unisi.it

Depression is a mood disorder characterized by complex alterations of neurotransmitters such as serotonin, norepinephrine, and dopamine. In particular, there is substantial evidence of abnormalities in serotonin neurotransmission. Peripheral parameters of serotoninergic transmission, such as the 5-hydroxytryptamine content of plasma and platelets, have been used to identify biochemical alterations related to depression. In recent years, these parameters have also been used to examine the mechanism of action of antidepressive drugs such as the selective serotonin reuptake inhibitors.This study investigated the interaction between the plasma and platelet levels of fluoxetine and serotonin after fluoxetine administration to depressed patients. Twelve patients affected by major depression (according to the DSM-IV criteria) received a single oral dose of fluoxetine in the morning: 5 mg in the first 5 days, 10 mg from day 6 to day 10, and 20 mg from day 11 to day 40. Blood samples were collected at 0, 7, 10, and 24 hours after drug administration on the day 1 of fluoxetine 5 mg and on the 1st and the 30th day of fluoxetine 20 mg (days 11 and 40 of treatment, respectively).Plasma fluoxetine and serotonin levels increased after drug administration, reaching the highest levels on the 30th day of fluoxetine 20 mg. Fluoxetine levels were also detectable in platelets, with a time variation similar to plasma values. Platelet serotonin levels decreased after drug administration, and the lowest values were observed on the 30th day of fluoxetine 20 mg.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11910257&dopt=Abstract fluoxetine




Pediatr Res. 2002 Apr;51(4):433-42.
Effect of maternal fluoxetine administration on uterine blood flow, fetal blood gas status, and growth.

Morrison JL, Chien C, Riggs KW, Gruber N, Rurak D.

Department of Obstetrics and Gynaecology, British Columbia Research Institute for Children's & Women's Health, Vancouver, BC, Canada.

Clinical depression, diagnosed in 5-15% of women during pregnancy, increases the risk of negative pregnancy outcomes including an increased incidence of low birth weight newborns and preterm delivery. Fluoxetine, a selective serotonin reuptake inhibitor, is often prescribed to treat depression due to its efficacy, high margin of safety, and mild side effects. However, fluoxetine initially increases plasma serotonin concentration, and serotonin causes uterine vasoconstriction in sheep, which could result in fetal hypoxemia. To assess fetal fluoxetine effects, late-gestation pregnant sheep were surgically prepared for the measurement of blood gases, heart rate, blood pressure, and uterine artery blood flow (n = 29). Ewes received a 70-mg bolus i.v. infusion of fluoxetine over 2 min in 10 mL of sterile water followed by continuous infusion at a rate of 100 microg/min for 8 d (n = 14), or continuous infusion of sterile water (n = 15). Transient decreases in uterine artery blood flow, fetal PO(2), and oxygen saturation were observed within the first 15 min after fluoxetine exposure, which did not return to normal values by 24 h. Fetal pH decreased and PCO(2) increased over the first 4 h with a return to normal by 24 h. However, there were no differences in uterine artery blood flow, blood gas status, or cardiovascular measures between the control and fluoxetine group over the rest of the 8-d infusion period. Thus, fluoxetine exposure during pregnancy has transient effects on fetal status that may be of developmental consequence if they occur repetitively.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11919327&dopt=Abstract fluoxetine

Lilly.com

RATIONALE: The selective serotonin uptake inhibitor (SSRI) fluoxetine has been shown to not only increase the extracellular concentrations of serotonin, but also dopamine and norepinephrine extracellular concentrations in rat prefrontal cortex. The effect of other SSRIs on monoamine concentrations in prefrontal cortex has not been thoroughly studied. OBJECTIVE: The aim of this study was to compare the ability of five systemically administered selective serotonin uptake inhibitors to increase acutely the extracellular concentrations of serotonin, norepinephrine and dopamine in rat prefrontal cortex. METHODS: The extracellular concentrations of monoamines were determined in the prefrontal cortex of conscious rats using the microdialysis technique. RESULTS: Fluoxetine, citalopram, fluvoxamine, paroxetine and sertraline similarly increased the extracellular concentrations of serotonin from 2- to 4-fold above baseline. However, only fluoxetine produced robust and sustained increases in extracellular concentrations of norepinephrine and dopamine after acute systemic administration. Fluoxetine at the same dose blocked ex vivo binding to the serotonin transporter, but not the norepinephrine transporter, suggesting that the increase of catecholamines was not due to non-selective blockade of norepinephrine uptake. Prefrontal cortex extracellular concentrations of fluoxetine at the dose that increased extracellular monoamines were 242 nM, a concentration sufficient to block 5-HT(2C) receptors which is a potential mechanism for the fluoxetine-induced increase in catecholamines. CONCLUSION: Amongst the S




Neurochem Res. 2002 Feb;27(1-2):113-20.
Up-regulation of 5-HT2B receptor density and receptor-mediated glycogenolysis in mouse astrocytes by long-term fluoxetine administration.

