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Chronic fluoxetine reduces serotonin transporter mRNA and 5-HT1B mRNA in a sequential manner in the rat dorsal raphe nucleus.

Neumaier JF, Root DC, Hamblin MW.

Department of Psychiatry, University of Washington, USA.

In major depression in humans and in animal models of depression, there is a defect in serotonergic neurotransmission that can be relieved by chronic antidepressant treatment. One possibility is that this pathologic state is caused by excessive presynaptic autoreceptor activity in serotonergic neurons, and that antidepressants down-regulate the number of these inhibitory receptors, allowing more normal serotonin release to occur. To evaluate this hypothesis, we measured the effects of the antidepressant fluoxetine on neuronal levels of 5-HT1B receptor mRNA, the putative serotonin terminal autoreceptor in rat brain, and on serotonin transporter mRNA, the direct site of fluoxetine binding. Fluoxetine reduced serotonin transporter mRNA briefly, but this was not sustained after 21 days of treatment. However, fluoxetine reduced dorsal raphe 5-HT1B mRNA levels in a time-dependent and washout-reversible manner. This reduction in 5-HT1B mRNA was specific to dorsal raphe nucleus and was not found in several postsynaptic (nonserotonergic) regions. These results suggest that chronic fluoxetine may increase serotonin release from axonal terminals by down-regulating the messenger RNA coding for presynaptic 5-HT1B autoreceptors while causing only transient effects on serotonin transporter mRNA.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8914125&dopt=Abstract fluoxetine Prozac



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[Comparison of the effect of fluoxetine combined with hormone replacement therapy (HRT) and single HRT in treating menopausal depression]

[Article in Chinese]

Yu Q, Yin CX, Hui Y, Yu J, He FF, Wei J, Wu YY.

Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy Medical Sciences, Beijing 100730, China.

OBJECTIVE: To compare the treatment effects between fluoxetine plus hormone replacement therapy (HRT) and HRT alone on menopausal depression. METHODS: A total of 54 women with climacteric symptoms and depression were enrolled and randomly divided into two groups. The fluoxetine plus HRT group received fluoxetine (20 mg, qd, po) and cyclic use of conjugated estrogen 0.625 mg and medroxyprogesterone acetate 5 mg, while HRT group was assigned to receive cyclic use of conjugated estrogen 0.625 mg and medroxyprogesterone acetate 5 mg only. All subjects were interviewed and evaluated with Hamilton Depression score (HAMD) and Kupperman menopause index (KMI) at week 0, 1, 2, 3, 4, 6 and 8 of the treatment. RESULTS: There was no difference between two groups in HAMD and KMI before the trial (P > 0.05). HAMD scores at the 8th week in fluoxetine plus HRT group and HRT group were 3.0 +/- 2.3 and 11.2 +/- 5.8 respectively, being significantly different (P < 0.001). At the 6th week of treatment KMIs in fluoxetine plus HRT group and HRT group were 9 +/- 6 and 14 +/- 7 respectively, also significantly different (P < 0.05). The healing rates of fluoxetine plus HRT group and HRT group were 92% and 48% respectively, which were statistically different by Chi square test (P < 0.001). CONCLUSIONS: The effect of fluoxetine plus HRT on menopausal depression is significantly superior than that of HRT only and the difference becomes more obvious with treatment time. Both groups could ameliorate the climacteric symptoms with the effect of fluoxetine plus HRT more obvious.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15347469&dopt=Abstract fluoxetine Prozac



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Chronic fluoxetine induces a gradual desensitization of 5-HT1A receptors: reductions in hypothalamic and midbrain Gi and G(o) proteins and in neuroendocrine responses to a 5-HT1A agonist.

Li Q, Muma NA, van de Kar LD.

Department of Pharmacology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, USA.

The time course of fluoxetine-induced desensitization of hypothalamic 5-hydroxytryptamine1A receptors was examined in rats. Daily injections of fluoxetine (10 mg/kg/day) for 0, 3, 7, 14 or 22 days gradually produced a shift to the right in the dose-response curve effects of 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) on plasma adrenal corticotropic hormone, corticosterone and oxytocin. A partial reduction was observed for the adrenal corticotropic hormone and oxytocin responses to 8-OH-DPAT (50 micrograms/kg s.c.) after 3 days, and a maximum reduction of all hormone responses was observed after 14 days of fluoxetine injections, when the adrenal corticotropic hormone and oxytocin responses to the 50-micrograms/kg dose of 8-OH-DPAT were virtually blocked. To begin to examine the mechanism of 5-hydroxytryptamine1A receptor desensitization, we determined levels of Gi and G(o) proteins in the hypothalamus, midbrain and frontal cortex by using immunoblots. The hypothalamic levels of Gi1 and Gi3 proteins were significantly reduced after 7 and 14 days of fluoxetine injections. The levels of G(o) and Gi2 proteins in the midbrain were significantly decreased after 3 days and remained reduced for the duration of fluoxetine injections. Fluoxetine did not reduce the concentrations of Gi and G(o) proteins in the frontal cortex at any time. The similarity in time course between fluoxetine-induced reductions in hormone responses to 8-OH-DPAT and the reduction in hypothalamic levels of Gi1 and Gi3 proteins suggests that a reduction in hypothalamic levels of Gi3 and/or Gi1 proteins plays a role in the gradual desensitization of 5-hydroxytryptamine1A receptors induced by fluoxetine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8930214&dopt=Abstract fluoxetine Prozac



