Brain Res. 1991 Feb 1;540(1-2):325-30.
Persistent blockade of potassium-evoked serotonin release from rat frontocortical terminals after fluoxetine administration.

Gardier AM, Wurtman RJ.

Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge 02139.

We examined 5-HT and 5-HIAA release from frontal cortex evoked by high potassium chloride concentrations in rats pretreated for 3 days with high doses of the 5-HT uptake blocker fluoxetine or of dexfenfluramine, which both releases 5-HT and blocks its reuptake. The standard fluoxetine dose (30 mg/kg i.p.) was about 4 times the drug's ED50 in producing a serotonin-related behavioral effect, anorexia, while the dexfenfluramine dose (7.5 mg/kg i.p.) was about 6 times its ED50. These high doses were chosen in order to elucidate the mechanism by which similar doses of fluoxetine and dexfenfluramine had been found to produce long-term changes in serotonin dynamics. Fluoxetine decreased the basal release of both compounds; dexfenfluramine decreased basal 5-HIAA efflux without affecting the release of 5-HT release. Potassium-evoked 5-HT release was unchanged after dexfenfluramine pretreatment but was suppressed by fluoxetine doses as low as 7.5 mg per kg per day. Basal release of 5-HT and 5-HIAA returned to normal after 7 days of fluoxetine pretreatment, but evoked release continued to be suppressed. These data suggest that long-term changes in brain serotonin dynamics after high doses of dexfenfluramine or fluoxetine are related to the drug's mechanisms of action, specifically their blockade of 5-HT reuptake.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1711396&dopt=Abstract fluoxetine




Res Commun Chem Pathol Pharmacol. 1991 Jul;73(1):31-40.
Role of norfluoxetine in the inhibition of desipramine metabolism and in the inhibition of serotonin uptake after fluoxetine administration to rats.

Fuller RW, Snoddy HD.

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

Fluoxetine, a serotonin uptake inhibitor, is known to inhibit the metabolism of some drugs including desipramine, resulting in increased brain and blood levels of desipramine when the drugs are co-administered to rats. Norfluoxetine, the N-desmethyl metabolite of fluoxetine, was found to be less potent than fluoxetine in increasing brain and blood levels of desipramine in rats. Norfluoxetine was essentially equipotent to fluoxetine in decreasing brain concentrations of 5-hydroxyindoleacetic acid (5-HIAA) as a consequence of serotonin uptake inhibition. After the injection of fluoxetine into rats, brain levels of fluoxetine predominated over those of norfluoxetine at 1 hour, but at longer times (out to 24 hours), norfluoxetine levels were higher in brain (and in liver) than fluoxetine levels. Brain levels of 5-HIAA were decreased for at least 24 hours after fluoxetine injection, due apparently to the persistence of and inhibition of serotonin uptake by norfluoxetine. When desipramine was injected 16 hrs after fluoxetine injection, brain levels of desipramine were no longer elevated. The results suggest that norfluoxetine contributes in a major way to the inhibition of serotonin uptake after fluoxetine administration but contributes less, if at all, to the inhibition of desipramine metabolism.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1715593&dopt=Abstract fluoxetine




J Pharmacol Exp Ther. 1992 Feb;260(2):533-40.
Effects of fluoxetine on convulsions and on brain serotonin as detected by microdialysis in genetically epilepsy-prone rats.

Dailey JW, Yan QS, Mishra PK, Burger RL, Jobe PC.

Department of Basic Sciences, University of Illinois College of Medicine, Peoria.

Fluoxetine, an antidepressant and inhibitor of serotonin reuptake, was evaluated as an anticonvulsant in genetically epilepsy-prone rats (GEPRs) because seizure predisposition in GEPRs is partially dependent on deficits in brain serotonin. Fluoxetine produced dose-dependent reductions in sound-induced convulsion intensity in both moderate seizure GEPRs and severe seizure GEPRs with the peak anticonvulsant effect occurring 4 hr after i.p. administration. A subchronic study in severe seizure GEPRs demonstrated that the ED50 after 28 days of dosing (8.2 mg/kg) was lower than the acute ED50 (15.9 mg/kg) so that there was no apparent development of tolerance. The lower ED50 after subchronic administration apparently resulted from accumulation of fluoxetine and its metabolite norfluoxetine in brain. Brain microdialysis studies showed that acute fluoxetine administration resulted in a significant increase in extracellular serotonin concentration in the thalamus. The increase in serotonin concentration in the dialysate corresponded temporally with the anticonvulsant effect produced by fluoxetine. Intrathalamic administration of fluoxetine via the dialysis probe caused an increase in serotonin concentration in the dialysate, suggesting that the effect of fluoxetine was on nerve terminals. Fluoxetine could be dialyzed from thalamus after its i.p. administration. Fluoxetine concentration in the thalamic dialysate was similar to the concentration found in plasma. We conclude that fluoxetine is an effective anticonvulsant in GEPRs and that the microdialysis results strongly suggest a relationship between the effects of fluoxetine on serotonergic neurons and the anticonvulsant effect produced by this drug.




