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Fluoxetine enhances cell proliferation and prevents apoptosis in dentate gyrus of maternally separated rats.

Lee HJ, Kim JW, Yim SV, Kim MJ, Kim SA, Kim YJ, Kim CJ, Chung JH.

Kohwang Medical Research Institute, College of Medicine, Kyung Hee University, 1 Hoegi-Dong, Tongdaemoon-Ku, Seoul, 130-701, Korea.

The mother-infant relationship is an instinctive phenomenon, and loss of maternal care in early life influences neonatal development, behavior and physiologic responses.(1,2) Furthermore, the early loss may affect the vulnerability of the infant to neuropsychiatric disorders, such as childhood anxiety disorders, personality disorders and depression, over its lifespan.(3,4) Fluoxetine is prescribed worldwide for depression and is often used in the treatment of childhood mental problems related to maternal separation or loss of maternal care.(5,6) In the present study, fluoxetine was administrated to rats with maternal separation to determine its effects on neuronal development, in particular with respect to cell proliferation and apoptosis in the dentate gyrus of the hippocampus. Rat pups were separated from their mothers and socially isolated on postnatal day 14 and were treated with fluoxetine (5 mg kg(-1)) and 5-bromo-2'-deoxyuridine (BrdU) (50 mg kg(-1)) for 7 days, after which immunohistochemistry and a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining were carried out. In the pups with maternal separation treated with fluoxetine, the number of BrdU-positive cells was significantly increased and that of TUNEL-positive cells was significantly decreased in the dentate gyrus compared to pups with maternal separation that did not receive fluoxetine treatment. These findings indicate that fluoxetine affects new cell proliferation and apoptosis, and we propose that fluoxetine may be useful in the treatment of maternal separation-related diseases.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11673802&dopt=Abstract fluoxetine Prozac



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Opposite effects of short- versus long-term administration of fluoxetine on the concentrations of neuroactive steroids in rat plasma and brain.

Serra M, Pisu MG, Muggironi M, Parodo V, Papi G, Sari R, Dazzi L, Spiga F, Purdy RH, Biggio G.

Department of Experimental Biology, University of Cagliari, 09100 Cagliari, Italy. mserra unica.it

RATIONALE: Recent preclinical and clinical studies have shown that selective serotonin re-uptake inhibitors modulate neurosteroid synthesis in an opposite manner. OBJECTIVES: The action of long-term administration of fluoxetine was investigated on the peripheral and central concentrations of 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-TH PROG) and 3alpha,5alpha-tetrahydrodeoxycorticosterone (of 3alpha,5alpha-TH DOC), progesterone, and pregnenolone in rats. We also investigated the effect of chronic treatment with fluoxetine on the foot-shock stress-induced increase in the plasma and brain concentrations of these steroids. METHODS: Fluoxetine was administered acutely (20 mg/kg) or chronically (10 mg/kg, once daily for 15 days). Steroids were extracted from plasma and brain, separated and purified by means of high-performance liquid chromatography, and quantified by means of radioimmunoassay. RESULTS: A single dose of fluoxetine (20 mg/kg, i.p.) induced in 20 min significant increases in the cerebral cortical and plasma concentrations of 3alpha,5alpha-TH PROG (+96% and +13%, respectively), 3alpha,5alpha-TH DOC (+129 and +31%, respectively), progesterone (+111 and +58%, respectively), and pregnenolone (+151 and +59%, respectively). In addition, the plasma concentration of corticosterone was also significantly increased (+24%) after acute administration of fluoxetine. In contrast, long-term administration of fluoxetine reduced the basal concentrations of these various steroids (ranging from -22 to -43%), measured 48 h after the last drug injection, in both brain and plasma. A challenge injection of fluoxetine (20 mg/kg, i.p.), however, was still able to increase the concentrations of steroids in both the brain and plasma of rats chronically treated with this drug. Acute foot-shock stress increased the cortical and plasma concentrations of steroids in rats chronically treated with fluoxetine to extents similar to those apparent in control rats. CONCLUSIONS: A repetitive increase in the brain concentrations of neuroactive steroids may contribute to the therapeutic action of fluoxetine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11685383&dopt=Abstract fluoxetine Prozac



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Long-term costs of treatment for depression: impact of drug selection and guideline adherence.

Crown WH, Treglia M, Meneades L, White A.

