Research and Clinical Trials on Fluoxetine (Prozac, Sarafem)

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By Dr Greg Mulhauser

This list of current clinical research trials on Fluoxetine (Prozac, Sarafem) is followed by a short set of abstracts from the most recent research articles published on the drug.

Article Contents

Fluoxetine (Prozac, Sarafem) Clinical Research Trials

From our searchable database at ClinicalTrialsFeeds.org, this list includes all the latest information about clinical trials involving Fluoxetine (Prozac, Sarafem).

 

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Current Research Literature on Fluoxetine (Prozac, Sarafem)

Here are abstracts for some of the latest research articles to have appeared on Fluoxetine (Prozac, Sarafem):

Fluoxetine improves the memory deficits caused by the chemotherapy agent 5Fluorouracil.

Behav Brain Res. 2009 Nov 12;
Elbeltagy M, Mustafa S, Umka J, Lyons L, Salman A, Tu , Gloria CY, Nikita B, Bennett G, Wigmore PM
Cancer patients who have been treated with systemic adjuvant chemotherapy have described experiencing deteriorations in cognition. A widely used chemotherapeutic agent, 5-fluorouracil (5-FU), readily crosses the blood- brain barrier and so could have a direct effect on brain function. In particular this anti mitotic drug could reduce cell proliferation in the neurogenic regions of the adult brain. In contrast reports indicate that hippocampal dependent neurogenesis and cognition are enhanced by the SSRI antidepressant Fluoxetine. In this investigation the behavioural effects of chronic (two week) treatment with 5-FU and (three weeks) with Fluoxetine either separately or in combination with 5-FU were tested on adult Lister hooded rats. Behavioural effects were tested using a context dependent conditioned emotional response test (CER) which showed that animals treated with 5-FU had a significant reduction in freezing time compared to controls. A separate group of animals was tested using a hippocampal dependent spatial working memory test, the object location recognition test (OLR). Animals treated only with 5-FU showed significant deficits in their ability to carry out the OLR task but co administration of Fluoxetine improved their performance. 5-FU chemotherapy caused a significant reduction in the number of proliferating cells in the sub granular zone of the dentate gyrus compared to controls. This reduction was eliminated when Fluoxetine was co administered with 5-FU. Fluoxetine on its own had no effect on proliferating cell number or behaviour. These findings suggest that 5-FU can negatively affect both cell proliferation and hippocampal dependent working memory and that these deficits can be reversed by the simultaneous administration of the antidepressant Fluoxetine.

[Effects of Chaihu Shugan San on behavior and plasma levels of corticotropin releasing hormone and adrenocorticotropic hormone of rats with chronic mild unpredicted stress depression.]

Zhong Xi Yi Jie He Xue Bao. 2009 Nov; 7(11): 1073-7
Li YH, Zhang CH, Wang SE, Qiu J, Hu SY, Xiao GL
Objective: To investigate the effects of Chaihu Shugan San (CHSGS), a compound traditional Chinese herbal medicine, on behavior and plasma levels of corticotropin releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) of rats with chronic mild unpredicted stress depression. Methods: Forty male Sprague-Dawley rats were randomly divided into 4 groups: normal control group, untreated group, fluoxetine group and CHSGS group. Except the normal control group, rats were singly housed and exposed to an unpredicted sequence of mild stressor for continuous 4 weeks to induce depression. Since the fifteenth day, rats were intragastrically administered with equal volume agents respectively for 2 weeks [normal saline for the normal control group and the untreated group, fluoxetine (1.8 mg/kg) for the fluoxetine group and CHSGS (5.9 g/kg) for the CHSGS group]. Behavioral scores of rats were detected by open-field test and sucrose preference test, and the plasma levels of CRH and ACTH in different groups were detected by radioimmunoassay. Results: Compared with the normal control group, body weights of the rats in the untreated group were significantly decreased. Scores of crossing, rears and grooming in open-field test were reduced significantly. Pure water consumption in sucrose preference test was increased significantly. The levels of plasma CRH and ACTH were significantly increased. The depressive behaviors of the rats were improved significantly and the levels of plasma CRH and ACTH were obviously reduced in the CHSGS group. Conclusion: Chronic mild unpredicted mild stress can affect the neuroendocrine and behavior and cause depression in rats. CHSGS can regulate HPA hyperactivity of rats caused by chronic stress and has antidepressive effects.

