Prozac
A placebo controlled crossover trial of liquid fluoxetine on repetitive behaviors in childhood and adolescent autism.

Hollander E, Phillips A, Chaplin W, Zagursky K, Novotny S, Wasserman S, Iyengar R.

[1] 1Seaver and New York Autism Center of Excellence, New York, USA [2] 2Department of Psychiatry, Mount Sinai School of Medicine, One Gustave L Levy Place, New York, USA.

Repetitive behaviors are a core symptom domain in autism that has been linked to alterations in the serotonin system. While the selective serotonin-receptive inhibitor fluvoxamine has been shown to be effective in adults with autism, as yet no published placebo controlled trials with these agents document safety and efficacy in children with autism. This study examines the selective serotonin reuptake inhibitor liquid fluoxetine in the treatment of repetitive behaviors in childhood and adolescent autism spectrum disorders (ASDs). In total, 45 child or adolescent patients with ASD were randomized into two acute 8-week phases in a double-blind placebo-controlled crossover study of liquid fluoxetine. Study design included two randomized 8-week fluoxetine and placebo phases separated by a 4-week washout phase. Outcome measures included measures of repetitive behaviors and global improvement. Low-dose liquid fluoxetine (mean final dose: 9.9+/-4.35 mg/day) was superior to placebo in the treatment of repetitive behaviors by CY-BOCS compulsion scale. The effect size was in the moderate to large range, and the doses used were low. Liquid fluoxetine was only slightly, and not significantly, superior to placebo on CGI autism score partially due to a phase order effect. However, fluoxetine was marginally superior to placebo on a composite measure of global effectiveness. Liquid fluoxetine did not significantly differ from placebo on treatment emergent side effects. Liquid fluoxetine in low doses is more effective than placebo in the treatment of repetitive behaviors in childhood autism. Limitations include small sample size and the crossover design of the study. Further replication and long-term maintenance trials are needed.Neuropsychopharmacology (2005) 30, 582-589, advance online publication, 15 December 2004; doi:10.1038/sj.npp.1300627.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15602505&dopt=Abstract fluoxetine Prozac



Prozac
Open prospective trial of fluoxetine for posttraumatic stress disorder.

Nagy LM, Morgan CA 3rd, Southwick SM, Charney DS.

Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.

Twenty-seven patients with combat-related posttraumatic stress disorder (PTSD) entered an open, prospective, 10-week trial of fluoxetine, beginning with 20 mg/day and increasing to 80 mg/day until response was optimal or side effects prohibited dose increase. Nineteen patients completed 3 or more weeks and were included in the data analysis. Total Clinician-Administered PTSD Scale scores decreased from a mean of 64.5 at baseline to 42.7 at endpoint (F = 7.17, p < 0.001), and improvement was significant in each of the three PTSD subscales (reexperiencing, avoidance/numbing, and hyperarousal). Depression and anxiety ratings showed similar improvements, and suicidality ratings did not increase. Global improvement scores decreased from 4.0 at baseline to 2.67 at endpoint (F = 12.08, p < 0.001); however, improvement in social and occupational functioning was minimal. Appreciable improvement tended to occur after 6 weeks, suggesting that higher fluoxetine doses and/or duration than that used for depression may be indicated in this population. Panic attack frequency decreased by at least 50% in six of eight patients who kept panic diaries. The high dropout rate reflects problems with side effects, anxiety symptoms, external events, and substance abuse. Our data suggest that fluoxetine is effective in reducing reexperiencing, avoidance, and hyperarousal symptoms of PTSD, and this improvement is independent of comorbid panic disorder. In addition, fluoxetine appears to be effective in reducing panic attacks in PTSD patients. The efficacy of fluoxetine for some PTSD patients is interesting in light of emerging neuropharmacologic data suggesting serotonergic dysregulation in some PTSD patients. Noradrenergic hypotheses are also discussed. The findings should be confirmed by double-blind, placebo-controlled studies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8463442&dopt=Abstract fluoxetine Prozac



Prozac
Ethanol consumption following acute fenfluramine, fluoxetine, and dietary tryptophan.

Lu MR, Wagner GC, Fisher H.

