Prozac
Further evidence that fluoxetine interacts with a 5-HT2C receptor in glial cells.

Chen Y, Peng L, Zhang X, Stolzenburg JU, Hertz L.

Department of Pharmacology, University of Saskatchewan, Saskatoon, Canada.

It is generally believed that the antidepressant drug fluoxetine (Prozac) exerts all its effects by inhibition of serotonin uptake into neurons and an ensuing increase in the extracellular concentration of serotonin. However, these studies have confirmed and expanded our previous observation that fluoxetine on its own exerts agonist effects on astrocytes (a glial cell type), which resemble those exerted by serotonin. Fluoxetine appears to act on a different subtype of receptor (the 5-HT2C receptor [in original terminology the 5-HT1C receptor]) than the one on which micromolar concentrations of serotonin are known to act in astrocytes (the 5-HT2A receptor [in original terminology the 5-HT2 receptor]). However, this study has shown that application of serotonin to these cells stimulates glycogenolysis and causes an increase in free cytosolic concentration of calcium that is not inhibited by the 5-HT2A selective antagonist, ketanserin. Moreover, both effects are pronounced at the low nanomolar level of serotonin and, therefore, by definition, act on the 5-HT2C receptor. The concentration/response correlation is identical for the serotonin effects on free cytosolic calcium concentration and on glycogenolysis. Fluoxetine exerts similar effects, but low nanomolar concentrations have no effect, and the concentration required to obtain half-maximum response is 1-3 microM, a concentration dependence that is consistent with the plasma levels of fluoxetine during treatment with this drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7583341&dopt=Abstract fluoxetine Prozac



Prozac
Listening to generic Prozac: winners, losers, and sideliners.

Druss BG, Marcus SC, Olfson M, Pincus HA.

Mental Health, Emory University in Atlanta, USA. bdruss emory.edu

This study tracks the diffusion of generic fluoxetine after its release in August 2001 within the largest U.S. pharmacy benefit manager (PBM). Within two weeks of the generic's release, prescriptions exceeded those of brand-name Prozac. The main winners proved to be Barr Laboratories, the first entrant to the generic market; large purchasers, who reaped substantial cost savings after Barr's period of exclusivity expired; and the PBM. The major loser was Eli Lilly, the manufacturer of Prozac. Consumers and makers of other antidepressants largely remained on the sidelines, with surprisingly little short-term impact evident from Prozac's patent expiration.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15371387&dopt=Abstract fluoxetine Prozac



Prozac
Postmarketing surveillance by patient self-monitoring: preliminary data for sertraline versus fluoxetine.

Fisher S, Kent TA, Bryant SG.

Department of Psychiatry and Behavioral Sciences, University of Texas Medical Branch, Galveston 77555, USA.

BACKGROUND: There have been no published postmarketing reports comparing sertraline with another serotonin selective reuptake inhibitor (SSRI) in large-sample, parallel groups. As part of an ongoing postmarketing surveillance study, this paper presents preliminary data for a number of adverse clinical events reported by outpatients being treated with either fluoxetine or sertraline. METHOD: Using a well-validated method developed to signal possible adverse drug reactions, data were collected on 1577 fluoxetine-treated and 1209 sertraline-treated patients who filled a prescription for either of the two targeted drugs. Pharmacists gave these patients an announcement, part of which served as an entry form, that described the purpose and details of the study. Volunteers (highly selective) were requested to report during the next month via a toll-free telephone interview "any new or unusual symptoms or unexpected improvements" in their health since starting the designated medication. RESULTS: Almost 1 (31.4%) of every 3 sertraline-treated patients called at least once to report one or more adverse clinical events compared with only about 1 (19.7%) of every 5 fluoxetine-treated patients. Most of the reported adverse clinical events--but not all--are well-known adverse drug reactions that seem common to SSRIs. Adverse clinical events reported more frequently by sertraline-treated patients included urinary, sexual, psychological, neurologic, gastrointestinal, and dermatological complaints. Drug discontinuation was also reported more frequently by sertraline-treated patients. Fluoxetine-treated patients reported an increased frequency of weight gain and anger or aggression. CONCLUSION: These data indicate that many adverse reactions known to be induced by fluoxetine are being reported with even greater frequency by sertraline-treated patients. Possible interpretations of these differences are discussed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7615482&dopt=Abstract fluoxetine Prozac



Prozac
Prolonged but not acute fluoxetine administration produces its inhibitory effect on hippocampal seizures in rats.

Wada Y, Shiraishi J, Nakamura M, Hasegawa H.

