Pharmacoepidemiol Drug Saf. 1998 Aug;7(S1):S54-7.
Study of haemostasis in depressive patients treated with fluoxetine.

Laine-Cessac P, Shoaay I, Garre JB, Glaud V, Turcant A, Allain P.

Laboratoire de Pharmacologie-Toxicologie, CHU 4 rue Larrey, 49033 Angers cedex 01, France.

The object of this study was to investigate a possible pharmacological effect of fluoxetine on haemostatic function, with special attention on primary haemostasis, in order to explain haemorrhagic complications reported in some treated, depressed patients. The haemostatic function of depressive patients, who required fluoxetine therapy, was studied before and after 1 month of treatment with fluoxetine 20 or 40 mg daily. Exclusion criteria were: pregnancy, initial abnormal haemostatic function, history of coagulation abnormalities, treatment with drugs that interfere with haemostasis, and recent fluoxetine therapy. The following tests were performed: prothrombin time, partial thromboplastin time, thrombin time, plasma fibrinogen, platelet counts, bleeding time, platelet aggregation induced by ADP, epinephrine, ristocetin, collagen, arachidonic acid, and plasma determination of fluoxetine and norfluoxetine levels. Statistical analysis was performed by Wilcoxon paired sample, one-tailed test (alpha=0.05). Among 18 patients included, only eight completed the trial. The single statistically significant difference was a decreased velocity in platelet aggregation induced by epinephrine without increased bleeding time. The results failed to demonstrate any compromised haemostatic function after 20 mg daily fluoxetine therapy in patients with initial haemostatic function. However, the results suggest possible effects of fluoxetine on platelet adrenoreceptors. Copyright 1998 John Wiley & Sons, Ltd.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15073961&dopt=Abstract fluoxetine




Neuropsychopharmacology. 2004 Apr 7 [Epub ahead of print]
Effects of Chronic Fluoxetine in Animal Models of Anxiety and Depression.

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

1Center for Neurobiology and Behavior, Columbia University, New York, NY, 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.Neuropsychopharmacology advance online publication, 07 April 2004; doi:10.1038/sj.npp.1300433

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Neuroreport. 2004 Mar 22;15(4):691-4.
The pineal gland and anxiogenic-like action of fluoxetine in mice.

Uz T, Dimitrijevic N, Akhisaroglu M, Imbesi M, Kurtuncu M, Manev H.

The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 West Taylor Street, MC912, Chicago, IL 60612, USA.

Fluoxetine produces initial paradoxical anxiogenic effect in some patients. In an elevated plus-maze (EPM), fluoxetine triggers an anxiogenic-like effect in rodents. Behavioral responses to psychoactive drugs can be modified by the pineal gland. We assessed the actions of fluoxetine in the EPM in melatonin-proficient C3H mice, melatonin-deficient C57BL6 mice, and in sham-operated and pinealectomized mice. Mice were assayed 30 min after the first injection and on day 14. Protracted fluoxetine treatment reduced the time on the anxiogenic open arms and increased the entries into the safe closed arms in sham-operated C3H mice. Fluoxetine was ineffective in pinealectomized C3H or C57BL6 mice. It is possible that the pineal system contributes to the previously observed anxiogenic action of fluoxetine in humans.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15094477&dopt=Abstract fluoxetine

lilly.com

BACKGROUND: Severity of anxiety does not appear to influence the antidepressant response to fluoxetine during acute treatment of major depressive disorder (MDD). We report a retrospective pooled analysis of 2 studies to assess the effect of associated anxiety on the efficacy of fluoxetine in the continuation treatment phase of MDD. METHOD: Patients whose MDD remitted (study 1) or responded (study 2) after approximately 12 to 13 weeks of open-label treatment with fluoxetine 20 mg daily were randomly assigned in double-blind fashion to placebo, continued treatment with fluoxetine 20 mg daily, or, in study 2 only, treatment with enteric-coated fluoxetine 90 mg once weekly, for at least 25 weeks. Both studies included male and female outpatients who met criteria for MDD as assessed by DSM-III-R (study 1) or DSM-IV (study 2). Patients were categorized into high anxiety (> or = 7) or low anxiety (< 7) subgroups based on baseline Hamilton Rating Scale for Depression (HAM-D) anxiety/somatization subfactor scores. Subgroups were compared by therapy for time from randomization to relapse and change in efficacy scores. RESULTS: No significant differences in time to relapse were observed between anxiety subgroups in either active treatment group. However, in patients switched to placebo for continuation treatment, the high anxiety subgroup had a significantly higher risk of relapse than those with low anxiety (risk ratio = 1.63, p =.013). Significant differences between anxiety groups were seen in change in HAM-D anxiety/somatization subfactor scores in the fluoxetine 20 mg and placebo treatment groups, and in change in HAM-D-17 scores in the placebo treatment group (p <.05)




