sertraline, Zoloft
The effects of single and repeated anorectic doses of 5-hydroxytryptamine uptake inhibitors on indole levels in rat brain.

Caccia S, Anelli M, Codegoni AM, Fracasso C, Garattini S.

Istituto di Ricerche Farmacologiche, Mario Negri, Milan, Italy.

1. The effects of acute and repeated equiactive anorectic doses (ED50) of recently marketed 5-hydroxytryptamine (5-HT) uptake inhibitors on the content of brain indoles were compared in rats in relation to the brain regional concentrations of unchanged drug and its known active metabolite. 2. Single intraperitoneal (i.p.) doses of the anorectic ED50 of fluoxetine (35 mumol kg-1), fluvoxamine (60 mumol kg-1), paroxetine (20 mumol kg-1) and sertraline (49 mumol kg-1) slightly reduced brain 5-hydroxyindoleacetic acid (5-HIAA), with regional differences, this being compatible with 5-HT uptake blockade. Only fluvoxamine and sertraline significantly enhanced the content of 5-HT in the cortex. 3. The regional sensitivity to the acute effect of a given drug was not related to any preferential drug distribution, as these compounds distributed almost uniformly in the brain areas considered (cortex, striatum and hippocampus). 4. Repeating the same doses twice daily, i.p. for 14 days, however gave a different picture, fluvoxamine having little or no effect on the content of indoles and fluoxetine, paroxetine and sertraline lowering both 5-HT and 5-HIAA in all the brain regions compared to pair-fed control animals, 1 h after the last dose. 5. One week later only fluoxetine-treated animals still had reduced brain 5-HT, this probably being related to the accumulation of its main metabolite norfluoxetine in rat brain after chronic dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7693282&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
The effects of sertraline on nicotine self-administration and food-maintained responding in squirrel monkeys.

Sannerud CA, Prada J, Goldberg DM, Goldberg SR.

Behavioral Pharmacology and Genetics Section, NIDA-Intramural Research Program, Baltimore, MD 21224.

Recent reports suggested the involvement of serotonergic mechanisms in nicotine self-administration. The present study assessed the effects of sertraline, a selective serotonergic uptake inhibitor, on the reinforcing effects of i.v. nicotine (30 microgram/kg per injection) in squirrel monkeys responding under a fixed-ratio schedule. Nicotine (10-100 micrograms/kg per injection) produced a significant inverted U-shaped distribution on FR rate. Vehicle or sertraline (3, 6, 12, 24 mg/kg, p.o.) produced no changes in the response rates maintained by 30 micrograms/kg per injection i.v. nicotine, but sertraline produced non-significant increases response rates maintained by 10 micrograms/kg per injection nicotine and vehicle. In a separate group of monkeys, sertraline given in combination with i.m. doses of nicotine produced a significant dose-dependent decrease in responding maintained by food-pellet delivery. Thus, sertraline produced differential effects on response rates that may be related to (1) route of nicotine administration and (2) whether the behavior was maintained by nicotine or food. In addition, the results of the self-administration study suggest that sertraline would not disrupt well-maintained responding for nicotine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7705446&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Role of serotonin receptors in the effect of sertraline on feeding behaviour.

Grignaschi G, Samanin R.

Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.

The effect of sertraline, a serotonin (5-HT) uptake inhibitor, on 1 h food intake of food-deprived rats was studied in male rats treated intraperitoneally with 1 and 2.5 mg/kg metergoline, a 5-HT1 and 5-HT2 receptor antagonist, 0.5 mg/kg GR 38032F, a 5-HT3 receptor antagonist, or intracerebroventricularly with 6-hydroxy-dopamine to destroy catecholamine-containing neurons. The feeding-suppressant effect of 10 mg/kg sertraline was not significantly modified by any treatment. At 1 and 2.5 mg/kg metergoline did not significantly modify the reduction in total intake and meal size induced by sertraline in slightly-deprived rats whereas at 1 mg/kg the 5-HT receptor antagonist completely blocked the effect of 1.5 mg/kg d-fenfluramine, a 5-HT releaser and uptake inhibitor. In a runway test, metergoline at 1 but not 2.5 mg/kg significantly attenuated the effect of 10 mg/kg sertraline on starting speed in the first and second trial blocks. Both doses tended to attenuate the effect of sertraline on running speed but the interaction was not significant. The reduction in food intake induced by sertraline was antagonized only by 1 mg/kg metergoline in the last trial block. The bulk of these findings argues against an important role of 5-HT receptors in the effect of sertraline on feeding behaviour.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7870886&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Sertraline versus fluoxetine in the treatment of major depression: a combined analysis of five double-blind comparator studies.

Feiger AD, Flament MF, Boyer P, Gillespie JA.