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Influence of fluoxetine on regional serotonin synthesis in the rat brain.

Muck-Seler D, Jevric-Causevic A, Diksic M.

Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.

The aim of the present study was to test the hypothesis that there should be a difference between the effects of an acute and an 8-day (chronic) administration of fluoxetine (10 mg/kg) on the rate of serotonin [5-hydroxytryptamine (5-HT)] synthesis. The 5-HT synthesis rate was measured in discrete regions of the rat brain using the alpha-[14C]methyl-L-tryptophan autoradiographic method. The results show that the acute and chronic fluoxetine treatments influence the 5-HT synthesis rate in different ways. A single dose of fluoxetine induced a significant increase in 5-HT synthesis in the visual, auditory, and parietal cortices, substantia nigra, hypothalamus, ventral thalamus, and dorsal hippocampus. In contrast, after a chronic treatment a decrease was observed in the substantia nigra, caudate, and nucleus accumbens, the auditory, parietal, sensorimotor, and frontal cortices, and ventral tegmental area. A significant decrease in the rate of 5-HT synthesis was observed in the dorsal raphe after both the single and chronic treatments. The results suggest that extracellular 5-HT has a delayed influence on the brain 5-HT synthesis rate in structures with serotonergic terminals. The findings from the acute study could be important for patients who have just started receiving fluoxetine treatment, as an increase in the 5-HT synthesis rate might occur in the acute phase of their treatment. In addition, the findings, from the chronic treatment study might give us a better understanding of how the brain serotonergic system adapts during a prolonged exposure to extracellular 5-HT.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8931476&dopt=Abstract fluoxetine Prozac



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Excretion of fluoxetine and its metabolite, norfluoxetine, in human breast milk.

Taddio A, Ito S, Koren G.

Faculty of Medicine, University of Toronto, Canada.

A study was conducted to measure breast milk concentrations of fluoxetine and its active metabolite, norfluoxetine, excreted in breast milk in a cohort of nursing women using fluoxetine, and to estimate infant dose from nursing. The study included 10 women nursing 11 infants (median age, 185 days). The mean fluoxetine dose was 0.39 mg/kg/day. Each patient manually collected 3 to 6 milk samples throughout a dosing interval. Concentrations of fluoxetine and norfluoxetine in milk were measured by gas-liquid chromatography. Mothers reported whether they observed adverse effects in their infants. The average infant doses of fluoxetine and norfluoxetine, as estimated for an exclusively breast-fed infant ingesting 1000 mL of milk per day, were 0.077 mg (SD = 0.054 mg) and 0.084 mg (SD = 0.043 mg), respectively. The total dose of fluoxetine and norfluoxetine (expressed as fluoxetine equivalents) was 0.165 mg (SD = 0.092 mg), which was equivalent to 10.8% (SD = 2.2%) of the maternal dose, adjusted on a mg/kg basis in a 4-kg infant. No adverse events were reported by mothers in their infants. Approximately one tenth of the adult therapeutic dose of fluoxetine is excreted in breast milk. Although short-term adverse effects in the infant from exposure through nursing were not reported in this cohort, future studies that assess the potential long-term consequences are needed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8932542&dopt=Abstract fluoxetine Prozac



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Fluoxetine treatment of children with selective mutism: an open trial.

Dummit ES 3rd, Klein RG, Tancer NK, Asche B, Martin J.

New York State Psychiatric Institute, Columbia University, New York, USA.

