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Contrasting Fos expression induced by acute reboxetine and fluoxetine in the rat forebrain: neuroanatomical substrates for the antidepressant effect.

Miyata S, Hamamura T, Lee Y, Miki M, Habara T, Oka T, Endo S, Taoka H, Kuroda S.

Department of Neuropsychiatry, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan.

RATIONALE: Antidepressants preferentially facilitating serotonin seem to be particularly effective for treating the anxiety and aggressive component of the depressive syndrome, whereas those with a noradrenergic profile seem to be more effective in reducing psychomotor retardation, although their overall antidepressant effects are about the same. However, the mechanism of this difference remains unknown. OBJECTIVES: To investigate the neural substrate for the different therapeutic efficacies of fluoxetine and reboxetine, we examined the regional Fos immunoreactivity (Fos-ir) induced by the two agents. METHODS: Male Wistar rats (290-330 g) were given a subcutaneous injection of fluoxetine (5 or 10 mg/kg), reboxetine (5 or 10 mg/kg) or saline. Two hours later, rats were perfused through the ascending aorta and their brains were processed for Fos immunohistochemistry. Fos-ir was quantified by counting the number of Fos-ir-positive nuclei in six areas of the forebrain. RESULTS: The shell of the nucleus accumbens was the only region in which both fluoxetine and reboxetine equally increased Fos-ir expression. Fluoxetine particularly induced Fos-ir in the central nucleus of the amygdala. In contrast, reboxetine induced Fos-ir in the cingulate cortex area 3 and the lateral orbital cortex. CONCLUSIONS: These results suggest that the shell region may be one possible target for the antidepressant effects of fluoxetine and reboxetine. Furthermore, the difference in their clinical effects may depend on their different target sites of action.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15609068&dopt=Abstract fluoxetine Prozac



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Norfluoxetine enantiomers as inhibitors of serotonin uptake in rat brain.

Wong DT, Bymaster FP, Reid LR, Mayle DA, Krushinski JH, Robertson DW.

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.

Like fluoxetine, the N-demethylated metabolite norfluoxetine exists in R- and S-enantiomeric forms. S-Norfluoxetine inhibited serotonin (5-HT) uptake and [3H]paroxetine binding to 5-HT uptake sites with a pKi of 7.86 and 8.88 or 14 and 1.3 nM, respectively, whereas R-norfluoxetine was 22 and 20 times, respectively, less potent. R- and S-Norfluoxetine were less potent than the corresponding enantiomers of fluoxetine as inhibitors of norepinephrine uptake and [3H]tomoxetine binding to norepinephrine uptake sites. Ex vivo studies showed that S-norfluoxetine inhibited 5-HT uptake with an ED50 of 3 mg/kg intraperitoneally, 4.7 mg/kg subcutaneously, and 9 mg/kg orally (7.3, 11.4 and 21.9 mumol/kg, respectively), while the ED50 for R-norfluoxetine exceeded 20 mg/kg intraperitoneally (48.6 mumol/kg). Inhibition of 5-HT uptake in cerebral cortex ex vivo and decrease in 5-HIAA levels in hypothalamus persisted for 24 hours after administration of S-norfluoxetine as demonstrated with the administration of fluoxetine. Thus, S-norfluoxetine is the active N-demethylated metabolite responsible for the persistently potent and selective inhibition of 5-HT uptake in vivo.

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Drug concentrations in mouse brain at pharmacologically active doses of fluoxetine enantiomers.

Fuller RW, Snoddy HD.

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.

