Drug Metab Dispos. 2004 Feb;32(2):212-21.
Stereoselective pharmacokinetics of fluoxetine and norfluoxetine enantiomers in pregnant sheep.

Kim J, Riggs KW, Rurak DW.

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

We examined the stereoselective disposition of fluoxetine (FX) and its metabolite norfluoxetine (NFX) in five pregnant sheep. Racemic FX was administered i.v. to the ewe (50 mg) and the fetus (10 mg) on separate occasions. Maternal and fetal blood, maternal urine, and fetal amniotic and tracheal fluid samples were collected for 72 h. FX and NFX isomers were quantified by gas chromatography-mass spectrometry. They rapidly crossed the placenta [maternal to fetal area under the plasma concentration versus time curve (AUC) ratios 0.59 and 0.65, respectively]. There was significant FX stereoselectivity with S/R FX AUC ratios averaging 1.65 +/- 0.33 and 1.73 +/- 0.29 in ewe and fetus, respectively, after maternal dosing. The maternal clearance and volume of distribution were also higher for (R)-fluoxetine than for (S)-fluoxetine. FX, NFX, and their glucuronides were present in maternal urine but accounted for only 3.4% of maternal drug elimination. In contrast, NFX was not detected in the fetus after fetal FX administration, which is consistent with the absence of measurable fetal nonplacental clearance of the drug and the lack of NFX formation in fetal hepatic microsomal incubations. There was also no fetal production of FX and NFX glucuronides in vivo. Both FX and NFX were extensively and stereoselectively bound in maternal and fetal plasma, with the free fraction S/R FX ratio averaging 0.46 +/- 0.06 and 0.58 +/- 0.10 in ewe and fetus, respectively. Thus, FX exhibits extensive stereoselective disposition, which is likely due to differential plasma protein binding of the FX isomers, and there is no detectable fetal formation of NFX, FX, and NFX glucuronides.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14744943&dopt=Abstract fluoxetine [Pu

lilly.com

BACKGROUND: Fluoxetine was the first molecule of a new generation of antidepressants, the Selective Serotonin Re-uptake Inhibitors (SSRIs). It is recurrently the paradigm for the development of any new therapy in the treatment of depression. Many controlled studies and meta-analyses were performed on Fluoxetine, to improve the understanding of its real impact in the psychiatric area. The main objective of this review is to assess the quality and the results reported in the meta-analyses published on Fluoxetine. METHODS: Published articles on Medline, Embase and Cochrane databases reporting meta-analyses were used as data sources for this review.Articles found in the searches were reviewed by 2 independent authors, to assess if these were original meta-analyses. Only data belonging to the most recent and comprehensive meta-analytic studies were included in this review. RESULTS: Data, based on a group of 9087 patients, who were included in 87 different randomized clinical trials, confirms that fluoxetine is safe and effective in the treatment of depression from the first week of therapy. Fluoxetine's main advantage over previously available antidepressants (TCAs) was its favorable safety profile, that reduced the incidence of early drop-outs and improved patient's compliance, associated with a comparable efficacy on depressive symptoms. In these patients, Fluoxetine has proven to be more effective than placebo from the first week of therapy.Fluoxetine has shown to be safe and effective in the elderly population, as well as during pregnancy. Furthermore, it was not associated with an increased risk of suicide in the overall evaluation of controlled clinical trials.The meta-analysis available on the use of Fluoxetine in the treatment of bulimia nervosa shows that

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There is evidence of derangement of oxidant and antioxidant defense systems in depression. The present study examined the effects of fluoxetine and citalopram, standard selective serotonin re-uptake inhibitors, on lipid peroxidation, superoxide dismutase (SOD) activity and ascorbic acid concentrations. For this, a prospective open-labeled, randomized design was utilized. Patients with major depression (n = 62) were compared with age- and sex-matched healthy volunteers (n = 40). There was a significant increase in serum SOD, serum MDA and decrease in plasma ascorbic acid levels in patients of major depression as compared to control subjects. The trend reversed significantly after treatment with fluoxetine and citalopram. Results indicate a greater reduction in oxidative stress with citalopram than fluoxetine. The Hamilton Rating Scale for Depression (HRSD) score also improved with fluoxetine and citalopram treatment. These findings indicate that major depression is associated with increased levels of serum SOD, serum MDA and decreased levels of plasma ascorbic acid. Treatment with fluoxetine and citalopram reversed these biochemical parameters. This study can be used as a predictor of drug response by fluoxetine and citalopram in major depression.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14980069&dopt=Abstract fluoxetine