J Pharm Pharmacol. 1992 Aug;44(8):696-8.
Anorectic activity of fluoxetine and norfluoxetine in mice, rats and guinea-pigs.

Anelli M, Bizzi A, Caccia S, Codegoni AM, Fracasso C, Garattini S.

Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.

The present study aimed to establish the role of the metabolite norfluoxetine in the anorectic activity of fluoxetine, and to relate the anorectic doses (ED50) to the brain concentrations of the parent drug and its metabolite. Fluoxetine showed anorectic activity at increasing intraperitoneal doses (ED50 = 39.1, 34.7 and 21.7 mumol kg-1 in mouse, rat and guinea-pig, respectively) and norfluoxetine was slightly more active (24.3, 22.9 and 19.1 mumol kg-1, respectively) in all three species. In terms of maximum concentration (Cmax) and area under the curve (AUC) within the experimental period (0-90 min), brain concentrations varied widely and were poorly related to the dose; guinea-pig appeared to be much more sensitive to fluoxetine than was mouse or rat. Administered norfluoxetine was present in the brain of the three species in approximately the same order as fluoxetine, i.e. lower in guinea-pig than in mouse or rat. The Cmax and AUC of norfluoxetine after fluoxetine administration was 50-60% of the values after an equiactive dose of norfluoxetine in mouse and guinea-pig, and more than 80% in rat.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1359101&dopt=Abstract fluoxetine




Clin Pharmacol Ther. 1991 Jul;50(1):10-5.
Increased carbamazepine plasma concentrations after fluoxetine coadministration.

Grimsley SR, Jann MW, Carter JG, D'Mello AP, D'Souza MJ.

Department of Pharmacy Practice, Mercer University School of Pharmacy, Atlanta, GA 30312.

The interaction between fluoxetine and carbamazepine was investigated in six normal, healthy male volunteers (aged 23 to 40 years). Subjects were given carbamazepine, 400 mg every morning, for 3 weeks. Venous carbamazepine blood samples were obtained at baseline and 1, 2, 4, 6, 8, 10, 12, and 24 hours after the morning dose. Fluoxetine, 20 mg every morning, was then coadministered with carbamazepine for 7 days. Venous carbamazepine blood samples were again obtained as described. Carbamazepine and carbamazepine-10,11-epoxide (CBZE) were assayed by HPLC. Addition of fluoxetine resulted in a significant increase in the area under the concentration-time curve of carbamazepine (105.93 +/- 18.05 micrograms/ml.hr versus 134.97 +/- 12.15 micrograms/ml.hr; t = 3.284; df = 5; p = 0.022) and CBZE (11.6 +/- 1.93 micrograms/ml.hr versus 15.2 +/- 2.4 micrograms/ml.hr; t = 2.805; df = 5; p = 0.038). Both oral and intrinsic clearance of carbamazepine was decreased significantly on fluoxetine addition (3.87 +/- 0.68 L/hr versus 2.98 +/- 0.26 L/hr; t = 3.025; df = 5; p = 0.029 and 17.90 +/- 4.9 L/hr versus 11.92 +/- 1.4 L/hr; t = 3.037; df = 5; p = 0.029, respectively). No significant changes were determined for fraction of absorbed dose, volume of distribution, absorption rate constant, and elimination rate constant. These findings suggest that fluoxetine can inhibit the metabolism of carbamazepine. Careful monitoring of patients is recommended when these two drugs are coadministered.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1855347&dopt=Abstract fluoxetine




J Clin Psychopharmacol. 1991 Feb;11(1):52-4.
Fluoxetine treatment of bipolar II depression.

Simpson SG, DePaulo JR.

Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland.