Department of Nutritional Sciences, State University of New Jersey, New Brunswick 08903.

Male Sprague-Dawley rats fed a commercial diet with or without tryptophan supplementation (0.5% L-TRP) were treated with single IP injections of fenfluramine or fluoxetine. Rats had been water deprived prior to injection and food was removed during the period of fluid availability. They were offered, following drug or saline injection, water, a 5% ethanol solution, or an isocaloric sucrose solution (8.75%) for 1 h. Fenfluramine injection significantly reduced intake of all fluids, but its effect on ethanol was significantly greater than for water or sucrose solutions. Fluoxetine suppressed water and ethanol intake but not that of sucrose; the reduction in ethanol intake was significantly greater than for water. Ingestion of the tryptophan-supplemented diet in the absence of any drug treatment had no effect on fluid intake. However, the tryptophan supplementation significantly enhanced the reduction in ethanol intake induced by fenfluramine and fluoxetine. It appears that both fenfluramine and fluoxetine decrease ethanol intake more so than that of water or sucrose and that this effect is exacerbated by tryptophan supplementation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8469702&dopt=Abstract fluoxetine Prozac



Prozac
Red cell and plasma concentrations of fluoxetine and norfluoxetine.

Amitai Y, Kennedy E, DeSandre P, Fawcett J, Frischer H.

Department of Pharmacology (Genetics), Rush-Presbyterian St. Luke's Medical Center, Chicago, Illinois 60612.

To study the distribution of fluoxetine and norfluoxetine in blood compartments we determined their concentrations in red cells and plasma after the addition of 500 ng/ml of each compound to human blood in vitro. Red cell and plasma fluoxetine concentrations were 493 +/- 79 ng/ml and 454 +/- 53 ng/ml, respectively (P > 0.1). To assess the potential implications of this distribution on routine monitoring of these compounds in plasma, we determined fluoxetine and norfluoxetine concentrations in red cells and plasma in 6 patients receiving various doses of fluoxetine. While in 4 patients the concentrations of fluoxetine and norfluoxetine in red cells and plasma were comparable, 2 patients had higher concentrations of both compounds in red cells. Variations in the distribution of fluoxetine and norfluoxetine in blood compartments are relatively small. Plasma levels may reflect the drug concentration in whole blood more reliably for fluoxetine and norfluoxetine than for tricyclic antidepressants.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8470355&dopt=Abstract fluoxetine Prozac



Prozac
Pregnancy outcome following first-trimester exposure to fluoxetine (Prozac)

Pastuszak A, Schick-Boschetto B, Zuber C, Feldkamp M, Pinelli M, Sihn S, Donnenfeld A, McCormack M, Leen-Mitchell M, Woodland C, et al.

Motherisk Program, Hospital for Sick Children, Toronto, Ontario, Canada.

OBJECTIVE--To compare pregnancy outcome following first-trimester fluoxetine (Prozac) exposure with pregnancy outcome in two matched control groups. Fluoxetine is a new antidepressant used by many young women. Currently, no published data exist on its safety in pregnancy. DESIGN--We prospectively collected and followed up 128 pregnant women exposed to a mean daily dose of 25.8 mg (+/- 13 mg) of fluoxetine during the first trimester and compared pregnancy outcome with two matched groups of women exposed during the first trimester of pregnancy to either nonteratogens or tricyclic antidepressants. RESULTS--Rates of major malformations were comparable within the three groups and did not exceed those expected in the general population. Women treated with fluoxetine had a tendency for increased risk for miscarriage when compared with women exposed to nonteratogens (relative risk, 1.9; 95% confidence interval, 0.92 to 3.92). The rate of miscarriages in the fluoxetine group was comparable with the tricyclic group (13.5% and 12.2% vs 6.8% in the nonteratogens). CONCLUSIONS--Our study suggests that the use of fluoxetine during embryogenesis is not associated with an increased risk of major malformations. Women exposed to both fluoxetine and tricyclic antidepressants tended to report higher rates of miscarriage; further studies will be needed to confirm this observation and to separate the effects of the psychiatric condition from the associated drugs. Long-term studies will be warranted to rule out potential developmental teratology of fluoxetine, which affects a central nervous system neurotransmitter.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8474204&dopt=Abstract fluoxetine Prozac



Prozac
Determination of fluoxetine and norfluoxetine in human plasma by capillary gas chromatography with electron-capture detection.