cnsunix.albany.edu

5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) in the ventral tegmental area (VTA) mediates lordosis of rodents. If fluoxetine's effects on lordosis are mediated in part by midbrain 3alpha,5alpha-THP, then fluoxetine regimens that decrease and increase lordosis would be expected to respectively lower and elevate midbrain 3alpha,5-THP levels. Experiment 1: Ovariectomized (ovx) rats received estradiol benzoate (EB; 5 micro g, SC) at 0 and 24 h and fluoxetine (20 mg/kg, IP) or vehicle 30 min before sex testing and tissue collection. Other rats received fluoxetine (10 mg/kg, IP) or vehicle for 15 days followed by EB-priming and testing. Systemic acute or chronic fluoxetine significantly decreased lordosis and midbrain 3alpha,5alpha-THP levels compared to vehicle. Experiment 2: Ovx rats with unilateral cannula to the VTA were primed with EB (5 micro g; 0, 24 h) and/or progesterone (0 or 100 micro g; 44 h, SC). At 47.5 h, fluoxetine (3.6 mM) or vehicle was infused to the VTA. At 48 h, rats were tested. Administering fluoxetine to the VTA significantly increased lordosis and midbrain 3alpha,5alpha-THP levels compared to vehicle infusions. Experiment 3: Ovx EB-primed rats were tested prior to, and 30 min after, treatmemt with acute fluoxetine (20 mg/kg, IP). Rats were then infused with 3alpha,5alpha-THP (100 ng) or vehicle to the VTA and were retested. 3alpha,5alpha-THP, but not vehicle, to the VTA reversed acute fluoxetine's inhibitory effects on lordosis. Together, these data suggest fluoxetine may alter lordosis in part through actions of 3alpha-THP in the midbrain.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1499303&dopt=Abstract

mail.med.upenn.edu

OBJECTIVES: Current guidelines for the initial treatment of bipolar type II (BP II) major depressive episode (MDE) recommend using either a mood stabilizer alone or a combination of a mood stabilizer plus a selective serotonin re-uptake inhibitor (SSRI). This recommendation is the result of concern over antidepressant-induced manic switch episodes. However, recent evidence suggests that the manic switch rate may be low in BP II MDE during SSRI therapy. METHODS: As part of a randomized, double-blind, placebo-controlled relapse-prevention study of fluoxetine monotherapy in BP II MDE, 37 patients received open-label fluoxetine 20 mg every day for up to 8 weeks. Outcome measures included the Hamilton Depression Rating (HAM-D 17) rating and the Young Mania Rating (YMR) scale. RESULTS: Eleven of 23 patients (48%) who completed 8 weeks of fluoxetine treatment showed a HAM-D 17 reduction of > or =50%, while 14 (38%) of all treated patients had > or =50% reduction in baseline HAM-D 17 score. Using a conservative YMR score of > or =8 to identify hypomanic symptoms, the frequency of patients with YMR score > or =8 during fluoxetine did not differ from that seen during the screen and baseline period. Only three patients (7.3%) had symptoms suggestive of hypomania, and only one patient stopped treatment because of a rapid mood swing into depression. LIMITATIONS: Fluoxetine was given at a fixed dose of 20 mg everyday. Fluoxetine was prescribed in an open-label manner, and the sample size was limited. CONCLUSIONS: These observations support the findings of a low manic switch rate during SSRI monotherapy of BP II MDE, and suggest that fluoxetine




Clin Gastroenterol Hepatol. 2003 May;1(3):219-28.
The selective serotonin reuptake inhibitor fluoxetine does not change rectal sensitivity and symptoms in patients with irritable bowel syndrome: a double blind, randomized, placebo-controlled study.

Kuiken SD, Tytgat GN, Boeckxstaens GE.

Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands.

BACKGROUND & AIMS: Although widely prescribed, the evidence for the use of antidepressants for the treatment of irritable bowel syndrome (IBS) is limited. In this study, we hypothesized that fluoxetine (Prozac), a selective serotonin reuptake inhibitor, has visceral analgesic properties, leading to increased sensory thresholds during rectal distention and improvement of symptoms, in particular in IBS patients with visceral hypersensitivity. METHODS: Forty non-depressed IBS patients underwent a rectal barostat study to assess the sensitivity to rectal distention before and after 6 weeks of treatment with fluoxetine 20 mg or placebo. Abdominal pain scores, individual gastrointestinal symptoms, global symptom relief, and psychologic symptoms were assessed before and after the intervention. RESULTS: At baseline, 21 of 40 patients showed hypersensitivity to rectal distention. Fluoxetine did not significantly alter the threshold for discomfort/pain relative to placebo, either in hypersensitive (19 +/- 3 vs. 22 +/- 2 mm Hg above MDP) or in normosensitive (34 +/- 2 vs. 39 +/- 4 mm Hg above MDP) IBS patients. Overall, 53% of fluoxetine-treated patients and 76% of placebo-treated patients reported significant abdominal pain scores after 6 weeks (not significant). In contrast, in hypersensitive patients only, fluoxetine significantly reduced the number of patients reporting significant abdominal pain. Gastrointestinal symptoms, global symptom relief, and psychologic symptoms were not altered. CONCLUSIONS: Fluoxetine does not change rectal sensitivity in IBS patients. Possible beneficial effects on pain perception need to be co




Biol Psychiatry. 2004 Mar 1;55(5):553-5.
A double-blind, placebo-controlled trial of olanzapine addition in fluoxetine-refractory obsessive-compulsive disorder.