Feiger Health Research Center, Wheat Ridge, Colorado 80033, USA. al feigerresearch.com

The aim of this study was to examine response and remission rates in outpatients treated with sertraline or fluoxetine who were suffering from two depression subtypes: anxious-depression and severe depression. Data were pooled from five double-blind studies comparing fluoxetine versus sertraline for the treatment of DSM-III-R or IV major depression. Clinical outcome was assessed using the Hamilton Depression Rating Scale (HAM-D) and the Clinical Global Impression-Improvement scale (CGI-I). One thousand and eighty-eight patients were randomized, with 654 (60%) meeting criteria for anxious depression and 212 (19%) meeting criteria for high severity depression. For the total sample, treatment response was similar for both sertraline and fluoxetine. In the high severity subgroup, the mean (+/-SD) HAM-D score at week 12 was 8.9+/-5.7 for sertraline and 10.8+/-6.9 for fluoxetine (P=0.07), and the mean (+/-SD) CGI-I score was 1.5+/-0.7 for sertraline and 2.0+/-1.1 for fluoxetine (P=0.005). CGI-I responder rates were 88% versus 71% (P=0.03) in the high severity subgroup, and 84% versus 79% (P=0.16) in the anxious-depression subgroup. Overall, sertraline and fluoxetine showed comparable antidepressant efficacy, although sertraline may offer an advantage in those patients with severe depression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12817154&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Effect of sertraline treatment on benzodiazepine receptors in the rat brain.

Giardino L, Zanni M, Velardo A, Amato G, Calza L.

Institute of Human Physiology, Medical School, University of Cagliari, Italy.

In this paper we describe the modification of benzodiazepine (BDZ) binding sites in the rat brain after different times of treatment with the 5-hydroxytryptamine-(5HT) uptake blocker sertraline. We investigated the effect of 8, 15 and 30 days sertraline treatment (10 mg/kg/day, i.p.) on 3 H-flunitrazepam binding sites. In order to describe the anatomical site of action of the drug, the experiment has been carried out by means of quantitative receptor autoradiography. After 8 days of sertraline treatment, an increase of BDZ receptor density is found in the olfactory tubercle. This effect is reversed at 15 and 30 days. At 15 days of treatment, an increase is found in the anterior cingulate cortex. This increase is still present after 30 days of treatment. At 30 days of treatment, we also found an increase of BDZ receptor density in the frontoparietal motor cortex and in the septal nuclei. The Scatchard plots obtained from the saturation experiments indicate that this increase of the receptor density is due to an increase of both the receptor number and affinity. All the other investigated areas are unaffected by the sertraline treatment. The possible neurochemical basis of these BDZ receptor regulation by sertraline and its influence in the therapeutical profile are discussed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7907484&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Distribution of sertraline in postmortem cases.

Levine B, Jenkins AJ, Smialek JE.

Office of the Chief Medical Examiner, State of Maryland, Baltimore 21201.

Sertraline is a potent inhibitor of serotonin reuptake in the central nervous system and is used clinically to treat depression and obsessive-compulsive behavior. Over the course of one year, there were seven cases investigated by the Office of the Chief Medical Examiner, State of Maryland, in which sertraline was identified in postmortem specimens. Heart blood concentrations in the seven cases ranged from 0.23 to 0.46 mg/L; desmethylsertraline concentrations ranged from 0.08 to 0.99 mg/L. One similarity with tricyclic antidepressants is the high liver concentrations of drug and metabolite relative to the blood. One unusual finding is the small concentrations of drug and metabolite in the urine relative to other specimens. In none of these cases was the cause of death related to sertraline intoxication.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7990446&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Occupancy of the serotonin transporter by fluoxetine, paroxetine, and sertraline: in vivo studies with [125I]RTI-55.

Scheffel U, Kim S, Cline EJ, Kuhar MJ.

Johns Hopkins University School of Medicine, Department of Radiology, Baltimore, MD 21205.

[125I]RTI-55 was used tracer doses to label serotonin (5-HT) transporters in vivo in the mouse brain. Fluoxetine, paroxetine, and sertraline, potent antidepressants and selective inhibitors of serotonin transporter sites, were administered in various doses and at various times. The doses and times that result in significant binding of the drugs to transporters correspond to doses and times where they are reported to have physiological effects. Estimates of occupancy rate and duration of binding to serotonin transporters were made. The rate of occupancy of the 5-HT transporter site was fastest for sertraline, intermediate for paroxetine and slowest for fluoxetine. Similarly, the duration of occupancy was significantly shorter for sertraline and paroxetine (approximately 10 h) than for fluoxetine (approximately 50 h). The results indicate that in competition studies, [125I]RTI-55 can be used to identify doses of drugs that are physiologically effective, to determine their relative rate of occupancy, and most importantly, to measure the residency time on the central serotonin transporter in vivo.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8059336&dopt=Abstract sertraline Zoloft