The i.p. injection of R-fluoxetine into mice at doses of 1-10 mg/kg led to higher concentrations of the desmethyl metabolite, R-norfluoxetine, in whole brain than was true for S-fluoxetine. R-Norfluoxetine, but not S-norfluoxetine, concentrations predominated over those of the parent drug at 7-24 hr after injection of the corresponding fluoxetine enantiomer. The more rapid N-demethylation of R-fluoxetine, and the relative inactivity of R-norfluoxetine as a serotonin uptake inhibitor compared with S-norfluoxetine, may explain the earlier report that R-fluoxetine is less potent than S-fluoxetine in antagonizing p-chloroamphetamine depletion of brain serotonin in mice. In the present study, a 10 mg/kg, i.p., dose of S-fluoxetine completely prevented p-chloroamphetamine given 24 hr later from depleting brain serotonin, whereas R-fluoxetine offered no protection at this time.

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A pharmacoeconomic evaluation of escitalopram, a new selective serotonin reuptake inhibitor Comparison of cost-effectiveness between escitalopram, citalopram, fluoxetine,and venlafaxine for the treatment of depression in Norway.

Francois C, Toumi M, Aakhus AM, Hansen K.

International Department of Health-Economics, Epidemiology and Pricing, Lundbeck A/S,Paris, France.

This study compared the cost-effectiveness of escitalopram to that of citalopram,fluoxetine, and venlafaxine in the treatment of depression in Norway.A two-path decision analytic model with a 6-month horizon was used.Patients start at the primary path and are referred to specialist care in the secondary care path. Model inputs included drugspecific probabilities from comparative trial data, literature, and a panel of experts.The main outcome measure is success (remission), and costs of treatment (total and drug costs).Treatment with escitalopram yielded lower expected cost and greater effectiveness than citalopram,fluoxetine, and venlafaxine. The expected success rate was 64.2% with escitalopram,58.7% with citalopram, 58.7% with fluoxetine, and 62.1% with venlafaxine.Average expected total costs per patient were similar with escitalopram (19,661 Norwegian crowns) and venlafaxine (20,989) and somewhat higher with citalopram (22,379) and fluoxetine (22,558).Budgetary impact estimates a decrease in total health care budget of 72 million crowns.Escitalopram is therefore the most cost-effective alternative and its use would significantly reduce health care costs for the treatment of depression in Norway.

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Comparison of frequencies of suicidal tendencies among patients receiving fluoxetine, lofepramine, mianserin, or trazodone.

Jick H, Ulcickas M, Dean A.

Boston Collaborative Drug Surveillance Program, Boston University Medical Center, Lexington, Massachusetts 02173.

To evaluate whether fluoxetine causes an important increased risk of suicidal behavior, we compared the frequency of attempted suicide, suicidal ideation, and aggressive behavior in persons who received fluoxetine, lofepramine, mianserin, and trazodone, based on information available on general practitioners' computers provided by Value Added Medical Products, Ltd. The frequency of these events was higher in fluoxetine users in the year prior to first treatment than in users of the other three antidepressants. The frequency of these events in the 90 days after the study drug was started was similar for the users of all four drugs. These data indicate that fluoxetine does not directly cause suicidal behavior at a substantially higher frequency than do lofepramine, mianserin, and trazodone.

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Antidepressant effects of nicotine and fluoxetine in an animal model of depression induced by neonatal treatment with clomipramine.

Vazquez-Palacios G, Bonilla-Jaime H, Velazquez-Moctezuma J.

Neuroscience Laboratory, Department of Reproductive Biology, Universidad Autonoma Metropolitana-Iztapalapa, Mexico City C.P. 09340. Mexico. jvm xanum.uam.mx

