Zh Nevropatol Psikhiatr Im S S Korsakova. 1997;97(4):53-7.
[A comparative clinical evaluation of the antidepressive activity of fluoxetine and fluvoxamine]

[Article in Russian]

Lopukhov IG.

Comparative study of the peculiarities of clinical action of fluoxetine and fluvoxamine in 65 patients with endogenous depressions revealed their high efficiency (in 74.3% and 64.3% respectively). Fluoxetine was characterised by predominance of a stimulating effect from the first days of treatment as well as by relatively late manifestation of very thymoleptic and tranquilizing impact (during 3-4 weeks). Fluvoxamin displayed relatively uniform occurrence of separate clinical effects together with predominance and early appearance of antidepressive influence. On the basis of the comparison of the peculiarities of either clinical action of fluoxetine and fluvoxamin or their side effects with those of traditional antidepressive drugs (amitryptilin and ludiomil) the preferable indications for their prescription were determined. Thus fluoxetine was very good in treatment of apathetic-adynamic depressions while fluvoxamin was recommended for therapy of anxious and melancholic depressions. Antidepressants studied were ranked in the following way in terms of decrease of sedative effect and increase of stimulating action: amitryptilin, fluvoxamin, ludiomil, fluoxetine. The proper thymoleptic effect of fluoxetine and fluvoxamin exceeded the same effect of amitryptilin and ludiomil.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9214192&dopt=Abstract fluoxetine




J Pharmacol Exp Ther. 1997 Aug;282(2):967-76.
Interaction between the forced swimming test and fluoxetine treatment on extracellular 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the rat.

Kirby LG, Lucki I.

Institute of Neurological Sciences, University of Pennsylvania, Philadelphia 19104-2649, USA.

We used in vivo microdialysis to examine extracellular levels of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in the striatum and the lateral septum during the forced swimming test, (FST) a behavioral test conducted in rats that is commonly used to predict the effect of antidepressant drugs. The forced swimming test consisted of a 15-min pretest swim and a 5-min test swim 24 hr later. The antidepressant fluoxetine (20 mg/kg s.c.) or saline was administered 23.5, 5 and 1 hr before the test swim. In the striatum, the pretest swim increased 5-HT in both treatment groups. On the second day, the test swim had no effect on 5-HT in saline-treated rats but slightly decreased striatal 5-HT in fluoxetine-treated rats. In the lateral septum, the pretest swim decreased 5-HT in both treatment groups. On the second day, the test swim had no effect on 5-HT in saline-treated rats but decreased lateral septum 5-HT in fluoxetine-treated rats. Ratings of behavior showed that fluoxetine treatment increased swimming behavior and decreased immobility during the test swim. Immobility was positively correlated and swimming was negatively correlated with changes in extracellular 5-HT in the lateral septum but not in the striatum. Therefore, fluoxetine treatment altered adaptation of the regional response of extracellular 5-HT ordinarily produced in the FST, reversing the 5-HT response to the initial swim in the striatum and restoring the response to the initial swim in the lateral septum.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9262365&dopt=Abstract fluoxetine




Naunyn Schmiedebergs Arch Pharmacol. 1996 Dec;354(6):785-90.
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.

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

pearl.edu

Biotransformation of the selective serotonin reuptake inhibitor antidepressant, fluoxetine, to its principal metabolite, norfluoxetine, was evaluated in human liver microsomes and in microsomes from transfected cell lines expressing pure human cytochromes. In human liver microsomes, formation of norfluoxetine from R,S-fluoxetine was consistent with Michaelis-Menten kinetics (mean K(m) = 33 microM), with evidence of substrate inhibition at high substrate concentrations in a number of cases. The reaction was minimally inhibited by coincubation with chemical probes inhibitory for P450-2D6 (quinidine), -1A2 (furafylline, alpha-naphthoflavone), and -2E1 (diethyldithiocarbamate). Substantial inhibition was produced by coincubation with sulfaphenazole (Ki = 2.8 microM), an inhibitory probe for P450-2C9, and by ketoconazole (Ki = 2.5 microM) and fluvoxamine (Ki = 5.2 microM). However, ketoconazole, relatively specific for P450-3A isoforms only at low concentrations, reduced norfluoxetine formation by only 20% at 1 microM, and triacetyloleandomycin (> or = 5 microM) reduced the velocity by only 20-25%. Microsomes from cDNA-transfected human lymphoblastoid cells containing human P450-2C9 produced substantial quantities of norfluoxetine when incubated with 100 microM fluoxetine. Smaller amounts of product were produced by P450-2C19 and -2D6, but no product was produced by P450-1A2, -2E1, or 3A4. Cytochrome P450-2C9 appears to be the principal human cytochrome mediating fluoxetine N-demethylation. P450-2C19 and -3A may make a further small contribution, but P450-2D6 is unlikely to make an important contribution.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9298519&dopt=Abstract fluoxetine




Am J Manag Care. 1997 Jan;3(1):125-9.
A cost-effective approach to the use of selective serotonin reuptake inhibitors in a Veterans Affairs Medical Center.

