Synapse. 1993 Aug;14(4):324-31.
Chronic fluoxetine treatment upregulates 5-HT uptake sites and 5-HT2 receptors in rat brain: an autoradiographic study.

Hrdina PD, Vu TB.

Department of Pharmacology, Faculty of Medicine, University of Ottawa, Ontario, Canada.

This study was undertaken to investigate the effect of chronic treatment with fluoxetine, a selective serotonin uptake inhibitor used widely in the treatment of depression, on the distribution and density of 5-HT uptake sites, 5-HT2 receptors, and vesicular amine uptake sites in rat brain. Fluoxetine (10 mg/kg i.p.) was administered daily for 21 days. The density of 5-HT uptake sites labelled by [3H]paroxetine, 5-HT2 receptors labelled by [3H]ketanserin in presence of tetrabenazine and vesicular amine uptake sites labelled by [3H]ketanserin in the presence of mianserin were measured by quantitative autoradiography in 22 areas of rat brain, using coronal tissue sections. Chronic administration of fluoxetine produced significant increases in the density of 5-HT uptake sites in layers of frontoparietal cortex (by 32-43%), of striate cortex (by 55%), in CA1 field of hippocampus (by 111%) and in superior colliculus (by 20%). Fluoxetine treatment also resulted in upregulation of 5-HT2 receptors in layers of frontoparietal cortex (31-38%) and in CA2-3 fields of hippocampus (by 39%). The density of tetrabenazine-sensitive vesicular amine uptake sites in the caudate-putamen was also significantly increased (by 66%). The observed alterations in 5-HT uptake site and 5-HT2 receptor densities are likely a part of adaptive neuronal changes that occur after chronic administration of fluoxetine and may be related to the antidepressant effect of the drug.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8248854&dopt=Abstract fluoxetine




Ther Drug Monit. 1993 Oct;15(5):405-9.
Evaluation of the effect of fluoxetine on the formation of carbamazepine epoxide.

Gidal BE, Anderson GD, Seaton TL, Miyoshi HR, Wilenksy AJ.

Department of Pharmacy, School of Pharmacy, University of Washington, Seattle 98195.

Fluoxetine has been reported to increase carbamazepine (CBZ) plasma concentrations and cause adverse effects. CBZ-10, 11 epoxide (CBZE), the major metabolite of CBZ, contributes to the clinical effect and toxicity of CBZ. The objective of the present study was to investigate the effect of fluoxetine and its major metabolite, norfluoxetine, on CBZE formation in isolated perfused rat liver, in vitro human liver (n = 5) microsomes, and patients (n = 14), after either CBZ monotherapy or polytherapy with fluoxetine. In isolated perfused rat liver, there was no effect of fluoxetine (n = 8) or norfluoxetine (n = 6) on the formation clearance of CBZE (12.8 +/- 5.3 and 11.7 +/- 3.8 ml/min, respectively) or the intrinsic metabolic clearance of CBZ (6.6 +/- 2.7 and 6.3 +/- 1.8 ml/min, respectively). Studies on human liver microsomes confirmed that neither fluoxetine or norfluoxetine inhibited formation of CBZE until concentrations were > 20 times those found clinically. In support of this, there was no difference in the ratio of CBZE to CBZ plasma concentrations in patients also receiving fluoxetine when compared to patients on CBZ monotherapy; however, there was a trend toward a decrease in the apparent plasma clearance of CBZ. In conclusion, increased plasma concentrations of CBZ found when fluoxetine is added are not due to decreased formation of CBZE. Clinically, if fluoxetine causes an increase in CBZ levels, CBZE plasma concentrations will increase proportionately and contribute to the toxicity.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8249047&dopt=Abstract fluoxetine




J Pharmacol Exp Ther. 1993 Dec;267(3):1256-63.
Fluoxetine prevents the disruptive effects of fenfluramine on differential-reinforcement-of-low-rate 72-second schedule performance.

Richards JB, Sabol KE, Seiden LS.

University of Chicago, Department of Pharmacological and Physiological Sciences, Illinois.