Department of Neuropsychiatry, Kanazawa University School of Medicine, Japan.

This study assessed the effects of acute as well as long-term administration of fluoxetine, a selective serotonin (5-HT) reuptake inhibitor with anti-depressant properties, on hippocampal (HIP) seizures elicited by electrical stimulation in rats. The fluoxetine effect on HIP seizures was also assessed following long-term treatment with gepirone, a 5-HT1A receptor agonist. Acute single administration of fluoxetine (1, 10 mg/kg; IP) was found to produce no significant effect on HIP seizure activity. Following daily IP administration of fluoxetine (10 mg/kg per day) or gepirone (10 mg/kg per day) for 21 days, animals were given a 7-day drug-free period and then challenged with an acute dose of 10 mg/kg fluoxetine. These treatment regimens resulted in a significantly increased afterdischarge threshold of HIP seizures in response to acute fluoxetine administration. The inhibitory effect of fluoxetine, however, was not present 4 weeks after long-term treatment with either fluoxetine or gepirone. The present results indicate that long-term treatment with these compounds enhances the antiepileptic effect of subsequent fluoxetine administration on the generation of HIP seizures. This effect is possibly related to the well-demonstrated evidence that fluoxetine and gepirone, on long-term treatment, facilitate net 5-HT neurotransmission through desensitization of presynaptic 5-HT autoreceptors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7617823&dopt=Abstract fluoxetine Prozac



Prozac
Acute and chronic toxicity of five selective serotonin reuptake inhibitors in Ceriodaphnia dubia.

Henry TB, Kwon JW, Armbrust KL, Black MC.

Department of Environmental Health Science, University of Georgia, Athens, Georgia 30602, USA. thenry uga.edu

Contamination of surface waters by pharmaceutical chemicals has raised concern among environmental scientists because of the potential for negative effects on aquatic organisms. Of particular importance are pharmaceutical compounds that affect the nervous or endocrine systems because effects on aquatic organisms are possible at low environmental concentrations. Selective serotonin reuptake inhibitors (SSRIs) are drugs used to treat clinical depression in humans, and have been detected in low concentrations in surface waters. In this investigation, the acute and chronic toxicity of five SSRIs (fluoxetine, Prozac; fluvoxamine, Luvox; paroxetine, Paxil; citalopram, Celexa; and sertraline, Zoloft) were evaluated in the daphnid Ceriodaphnia dubia. For each SSRI, the 48-h median lethal concentration (LC50) was determined in three static tests with neonate C. dubia, and chronic (8-d) tests were conducted to determine no-observable-effect concentrations (NOEC) and lowest-observable-effect concentrations (LOEC) for reproduction endpoints. The 48-h LC50 for the SSRIs ranged from 0.12 to 3.90 mg/L and the order of toxicity of the compounds was (lowest to highest): Citalopram, fluvoxamine, paroxetine, fluoxetine, sertraline. Mortality data for the 8-d chronic tests were similar to the 48-h acute data. The SSRIs negatively affected C. dubia reproduction by reducing the number of neonates per female, and for some SSRIs, by reducing the number of broods per female. For sertraline, the most toxic SSRI, the LOEC for the number of neonates per female was 0.045 mg/L and the NOEC was 0.009 mg/L. Results indicate that SSRIs can impact survival and reproduction of C. dubia; however, only at concentrations that are considerably higher than those expected in the environment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15379001&dopt=Abstract fluoxetine Prozac



Prozac
Effect of Prozac on whole cell ionic currents in lens and corneal epithelia.

Rae JL, Rich A, Zamudio AC, Candia OA.

Department of Physiology, Mayo Foundation, Rochester, Minnesota 55905, USA.

Prozac (fluoxetine), a compound used therapeutically in humans to combat depression, has substantial effects on ionic conductances in rabbit corneal epithelial cells and in cultured human lens epithelium. In corneal epithelium, it reduces the current due to the large-conductance potassium channels that dominate this preparation. Its effects seem largely to decrease the open probability while leaving the single-channel current amplitude unaltered. In cultured human epithelium, currents from calcium-activated potassium channels and inward rectifiers are unaffected by Prozac. Delayed-rectifier potassium currents are reduced by Prozac in a complicated way that involves both gating and single-channel current amplitude. Fast tetrodotoxin-blockable sodium currents are also decreased by Prozac in this preparation. For all of these ion conductance effects, Prozac concentrations of 10(-5) to 10(-4) M are required. Whereas these levels are 10- to 100-fold higher than the plasma levels achieved in therapeutic use in humans, they are comparable to or less than levels needed for many other blockers of the ionic conductances studied here.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7631752&dopt=Abstract fluoxetine Prozac



Prozac
Gestational treatment with cocaine and fluoxetine alters oxytocin receptor number and binding affinity in lactating rat dams.