Differential inhibitory effects of drugs acting at the noradrenaline and 5-hydroxytrptamine transporters in rat and human neocortical synaptosomes.

Br J Pharmacol. 2009 Nov 12;
Mantovani M, Dooley D, Weyerbrock A, Jackisch R, Feuerstein T
Background and purpose: Although the amino acid sequences of rat and human 5-hydroxytryptamine (5-HT) and noradrenaline (NA) transporters (i.e. SERT and NET) are highly homologous, species differences exist in the inhibitory effects of drugs acting at these transporters. Therefore, comparison of the potencies of drugs acting at SERT and NET in native human and rat neocortex may serve to more accurately predict their clinical profile. Experimental approach: Synaptosomes prepared from fresh human and rat neocortical tissues were used for [(3)H]-5-HT and [(3)H]-NA saturation and competition uptake experiments. The drugs tested included NA reuptake inhibitors (desipramine, atomoxetine and (S,S)-reboxetine), 5-HT reuptake blockers (citalopram, fluoxetine and fluvoxamine) and dual 5-HT/NA reuptake inhibitors (duloxetine and milnacipran). Key results: In saturation experiments on synaptosomal [(3)H]-5-HT and [(3)H]-NA uptake, the dissociation constants did not indicate species differences although a smaller density of both SERT and NET was observed in human tissues. In competition experiments with the various drugs, marked species differences in their potencies were observed, especially at SERT. The rank order of selectivity ratios (SERT/NET) in human neocortex was as follows: citalopram >/= duloxetine = fluvoxamine >/= fluoxetine > milnacipran > desipramine = atomoxetine > (S,S)-reboxetine. Significant species differences in these ratios were observed for duloxetine, atomoxetine and desipramine. Conclusions and implications: This study provides the first compilation of drug potency at native human neocortical SERT and NET. The significant species differences (viz., human vs. rat) in drug potency suggest that the general use of rodent data should be limited to predict clinical efficacy or profile.

Effects of Selective Serotonin Reuptake Inhibitors on Timolol Metabolism in Human Liver Microsomes and Cryo-Preserved Hepatocytes.

Basic Clin Pharmacol Toxicol. 2009 Nov 11;
Volotinen M, Korjamo T, Tolonen A, Turpeinen M, Pelkonen O, Hakkola J, Mäenpää J
Timolol has been widely used in the treatment of glaucoma. Topically applied, timolol may cause adverse cardiovascular effects due to systemic absorption through the nasolacrimal duct. Timolol is mainly metabolized by cytochrome P450 2D6 (CYP2D6) in the liver. The aim of the present study was to characterize further the metabolism of timolol in vitro. Especially the effect of several drugs such as selective serotonin reuptake inhibitors on the metabolism of timolol was evaluated. In human liver microsomes, four timolol metabolites were identified, in cryo-preserved hepatocytes nine. In both in vitro experiments, the hydroxy metabolite M1 was the main metabolite. The in vivo half-life predicted for timolol was 3.7 hr. in cryo-preserved hepatocytes, corresponding to the half-life of timolol in humans in vivo. Fluoxetine, paroxetine, sertraline, citalopram and fluvoxamine inhibited the formation of M1 in microsomes with IC(50) values of 1.4, 2.0, 3.5, 21 and 20 muM, respectively. In human cryo-preserved hepatocytes, the IC(50) values for fluoxetine, paroxetine and fluvoxamine were 0.7, 0.5 and 5.9 muM, respectively. In conclusion, compounds known to be potent CYP2D6 inhibitors inhibited timolol metabolism in in vitro experiments. The present results strongly suggest that fluoxetine and paroxetine may significantly affect the metabolism of timolol also in vivo and may thus potentiate the adverse cardiovascular effects of topically administered timolol.

Olanzapine/fluoxetine combination for the treatment of mixed depression in bipolar I disorder: a post hoc analysis.