OBJECTIVE: A pilot study was designed to evaluate the safety and efficacy of fluoxetine treatment for children with selective mutism (elective mutism in DSM-III-R). METHOD: Twenty-one children (mean age 8.2 years, range 5 through 14) participated in a 9-week open trial of fluoxetine in graduated doses (mean end dose 28.1 mg, range 10 to 60 mg) with systematic baseline and outcome evaluations and weekly clinical assessment. RESULTS: All 21 children met DSM-III-R and DSM-IV criteria for anxiety disorders. After fluoxetine treatment, 76% were improved, with diminished anxiety and increased speech in public settings, including school. Improvement at week 9 was inversely correlated with age. CONCLUSIONS: Persistent selective mutism presenting with comorbid anxiety disorders may respond to fluoxetine treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8935208&dopt=Abstract fluoxetine Prozac



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The disposition of fluoxetine but not sertraline is altered in poor metabolizers of debrisoquin.

Hamelin BA, Turgeon J, Vallee F, Belanger PM, Paquet F, LeBel M.

School of Pharmacy, Universite Laval, Quebec Heart Institute, Laval Hospital, Sainte-Foy, Canada.

BACKGROUND: Substrates and inhibitors of the cytochrome P450 isozyme CYP2D6 have overlapping structural characteristics. Two prototype serotonin uptake inhibitors, sertraline and fluoxetine, share these structural criteria and have been identified as potent inhibitors of CYP2D6 in vitro. The current study was undertaken to investigate whether genetically determined CYP2D6 activity alters the disposition of sertraline or fluoxetine or both. METHODS: Single doses of sertraline (50 mg) and fluoxetine (20 mg) were administered successively to 20 young men with high (extensive metabolizers; n = 10) and low (poor metabolizers; n = 10) CYP2D6 activity. Blood and urine samples were collected for 5 to 7 half-lives and sertraline, desmethylsertraline, fluoxetine, and norfluoxetine were determined by GC and HPLC techniques. RESULTS: Poor metabolizers had significantly greater fluoxetine peak plasma concentrations (Cmax; increases 57%), area under the concentration versus time curve (AUCzero-->infinity; increases 290%), and terminal elimination half-life (increases 216%) compared with extensive metabolizers. The total amount of fluoxetine excreted in the urine during 8 days was almost three times higher in poor metabolizers than in extensive metabolizers (719 versus 225 micrograms; p < 0.05), whereas the total amount of norfluoxetine excreted in urine of poor metabolizers was about half of that of extensive metabolizers (524 versus 1047 micrograms; p < 0.05). Norfluoxetine Cmax and AUCzero-->t were significantly smaller in poor metabolizers (decreases 55% and decreases 53%, respectively), and the partial metabolic clearance of fluoxetine into norfluoxetine was 10 times smaller in this group (4.3 +/- 1.9 versus 0.4 +/- 0.1 L/hr; p < 0.05). No significant differences between extensive and poor metabolizers were found for sertraline and desmethylsertraline pharmacokinetics. CONCLUSION: These data indicate that poor metabolizers accumulate fluoxetine but not sertraline and that CYP2D6 plays an important role in the demethylation of fluoxetine but not of sertraline.

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Regional differences in the effect of the combined treatment of WAY 100635 and fluoxetine: an in vivo microdialysis study.

Malagie I, Trillat AC, Douvier E, Anmella MC, Dessalles MC, Jacquot C, Gardier AM.

Laboratoire de Neuropharmacologie JE MESR 92-372, Faculte de Pharmacie, Universite Paris-Sud, Chatenay-Malabry 2, France.

We studied the changes in extracellular serotonin (5-HT) levels in the frontal cortex (FC) and ventral hippocampus (vHi) in conscious rats, induced by the combined administration of a highly selective 5-HT1A receptor antagonist, WAY 100635 (0.1 mg/kg, i.v.), and fluoxetine (1 mg/kg, i.p.), a selective 5-HT reuptake inhibitor (SSRI). In the two brain areas studied, no change in extracellular 5-HT concentrations was observed following fluoxetine administration over the 210 min post-injection period. However, in animals co-administered with [WAY 100635 + fluoxetine], the maximal increase in 5-HT levels in the FC was to 215% of the respective basal value (100%), while no significant change in 5-HT was observed in dialysates from the vHi. Furthermore, the [norfluoxetine]-to-[fluoxetine] ratio in the FC was significantly higher than in the hippocampus as measured in homogenates of animals treated with either fluoxetine alone or a prior administration of WAY 100635. Thus, WAY 100635 made the fluoxetine short-lasting effect apparent in the FC, but not by interfering with pharmacokinetic parameters of fluoxetine. Taken together, our data suggest the possibility, that either 5-HT1A autoreceptor sensitivity or uptake carrier density or higher [metabolite]-to-[parent drug] ratios in the FC than in the hippocampus may be involved in regional specific responses to SSRIs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8971740&dopt=Abstract fluoxetine Prozac