Shapira NA, Ward HE, Mandoki M, Murphy TK, Yang MC, Blier P, Goodman WK.

Department of Psychiatry, College of Medicine, University of Florida, Gainesville, Florida 32610-0256, USA.

BACKGROUND: One of the few combination approaches to the treatment of obsessive-compulsive disorder (OCD) with encouraging support is the addition of an antipsychotic to a serotonin reuptake inhibitor. METHODS: The study consisted of a 6-week, placebo-controlled addition of olanzapine 5-10 mg (6.1 +/- 2.1 mg, mean +/- SD) to fluoxetine in OCD subjects who were partial or nonresponders to an 8-week, open-label fluoxetine trial (40 mg in 43 subjects, 20 mg in 1 subject). RESULTS: Both the fluoxetine-plus-olanzapine (n = 22) and fluoxetine-plus-placebo (n = 22) groups improved significantly over 6 weeks [F(3,113) = 11.64, p <.0001] according to Yale-Brown Obsessive Compulsive Scale scores with repeated-measures analysis of variance; however, the treatment x time interaction was not significant for olanzapine versus placebo addition to fluoxetine. CONCLUSIONS: These findings indicate no additional advantage of adding olanzapine for 6 weeks in OCD patients who have not had a satisfactory response to fluoxetine for 8 weeks, compared with extending the monotherapy trial.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15023585&dopt=Abstract fluoxetine




Int J Neuropsychopharmacol. 2004 Sep;:1-6. [Epub ahead of print]
A pilot study of newer antidepressant concentrations in cord and maternal serum and possible effects in the neonate.

Rampono J, Proud S, Hackett LP, Kristensen JH, Ilett KF.

Department of Psychological Medicine, Womens and Childrens Health Service Subiaco, WA, Australia.

Antidepressants are often used antenatally, and placental transfer may lead to adverse effects (toxicity) in the neonate. Pregnant women taking fluoxetine (n=4), sertraline (n=4), paroxetine (n=2) or venlafaxine (n=1) in the last trimester were studied. Maternal and cord sera were collected at delivery and infant serum on day 5 after birth for measurement of antidepressant concentrations. Neonatal Abstinence Scores (NAS) were measured in the infants on days 13 after birth. In maternal serum, median drug concentrations were: fluoxetine (96 gl), norfluoxetine (110 gl), sertraline (11 gl), desmethylsertraline (38 gl), paroxetine (mean 12 gl), venlafaxine (220 gl), and O-desmethylvenlafaxine (392 gl). Corresponding median values in cord serum were: fluoxetine (65 gl), norfluoxetine (81 gl), sertraline (10 gl), desmethylsertraline (27 gl), paroxetine (mean 6 gl), venlafaxine (232 gl), and O-desmethylvenlafaxine (406 gl). Corresponding median cordmaternal concentration ratios were 0.67 for fluoxetine and 0.72 for norfluoxetine, 0.67 for sertraline and 0.63 for demethylsertraline, 0.52 (mean) for paroxetine, and 1.1 and 1.0 for venlafaxine and O-desmethylvenlafaxine respectively. The neonates of two patients taking fluoxetine had high NAS. Only fluoxetine and norfluoxetine were detected in infant serum. Our data show substantial placental transfer of antidepressants, but only fluoxetine persisted in the infants serum. Neonatal toxicity may be associated with serotonin uptake blockade, and also be influenced by neonatal clearance.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15035694&dopt=Abstract fluoxetine

lycos.com

This paper reviews the cardiovascular effects of fluoxetine and other selective serotonin reuptake inhibitors comparing with those of tricyclic antidepressants. The authors survey the electrophysiological mechanisms and the recent data referring on drug's actions on different ionic currents/channels. The paper primarily focuses on preclinical data, showing various effects of fluoxetine and citalopram on cardiac and smooth muscle preparations and on cardiac ionic currents. At concentrations of 0.5-50 microM, fluoxetine and citalopram exhibit depressant effects on Ca(2+)- and Na(+)-dependent electrophysiological parameters of different cardiac preparations and on cardiac Ca2+ current. At concentrations of 0.1-10 microM, fluoxetine and citalopram elicit relaxation of both vascular and intestinal smooth muscles. These results provide evidence for inhibition of cardiac Na+, Ca2+ and more recently K+ channels by fluoxetine and citalopram at concentrations close to therapeutic level. The inhibition of cardiac Ca2+, Na+ and K+ and vascular Ca2+ channels by fluoxetine and citalopram may explain most cardiovascular side effects observed occasionally with the drugs during the chronic treatment. The inhibitory effects on cardiac Ca2+, Na+ and K+ channels of fluoxetine and citalopram may result in antiarrhythmic/proarrhythmic actions. Thus fluoxetine, citalopram and other selective serotonin reuptake inhibitors similarly to tricyclic antidepressants, may exhibit cardiovascular depressant effects. The paper summarizes drug interactions that may lead risk of arrhythmia and vascular side effects. Taking all these into consideration, in depressed patients having also cardiac or liver disorders, these antidepressants should be also more rigorously applied.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1506102&dopt=Abstract