J Clin Psychiatry. 2009 Oct; 70(10): 1424-31
Benazzi F, Berk M, Frye MA, Wang W, Barraco A, Tohen M
OBJECTIVE: Mixed depression (ie, co-occurrence of syndromal depression and subsyndromal mania/hypomania) is a common variant of bipolar depression. However, its treatment is much understudied. The aim of the study was to assess the efficacy of the antipsychotic and mood-stabilizing agent olanzapine and the efficacy of the combination of an antidepressant (fluoxetine) and olanzapine (olanzapine/fluoxetine combination; OFC) for the treatment of bipolar I mixed depression. METHOD: We carried out a post hoc analysis of an 8-week, double-blind trial of adult bipolar I depression treated with placebo (n = 355), olanzapine (5-20 mg/d; n = 351), or OFC (olanzapine/fluoxetine doses: 6/25, 6/50, 12/50 mg/d; n = 82). Studying mixed depression was not a previous goal of the double-blind trial. Subjects in the trial were diagnosed according to DSM-IV and were randomly assigned to treatment during the period June 2000 to December 2001. Mixed depression was defined as the co-occurrence of a major depressive episode and > or = 2 manic/hypomanic symptoms (ie, > or = 2 Young Mania Rating Scale [YMRS] items scoring > or = 2). Response was defined as a > or = 50% reduction in Montgomery-Asberg Depression Rating Scale score and < 2 concurrent manic/hypomanic symptoms. Switching to mania/hypomania was defined as a YMRS score > or = 15. RESULTS: Frequency of mixed depression was 45.1% in the OFC arm, 49.3% in the olanzapine arm, and 46.8% in the placebo arm (P = .705). The most frequent manic/ hypomanic symptoms of mixed depression were irritability, reduced need for sleep, talkativeness, and racing thoughts. Response rates in patients with nonmixed depression versus patients with mixed depression were the following: in the OFC arm, 48.9% versus 43.2% (OR = 1.24; 95% CI, 0.51-2.98); in the olanzapine arm, 39.9% versus 26.6% (OR = 1.84; 95% CI, 1.17-2.90); in the placebo arm, 27.5% versus 16.3% (OR = 1.94; 95% CI, 1.15-3.28). Response rates in the samples of patients with mixed depression were the following: OFC versus olanzapine, OR = 2.00 (95% CI, 0.96-4.19); OFC versus placebo, OR = 3.91 (95% CI, 1.80-8.49); olanzapine versus placebo, OR = 1.95 (95% CI, 1.14-3.34). It was found that no baseline manic/hypomanic symptom of mixed depression predicted treatment response. A higher number of baseline concurrent manic/hypomanic symptoms predicted a lower response rate in the olanzapine and placebo arms, but not in the OFC arm. The rates of switching were the following: in the OFC arm, 8.5%; in the olanzapine arm, 6.8%; and in the placebo arm, 7.9% (P = .808). The rates of dropouts in patients with mixed depression versus patients with nonmixed depression were not significantly different within any of the treatment arms. The rates of dropouts in the samples of patients with mixed depression were the following: in the OFC arm, 29.7%; in the olanzapine arm, 53.8%; and in the placebo arm, 59.6% (olanzapine vs OFC: OR = 2.66; 95% CI, 1.23-5.75; placebo vs OFC: OR = 3.48; 95% CI, 1.61-7.54; placebo vs olanzapine: OR = 1.30; 95% CI, 0.84-2.01). CONCLUSION: Olanzapine/fluoxetine combination may be an effective treatment for bipolar I mixed depression. Statistically, the efficacy of OFC was not significantly different from that of olanzapine, but inspection of the 95% CI showed a trend in favor of a possible superiority of OFC. Supporting the study findings are the similar efficacy of OFC in bipolar mixed depression independent of the number of concurrent manic/hypomanic symptoms, a lower dropout rate, and a similarly low switching rate compared to olanzapine. Contrary to other current limited evidence, an antidepressant (fluoxetine) showed efficacy and did not worsen bipolar mixed depression if combined with a mood-stabilizing agent (olanzapine).

 

This page was last reviewed by Dr Greg Mulhauser, Monday, 1 June 2009.

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