Kong EK, Peng L, Chen Y, Yu AC, Hertz L.

Department of Biology, The Hong Kong University of Science and Technology, China.

The effects were studied of short-term (1 week) versus long-term (2-3 weeks) fluoxetine treatment of primary cultures of mouse astrocytes, differentiated by treatment with dibutyryl cyclic AMP. From previous experiments it is known that acute treatment with fluoxetine stimulates glycogenolysis and increases free cytosolic Ca2+ concentration ([Ca2+]i]) in these cultures, whereas short-term (one week) treatment with 10 microM down-regulates the effects on glycogen and [Ca2+]i, when fluoxetine administration is renewed (or when serotonin is administered). Moreover, antagonist studies have shown that these responses are evoked by activation of a 5-HT2, receptor that is different from the 5-HT2A receptor and therefore at that time tentatively were interpreted as being exerted on 5-HT2C receptors. In the present study the cultures were found by RT-PCR to express mRNA for 5-HT2A and 5-HT2B receptors, but not for the 5-HT2C receptor, identifying the 5-HT2 receptor activated by fluoxetine as the 5-HT2B receptor, the most recently cloned 5-Ht2 receptor and a 5-HT receptor known to be more abundant in human, than in rodent, brain. Both short-term and long-term treatment with fluoxetine increased the specific binding of [3H]mesulergine, a ligand for alL three 5-HT2 receptors. Long-term treatment with fluoxetine caused an agonist-induced up-regulation of the glycogenolytic response to renewed administration of fluoxetine, whereas short-term treatment abolished the fluoxetine-induced hydrolysis of glycogen. Thus, during a treatment period similar to that required for fluoxetine's clinical response to occur, 5-HT2B-mediated effects are initially down-regulated and subsequently up-regulated.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=119309&dopt=Abstract




Convuls Ther. 1989;5(4):344-348.
Does Fluoxetine Prolong Electrically Induced Seizures?

Gutierrez-Esteinou R, Pope HG Jr.

Biological Psychiatry Laboratory, Laboratories for Psychiatric Research, Psychosis Program, McLean Hospital, Belmont, Massachusetts, and Harvard Medical School, Boston, Massachusetts, USA.

The product literature for the novel antidepressant fluoxetine states that prolonged seizures may occur in patients receiving electroconvulsive therapy (ECT). We compared the seizure durations and incidence of prolonged seizures in 12 consecutive patients receiving ECT plus fluoxetine (20-140 mg/day) with 25 controls receiving ECT in the absence of fluoxetine. No differences were found between the groups. Indeed, within the fluoxetine group, higher doses were associated with slightly shorter average seizure durations, and greater stimulus energy was required to elicit a seizure. We find no evidence that fluoxetine prolongs electrically induced seizures.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11941033&dopt=Abstract fluoxetine




Am J Phys Med Rehabil. 2002 May;81(5):364-72.
Effects of fluoxetine on the 5-HT1A receptor and recovery of cognitive function after traumatic brain injury in rats.

Wilson MS, Hamm RJ.

Department of Psychology, Virginia Commonwealth University, Richmond, Virginia 23284-2018, USA.

OBJECTIVE: This study examined the effects of chronic administration of fluoxetine, a selective serotonin reuptake inhibitor, on cognitive performance and 5-HT1A receptor immunoreactivity following traumatic brain injury. DESIGN: Rats received a moderate severity of lateral fluid percussive injury or sham injury 24 hr after surgical preparation. Fluoxetine or vehicle was administered chronically on postinjury days 1-15. Motor performance and Morris water maze performance were assessed on postinjury days 1-5 and 11-15, respectively. RESULTS: Results indicated that chronic fluoxetine treatment did not affect motor or maze performance. Injured groups showed significantly higher 5-HT1A receptor immunoreactivity on postinjury day 15 than sham-injured rats, and fluoxetine treatment did not alter 5-HT1A receptor immunoreactivity. CONCLUSIONS: These results indicate that chronic postinjury fluoxetine administration did not influence the recovery of motor or Morris water maze performance following lateral fluid percussive injury. They also indicate that injury-induced changes in the 5-HT1A receptor may contribute to traumatic brain injury-induced cognitive deficits.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11964577&dopt=Abstract fluoxetine

