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Buspirone modulates basal and fluoxetine-stimulated dialysate levels of dopamine, noradrenaline and serotonin in the frontal cortex of freely moving rats: activation of serotonin1A receptors and blockade of alpha2-adrenergic receptors underlie its actions.

Gobert A, Rivet JM, Cistarelli L, Melon C, Millan MJ.

Institut de Recherches Servier, Psychopharmacology Department, Croissy-sur-Seine, Paris, France.

The serotonin1A receptor partial agonist, buspirone, also displays antagonist properties at D2 receptors and is metabolized to the alpha2-adrenergic receptor antagonist, 1-(2-pyrimidinyl-piperazine). Herein, we examined mechanisms underlying the influence of buspirone alone, and in association with the serotonin reuptake inhibitor, fluoxetine, upon extracellular levels of serotonin, dopamine and noradrenaline simultaneously quantified in the frontal cortex of freely moving rats. Buspirone (0.01-2.5 mg/kg, s.c.) dose-dependently decreased dialysate levels of serotonin (-50%), and increased those of dopamine (+100%) and noradrenaline (+140%). The reduction by buspirone of serotonin levels was abolished by the serotonin1A receptor antagonist, WAY 100,635 (0.16), which did not, however, modify its influence upon dopamine and noradrenaline. In contrast to buspirone, the serotonin reuptake inhibitor, fluoxetine (10.0), increased frontocortical levels of serotonin (+ 120%), dopamine (+55%) and noradrenaline (+90%). Buspirone dose-dependently (0.01-2.5) decreased the induction by fluoxetine of serotonin levels yet potentiated (three-fold) its elevation of dopamine and noradrenaline levels. The serotonin1A agonist, 8-hydroxy-2-(di-n-propyl-amino)-tetralin (0.16), mimicked the action of buspirone in reducing resting levels of serotonin (-60%) and in enhancing those of dopamine (+135%) and noradrenaline (+165%). Like buspirone, it attenuated the influence of fluoxetine upon serotonin levels, yet facilitated its influence upon dopamine and noradrenaline levels. In contrast, WAY 100,635 selectively potentiated the increase in levels of serotonin (two-fold) versus dopamine and noradrenaline elicited by fluoxetine. Further, WAY 100,635 abolished the inhibitory influence of buspirone upon fluoxetine-induced serotonin release, but only partly interfered with its potentiation of fluoxetine-induced increases in dopamine and noradrenaline levels. The D2/D3 receptor antagonist, raclopride (0.16), increased basal dopamine (+60%) levels but little influenced those of serotonin and noradrenaline, and failed to modify the action of fluoxetine. The alpha2-adrenergic receptor antagonist, 1-(2-pyrimidinyl-piperazine) (2.5), which did not modify resting levels of serotonin, markedly increased those of dopamine (+90%) and noradrenaline (+190%) and potentiated (two-fold) the increases in dialysate levels of dopamine, noradrenaline and serotonin provoked by fluoxetine. Further, the alpha2-adrenergic receptor agonist, S18616, attenuated the enhancement by buspirone of the fluoxetine-induced increase in levels of dopamine and noradrenaline. In conclusion, the inhibitory influence of buspirone upon resting and fluoxetine-stimulated serotonin levels reflects its agonist properties at serotonin1A autoreceptors. The facilitatory influence of buspirone upon resting and fluoxetine-stimulated dopamine and noradrenaline levels may also involve its serotonin1A properties. However, its principal mechanism of action in this respect is probably the alpha2-adrenergic antagonist properties of its metabolite, 1-(2-pyrimidinyl-piperazine). The present observations are of significance to experimental and clinical studies of the influence of buspirone upon depressive states, alone and in association with antidepressant agents.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10501449&dopt=Abstract fluoxetine Prozac



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Economic appraisal of citalopram in the management of single-episode depression.

Sclar DA, Skaer TL, Robison LM, Galin RS.

Pharmacoeconomics and Pharmacoepidemiology Research Unit, College of Pharmacy, Washington State University, Pullman 99164-6510, USA. sclar mail.wsu.edu

