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Fluoxetine may influence lordosis of rats through effects on midbrain 3 alpha,5 alpha-THP concentrations.

Frye CA, Petralia SM, Rhodes ME, Stein B.

Departments of Psychology, Biological Sciences, and The Center for Neuroscience Research, The University at Albany-State University of New York, 1400 Washington Avenue, Albany, New York 12222, USA. cafrye 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.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14993038&dopt=Abstract fluoxetine Prozac



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Treatment effect of sibutramine compared to fluoxetine on leptin levels in polycystic ovary disease.

Karabacak IY, Karabacak O, Toruner FB, Akdemir O, Arslan M.

Department of Nuclear Medicine, Gazi University Medical Faculty, Ankara, Turkey. iyetkin tr.net

Weight reduction on its own is observed to cause improvement in some of the abnormalities seen in patients with polycystic ovary syndrome (PCOS). With respect to this observation, we studied the possible effects of different serotonin reuptake inhibitors (fluoxetine and sibutramine) on serum leptin levels that might play a role in the obesity component seen in patients with PCOS. In a random design, sixteen patients were assigned to fluoxetine and sibutramine for a period of 10 days. In both treatment groups, no significant differences were observed between pre-treatment and post-treatment values in insulin levels (p > 0.05). There was no significant difference between pretreatment and post-treatment serum leptin levels in the fluoxetine treatment group (p > 0.05). However, a significant reduction was observed in the serum leptin levels at the end of treatment in the sibutramine group (p < 0.05). The observed difference in the serum leptin response to the treatment effect of sibutramine compared to fluoxetine seems to be due to a mechanism independent of serotonin reuptake inhibition, possibly to the thermogenic effect of the sibutramine itself. Further studies with larger groups are warranted, to examine the mechanism of the weight-reducing effect of sibutramine. Detailed analyses of basal metabolic activity and change in serum leptin levels should be carried out.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15724802&dopt=Abstract fluoxetine Prozac



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Antidepressant-like actions of intra-accumbens infusions of allopregnanolone in ovariectomized Wistar rats.

Molina-Hernandez M, Tellez-Alcantara NP, Perez Garcia J, Olivera Lopez JI, Teresa Jaramillo M.

Laboratorio de Conducta, Instituto de Investigaciones Psicologicas, Universidad Veracruzana, Jalapa, POB 361, Veracruz, 91000, Mexico.

This study was aimed to verify the role of the nucleus accumbens (NAcc) in the antidepressant-like effects of allopregnanolone in ovariectomized rats forced to swim. The interaction between infusions of allopregnanolone (intra-NAcc) with systemic administrations of allopregnanolone, muscimol, fluoxetine and GABA-A antagonists was assessed. Results showed that allopregnanolone (intra-NAcc; 1.5 mug, p<0.05; 2.0 mug, p<0.05) or systemic injections of allopregnanolone (1.5 mg/kg, p<0.05; 2.0 mg/kg, p<0.05; s.c.) or muscimol (0.3 mg/kg, p<0.05; 0.6 mg/kg, p<0.05; i.p.) reduced immobility by increasing climbing in the forced swimming task (FST), whereas fluoxetine (1.0 mg/kg, p<0.05; 2.0 mg/kg, p<0.05; i.p.) reduced immobility by increasing swimming. Allopregnanolone (intra-NAcc; 0.5 mug/side) synergized with systemic doses of allopregnanolone (0.5 mg/kg; p<0.05), muscimol (0.1 mg/kg; p<0.05) or fluoxetine (0.5 mg/kg; p<0.05) and reduced immobility by increasing climbing. Picrotoxin (0.125 mg/kg; i.p.) attenuated the synergism of the combination allopregnanolone (intra-NAcc; 0.5 mug/side) plus fluoxetine (i.p.) or allopregnanolone (s.c.) and the effects of allopregnanolone (intra-NAcc; 1.5 mug/side). Bicuculline (2.0 mg/kg; i.p.) attenuated the synergism between the combination allopregnanolone (intra-NAcc; 0.5 mug/side) plus muscimol (i.p.), but not the synergism of the combination allopregnanolone (intra-NAcc; 0.5 mug/side) plus allopregnanolone (s.c.). In conclusion, allopregnanolone (systemic injections or intra-NAcc), fluoxetine or muscimol produced antidepressant-like effects in the FST. Subthreshold doses of allopregnanolone (intra-NAcc) synergized with systemic subthreshold doses of fluoxetine, muscimol or allopregnanolone. Antagonists of the GABA-A receptor canceled the synergism.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15740782&dopt=Abstract fluoxetine Prozac



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Plasma Catecholamine Levels after Fluoxetine Treatment in Depressive Patients.

