with nonendogenous depression and 6 with endogenous depression, as diagnosed by both Research Diagnostic Criteria (RDC) and Kiddie-SADS-P DSM-III-R endogenous subtype criteria. These patients were followed for an inpatient length of stay ranging from 9 to 38 days (mean 19 days), with later outpatient follow-up for a total of 12 weeks. Measures of depression were found to improve significantly, including suicidal ideation and most of the DSM-III-R symptoms of major depression. Sertraline (mean 110 mg or 1.96 mg/kg daily) significantly decreased scores on the 24-item Hamilton Depression Rating Scale and Montgomery-Asberg Depression Rating Scale from premedication baseline to treatment week 12, and also between weeks 1 (after a large week 1 improvement, presumably due to nondrug effects) and 12. There was a small but significant improvement on the Children's Global Assessment Scale between baseline and week 12, but the Family Global Assessment Scale showed no significant change; neither global assessment scale showed significant effects between weeks 1 and 12. Sleep disturbance was common (69%) after 12 weeks of treatment, but clinically significant improvements in sleep patterns were also observed. This open-label prospective study suggests that sertraline might be useful in treating adolescents with major depression. Adverse effects, mainly insomnia and drowsiness, were relatively common but usually manageable. One patient developed mania after 8 days of sertraline treatment at a dose of 100 mg daily.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9231298&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Sertraline and desmethylsertraline in human breast milk and nursing infants.

Stowe ZN, Owens MJ, Landry JC, Kilts CD, Ely T, Llewellyn A, Nemeroff CB.

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA.

OBJECTIVE: The purpose of this study was to determine the concentrations of sertraline and desmethylsertraline in both human breast milk and infant serum. METHOD: Breast milk samples from 12 women were collected at specific time intervals after oral doses of sertraline (25-200 mg once daily). For 11 mother-infant pairs, maternal serum levels 24 hours after a dose and their infants' serum levels 2-4 hours after nursing were ascertained by high-performance liquid chromatography. RESULTS: Sertraline and desmethylsertraline were present in all breast milk samples, with a gradient from "fore" milk to "hind" milk. The highest concentrations of sertraline were observed in hind milk 7-10 hours after maternal dose. Increasing the maternal dose of sertraline resulted in increased breast milk concentrations of both sertraline and desmethylsertraline. Detectable concentrations of sertraline were found in three nursing infants and desmethylsertraline in six. No adverse effects of exposure were observed in any infant. CONCLUSIONS: Sertraline and desmethylsertraline were present in the breast milk of nursing women treated with sertraline. Concentrations were affected by aliquot of milk sampled, time after maternal dose, and maternal daily dose. The infants' serum concentrations detected were below the detection limit of most commercial laboratories. The presence of desmethylsertraline in six infants' samples underscores the importance of metabolite monitoring in determining infant exposure. Estimates of daily infant exposure can be determined after analysis of sertraline and desmethylsertraline concentrations from one full breast at maternal serum steady state. Future studies of breast milk and infant serum samples should address these issues.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9286185&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Influence of anxiolytic drugs on the effects of specific serotonin reuptake inhibitors in the forced swimming test in mice.

Da-Rocha MA Jr, Puech AJ, Thiebot MH.

Department of Pharmacology, Faculty of Medicine Pitie-Salpetriere, Paris, France.