A retrospective intent-to-treat analysis (N = 1,339) was conducted to discern the natural course of antidepressant use and direct health service expenditures for the treatment of single-episode depression (DSM-IV code 296.20) among patients initiating antidepressant pharmacotherapy with either a tricyclic antidepressant (TCA) (amitriptyline, N = 237) or a selective serotonin reuptake inhibitor (SSRI) (citalopram, N = 71; fluoxetine, N = 411; paroxetine, N = 334; or sertraline, N = 286). Data were derived from the computer archive of a network-model health maintenance organization for the period of January 1, 1996, through April 30, 1999. Comparisons at the end of the 6-month post-period (180 days) were undertaken between cohorts initiating antidepressant pharmacotherapy with citalopram and each SSRI or TCA. Consistent with the intent-to-treat design, all accrued health service expenditures were assigned to the pharmacotherapeutic option initially prescribed. Multivariate models were adjusted for patient's age, gender, number of concomitant disease state processes, use of health services in the 6-month time frame (180 days) before initiating antidepressant pharmacotherapy, specialty of physician recording a diagnosis of single-episode depression, and the presence or absence of a previous diagnosis of single-episode depression and receipt of antidepressant pharmacotherapy. Patients initiating antidepressant pharmacotherapy with citalopram were far more likely to (1) have been diagnosed by a psychiatrist (37%; p < or = 0.05); (2) continue with the original pharmacotherapeutic option (79%) compared with patients originally prescribed amitriptyline (51%; chi2 = 17.29, df = 1, p < or = 0.05) or sertraline (65%; chi2 = 36.91, df = 1, p < or = 0.05); no significant difference was found compared with patients initiating antidepressant pharmacotherapy with paroxetine (72%; p = not significant [NS]) or fluoxetine (83%; p = NS); (3) obtain 90 days or more of antidepressant pharmacotherapy (86%) compared with those prescribed amitriptyline (69%; chi2 = 8.09, df = 1, p < or = 0.05); no significant difference was found compared with sertraline (77%), paroxetine (81%), or fluoxetine (84%); and (4) obtain 6 months (180 days) of antidepressant pharmacotherapy (68%) compared with those prescribed amitriptyline (39%; chi2 = 18.26, df = 1, p < or = 0.05) or sertraline (51%; chi2 = 6.02, df = 1, p < or = 0.05); no significant difference was found compared with paroxetine (56%) or fluoxetine (59%). Receipt of amitriptyline or sertraline as initial medication was associated with a per capita increase (p < or = 0.05) in health service utilization (17% and 9%, respectively) relative to citalopram. No significant difference (p > 0.05) in health service utilization was discerned between citalopram and either fluoxetine or paroxetine. Multivariate models adjusted for nonrandom assignment to the initial pharmacotherapeutic option confirmed these findings. Further research over a longer time course is warranted.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10507508&dopt=Abstract fluoxetine Prozac



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Fluoxetine efficacy in menopausal women with and without estrogen replacement.

Amsterdam J, Garcia-Espana F, Fawcett J, Quitkin F, Reimherr F, Rosenbaum J, Beasley C.

Depression Research Unit, University of Pennsylvania Medical Center, Philadelphia 19104, USA.

A gradual decline in estrogen levels after the age of 40 may contribute to a higher rate of depression in women over 45 years of age. Estrogen replacement therapy (ERT) has been shown to produce cognitive and mood-enhancing effects in women and may facilitate antidepressant activity. METHODS: We examined the efficacy rates in women on ERT > or = 45 years (n = 40) compared to women > or = 45 years not on ERT (n = 132) and to women < 45 years (n = 396) and to men (n = 262) with major depression during fluoxetine 20 mg daily up to 8 weeks. Remitters with a HAM-D17 score < or = 7 from week 9 to 12 were then treated up to 1-year in a placebo-controlled, relapse-prevention trial. RESULTS: Efficacy rates were similar in women > or = 45 years on ERT when compared to women > or = 45 years taking fluoxetine alone, and when compared to women < 45 years and men taking fluoxetine. A Kaplan-Meier survival analysis in fluoxetine responders treated up to 26 weeks showed a somewhat greater relapse rate in women > or = 45 years taking ERT compared to other treatment groups (P < 0.06). LIMITATIONS: This study was retrospective nature and ERT was given in an uncontrolled fashion: 63% of women received estrogen alone while 37% also took intermittent progesterone. Other variables include the absence of hormonal documentation of menopausal status, no direct assessment of ERT compliance and the use of fixed-dose fluoxetine 20 mg daily. CONCLUSION: In contrast to prior reports suggesting that ERT may facilitate antidepressant activity, we observed similar efficacy in depressed women > or = 45 years taking fluoxetine plus ERT compared to those taking fluoxetine alone.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10512601&dopt=Abstract fluoxetine Prozac



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Difference in the in vivo influence of serotonin1A autoreceptors on serotonin release in prefrontal cortex and dorsal hippocampus of the same rat treated with fluoxetine.

Li XM, Perry KW, Wong DT.