Blardi P, de Lalla A, Auteri A, Iapichino S, Dell'erba A, Castrogiovanni P.

Center of Clinical Pharmacology, Department of Clinical Medicine and Immunological Sciences, University of Siena, Siena, Italy.

It is known that selective serotonin reuptake inhibitors, widely used as antidepressive drugs, act by inhibiting the cell reuptake of serotonin, but their effect on the catecholaminergic system is not yet completely understood. In this study, we investigated plasma concentrations of norepinephrine, epinephrine and dopamine after acute and chronic administration of fluoxetine in depressive patients. Twelve patients affected by major depression received a single oral dose of fluoxetine in the morning, 5 mg in the first 5 days, 10 mg from the 6th to the 10th day and 20 mg from the 11th to the 40th day. Twelve healthy subjects received a placebo under identical testing procedures. Blood samples were collected at baseline and 7, 10 and 24 h after drug administration on the 1st day of fluoxetine administration at a dose of 5 mg, and on the 1st and the 30th day of fluoxetine administration at a dose of 20 mg (days 11 and 40 of treatment, respectively). We found that plasma norepinephrine, epinephrine and dopamine levels significantly increased after acute and chronic treatment (p < 0.001), reaching the highest concentrations on the last day. No significant changes of these parameters were observed in control patients. Copyright (c) 2005 S. Karger AG, Basel.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15741747&dopt=Abstract fluoxetine Prozac



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Brambilla P, Cipriani A, Hotopf M, Barbui C.

Department of Pathology and Experimental Medicine, Section of Psychiatry, University of Udine, Udine, Italy.

BACKGROUND: In the last ten years, SSRIs have increasingly replaced TCAs as comparators of newer antidepressants (ADs), because of their better tolerability profile. In particular, fluoxetine has become a reference drug for the treatment of depression, but the occurrence of individual side effects in depressed subjects treated with fluoxetine and each comparator AD have not been systematically investigated. METHODS: This meta-analysis investigated the frequency of side effects induced by fluoxetine or alternative ADs and compared the occurrence of individual side effects in depressed subjects. All randomised clinical trials (RCTs) comparing fluoxetine with any other AD drug in patients with major depression were located by searching the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register and the Cochrane Controlled Trials Register. Two reviewers independently extracted information. RESULTS: Significantly less percentage of patients treated with fluoxetine experienced any side effects in comparison with TCAs (50.9 % vs 60.3 %, 29 RCTs; RR = 0.84, p = 0.003), but not in comparison with other SSRIs (59.4 % vs 59.3 %, 15 RCTs; RR = 1.00, p = 0.902). In addition, fluoxetine was better tolerated in comparison with TCAs and related ADs (RR 0.61, 95 % CI 0.52, 0.71), but not in comparison with other SSRIs. Regard to individual side effects, activating (insomnia, agitation, tremor and anxiety) and gastrointestinal adverse events (nausea, vomiting, diarrhoea, weight loss and anorexia) were significantly more frequent in fluoxetine-treated patients, whereas cholinergic side effects were significantly less frequent. CONCLUSIONS: Fluoxetine compared to other ADs had more activating and gastrointestinal adverse effects, which often require additional pharmacotherapy or other managements strategies, leading to discontinuation and non-compliance and increasing the costs. This information is relevant to base on evidence the prescription of ADs in everyday clinical practice.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15744630&dopt=Abstract fluoxetine Prozac



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Economic impact of olanzapine plus fluoxetine combination therapy among patients treated for depression: a pilot study.

Corey-Lisle PK, Birnbaum H, Greenberg P, Marynchenko M, Dube S.

Eli Lilly and Company, Indianapolis, IN, USA.

Individuals with treatment-resistant depression (TRD) utilize more health care services and are significantly more costly. Drug treatments for TRD may include concomitant administration of multiple antidepressants or augmentation with mood stabilizers or antipsychotic agents. An augmentation strategy currently under investigation is the use of an olanzapine plus fluoxetine combination (OFC) therapy. The objectives for this pilot study were to use claims data to: (1) describe the extent of current use of OFC in patients with depressive disorders, and (2) compare health care utilization patterns and medical costs of patients receiving fluoxetine therapy before and after the initiation of olanzapine treatment. Data source consisted of medical, pharmaceutical, and disability claims from a Fortune 100 manufacturer from 1996 to 1998 (N>100,000). The sample included individuals with medical or disability claims for major depressive disorders treated with OFC (nOFC=36). Resource utilization and costs were compared for fluoxetine patients before and after the initiation of olanzapine treatment. Eleven percent of patients on combination therapy received olanzapine and fluoxetine. For patients on fluoxetine, there was a statistically significant reduction in health care utilization, and overall medical costs (20%), following initiation of olanzapine therapy. Overall, it appears the addition of olanzapine to ongoing fluoxetine therapy is effective in reducing outpatient, office, and inpatient utilization, as well as medical costs of patients treated for depression. Further research is needed to investigate combination therapy more fully.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14608242&dopt=Abstract fluoxetine Prozac