Johns JM, Lubin DA, Walker CH, Joyner P, Middleton C, Hofler V, McMurray M.

Department of Psychiatry, The University of North Carolina at Chapel Hill, 424 Taylor Hall, CB #7096, Chapel Hill, NC 27599-7096, USA. jjohns med.unc.edu

Cocaine administered chronically throughout gestation has been correlated with deficits in maternal behavior, increased maternal aggressive behavior and decreased oxytocin levels in rats. In addition to its effects on oxytocin levels, cocaine is a potent serotonergic, dopaminergic and noradrenergic reuptake inhibitor. Alterations in the dopaminergic and serotonergic systems have been suggested as possibly having a role in cocaine-induced maternal aggression. This study was in part, an attempt to understand some of the mechanisms by which cocaine increases postpartum aggression, particularly as they relate to changes in the oxytocin system. Oxytocin receptor number and binding affinity in the medial preoptic area of the hypothalamus, ventral tegmental area, hippocampus and amygdala were determined for lactating rat dams on postpartum day 6 (PPD 6) that were gestationally treated with cocaine, fluoxetine, saline or an amfonelic acid/fluoxetine drug combination. Cocaine and fluoxetine treatment both resulted in a significant up-regulation of oxytocin receptor number and lower receptor affinity in the amygdala of lactating rat dams compared to saline controls and the amfonelic acid/fluoxetine combination treatment group. Cocaine treatment also resulted in a significant down-regulation of oxytocin receptors in the medial preoptic area and both cocaine and fluoxetine treated dams had the highest affinity for oxytocin receptors in this brain region. Results of the present study support previous data indicating that alterations in oxytocinergic and perhaps serotonergic system dynamics in the amygdala may play a role in cocaine-induced postpartum aggression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15380831&dopt=Abstract fluoxetine Prozac



Prozac
Fluoxetine-induced change in rat brain expression of brain-derived neurotrophic factor varies depending on length of treatment.

De Foubert G, Carney SL, Robinson CS, Destexhe EJ, Tomlinson R, Hicks CA, Murray TK, Gaillard JP, Deville C, Xhenseval V, Thomas CE, O'Neill MJ, Zetterstrom TS.

Leicester School of Pharmacy, Faculty of Health and Life Sciences, De Montfort University, The Gateway, Leicester, LE1 9BH, UK.

Recent studies indicate that brain-derived neurotrophic factor (BDNF) may be implicated in the clinical action of antidepressant drugs. Repeated (2-3 weeks) administration of antidepressant drugs increases BDNF gene expression. The onset of this response as well as concomitant effects on the corresponding BDNF protein is however, unclear. The present study investigated the effects of acute and chronic administration of the selective serotonin reuptake inhibitor, fluoxetine (10mg/kg p.o.), upon regional rat brain levels of BDNF mRNA and protein expression. To improve the clinical significance of the study, fluoxetine was administered orally and mRNA and protein levels were determined ex vivo using the techniques of in situ hybridisation histochemistry and immunocytochemistry respectively. Direct measurement of BDNF protein was also carried out using enzyme-linked immunosorbent assay (ELISA). Four days of once daily oral administration of fluoxetine induced decreases in BDNF mRNA (hippocampus, medial habenular and paraventricular thalamic nuclei). Whilst 7 days of treatment showed a non-significant increase in BDNF mRNA, there were marked and region-specific increases following 14 days of treatment. BDNF protein levels remained unaltered until 21 days of fluoxetine treatment, when the numbers of BDNF immunoreactive cells were increased, reaching significance in the pyramidal cell layer of CA1 and CA3 regions of Ammon's horn (CA1 and CA3) but not in the other sub-regions of the hippocampus. Indicative of the highly regional change within the hippocampus, the ELISA method failed to demonstrate significant up-regulation at 21 days, measuring levels of BDNF protein in the whole hippocampus. In contrast to the detected time dependent and biphasic response of the BDNF gene, activity-regulated, cytoskeletal-associated protein (Arc) mRNA showed a gradual increase during the 14-day course of treatment. The results presented here show that BDNF is expressed differentially depending on length of fluoxetine administration, which could contribute in explaining the slow onset of antidepressant activity observed with selective serotonin reuptake inhibitors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15381288&dopt=Abstract fluoxetine Prozac