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

Recent studies have demonstrated that antagonism of somatodendritic serotonin1A (5-HT1A) autoreceptors can potentiate the increase of extracellular 5-HT concentrations induced by selective serotonin reuptake inhibitors including fluoxetine. The present study was conducted to uncover any functional difference between the 5-HT1A autoreceptors located on the cell bodies of 5-HT neurons in the dorsal (DRN) and median (MRN) raphe nuclei. The investigational approach used in the present study was to detect extracellular 5-HT concentrations in two terminal areas, prefrontal cortex (Pfc) and dorsal hippocampus (Dhp), which are mainly innervated by the 5-HT neurons located in the DRN and MRN respectively. To avoid possible variation between individual animals a dual-probe microdialysis procedure was applied to determine 5-HT concentrations in both brain areas of the same rat. Fluoxetine (10 mg/kg, s.c.) alone produced a smaller increase in the extracellular 5-HT concentration in the Pfc than Dhp of the same rat (maximal 5-HT concentrations were 183% and 223% of the baseline values in Pfc and Dhp respectively). However, an antagonist of 5-HT1A receptors, WAY100635, subsequently injected (s.c.) at 1 mg/kg brought the 5-HT concentrations to similar levels in the Pfc (332%) and Dhp (308%). Since the 5-HT concentrations immediately before the injection of WAY100635 were lower in the Pfc (102%) than Dhp (186%), WAY100635 induced a larger 5-HT net increase in the Pfc (332%-102%=230%) than Dhp (308%-186%=122%). On the other hand, WAY100635 alone did not significantly change the extracellular 5-HT concentrations in both areas. Furthermore, extracellular concentrations of dopamine (DA) and two DA metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, in both areas were not altered by the administrations of fluoxetine and WAY100635. In conclusion, the present study demonstrated that the antagonist of 5-HT1A receptors, WAY100635, produced a more robust potentiation in the fluoxetine-induced 5-HT increases in the Pfc than Dhp. Since Pfc and Dhp are predominately innervated by 5-HT neurons located in the DRN and MRN respectively, this result may indicate a functional difference between the 5-HT1A autoreceptors located on the cell bodies of 5-HT neurons in the DRN and MRN.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10513599&dopt=Abstract fluoxetine Prozac



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Course and cost of treatment for depression with fluoxetine, paroxetine, and sertraline.

Russell JM, Berndt ER, Miceli R, Colucci S, Grudzinski AN.

University of Texas Medical Branch, Galveston 77555-0191, USA. jrussell utmb.edu

OBJECTIVE: To compare depression-related treatment costs and total healthcare costs for patients diagnosed with depression and treated with either sertraline, paroxetine, or fluoxetine. PATIENTS AND METHODS: Claims records from a national database of patients diagnosed with depression who began treatment with an SSRI in 1995, following an antidepressant medication-free period of at least 6 months, were included. Treatment course and associated depression-related treatment and total healthcare costs during the subsequent 12-month treatment period were examined using univariate and multivariate methods. RESULTS: Nine-hundred five (905) patients taking sertraline, 492 on paroxetine, and 945 on fluoxetine met inclusion criteria. The groups were similar and representative with respect to gender and age. Mean dose over the 12-month treatment period increased 24%, indicating significant titration in all cohorts. Patients treated with paroxetine had shorter treatment duration (157.0 days) than did patients treated with fluoxetine (192.6 days) or sertraline (166.9 days, P < 0.001). Patients receiving index treatment with paroxetine were most likely to switch to another SSRI (21.3%); those taking sertraline were second most likely to switch (16.1%); and those on fluoxetine were least likely (12.4%, P = 0.001). Mean costs for depression-related outpatient visits and hospitalizations were similar. Mean antidepressant prescription costs differed, being $586, $419, and $446 for fluoxetine, paroxetine and sertraline cohorts, respectively (P < 0.001). In this sample, the fluoxetine cohort did not have lower nonpharmaceutical healthcare costs to offset higher pharmaceutical acquisition costs. Conclusions from median and multivariate analyses were robust to these findings. CONCLUSIONS: During this study period when fluoxetine, paroxetine, and sertraline were all well-established agents, similar depression-related treatment courses and cost characteristics among all 3 drugs were observed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10537866&dopt=Abstract fluoxetine Prozac



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Obsessive-compulsive disorder: evaluation of clinical and biological circadian parameters during fluoxetine treatment.

Millet B, Touitou Y, Poirier MF, Bourdel MC, Amado I, Hantouche EG, Bogdan A, Olie JP.

Service Hospitalo-Universitaire de Psychiatrie, Hopital Sainte-Anne, 7 rue Cabanis, F-75674 Paris Cedex 14, France. Millet.Bruno wanadoo.fr

RATIONALE: Many biological abnormalities have been found in obsessive-compulsive disorder (OCD). The circadian rhythm investigations of different clinical and biological parameters may provide a comparison with depression. Fluoxetine is one of the efficient drugs in alleviating symptoms of OCD. The effect of fluoxetine can highlight some clues to the neurotransmitter alterations in the disorder. OBJECTIVE: The present study investigated clinical and biological circadian modifications in OCD patients during a fluoxetine treatment. METHODS: Daily clinical symptoms, and circadian rhythms of axillary temperature, plasma cortisol and plasma melatonin were assessed in eight patients suffering from OCD. These parameters were compared in the same patients, before and after an 8-week fluoxetine treatment period. RESULTS: A therapeutic effect of fluoxetine was obtained. No significant differences were observed either in daily clinical variations or in biological circadian rhythms measured before and after treatment. CONCLUSION: The therapeutic efficacy of fluoxetine was not related to the biological parameters assessed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10541726&dopt=Abstract fluoxetine Prozac



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Fluoxetine interacts with the lipid bilayer of the inner membrane in isolated rat brain mitochondria, inhibiting electron transport and F1F0-ATPase activity.