Lantz RJ, Farid KZ, Koons J, Tenbarge JB, Bopp RJ.

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.

A capillary gas chromatographic method with 63Ni electron-capture detection is reported for the determination of fluoxetine (Prozac) and its metabolite norfluoxetine in human plasma. A liquid-liquid extraction is used, followed by derivatization with heptafluorobutyric anhydride to increase the sensitivity of detection. A 30 m x 0.25 mm I.D. DB-17 capillary column resolves the compounds from endogenous matrix interferences. The limit of quantitation by this method is 5 ng/ml for each compound. Stability studies show that fluoxetine and norfluoxetine are stable in human plasma for up to 96 h at room temperature and up to one year at -20 degrees C.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8496280&dopt=Abstract fluoxetine Prozac



Prozac
Potentiation of the vasospastic response to angioplasty by pretreatment with fluoxetine. A study in the atherosclerotic rabbit.

Sigal SL, Gellman J, Anderson GM, True LD, Chen Q, Tselentakis MJ, Ling FS, Ezekowitz MD.

Yale University School of Medicine/West Haven VA Department of Medicine, Conn.

There is evidence that angioplasty-induced vasospasm is mediated by serotonin (5-hydroxytryptamine [5-HT]) release from platelets. We tested the hypothesis that pretreatment of the atherosclerotic rabbit with fluoxetine, a platelet-uptake inhibitor of 5-HT, would reduce vasospasm after balloon angioplasty. Short-term administration of fluoxetine reduced platelet 5-HT uptake to 4% of baseline. Daily administration of fluoxetine for 7 days reduced whole-blood 5-HT levels to 28% of baseline. Thus, fluoxetine inhibited platelet 5-HT uptake in this model as predicted. Contrary to our expectations and despite the substantial reduction in whole-blood 5-HT levels, pretreatment with fluoxetine for 1 week resulted in augmentation of angioplasty-induced vasospasm in atherosclerotic rabbits. Intraperitoneal administration of fluoxetine produced vasoconstriction in normal rabbits that was augmented by 5-HT and not reversed with LY53857, a specific serotonin receptor antagonist. We postulate that this new observation is probably a result of the inhibition of the clearance mechanism for serotonin, with resultant enhancement of the effect of serotonin released by the activated platelets that are deposited on the vessel wall surface at the time of angioplasty. A direct effect of fluoxetine on serotonergic receptors is a second possible mechanism for the observed effect.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8499412&dopt=Abstract fluoxetine Prozac



Prozac
Effect of activation of the serotoninergic system during prolonged starvation on subsequent caloric intake and macronutrient selection in the Zucker rat.

Duhault J, Lacour F, Espinal J, Rolland Y.

Institut de Recherches Servier, Suresnes, France.

Starvation or dietary restriction are known to modify post-fasting dietary self-selection. We have examined the effects of activation of the serotoninergic system and food deprivation on macronutrient self-selection following a period of starvation. Rats were starved for 4 days and either treated or not with dl-fenfluramine or fluoxetine. Starved untreated animals showed a post-fasting anorexia and an increased preference for carbohydrate intake, even though lipids remained the preferred source of calories. Treatment with fenfluramine or fluoxetine increased post-fasting anorexia, abolished the preference for carbohydrates and decreased lipid intake. Fluoxetine, but not fenfluramine, resulted in decreased protein intake as well. Following a 2-day refeeding period ad libitum, during which the animals were not treated with drugs, the anorectic effect of fenfluramine disappeared but that of fluoxetine remained unchanged. In addition, we noted that at an equimolar dose to dl-fenfluramine (100 mumol/kg/day) fluoxetine treatment resulted in the death of all the animals in the group by the second day of refeeding; no deaths were observed in any of the other groups. In conclusion, we confirm a post-starvation anorexia and increased carbohydrate intake following long-term fasting. In addition we show that activation of the serotoninergic system abolishes the increase in carbohydrate intake and potentiates post-starving anorexia.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8507069&dopt=Abstract fluoxetine Prozac