Singletary T, North DS, Weiss M, Marman G.

Denver VA Medical Center, Denver, CO 80220, USA.

In light of the tremendous expansion in the number of selective serotonin reuptake inhibitors available to the clinician, the Pharmacy and Therapeutics Committee of the Denver Veterans Affairs Medical Center considered the advantages and disadvantages of fluoxethine, paroxetine, and sertraline, to determine which agent or agents would be carried on the formulary. The committed recommended sertraline as the preferred agent for the treatment of depression, panic disorders, and obsessive-compulsive disorders. The purpose of this retrospective study was to assess the economic outcome of that decision. The study population consisted of patients at the medical center who were receiving selective serotonin reuptake inhibitors during January through March of 1994 and those were receiving these agents between September 1995 and January 1996. The expanded collection period in 1995-96 was due to a relatively new medical center policy to offer 90-day fills on medication to reduce costs. The extended collection period assured a 100% sample of patients receiving these agents. The 1994 fluoxetine to sertraline dosage equivalency ratio was 20 mg:55.6 mg, based on average daily doses of fluoxetine and sertraline of 32.7 and 90.9 mg, respectively. The cost to the medical center for an average daily dose of fluoxetine was $1.86; sertraline cost $1.22 per day. The 1996 fluoxetine to sertraline dosage equivalency ratio (20 mg:51.3 mg) had not changed significantly since 1994, indicating that the dose of 20 mg of fluoxetine remained very close to a 50-mg dose of sertraline. The average daily doses of fluoxetine and sertraline (34.9 mg and 89.7 mg, respectively) were not significantly different than the 1994 doses. Only 33 patients had been prescribed paroxetine (aver




J Forensic Sci. 1997 Sep;42(5):812-6.
Postmortem serum and tissue redistribution of fluoxetine and norfluoxetine in dogs following oral administration of fluoxetine hydrochloride (Prozac).

Pohland RC, Bernhard NR.

Toxicology Research Laboratories, Lilly Research Laboratories, A Division of Eli Lilly and Company, Green-field, IN, USA.

Antemortem serum and postmortem serum and tissues were evaluated to determine if postmortem redistribution of the antidepressant, fluoxetine (Prozac) and its major active metabolite, norfluoxetine, occurred in dogs following oral administration of fluoxetine hydrochloride. Beagle dogs (four males) received daily oral doses of 10 mg fluoxetine/kg for five days. Antemortem serum concentrations of fluoxetine and norfluoxetine were determined 3 and 24 h following administration of the first four daily doses of fluoxetine and 3 h after the fifth dose in order to monitor for steady-state serum concentrations of parent and metabolite prior to postmortem serum concentration determinations. Antemortem serum concentrations of fluoxetine and norfluoxetine 3 h postdose on Day 5 ranged from 530 to 1210 ng/mL and 1460 to 1980 ng/ mL, respectively. Immediately following the 3 h blood sample on Day 5, each dog was euthanized. Serum concentrations of fluoxetine and norfluoxetine were determined from blood samples collected from the vena cava, heart, and clotted blood within the heart at 2 h after death in two dogs and 12 h after death in the remaining two dogs. Similarly, tissue concentrations of fluoxetine and norfluoxetine in heart, liver, and lung were determined 2 and 12 h postmortem. Serum concentrations of fluoxetine and norfluoxetine from the vena cava and heart 2 h postmortem were 2.2- to 6.0-fold and 2.3- to 3.6-fold higher, respectively, than antemortem serum concentrations. Similarly, serum concentrations of fluoxetine and norfluoxetine from vena cava and heart 12 h postmortem were 1.3- to 3.5-fold and 1.7- to 3.3-fold higher, respectively, than antemortem serum co




J Anal Toxicol. 1997 Oct;21(6):415-9.
Simultaneous identification and quantitation of fluoxetine and its metabolite, norfluoxetine, in biological samples by GC-MS.

Crifasi JA, Le NX, Long C.

St. Louis University, Forensic Toxicology Laboratory, Missouri 63134, USA.