We have previously reported on the familial aggregation of bipolar II affective disorder and have speculated that new treatment approaches might be required for this difficult disorder. Based on Reimherr's report that fluoxetine responders were more likely to have poor prior responses to tricyclics and to have chronic depressions with "atypical" clinical features, we used fluoxetine to treat the chronic atypical depression in selected bipolar II outpatients. The 16 bipolar II patients in our series had been depressed for an average of 5.3 years prior to starting fluoxetine and had had poor responses to tricyclics, MAOIs, and lithium. All but one have had some response to fluoxetine. Ten of the 13 patients who have been taking fluoxetine for 10 or more months have had a good to very good response and the other 3 have had a fair response. Only one patient discontinued fluoxetine because of side effects. These findings should encourage further treatment research using fluoxetine and other serotonin reuptake blockers as well as research into the pathophysiologic identity of bipolar II as a possible distinct form of affective disorder.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2040716&dopt=Abstract fluoxetine




Neuropharmacology. 1992 Apr;31(4):343-7.
Effects of short- and long-term administration of fluoxetine on the monoamine content of rat brain.

Caccia S, Fracasso C, Garattini S, Guiso G, Sarati S.

Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.

The effects of repeated doses of fluoxetine over time and dose-responses of the content of indoles and catecholamines and metabolism, were examined in rats in relation to the concentrations of the parent compound and its active metabolite norfluoxetine in brain. Brains were removed for assays of the regional content of monoamines and concentrations of drugs 24 hr after the last dose on days 1, 7 and 21 of a twice-daily schedule of fluoxetine (15 mg/kg, i.p.). Measurements were also taken 1 week after the last dose (7.5 and 15 mg/kg, b.i.d.) of the 21-day regimen. On day 1 fluoxetine did not change the content of serotonin (5-HT) but reduced the concentrations of 5-hydroxyindolacetic acid (5-HIAA) in the hippocampus and cortex, compatible with the action of a blocker of the uptake of 5-HT. Continued injections of fluoxetine, however, significantly reduced 5-HT in the brain of the rat, the depletion being significant on days 7 and 21 in the hippocampus and cortex, respectively. The content of indoles remained significantly decreased for at least a week after the last dose of fluoxetine in the 21-day regimen, although the concentrations of 5-HIAA (but not 5-HT) totally recovered at the smaller dose (7.5 mg/kg) in all regions of the brain (cortex, hippocampus and striatum). In spite of slight changes in the concentrations and metabolism of dopamine (DA) in the striatum, 24 hr after the last dose (15 mg/kg), treatment with drug had no significant long-term effects on the content of catecholamines in these regions of the brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1381817&dopt=Abstract fluoxetine




J Chromatogr. 1991 Feb 15;563(2):379-84.
Solid-phase extraction of fluoxetine and norfluoxetine from serum with gas chromatography-electron-capture detection.

Dixit V, Nguyen H, Dixit VM.

Varian Sample Preparation Products, Harbor City, CA 90710.

A rapid, selective, and sensitive method is described for the purification and analysis of fluoxetine and norfluoxetine using a solid-phase extraction column and gas chromatography-electron-capture detection. Linear quantitative response curves for fluoxetine and norfluoxetine are generated over a concentration range of 20-200 ng/ml. Overall extraction efficiency of the extraction procedure is found to be greater than 90% and greater than 75% with correlation coefficients of 0.997 and 0.993 for fluoxetine and norfluoxetine, respectively.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2056002&dopt=Abstract fluoxetine




J Clin Psychiatry. 1992 Aug;53(8):278-82.
Does fluoxetine exacerbate Parkinson's disease?

Caley CF, Friedman JH.

University of Rhode Island, Cranston.

BACKGROUND: Because fluoxetine may be associated with an induction or exacerbation of parkinsonism, caution has been suggested when considering fluoxetine as an antidepressant for patients with Parkinson's disease. METHOD: We retrospectively reviewed the medical records of 23 outpatients with Parkinson's disease who were receiving or had received fluoxetine. One author evaluated all patients using the Northwestern University Disability Scale for scoring parkinsonism. Rather than employing a formal depression scale, we assessed depression globally. Concurrent medications were permitted. RESULTS: Twenty of the 23 patients experienced no worsening of parkinsonism while being treated with up to 40 mg of fluoxetine per day. The other 3 patients' parkinsonism worsened to a mild degree: a 74-year-old man experienced an increase in akinesia, tremor, and rigidity; a 77-year-old man experienced a slight worsening in tremor and rigidity; and a 56-year-old man experienced a decline in gait and akinesia. It was unclear if these declines, which were neither acute nor severe, were due to fluoxetine treatment or the progression of the disease. Signs of parkinsonism in 2 patients appeared to improve during fluoxetine treatment. CONCLUSION: Fluoxetine, in doses up to 40 mg/day, does not appear to be associated with exacerbations of parkinsonian signs and symptoms in outpatients with Parkinson's disease. Further investigation of fluoxetine for the treatment of depression in patients with Parkinson's disease is warranted.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1500404&dopt=Abstract fluoxetine