MEDSTAT Group, Inc., Cambridge, MA, USA.

OBJECTIVES: This paper examines three processes: SSRI antidepressant choice, adherence to treatment guidelines, and long-term health care expenditures associated with antidepressant treatment for patients with a diagnosis of depression. METHODS: Patient records were abstracted from a medical claims database covering employer-provided health care plans. Treatment episodes required a 6-month antidepressant-free prior period; initial treatment with sertraline, paroxetine or fluoxetine; and data on direct medical costs over the 24 months following the initial prescription. The multivariate model of drug selection, patient adherence to antidepressant use guidelines, and cost was subjected to specification testing to rule out the possibility that nonrandom initial antidepressant selection might lead to sample selection bias. Further tests indicated that the results were free of bias due to a possible correlation between antidepressant selection and use of the medication, or because of the endogeneity of use patterns in the process driving cost. However, there was evidence of unobserved variables correlated with both achieving guideline adherent use and expenditures, which might have led to sample selection bias. RESULTS: Subjects who met the study criteria included 796 initiating therapy with sertraline, 352 with paroxetine, and 882 with fluoxetine. Fluoxetine patients were significantly more likely than sertraline or paroxetine patients to achieve a use pattern that was consistent with guidelines for treating depressive disorder (p < .05). There were no statistically significant differences between the three treatment cohorts in total direct health care expenditures over the 2-year period (p < .05), and depression-related expenditures, other mental health expenditures, and non-mental health care expenditures did not show significant differences across the treatments (p < .05). Natural logged values of antidepressant drug expenditures were predicted to be highest for fluoxetine, followed by sertraline, then paroxetine (p < .01). Predicted log values of mental health expenditures were lower for sertraline relative to fluoxetine. CONCLUSIONS: Fluoxetine patients had the highest likelihood of using antidepressant medication according to treatment guidelines that were developed to assure quality care. This benefit was achieved without incurring greater total health care expenditures.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11705297&dopt=Abstract fluoxetine Prozac



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Fluoxetine and norfluoxetine concentrations in nursing infants and breast milk.

Hendrick V, Stowe ZN, Altshuler LL, Mintz J, Hwang S, Hostetter A, Suri R, Leight K, Fukuchi A.

UCLA Neuropsychiatric Institute and Hospital, Los Angeles, California 90095, USA.

BACKGROUND: This study's goal was to characterize nursing infants' exposure to fluoxetine through breast milk and to identify variables for minimizing such exposure. METHODS: Nursing women on stable daily doses of fluoxetine were recruited into the study. Breast milk, maternal and infant serum concentrations of fluoxetine and norfluoxetine were determined with high-performance liquid chromatography. RESULTS: Nineteen nursing women one with a pair of dizygotic twins participated in the study. The women were on stable daily doses of fluoxetine (10-60 mg/day) and all but two took the medication during the last trimester of pregnancy. Fluoxetine was detectable in 30% (n = 6) of the nursing infant sera (< 1-84 ng/mL), whereas norfluoxetine was found in 85% (N = 17) (< 1-265 ng/mL). Peak breast milk concentrations occurred approximately 8 hours after maternal dosing and predicted norfluoxetine concentrations in infant serum. Maternal serum fluoxetine and norfluoxetine concentrations correlated highly with infant norfluoxetine concentrations. A daily maternal fluoxetine dosage of 20 mg or lower was significantly less likely to produce detectable concentrations of either fluoxetine or norfluoxetine in infants compared to higher daily dosages. No adverse effects were reported in any infant. CONCLUSIONS: Our findings demonstrate that maternal serum and peak breast milk concentrations of fluoxetine and norfluoxetine predict nursing infant serum norfluoxetine concentrations. In nursing women taking 20 mg/day or less of fluoxetine, infant serum concentrations were typically low.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11720696&dopt=Abstract fluoxetine Prozac



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Effects of CYP2C19 genotype and CYP2C9 on fluoxetine N-demethylation in human liver microsomes.

Liu ZQ, Shu Y, Huang SL, Wang LS, He N, Zhou HH.

Pharmacogenetics Research Institute, Hunan Medical University, Changsha 410078, China.