This study compared the effects of fenfluramine and fluoxetine on the differential-reinforcement-of-low-rate 72-s schedule of reinforcement. Fluoxetine, a clinically effective antidepressant, increases extracellular serotonin (5-HT) by blocking the uptake of 5-HT after release. Fenfluramine increases extracellular 5-HT through transporter-mediated release (although it also blocks 5-HT uptake). The following characteristics were identified. First, fenfluramine and fluoxetine had two different effects on the differential-reinforcement-of-low-rate 72-s schedule. Fluoxetine had an antidepressant-like effect by increasing reinforcement rate without disrupting the interresponse time distribution. Fenfluramine's effect on the differential-reinforcement-of-low-rate 72-s schedule was not antidepressant-like: it did not increase the reinforcement rate, whereas it did disrupt the interresponse time distribution. Second, when fluoxetine and fenfluramine were given in combination, fluoxetine prevented the disruptive effects of fenfluramine. This result is consistent with fluoxetine's ability to block fenfluramine-induced 5-HT release, and supports the argument that the uptake transporter mediates fenfluramine's effects on both 5-HT release and behavior. Putative behavioral mechanisms (waiting capacity and temporal discrimination) which may mediate the acute effects of fluoxetine are discussed.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8263788&dopt=Abstract fluoxetine




J Clin Psychiatry. 1993 Dec;54(12):459-65.
Improvement in fluoxetine-associated sexual dysfunction in patients switched to bupropion.

Walker PW, Cole JO, Gardner EA, Hughes AR, Johnston JA, Batey SR, Lineberry CG.

Department of Psychiatry, University of Tennessee, Memphis.

BACKGROUND: This study was conducted to determine the effect of bupropion on the sexual functioning of male and female outpatients who developed anorgasmia or delayed orgasm while receiving fluoxetine treatment for depression. METHOD: Thirty-nine patients who satisfied criteria for participation in the study discontinued fluoxetine treatment and entered a 2-week washout phase followed by an open 8-week bupropion treatment phase. Three parameters of sexual functioning were followed throughout the study: orgasm function, libido, and satisfaction with overall sexual functioning. Depression was also evaluated at each visit. RESULTS: All patients reported orgasm delay and/or failure at the time of fluoxetine discontinuation. Orgasm function, libido, and satisfaction with sexual functioning improved during the 2-week fluoxetine washout period and during the bupropion treatment phase. Ninety-four percent of patients (29/31) had complete or partial resolution of their orgasm dysfunction at the end of bupropion treatment, and 81% of patients (25/31) were "much" or "very much" more satisfied with their overall sexual functioning. Most patients entered the study with decreased libido on fluoxetine. Libido was "much" or "very much" increased for 81% of patients (25/31) at the end of the study. In addition, depression scores on the Hamilton Rating Scale for Depression and Clinical Global Impressions-Severity scale significantly improved during the bupropion treatment phase. Finally, bupropion was well tolerated by most patients. CONCLUSION: Bupropion may be an appropriate antidepressant for patients who develop sexual dysfunction during fluoxetine treatment or for whom sexual dysfunction is a conce




Ann Pharmacother. 1993 Dec;27(12):1443-7.
Prescribing attitudes of different physician groups regarding fluoxetine.

Levin GM, DeVane CL.

Department of Pharmacy Practice, Albany College of Pharmacy, Union University, NY 12208.

OBJECTIVE: To determine the attitudes and prescribing patterns of family medicine and psychiatric physicians regarding fluoxetine. DESIGN: A three-part questionnaire was distributed to the Departments of Family Medicine and Psychiatry. The survey included topics associated with fluoxetine use that have received broad professional attention, such as drug-induced suicidal and aggressive behavior. SETTING: The Family Practice Medical Group and the Department of Psychiatry at the University of Florida. PARTICIPANTS: Mailing lists from both above departments were used to distribute surveys to residents, fellows, and attending/faculty members of each department. Eighty-seven surveys were mailed. MAIN OUTCOME MEASURES: Survey questions were divided into three sections to help determine current attitudes of prescribing fluoxetine: eight short cases, 16 statements, and demographic data. RESULTS: The return rate was 69 percent following a mailing and a hand-delivered copy. Responses were dichotomized to agree or disagree and were analyzed by Fisher's exact test. Psychiatrists were much more likely than family practitioners to prescribe fluoxetine for obsessive-compulsive disorder (OCD), and more likely to prescribe for a patient with a history of substance abuse or seizure disorder. Psychiatrists were more aware of safety issues; however, drug-interaction knowledge was weak in both groups. CONCLUSIONS: Family practitioners, being the most predominant of medical specialists, appeared equally comfortable with prescribing fluoxetine in most circumstances compared with psychiatrists. However, there is a need for pharmacists to provide up-to-date drug information on fluoxetine to all healthcare professionals.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8305772&dopt=Abstract fluoxetine




J Pharmacol Exp Ther. 1993 Aug;266(2):964-71.
Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450.