Pharmacotherapy. 2004 Apr;24(4):482-7.
Lack of a fluoxetine effect on prednisolone disposition and cortisol suppression.

Carson SW, Letrent KJ, Kotlyar M, Foose G, Tancer ME.

Department of Pharmacotherapy, University of North Carolina at Chapel Hill, USA.

STUDY OBJECTIVE: To evaluate the potential effect of fluoxetine, a cytochrome P450 isoenzyme inhibitor, on prednisolone disposition and cortisol suppression. DESIGN: Sequential, two-phase, crossover, open-label pharmacokinetic study. SETTING: General clinical research center. SUBJECTS: Fourteen healthy volunteers. INTERVENTION: A single intravenous dose of prednisolone 40 mg before and after 14 days of treatment with fluoxetine 20 mg/day for 5 days followed by 60 mg/day for 9 days to achieve steady-state concentrations. MEASUREMENTS AND MAIN RESULTS: Pharmacokinetic parameters of the prednisolone and resulting pharmacodynamic effects on the time course of plasma cortisol suppression before and after fluoxetine administration were evaluated. No significant differences were observed for the mean +/- SD area under the prednisolone concentration-time curve (3739 +/- 992 vs 3498 +/- 797 microg x hr/L, respectively), clearance (8.58 +/- 2.62 vs 8.92 +/- 2.05 L/hr, respectively), volume of distribution (39.5 +/- 12.4 vs 38.2 +/- 9.9 L, respectively), elimination half-life (3.32 +/- 0.83 vs 3.05 +/- 0.80 hrs, respectively), or duration of plasma cortisol suppression (23.5 +/- 3.1 vs 22.0 +/- 4.2 hrs, respectively). CONCLUSION: Fluoxetine administration did not significantly affect prednisolone disposition or prolong cortisol suppression. This finding suggests that coadministration of these agents is unlikely to result in clinically important pharmacokinetic or pharmacodynamic drug interactions. Prednisolone may be a useful alternative for patients who require both glucocorticoid and fluoxetine therapy.

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bri.niigata-u.ac.jp

1. The effects of fluoxetine, a commonly used antidepressant drug, on G protein-activated inwardly rectifying K(+) channels (GIRK, Kir3) were investigated using Xenopus oocyte expression assays. 2. In oocytes injected with mRNAs for GIRK1/GIRK2, GIRK2 or GIRK1/GIRK4 subunits, fluoxetine reversibly reduced inward currents through the basal GIRK activity. The inhibition by fluoxetine showed a concentration-dependence, a weak voltage-dependence and a slight time-dependence with a predominant effect on the instantaneous current elicited by voltage pulses and followed by slight further inhibition. Furthermore, in oocytes expressing GIRK1/2 channels and the cloned Xenopus A(1) adenosine receptor, GIRK current responses activated by the receptor were inhibited by fluoxetine. In contrast, ROMK1 and IRK1 channels in other Kir channel subfamilies were insensitive to fluoxetine. 3. The inhibitory effect on GIRK channels was not obtained by intracellularly applied fluoxetine, and not affected by extracellular pH, which changed the proportion of the uncharged to protonated fluoxetine, suggesting that fluoxetine inhibits GIRK channels from the extracellular side. 4. The GIRK currents induced by ethanol were also attenuated in the presence of fluoxetine. 5. We demonstrate that fluoxetine, at low micromolar concentrations, inhibits GIRK channels that play an important role in the inhibitory regulation of neuronal excitability in most brain regions and the heart rate through activation of various G-protein-coupled receptors. The present results suggest that inhibition of GIRK channels by fluoxetine may contribute to some of its therapeutic effects and adverse side effects, particul