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Serotonin 5-HT(2C) receptor-mediated phosphoinositide hydrolysis in rat choroid plexus after fluoxetine and citalopram treatments.

Palvimaki EP, Majasuo H, Syvalahti E, Hietala J.

Department of Neurosurgery, Helsinki University Central Hospital, 00029 HUS, Finland.

Selective serotonin reuptake inhibitors (SSRIs) bind directly to various neurotransmitter receptors. The clinical effects of SSRIs appear gradually during weeks of treatment, suggesting a role for adaptive changes in neurotransmitter receptors. Most clinically used antidepressants, e.g. fluoxetine, bind to 5-HT(2C) receptors. When administered chronically, many antidepressants elicit adaptive regulation of 5-HT(2C) receptors. The present study was conducted in order to determine the effects of acute and chronic fluoxetine and citalopram treatments on the density and function of 5-HT(2C) receptors in the rat choroid plexus. Acute and chronic treatments followed by phosphoinositide (PI) hydrolysis assays and quantitative receptor autoradiography were performed. Acute (single-dose) treatment with neither drug significantly affected basal or 5-HT-stimulated PI hydrolysis, but acute citalopram (20mg/kg) treatment increased both agonist and antagonist binding to 5-HT(2C) receptors. Chronic (14 days) citalopram treatment (20mg/kg) increased the maximal PI hydrolysis response by 40%, but fluoxetine lacked this effect. The present data suggest that sensitisation of 5-HT(2C) receptor-mediated intracellular signal transduction may play a role in the effects of citalopram. In contrast, fluoxetine treatment does not functionally sensitise 5-HT(2C) receptors. Thus, functional 5-HT(2C) receptor sensitisation is not a common effect of antidepressants, but the differential effects may explain some of the pharmacodynamic differences seen with these drugs, especially upon repeated administration.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15749456&dopt=Abstract fluoxetine Prozac



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Repeated ECS and fluoxetine administration have equivalent effects on hippocampal synaptic plasticity.

Stewart CA, Reid IC.

Department of Psychiatry, University of Dundee, Ninewells Hospital & Medical School, UK. c.a.stewart dundee.ac.uk

RATIONALE: Recent studies have implicated intracellular transduction pathways and neurotrophic factors in the action of antidepressants. Adaptation in these pathways may ultimately affect electrophysiological and morphological properties of neurones. We have previously shown that repeated electroconvulsive stimulation, a safe and effective antidepressant treatment, has profound effects on hippocampal synaptic connectivity and plasticity in the rat. Here, we investigated whether these electrophysiological properties were shared by the chemical antidepressant, fluoxetine. OBJECTIVES: To compare the electrophysiological and cognitive effects of two very different antidepressant treatments: repeated electroconvulsive stimulation (rECS); and chronic administration of the serotonin specific re-uptake inhibitor (SSRI), fluoxetine. METHODS: Rats were exposed to either rECS or daily fluoxetine administration for 15 days. The animals were then anaesthetised and dentate field excitatory post-synaptic potential (fEPSP) characteristics were measured before and after the induction of long-term potentiation (LTP) by high frequency perforant path stimulation. In a separate experiment, the effects of rECS and chronic fluoxetine administration on acquisition and retention of a spatial learning task in the Morris watermaze were determined. RESULTS: Chronic fluoxetine administration and rECS produced equivalent increases in dentate fEPSP compared to respective control groups. LTP induction was attenuated in both groups. Spatial learning was, in contrast, unaffected by fluoxetine treatment but significantly impaired following rECS. CONCLUSIONS: Given that fluoxetine and rECS share antidepressant properties, but differ in their effects on learning and memory, we propose that the common effects on dentate connectivity and synaptic plasticity described here are more likely to relate to affective rather than cognitive function. This result is consistent with other experiments showing that a reduction in dentate connectivity correlates with stress susceptibility in animals.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10755734&dopt=Abstract fluoxetine Prozac