AIM: The present study was designed to define the kinetic behavior of fluoxetine N-demethylation in human liver microsomes and to identify the isoforms of cytochrome P-450 (CYP) involved in this metabolic pathway. METHODS: The kinetics of Ne formation of norfluoxetine was determined in human liver microsomes from six genotyped CYP2C19 extensive metabolizers (EM). The correlation studies between the fluoxetine N-demethylase activity and various CYP enzyme activities were performed. Selective inhibitors or chemical probes of various cytochrome P-450 isoforms were also employed. RESULTS: The kinetics of norfluoxetine formation in all liver microsomes were fitted by a single-enzyme Michaelis-Menten equation (mean Km=32 micromol/L+/-7 micromol/L). Significant correlations were found between N-demethylation of fluoxetine at both 25 micromol/L and 100 micromol/L and 3-hydroxylation of tolbutamide at 250 micromol/L (r1=0.821, P1=0.001; r2=0.668, P2=0.013), respectively, and S-mephenytoin 4'-hydroxylase activity (r=0.717, P=0.006) at high substrate concentration of 100 micromol/L. S-mephenytoin (SMP) (a CYP2C19 substrate) at high concentration and sulfaphenazole (SUL) (a selective inhibitor of CYP2C9) substantially inhibited norfluoxetine formation. The reaction was minimally inhibited by coincubation with chemical probe, inhibitor of CYP3A4 (triacetyloleandomycin, TAO). The inhibition of fluoxetine N-demethylation at high substrate concentration (100 micromol/L) was greater in PM livers than in EM livers (73 % vs 45 %, P < 0.01) when the microsomes were precoincubated with SUL plus TAO. CONCLUSION: Cytochrome P-450 CYP2C9 is likely to be a major CYP isoform catalyzing fluoxetine N-demethylation in human liver microsomes at a substrate concentration close to the therapeutic level, while polymorphic CYP2C19 may play a more important role in this metabolic pathway at high substrate concentration.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11730569&dopt=Abstract fluoxetine Prozac



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LY393558, a 5-hydroxytryptamine reuptake inhibitor and 5-HT(1B/1D) receptor antagonist: effects on extracellular levels of 5-hydroxytryptamine in the guinea pig and rat.

Mitchell SN, Greenslade RG, Cooper J.

Eli Lilly and Company Ltd., Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK. mitchell_stephen lilly.com

The stimulation of terminal 5-HT(1B/1D) autoreceptors limits the effects of selective serotonin reuptake inhibitors on extracellular levels of 5-hydroxytryptamine (5-HT, serotonin) in vivo. Microdialysis studies show that acute oral administration of LY393558-a 5-HT reuptake inhibitor and antagonist at both the human 5-HT(1B) and 5-HT(1D) receptor-in the dose range 1-20 mg/kg, increases extracellular levels of 5-HT in both the guinea pig hypothalamus and rat frontal cortex. In both species, the levels of 5-HT that were attained were higher than following an acute, maximally effective dose of fluoxetine (20 mg/kg orally), reaching approximately 1500% in the guinea pig hypothalamus and 700% in the rat frontal cortex. In both species, the response to LY393558 (10 mg/kg p.o.) was impulse dependent, being absent in the presence of tetrodotoxin delivered at 1 microM via the microdialysis probe. The sensitivity to tetrodotoxin contrasted with the effects seen with DL-fenfluramine. Studies in rats showed that the microdialysate 5-HT concentration achieved in the frontal cortex after an acute challenge with LY393558 (5 mg/kg p.o.) was significantly greater than following a chronic regime of fluoxetine treatment (10 mg/kg/day orally for 21 days). Moreover, in rats chronically treated with LY393558 (5 mg/kg/day orally for 21 days), the mean basal concentration, 24 h after the final pretreatment dose, was of the same magnitude as that following chronic fluoxetine. However, in contrast to the response seen in fluoxetine-pretreated animals, a challenge dose of LY393558 still elicited a further increase in extracellular 5-HT in LY393558-pretreated animals. LY393558 is a potent 5-HT reuptake inhibitor and 5-HT(1B/1D) receptor antagonist. Microdialysis studies show that acute oral administration increases extracellular levels of 5-HT, by an impulse-dependent mechanism, above those produced by a maximally effective dose of fluoxetine, and in rats to levels only achieved following chronic fluoxetine treatment. Its neurochemical profile in vivo suggests that it may be a more effective antidepressant with the potential for producing an earlier onset of clinical activity than selective serotonin reuptake inhibitors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11734183&dopt=Abstract fluoxetine Prozac



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Effects of chronic fluoxetine in animal models of anxiety and depression.