mails.fju.edu.tw

Fluoxetine, an antidepressant that is used clinically in the treatment of mood disorders, is a selective serotonin reuptake inhibitor. In the present study we investigated the effects of fluoxetine on 4-aminopyridine (4AP)-evoked glutamate release in cerebrocortical nerve terminals (synaptosomes). Fluoxetine suppressed the release of glutamate evoked by 4AP in a concentration-dependent manner. This effect was associated with a reduction in the depolarization-evoked increase in cytosolic free calcium levels in the absence of significant effect on the synaptosomal membrane potential. In addition, both ionomycin- and sucrose-evoked glutamate releases were not affected by fluoxetine, indicating that fluoxetine-mediated inhibition of glutamate release is not a direct effect on the exocytotic machinery. Furthermore, the inhibitory action of fluoxetine was completely abolished in synaptosomes pretreated with P/Q type Ca(2+) channel blocker omega-agatoxin IVA (omega-AgTX IVA) or protein kinase C (PKC) stimulator 4beta-phorbol 12, 13-dibutyrate (PDBu). These results suggest that, in cerebrocortical nerve terminals, fluoxetine inhibits glutamate release through the suppression of P/Q type Ca(2+) channel activity. The presynaptic action of fluoxetine is mediated by a PKC-sensitive signaling pathway. Synapse 48:170-177, 2003. Copyright 2003 Wiley-Liss, Inc.

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J Am Geriatr Soc. 1992 Sep;40(9):902-5.
Fluoxetine in elderly patients: is there cause for concern?

Brymer C, Winograd CH.

Palo Alto Veterans Affairs Medical Center, California.

OBJECTIVE: To assess whether fluoxetine use is associated with significant weight loss or other side effects in depressed elderly patients with concomitant medical illness. DESIGN: A retrospective chart review. SETTING: A tertiary care VA hospital. PATIENTS: Five groups of outpatients were studied: (1) patients greater than 75 years old receiving fluoxetine (n = 15); (2) patients 60 to 71 years old receiving fluoxetine (n = 20); (3) patients greater than 75 years old receiving nortryptiline or desipramine (n = 20); (4) patients greater than 75 years old with a history of depression but on no antidepressant medication (n = 20); and (5) patients greater than 75 years old with no history of depression (n = 28). MEASUREMENTS: Mortality, change in weight, reports of anorexia or nausea, and serum sodium and glucose measurements. MAIN RESULTS: Patients greater than 75 years of age taking fluoxetine experienced significantly greater weight loss (average 4.6 kilograms, P = 0.0062) than the other groups. Both groups of patients taking fluoxetine were significantly more likely to report nausea (P = 0.0095) and anorexia (P = 0.0009). No significant differences were noted in mortality or the frequency of hypoglycemia or hyponatremia between groups. CONCLUSION: The frequency and degree of weight loss noted here in medically ill elderly receiving fluoxetine warrants further investigation.

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Clin Chem. 1992 Sep;38(9):1756-61.
Sensitive and selective liquid-chromatographic assay of fluoxetine and norfluoxetine in plasma with fluorescence detection after precolumn derivatization.

Suckow RF, Zhang MF, Cooper TB.

Analytical Psychopharmacology Division, New York State Psychiatric Institute, NY 10032.

We determined fluoxetine (Prozac) and its major metabolite norfluoxetine in plasma by liquid chromatography with fluorescence detection. After liquid-liquid extraction from 1 mL of plasma, the extract was derivatized at room temperature with dansyl chloride, and the highly fluorescent derivatives were chromatographed with a reversed-phase C18 column and a mobile phase of phosphate buffer and acetonitrile. Dansylated fluoxetine, norfluoxetine, and the internal standard were eluted in less than 14 min with no interference from endogenous material. The calibration curve was linear over the concentration range 25-800 micrograms/L with inter- and intra-assay imprecision (CV) of less than 10%. Validity of the assay was checked by comparing results for 110 patients' samples with those by a liquid-chromatographic method with ultraviolet detection (r = 0.993 for fluoxetine, 0.957 for norfluoxetine). The identity of the dansylated derivatives was verified by positive chemical ionization mass spectroscopy. The lower limit of detection was approximately 3 micrograms/L. Because no major antidepressant, neuroleptic, or respective drug metabolites interfere with the quantification of fluoxetine and norfluoxetine, this is a useful procedure for pharmacokinetic studies and in clinical settings.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1526010&dopt=Abstract fluoxetine