This study aimed at investigating the effect of several selective serotonin reuptake inhibitors (SSRIs), given alone or in combination with anxiolytic drugs, on the time spent immobile in the forced swimming test in mice. The time spent immobile was dose-dependently reduced by acute administration of fluoxetine (4-64 mg/ kg, i.p.), paroxetine (1-32 mg/kg, s.c.) or sertraline (4-32 mg/kg, s.c.), indalpine was active at only one dose (16 mg/kg, i.p.), fluvoxamine (up to 16 mg/kg, i.p.) and citalopram (up to 4 mg/kg, i.p.) were inactive. The anti-immobility effect of fluoxetine (32 mg/kg) was antagonized by an acute co-administration of all anxiolytics tested, the GABAA/BZD receptor agonists, diazepam (2 mg/kg, i.p.), chlordiazepoxide (8 mg/kg, i.p.), lorazepam (0.125 mg/kg, i.p.), triazolam (0.06 mg/kg, i.p.) and alpidem (8 mg/kg, i.p.) and the 5-HT1A receptor partial agonist, buspirone (0.5 mg/kg, s.c.). The sedative neuroleptic, thioridazine (4 mg/kg, i.p.), was also found to counteract the effect of fluoxetine. Lorazepam, triazolam and buspirone also reversed the anti-immobility effect of paroxetine and sertraline, while diazepam and chlordiazepoxide did not. Alpidem reduced the effect of sertraline but not paroxetine, whereas the reverse was found with thioridazine. These data indicate that the influence of anxiolytics on the action of SSRI antidepressants is variable, depending on both the SSRI and the anxiolytic considered. The co-administration of the GABAA/BZD receptor antagonist, flumazenil (16 mg/kg, i.p.), with behaviourally inactive doses of fluoxetine, fluvoxamine and citalopram, resulted in a reduction of immobility. The 5-HT1A receptor antagonist, (+)-WAY 100135 (8 mg/kg, s.c.), combined with a subactive dose of fluoxetine, but not with fluvoxamine, significantly reduced the time spent immobile. The 5-HT2A receptor antagonist, ketanserin (32 mg/kg, s.c.), which reduced immobility when given alone, did not interfere with fluoxetine given at a subactive dose. Although non-specific sedative and/or motor effects cannot be totally ruled out, these results suggest that pharmacodynamic interactions exist between various anxiolytics and SSRIs. These interactions probably involve both serotonergic and GABAergic processes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9305412&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
The role of serotonin re-uptake inhibitors in preventing recurrent unexplained childhood syncope -- a preliminary report.

Lenk M, Alehan D, Ozme S, Celiker A, Ozer S.

Department of Paediatrics, Hacettepe University, Faculty of Medicine, Ankara, Turkey.

To assess the efficacy of a serotonin re-uptake inhibitor, sertraline hydrochloride, in preventing recurrent neurocardiogenic syncope, we studied 15 patients (10 female; mean age 12.9 +/- 2 years) with positive head-upright tilt test and resistant to standard pharmacotherapy, atenolol or disopyramide. The patients were given 50 mg oral sertraline hydrochloride daily for 6 weeks. Intolerance to the drug was seen in 3 patients and 2 had syncopal episodes during the therapy. A head-upright tilt table test was then repeated in 10 patients. Six were tilt negative and asymptomatic over a mean follow up period of 7 +/- 3 months while four remained tilt positive: two experienced marked hypotension and bradycardia, characterized as mixed type syncope, and two had cardiac asystole, lasting > 10 s, during tilting, thereby exhibiting a cardio-inhibitory response. CONCLUSION: Sertraline hydrochloride may be useful in preventing recurrent neurocardiogenic syncope resistant to standard pharmacotherapy but careful clinical studies are essential before such a treatment strategy can be recommended since serious asystole could develop.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9365060&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Effect of sertraline on plasma nortriptyline levels in depressed elderly.

Solai LK, Mulsant BH, Pollock BG, Sweet RA, Rosen J, Yu K, Reynolds CF 3rd.

Mental Health Clinical Research Center for the Study of Late-Life Mood Disorders, University of Pittsburgh School of Medicine, Pa., USA.

BACKGROUND: Several serotonin selective reuptake inhibitors have been reported to be inhibitors of the cytochrome P450 2D6 (CYP2D6). Thus, they may increase the plasma level of secondary amine tricyclic antidepressants, which are predominantly metabolized through this enzyme. Except for a few case reports, no clinical data document the degree of this drug-drug interaction in elderly depressed patients. METHOD: We systematically examined this interaction by determining the change in plasma nortriptyline levels in 14 elderly depressed patients in whom sertraline was added to nortriptyline. RESULTS: After addition of 50 mg/day of sertraline, the median increase in plasma nortriptyline level over baseline was 2% (range, -26% to 117%; p = .30). In 2 patients (14%), there was an increase of 50% or more. For patients taking higher sertraline doses (N = 7; 100 or 150 mg/day), the median increase in plasma nortriptyline level over baseline was 40% (range, -12% to 239%; p = .08). CONCLUSION: Overall, a modest effect of sertraline was observed on nortriptyline metabolism in these elderly depressed patients. This is consistent with prior reports of a weak inhibition of CYP2D6 by sertraline in vitro and in young healthy volunteers. However, some patients showed a change in plasma nortriptyline level that would be considered clinically significant. Thus, careful monitoring of plasma nortriptyline levels is recommended in all patients treated with a combination of nortriptyline and sertraline.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9375595&dopt=Abstract sertraline Zoloft