Prozac
Modelling the cost effectiveness of antidepressant treatment in primary care.

Revicki DA, Brown RE, Palmer W, Bakish D, Rosser WW, Anton SF, Feeny D.

MEDTAP International, Arlington, VA 22201, USA.

The aim of this study was to estimate the cost effectiveness of nefazodone compared with imipramine or fluoxetine in treating women with major depressive disorder. Clinical decision analysis and a Markov state-transition model were used to estimate the lifetime health outcomes and medical costs of 3 antidepressant treatments. The model, which represents ideal primary care practice, compares treatment with nefazodone to treatment with either imipramine or fluoxetine. The economic analysis was based on the healthcare system of the Canadian province of Ontario, and considered only direct medical costs. Health outcomes were expressed as quality-adjusted life years (QALYs) and costs were in 1993 Canadian dollars ($Can; $Can1 = $US0.75, September 1995). Incremental cost-utility ratios were calculated comparing the relative lifetime discounted medical costs and QALYs associated with nefazodone with those of imipramine or fluoxetine. Data for constructing the model and estimating necessary parameters were derived from the medical literature, clinical trial data, and physician judgement. Data included information on: Ontario primary care physicians' clinical management of major depression; medical resource use and costs; probabilities of recurrence of depression; suicide rates; compliance rates; and health utilities. Estimates of utilities for depression-related hypothetical health states were obtained from patients with major depression (n = 70). Medical costs and QALYs were discounted to present value using a 5% rate. Sensitivity analyses tested the assumptions of the model by varying the discount rate, depression recurrence rates, compliance rates, and the duration of the model. The base case analysis found that nefazodone treatment costs $Can1447 less per patient than imipramine treatment (discounted lifetime medical costs were $Can50,664 vs $Can52,111) and increases the number of QALYs by 0.72 (13.90 vs 13.18). Nefazodone treatment costs $Can14 less than fluoxetine treatment (estimated discounted lifetime medical costs were $Can50,664 vs $Can50,678) and produces slightly more QALYs (13.90 vs 13.79). In the sensitivity analyses, the cost-effectiveness ratios comparing nefazodone with imipramine ranged from cost saving to $Can17,326 per QALY gained. The cost-effectiveness ratios comparing nefazodone with fluoxetine ranged from cost saving to $Can7327 per QALY gained. The model was most sensitive to assumptions about treatment compliance rates and recurrence rates. The findings suggest that nefazodone may be a cost-effective treatment for major depression compared with imipramine or fluoxetine. The basic findings and conclusions do not change even after modifying model parameters within reasonable ranges.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10160081&dopt=Abstract fluoxetine Prozac



Prozac
Differential effects of acute and chronic fluoxetine administration on the spontaneous activity of dopaminergic neurones in the ventral tegmental area.

Prisco S, Esposito E.

Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, Chieti, Italy.

1. Electrophysiological techniques were used to study the effects of fluoxetine and citalopram on the basal activity of dopaminergic neurones in the ventral tegmental area (VTA) and substantia nigra, pars compacta (SNc) of rats. 2. Acute i.v. injection of fluoxetine (20-1280 micrograms kg-1) caused a dose-dependent inhibition of the firing rate of VTA dopaminergic neurones, but did not affect the activity of dopaminergic cells in the SNc. Citalopram (20-1280 micrograms kg-1, i.v.) inhibited the firing rate of dopaminergic neurones in the VTA, but its effect (maximal inhibition: 14 +/- 7%) was less pronounced than that of fluoxetine (maximal inhibition: 34 +/- 7%). 3. Pretreatment with mesulergine (80 micrograms kg-1, i.v.), a 5-hydroxytryptamine2C/2B (5-HT2C/2B) receptor antagonist, blocked the inhibitory effect of fluoxetine on VTA dopaminergic cells. Selective lesions of 5-hydroxytryptaminergic neurones by the neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), abolished the fluoxetine-induced reduction of VTA dopaminergic activity. 4. In a series of experiments, fluoxetine (10 mg kg-1, i.p.) was administered once daily for 21 consecutive days. Acute i.v. administration of fluoxetine (20-1280 micrograms kg-1, 72 h after the last i.p. injection) did not cause any change in the basal firing rate of VTA dopaminergic neurones in treated rats, whereas it induced the typical inhibitory effect in control animals. A group of rats chronically treated with fluoxetine, received i.v. m-chlorophenylpiperazine (mCPP; 10-320 micrograms kg-1), a 5-HT2C/2B receptor agonist. This drug significantly inhibited VTA dopaminergic function in control rats, but did not modify the basal activity of dopaminergic cells in animals given chronic fluoxetine.(ABSTRACT TRUNCATED AT 250 WORDS)

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Prozac
Effect of fluoxetine, norfluoxetine, sertraline and desmethyl sertraline on human CYP3A catalyzed 1'-hydroxy midazolam formation in vitro.