A sensitive method for the quantitation of fluoxetine and norfluoxetine in biological samples was developed. Blood, urine, and tissue samples were alkalinized and extracted with N-butyl chloride. The extracts were derivatized with pentafluoropropionic anhydride before gas chromatography-mass spectrometry (GC-MS). Selected ions were monitored at m/z 117 and 294 for fluoxetine; m/z 117, 176, and 280 for norfluoxetine; and m/z 122 and 299 for the internal standard fluoxetine-d5. The within-run and between-run precision as well as recovery were determined for both analytes. The empirical limit of detection was determined to be 12.5 micrograms/L for both fluoxetine and norfluoxetine, whereas the empirical limit of quantitation was 25 micrograms/L for both drugs. Calibration curves were linear in the range of 50-1000 micrograms/L for both analytes. Some drugs that were known or suspected of interfering with high-performance liquid chromatography and GC methods for fluoxetine and norfluoxetine were tested for interference. This is the only reported method that combines the use of a deuterated internal standard, selected ion monitoring by GC-MS, and derivatization for the identification and quantitation of fluoxetine and norfluoxetine.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9323519&dopt=Abstract fluoxetine




Pharmacol Biochem Behav. 1997 Nov;58(3):767-73.
Fluoxetine decreases fat and protein intakes but not carbohydrate intake in male rats.

Heisler LK, Kanarek RB, Gerstein A.

Department of Psychology, Tufts University, Medford, MA 02215, USA.

Administration of fluoxetine, a selective serotonin reuptake inhibitor, results in decreases in food intake and body weight. The present study investigated whether the anorectic actions of fluoxetine were due to a general decrease in caloric intake or macronutrient specific. Male Long-Evans rats were maintained on a dietary self-selection regime with separate sources of protein, fat, and carbohydrate. During the acute phase of the experiment, nutrient intakes were measured 2, 4, 6, and 24 h after injections of 0, 5.0, and 10.0 mg/kg fluoxetine hydrochloride. Fluoxetine significantly decreased protein and fat intakes in a dose-related manner at all measurement times. In comparison, fluoxetine had a less pronounced effect on carbohydrate intake. During the chronic phase, rats were divided into two groups, one receiving daily injections of 10.0 mg/kg fluoxetine, and the other, vehicle injections. Drug injections continued for 28 days, and were followed by a 28-day withdrawal period. Rats given fluoxetine on a chronic basis consumed significantly less calories and gained significantly less weight than rats injected with the vehicle. Both caloric intake and body weight returned to control values during the withdrawal period. Fat and protein intakes also were significantly reduced throughout the drug injection period, and were restored to baseline levels during the withdrawal period. In contrast, carbohydrate intake was not reduced on an absolute basis, and actually was increased as percent of total caloric intake during the drug period. The results of this experiment call into question the idea that increased serotoninergic activity is related to selective reductions in carbohydrate intake.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9329071&dopt=Abstract fluoxetine




J Child Adolesc Psychopharmacol. 1997 Summer;7(2):97-107.
Trazodone is only slightly faster than fluoxetine in relieving insomnia in adolescents with depressive disorders.

Kallepalli BR, Bhatara VS, Fogas BS, Tervo RC, Misra LK.

Department of Psychiatry, University of South Dakota School of Medicine, Sioux Falls, USA.

This retrospective chart review examined the relative effectiveness of fluoxetine and trazodone in relieving insomnia associated with depressive disorders in adolescents (aged 13-17 years). We reviewed the hospital charts of consecutively admitted adolescents with a depressive disorder and insomnia, who received one of three treatments: fluoxetine (20 +/- 2.2 mg), trazodone (71 +/- 32 mg), or a fluoxetine-trazodone combination (fluoxetine 29 +/- 2.2 mg, trazodone 68 +/- 29 mg). Each treatment was examined in 20 patients. Insomnia was defined as a change in sleep patterns characterized by decreased total sleep time that was sufficient to cause clinical concern, and insomnia resolution was defined as sleep starting by midnight and lasting 6 hours. Mean time to resolution of insomnia was significantly faster in adolescents treated with trazodone rather than fluoxetine (2.5 vs. 5.1 days, p < 0.05). Trazodone seemed to save only about 3 days and insomnia resolved in all subjects by the 11th day of antidepressant treatment. Median time to insomnia resolution was 2 days (range 1-5 days) in the trazodone group and 4 days (range 1-11 days) in the fluoxetine group. This difference between trazodone and fluoxetine, although statistically significant, was generally not clinically significant in the management of insomnia associated with depressive disorders in adolescents. The resolution of insomnia was not faster for treatment with a combination of fluoxetine and trazodone in comparison to fluoxetine monotherapy. Insomnia resolution was slightly later in older children. These clinical findings await confirmation by a controlled study. Both drugs seemed effective in ameliorating sleep symptoms in this s