Dulawa SC, Holick KA, Gundersen B, Hen R.

Center for Neurobiology and Behavior, Columbia University, New York, NY 10032, USA.

The onset of the therapeutic response to antidepressant treatment exhibits a characteristic delay. Animal models sensitive to chronic, but not acute, antidepressant treatment are greatly needed for studying antidepressant mechanisms. We initially assessed four inbred mouse strains for their behavioral response to chronic treatment with the selective-serotonin reuptake inhibitor fluoxetine (0, 5, 10 mg/kg/day in drinking water), which is used for the treatment of mood and anxiety disorders. Only the highly anxious BALB/c strain exhibited sensitivity to fluoxetine in the forced swim test. Additionally, fluoxetine reduced locomotion in C57BL/6 and 129SvEv, but not BALB/c and DBA/2, strains. We then evaluated the effects of subchronic (approximately 4 days) and chronic (approximately 24 days) fluoxetine treatment (0, 10, 18, 25 mg/kg/day) on measures of anxiety and depression in BALB/c mice. Anxiety measures were obtained using the open field and novelty-induced hypophagia tests. Antidepressant effects were evaluated using the forced swim test. We found 18 mg/kg/day of chronic fluoxetine to be active in all three paradigms; subchronic treatment had no effect. Anxiety-related measures were reduced by 18 mg/kg/day. In the forced swim test, 10 and 18 mg/kg/day increased swimming and reduced immobility. Here we present several novel effects of chronic, but not subchronic, antidepressant treatment. Copyright 2004 Nature Publishing Group

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15085085&dopt=Abstract fluoxetine Prozac



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O-Dealkylation of fluoxetine in relation to CYP2C19 gene dose and involvement of CYP3A4 in human liver microsomes.

Liu ZQ, Zhu B, Tan YF, Tan ZR, Wang LS, Huang SL, Shu Y, Zhou HH.

Pharmacogenetics Research Institute, Xiang-Ya School of Medicine, Central South University, Changsha, Hunan, People's Republic of China.

This work evaluated the kinetic behavior of fluoxetine O-dealkylation in human liver microsomes from different CYP2C19 genotypes and identified the isoenzymes of cytochrome P450 involved in this metabolic pathway. The kinetics of the rho-trifluoromethylphenol (TFMP) formation from fluoxetine was determined in human liver microsomes from three homozygous (wt/wt) and three heterozygous (wt/m1) extensive metabolizers (EMs) and three poor metabolizers (PMs) with m1 mutation (m1/m1) with respect to CYP2C19. The formation rate of TFMP was determined by gas chromatograph with electron-capture detection. The kinetics of TFMP formation was best described by the two-enzyme and single-enzyme Michaelis-Menten equation for liver microsomes from CYP2C19 EMs and PMs, respectively. The mean intrinsic clearance (V(max)/K(m)) for the high- and low-affinity component was 25.2 microl/min/nmol and 3.8 microl/min/nmol of cytochrome P450 in the homozygous EMs microsomes and 12.8 microl/min/nmol and 2.9 microl/min/nmol of cytochrome P450 in the heterozygous EMs microsomes, respectively. Omeprazole (a CYP2C19 substrate) at a high concentration and triacetyloleandomycin (a selective inhibitor of CYP3A4) substantially inhibited O-dealkylation of fluoxetine. Furthermore, fluoxetine O-dealkylation was correlated significantly with S-mephenytoin 4'-hydroxylation at a low substrate concentration and midazolam 1'-hydroxylation at a high substrate concentration in liver microsomes of 11 Chinese individuals, respectively. Moreover, there were obvious differences in the O-dealkylation of fluoxetine in liver microsomes from different CYP2C19 genotypes and in microsomal fractions of different human-expressed lymphoblast P450s. The results demonstrated that polymorphic CYP2C19 and CYP3A4 enzymes were the major cytochrome P450 isoforms responsible for fluoxetine O-dealkylation, whereas CYP2C19 catalyzed the high-affinity O-dealkylation of fluoxetine, and its contribution to this metabolic reaction was gene dose-dependent.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11752104&dopt=Abstract fluoxetine Prozac