bradford.ac.uk

The effect of the selective serotonin reuptake inhibitor fluoxetine was examined on the 5-HT4 receptor-mediated relaxation in the rat isolated ileum. Fluoxetine unsurmountably antagonized the relaxation to exogenous 5-HT with abolition of the response at 10 microM. Fluoxetine (10 microM) also caused a gradual loss of the resting tension. These effects of fluoxetine were prevented by a prior addition of the 5-HT4 receptor selective antagonist GR113808 (100 nM), which itself caused a contraction of the tissues when administered alone. Fluoxetine (10 microM) also failed to prevent the relaxation due to exogenous 5-HT and the 5-HT4 receptor agonist 5-methoxytryptamine in tissues taken from the rats treated with para-chlorophenylalanine (300 mg kg-1) for 3 and 6 days, which reduced the 5-HT level in the mucosa by 88 and 97.5% respectively. The contraction of the tissues with GR113808 indicates the presence of an endogenous 5-HT tone at the 5-HT4 receptor in the rat ileum. It is hypothesized that in the presence of fluoxetine, the concentration of endogenous 5-HT at the receptor was increased sufficiently to reduce or abolish the relaxation to 5-HT added exogenously. The inability of fluoxetine to prevent the relaxation to 5-HT in the presence of GR113808 or after the p-CPA treatment supports this hypothesis.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11976280&dopt=Abstract fluoxetine




Am J Psychiatry. 2002 May;159(5):755-60.
Fluorine magnetic resonance spectroscopy measurement of brain fluvoxamine and fluoxetine in pediatric patients treated for pervasive developmental disorders.

Strauss WL, Unis AS, Cowan C, Dawson G, Dager SR.

Center on Human Development and Disability, University of Washington, Seattle, 98105-6099, USA.

OBJECTIVE: Pediatric populations, including those with autistic disorder or other pervasive developmental disorders, increasingly are being prescribed selective serotonin reuptake inhibitors (SSRIs). Little is known about the age-related brain pharmacokinetics of SSRIs; there is a lack of data regarding optimal dosing of medications for children. The authors used fluorine magnetic resonance spectroscopy ((19)F MRS) to evaluate age effects on whole-brain concentrations of fluvoxamine and fluoxetine in children taking SSRIs. METHOD: Twenty-one pediatric subjects with diagnoses of autistic disorder or other pervasive developmental disorders, 6-15 years old and stabilized with a consistent dose of fluvoxamine or fluoxetine, were recruited for the study; 16 successfully completed the imaging protocol. Whole-brain drug levels in this group were compared to similarly acquired data from 28 adults. RESULTS: A significant relationship between dose and brain drug concentration was observed for both drugs across the age range studied. Brain fluvoxamine concentration in the children was lower, consistent with a lower dose/body mass drug prescription; when brain concentration was adjusted for dose/mass, age effects were no longer significant. Brain fluoxetine concentration was similar between age groups; no significant age effects on brain fluoxetine drug levels remained after adjustment for dose/mass. Observations of brain fluoxetine bioavailability and elimination half-life also were similar between age groups. CONCLUSIONS: These findings suggest that fluvoxamine or fluoxetine prescriptions adjusted for dose/mass are an acceptable treatment approach for medicating




J Chromatogr B Analyt Technol Biomed Life Sci. 2002 Apr 5;769(2):305-11.
Simultaneous determination of fluoxetine and its metabolite p-trifluoromethylphenol in human liver microsomes using a gas chromatographic-electron-capture detection procedure.

Liu ZQ, Tan ZR, Wang D, Huang SL, Wang LS, Zhou HH.

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

An gas chromatography-electron-capture detection method has been developed for simultaneous determination of fluoxetine and p-trifluoromethylphenol (TFMP), an O-dealkylated metabolite of fluoxetine in human liver microsomes. Prior to the analysis, aliquots of alkalinized microsomal mixture were extracted with ethyl acetate solvent containing acetonitrile (10%, v/v) and the derivatizing reagent, pentafluorobenzenesulfonyl chloride (0.1%, v/v). The organ phase was retained and taken to dryness, the residue was reconstituted in methanol, and the aliquot of extracts was injected directly into a gas chromatograph equipped with an electron-capture detector. 2,4-Dichlorophenol was added to the initial incubation mixture and carried through the procedure as the internal standard. The method provided the mean recoveries of up to 103% for fluoxetine and 104% for TFMP. Acceptable relative standard deviations were found for both within-run and day-to-day assays. The practical limit of detection (signal-to-noise ratio=3) was 1.62 ng/ml for TFMP and 6.92 ng/ml for fluoxetine in human liver microsomes, and the limit of quantitation was 8.1 pg for TFMP and 34.6 pg for fluoxetine. The assay is rapid and sensitive and has been applied successfully to simultaneous quantification of fluoxetine and TFMP in human liver microsomes with different CYP2C19 genotypes.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11996496&dopt=Abstract fluoxetine