Ring BJ, Binkley SN, Roskos L, Wrighton SA.

Department of Drug Metabolism and Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

The ability of fluoxetine, norfluoxetine, sertraline and desmethyl sertraline to inhibit the CYP3A subfamily of cytochromes P450 was examined in vitro, using the formation of 1'-hydroxy midazolam as a probe for CYP3A catalytic activity. The inhibition observed with these four compounds was modeled using competitive, noncompetitive, uncompetitive and mixed competitive/noncompetitive relationships by nonlinear regression analysis. The best fit model of the inhibition of CYP3A-mediated 1'-hydroxy midazolam formation by all four compounds examined was determined to be mixed inhibition. The calculated Ki values were 65.7 +/- 12.0 microM for fluoxetine, 19.1 +/- 1.9 microM for norfluoxetine, 64.4 +/- 11.6 microM for sertraline and 48.1 +/- 11.6 microM for desmethyl sertraline. Steady-state plasma levels of fluoxetine and norfluoxetine can approach a concentration of 1 microM (approximately 350 ng/ml of plasma). Assuming an inhibitor concentration of 1 microM and a concentration of the substrate substantially below its Km (at least 10-fold lower), the results reported predict that fluoxetine and norfluoxetine together would inhibit CYP3A catalytic activity by less than 7% (less than 0.7% if the unbound plasma concentration of fluoxetine is considered). By using the same assumptions and concentrations for sertraline and desmethyl sertraline, these agents together would be predicted to inhibit the metabolic clearance of a coadministered CYP3A metabolized drug by less than 4%. The observations reported here suggest that fluoxetine and sertraline would have little effect on CYP3A-mediated clearance of coadministered drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8531073&dopt=Abstract fluoxetine Prozac



Prozac
Fluoxetine treatment of depressed patients with HIV infection.

Judd FK, Mijch AM, Cockram A.

Fairfield Infectious Diseases Hospital, Victoria.

OBJECTIVE: The aim of this paper is to describe the outcome of fluoxetine treatment of depressed patients with HIV infection. METHOD: An open study was made of 20 patients with varying stages of HIV infection treated for depression with fluoxetine. RESULTS: 15 of 20 patients improved with fluoxetine treatment; the drug was generally well tolerated, with no significant drug-drug interactions. CONCLUSIONS: Fluoxetine appears to be effective for the treatment of depression in patients with HIV infection.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8573046&dopt=Abstract fluoxetine Prozac



Prozac
Effect of fluoxetine on learning and memory involves multiple 5-HT systems.

Meneses A, Hong E.

Terapeutica Experimental Depto. de Farmacologia y Toxicologia, CINVESTAV-IPN, Tepepan, Mexico, Mexico.

Diverse evidence suggests that 5-HT uptake blockers enhance learning and memory. However, there is no information about the mechanisms of action involved in such effects. The aim of the present work was to investigate the nature of the receptors involved in the effects of fluoxetine on learning. Therefore, a dose-response curve of posttraining injection (intraperitoneal) of fluoxetine was carried out in an associative learning task (auto-shaping). Fluoxetine or the vehicle was injected 10 min after 5-HT antagonists: (+/-)-pindolol, (+/-)-propanolol, NAN-190, ketanserin, ritanserin, mesulergine, MDL 72222, or SDZ 205-557. Presynaptic activity was eliminated by means of chloroamphetamine pretreatment. Scopolamine (an anticholinergic) and dizocilpine (a noncompetitive NMDA receptor antagonist) were also used. Results showed that fluoxetine enhanced learning of the conditioned response (CR) in a dose-dependent fashion. All 5-HT antagonists had no effects by themselves but inhibited the effects of fluoxetine at different degrees. Decrement of CR produced by scopolamine was reversed by fluoxetine. Dizocilpine did not affect CR but prevented the effects of fluoxetine. The present findings suggest that the actions of fluoxetine on learning are due to an interaction with multiple receptors of postsynaptic nature.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8577800&dopt=Abstract fluoxetine Prozac



Prozac
Repeated administration of the 5-HT(1B) receptor antagonist SB-224289 blocks the desensitisation of 5-HT(1B) autoreceptors induced by fluoxetine in rat frontal cortex.

Shalom G, Gur E, Van de Kar LD, Newman ME.

Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Desensitisation of 5-HT(1A) and 5-HT(1B) autoreceptors is thought to be the mechanism underlying the therapeutic effects of fluoxetine and other selective serotonin re-uptake inhibitors (SSRIs) when these are administered chronically, while blockade of these autoreceptors occurring on administration of an SSRI together with an autoreceptor antagonist is responsible for the acute increase in 5-HT levels in vivo observed under these circumstances. The effects of repeated administration of SSRIs together with 5-HT(1B) receptor antagonists on 5-HT levels and autoreceptor activity have not been studied previously with an in vivo method. In this work we found, using in vivo microdialysis that the effect of fluoxetine (5 mg/kg i.p. daily for 7 days) to desensitise 5-HT(1B) autoreceptors in frontal cortex, as measured by the action of CP 93129 (10 microM) to reduce 5-HT levels, was prevented by concomitant administration of the 5-HT(1B) receptor antagonist SB 224289 (2.5 mg/kg s.c.). 5-HT(1B) receptor activity in hypothalamus and 5-HT(1A) autoreceptor activity, as determined by the effects of s.c. 8-OH-DPAT to reduce 5-HT levels, were not altered either by fluoxetine alone at this dose or by fluoxetine in the presence of SB 224289. We conclude that the effects obtained when 5-HT(1B) autoreceptor antagonists are administered acutely together with SSRIs may not be maintained after repeated administration.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15309378&dopt=Abstract fluoxetine Prozac



Prozac
Serotonin regulates osteoclast differentiation through its transporter.

Battaglino R, Fu J, Spate U, Ersoy U, Joe M, Sedaghat L, Stashenko P.

Department of Cytokine Biology, The Forsyth Institute, Boston, Massachusetts 02115, USA.

5-HTT mediates antidepressant-sensitive clearance of 5-HT after its release into neural synapses. We found increased expression of 5-HTT in RANKL-induced osteoclast-like cells. Fluoxetine, an inhibitor of 5-HTT, reduced osteoclast differentiation but not activation. Reserpine, an inhibitor of 5-HT intracellular transport, potentiated differentiation. These results indicate a role for 5-HTT in osteoclast function and suggest that commonly used antidepressive agents may affect bone mass. INTRODUCTION: Interactions between the serotonergic and skeletal systems are suggested by various clinical observations but are poorly understood. MATERIALS AND METHODS: Using gene microarrays, we found that the serotonin transporter (5-HTT) was strongly expressed in RANKL-induced osteoclasts. Using RANKL stimulation of RAW264.7 cells and mouse bone marrow cells as a model system for osteoclast differentiation, we studied the possible role/s of the different components of the serotonin (5-HT) system on the differentiation process. RESULTS: Osteoclast 5-HTT exhibited typical 5-HT uptake activity that was inhibitable by fluoxetine (Prozac). Fluoxetine reduced osteoclast differentiation but did not inhibit the activation of preformed osteoclasts, whereas the addition of 5-HT itself enhanced differentiation. Fluoxetine-treated osteoclast precursors had reduced NF-kappa B activation and elevated inhibitory protein kappa B alpha (I kappa B alpha) levels compared with untreated cells. 5-HT, on the other hand, resulted in activation of NF-kappa B. Reserpine inhibition of intracellular transport of 5-HT into cytoplasmic vesicles potentiated RANKL-induced osteoclast formation, suggesting the importance of intracellular 5-HT in regulating osteoclast differentiation. Reserpine also modestly enhanced the expression of the osteoclast marker TRACP in the absence of RANKL. CONCLUSIONS: Taken together, these data suggest that the 5-HT system plays an important role in bone homeostasis through effects on osteoclast differentiation and implies that commonly used antidepressive agents may affect bone mass.

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Prozac
Modulation of ionic currents in isolated canine and human jejunal circular smooth muscle cells by fluoxetine.

Farrugia G.

Division of Gastroenterology and Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.

BACKGROUND & AIMS: Fluoxetine is a commonly prescribed antidepressant with frequent gastrointestinal side effects. The aim of this study was to examine the effects of fluoxetine on isolated canine and human jejunal circular smooth muscle cells. METHODS: Patch clamp and dual wavelength ratio techniques were used. RESULTS: In amphotericin-perforated patch whole-cell recordings, fluoxetine at 100 nmol/L, 1 mumol/L, and 10 mumol/L concentrations decreased the outwardly delayed rectifier potassium current in canine cells by 12% +/- 3%, 27% +/- 12%, and 37% +/- 3%, respectively, and depolarized the membrane potential by 9.7 +/- 1.8 mV at 10 mumol/L. At 100 mumol/L and 1 mmol/L concentrations, fluoxetine increased the outward current by 88% +/- 40% and 475% +/- 270%, respectively. The increase in the outward current was blocked by charybdotoxin, suggesting an effect on the calcium-activated potassium current. In human cells, fluoxetine at 1 mumol/L decreased the outward potassium current by 26% +/- 4% and at 100 mumol/L increased the outward potassium current by 134% +/- 22%. CONCLUSIONS: Fluoxetine had direct effects on canine and human jejunal circular smooth muscle cells. Low concentrations decreased the outwardly delayed rectifier potassium current, and higher concentrations activated calcium-activated potassium channels. The results may in part explain the frequent gastrointestinal side effects of the drug.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8613049&dopt=Abstract fluoxetine Prozac