Curti C, Mingatto FE, Polizello AC, Galastri LO, Uyemura SA, Santos AC.

Department of Physics and Chemistry, School of Pharmaceutical Sciences, University of Sao Paulo, Brasil.

The effects of fluoxetine on the oxidative phosphorylation of mitochondria isolated from rat brain and on the kinetic properties of submitochondrial particle F1F0-ATPase were evaluated. The state 3 respiration rate supported by pyruvate + malate, succinate, or ascorbate + tetramethyl-p-phenylenediamine (TMPD) was substantially decreased by fluoxetine. The IC50 for pyruvate + malate oxidation was approximately 0.15 mM and the pattern of inhibition was the typical one of the electron-transport inhibitors, in that the drug inhibited both ADP- and carbonyl cyanide m-chlorophenylhydrazone (CCCP)-stimulated respirations and the former inhibition was not released by the uncoupler. Fluoxetine also decreased the activity of submitochondrial particle F1F0-ATPase (IC50 approximately 0.08 mM) even though K0.5 and activity of Triton X-100 solubilized enzyme were not changed substantially. As a consequence of these effects, fluoxetine decreased the rate of ATP synthesis and depressed the phosphorylation potential of mitochondria. Incubation of mitochondria or submitochondrial particles with fluoxetine under the conditions of respiration or F1F0-ATPase assays, respectively, caused a dose-dependent enhancement of 1-anilino-8-naphthalene sulfonate (ANS) fluorescence. These results show that fluoxetine indirectly and nonspecifically affects electron transport and F1F0)-ATPase activity inhibiting oxidative phosphorylation in isolated rat brain mitochondria. They suggest, in addition, that these effects are mediated by the drug interference with the physical state of lipid bilayer of inner mitochondrial membrane.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10544958&dopt=Abstract fluoxetine Prozac



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Weight gain in infants breastfed by mothers who take fluoxetine.

Chambers CD, Anderson PO, Thomas RG, Dick LM, Felix RJ, Johnson KA, Jones KL.

Departments of Pediatrics, University of California, San Diego, California 92103, USA. chchambers ucsd.edu

OBJECTIVE: Despite the manufacturer's recommendation that fluoxetine not be used by women while breastfeeding, many women choose to do so. There is little information available in the literature to suggest that this practice is or is not safe. The purpose of this study was to examine weight gain in infants who are breastfed by mothers who take fluoxetine, compared with weight gain in infants who are breastfed by mothers who do not take any psychotherapeutic medication. A secondary goal was to assess the frequency of reported side effects in infants who are breastfed by mothers who take fluoxetine. METHODOLOGY: A retrospective cohort study design was used. Subjects were identified from an ongoing pregnancy outcome study conducted through the California Teratogen Information Service and Clinical Research Program. A total of 64 women were interviewed who had taken fluoxetine during a pregnancy between the 1989 and 1997; 26 of these women breastfed their infants and continued to take the medication, and 38 breastfed their infants but did not take the medication. Postnatal weight gain was taken from pediatric records, and the frequency of side effects was measured by maternal response to the interview questionnaire. RESULTS: Using linear regression analysis, the infants who were breastfed by mothers taking fluoxetine demonstrated a growth curve significantly below that of infants who were breastfed by mothers who did not take the drug. The average deficit in measurements taken between 2 weeks and 6 months of age was 392 g (95% confidence interval: -5, -780). Using a repeated measures analysis of covariance for those infants with more than one postnatal weight measurement available, the difference between the two groups was similar, approximately 1.2 standard deviations (P =.005). In response to interview questions regarding side effects, no mother who breastfed her infant while taking fluoxetine reported any unusual symptoms that could be attributed to the medication. CONCLUSIONS: These data do not suggest that women who breastfeed while taking fluoxetine are likely to note unusual behavior in their infants that they consider related to use of the medication. However, although there was no excess of infants in the fluoxetine group with postnatal weight measurements >2 standard deviations below the mean, these data indicate that breastfeeding while taking fluoxetine is associated with reduced growth that may be of clinical importance in situations in which infant weight gain is already of concern.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10545587&dopt=Abstract fluoxetine Prozac