The association between smoking and depression has been widely investigated. Most of these reports suggest that nicotine (NIC) may act as an antidepressant. To examine the suggested antidepressant effect of nicotine and its possible interaction with the serotonergic system, we assessed the effect of nicotine and fluoxetine (FLX) in an animal model of depression induced by neonatal treatment with clomipramine (CLI) and submitted to the forced swim test (FST). Results corroborated that CLI-treated rats displayed higher levels of immobility. After the administration of nicotine (0.4 mg/kg sc) acutely (1 day), subchonically (7 days), and chronically (14 days), CLI-treated rats significantly reduced the immobility and increased swimming without affecting climbing. These effects were similar to the effects induced for subchronic and chronic administration of the antidepressant fluoxetine (5 mg/kg sc), a selective serotonin re-uptake inhibitor. However, fluoxetine failed to affect immobility when it was administered acutely. No synergism was observed when both drugs were administered simultaneously. The present results further corroborate the antidepressant action of nicotine and fluoxetine. The increase of swimming during the FST has been linked to an increase of serotonergic activity. Thus, it could be possible that the antidepressant action of nicotine is mediated by the serotonergic system.

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Releasing activities of d-fenfluramine and fluoxetine on rat hippocampal synaptosomes preloaded with [3H]serotonin.

Gobbi M, Frittoli E, Mennini T, Garattini S.

Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.

Rat hippocampal synaptosomes preloaded with [3H]serotonin and maintained in a superfusion apparatus were exposed for 3 min to d-fenfluramine or fluoxetine. Both drugs evoked a tritium overflow which was reserpine-sensitive requiring the presence of intact synaptic vesicles. However the two drugs displayed different characteristics: 1) the overflow was immediate with d-fenfluramine whereas the releasing activity of fluoxetine showed a delay of about 2 min; 2) d-fenfluramine-induced overflow was already apparent at 0.15 mumol/l whereas the minimal effective concentration of fluoxetine was 2.5 mumol/l. Their concentration-effect curves were differently shaped, the effect of d-fenfluramine being saturable at 5-20 mumol/l (EC50 about 1 mumol/l) while no saturation was observed with fluoxetine up to 10 mumol/l; 3) only 19% of the tritium overflow evoked by fluoxetine (2.5-10 mumol/l) consisted of true [3H]serotonin, compared with 70% when 0.5 mumol/l d-fenfluramine was used; 4) the releasing action of 0.5 mumol/l d-fenfluramine was completely Ca(++)-dependent, while at higher d-fenfluramine concentrations the Ca(++)-independent overflow became more important. The fluoxetine induced overflow was mainly (70%) Ca(++)-independent; 5) the releasing activity of d-fenfluramine was mainly (80%) blocked by the serotonin uptake blockers indalpine, midalcipram and also fluoxetine whereas fluoxetine-induced overflow was insensitive to inhibition of the serotonin carrier. In conclusion, the releasing activity of d-fenfluramine is already present at a very low concentration (0.5 mumol/l) and at this concentration its mechanism of action was Ca(++)-dependent, together with the requirement of a functional serotonin carrier.(ABSTRACT TRUNCATED AT 250 WORDS)

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A pharmacokinetic evaluation of the combined administration of triazolam and fluoxetine.

Wright CE, Lasher-Sisson TA, Steenwyk RC, Swanson CN.

Clinical Pharmacokinetics Unit, Upjohn Company, Kalamazoo, Michigan 49007.

The influence of fluoxetine on triazolam pharmacokinetics was studied because of changes in diazepam pharmacokinetics reportedly produced by fluoxetine. Twenty-four healthy volunteers received a single 0.25-mg triazolam tablet alone, and another 0.25-mg tablet after 8 days of fluoxetine therapy 60 mg/day. All subjects received these treatments in the same sequence. Several blood samples were drawn from the subjects after the triazolam doses and were assayed by high-performance liquid chromatography (HPLC). Blood samples were drawn immediately before the last three fluoxetine doses to determine the concentration of fluoxetine and its metabolite norfluoxetine, also by HPLC. The pharmacokinetics of triazolam did not change significantly when the tablets were administered after multiple doses of fluoxetine. These results indicate that no pharmacokinetic interaction exists between triazolam and fluoxetine or norfluoxetine. However, each patient's clinical response to therapy should be monitored when triazolam tablets and fluoxetine capsules are administered concomitantly.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1570226&dopt=Abstract fluoxetine Prozac