Stevens JC, Wrighton SA.

Department of Drug Metabolism and Disposition, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.

(R)- and (S)-fluoxetine were found to be competitive inhibitors of P450 2D6-mediated bufuralol 1'-hydroxylation in vitro, yielding Ki values of 1.38 +/- 0.48 and 0.22 +/- 0.11 microM, respectively. Their N-demethylated metabolites were also found to be potent inhibitors (Ki, (R)-norfluoxetine, 1.48 +/- 0.27 microM; (S)-norfluoxetine, 0.31 +/- 0.04 microM). The microsomal (R)- and (S)-fluoxetine N-demethylase activities for 14 human liver samples were on average 29.6 +/- 13.5 and 19.4 +/- 11.8 pmol of product/min/mg of protein, respectively. The individual rates of N-demethylation correlated with microsomal immunodetectable P450 2D6 levels; (R)-fluoxetine, r = 0.64, P < .05; (S)-fluoxetine, r = 0.63, P < .05. However, this correlation was significantly weaker than the excellent correlation obtained for P450 2D6-marker bufuralol 1'-hydroxylase activity and P450 2D6 levels (r = 0.92, P < or = .01). Quinidine, a potent inhibitor of P450 2D6, inhibited the demethylation of each enantiomer by only approximately 20% at a concentration 300 times greater than the Ki determined for the quinidine inhibition of bufuralol 1'-hydroxylase. Furthermore, antiserum recognizing P450 2D6 inhibited 82% of microsomal bufuralol 1'-hydroxylase activity but only 27% of the (R)-fluoxetine N-demethylase activity in the same human liver sample. In summary, these data indicate that the enantiomers of fluoxetine and norfluoxetine are potent inhibitors of P450 2D6 and that P450 forms other than P450 2D6 appear to be responsible for the majority of microsomal fluoxetine N-demethylation.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8355218&dopt=Abstract fluoxetine




J Pharmacol Exp Ther. 1993 Aug;266(2):836-44.
Long-term treatment with the antidepressants fluoxetine and desipramine potentiates endocrine responses to the serotonin agonists 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212) and (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI).

Li Q, Brownfield MS, Battaglia G, Cabrera TM, Levy AD, Rittenhouse PA, van de Kar LD.

Department of Pharmacology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois.

Various endocrine responses to 5-hydroxytryptamine (serotonin, 5-HT) agonists were used to assess serotonergic receptor function after chronic treatment with the antidepressants fluoxetine (10 mg/kg), a 5-HT uptake blocker and the norepinephrine uptake blocker desipramine (DMI, 5 mg/kg). Both were injected (i.p.) once a day for 21 days. DOI (5-HT1C/2 agonist, 0-5 mg/kg i.p.) and 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212) (less selective, but predominantly a 5-HT1C agonist, 0-20 mg/kg i.p.) were administered 18 hr after the final antidepressant injection and 30 min before decapitation. Chronic treatment with both fluoxetine and DMI produced a potentiation in most hormone responses to the 5-HT agonists (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane HCl (DOI) and MK-212, although there were several differences in individual hormone responses to the two 5-HT agonists. Fluoxetine and DMI potentiated the MK-212- and DOI-induced increase of plasma oxytocin levels and potentiated the effect of DOI on plasma adrenocorticotropic hormone (corticotropin) and prolactin levels. In contrast, the effect of the high dose of MK-212 on plasma prolactin concentration was reduced by both antidepressants. Only MK-212 increased vasopressin levels and this effect was potentiated by fluoxetine, but not by DMI. Fluoxetine also significantly increased the resting level of plasma vasopressin. DMI potentiated the effect of MK-212 on plasma renin concentration. Pretreatment with fluoxetine significantly increased (38%) the Bmax for the 5-HT1C/2 agonist




Pharmacol Biochem Behav. 1993 Aug;45(4):959-62.
In utero exposure to fluoxetine HCl increases hematoma frequency at birth.

Stanford MS, Patton JH.

Department of Psychology, Baylor University, Waco, TX 76798.

The present study was undertaken to determine if fluoxetine HCl (Prozac, Dista Products Ltd., Liverpool, UK) might cause adverse vascular effects, such as hematomas, in rats exposed in utero. Gravid Sprague-Dawley rats were administered 5.62 mg/kg fluoxetine HCl by oral gavage beginning on day 7 of gestation and ending the day of birth. A control group received distilled water by oral gavage during gestation. At birth, offspring of both groups were assessed for visible adverse vascular effects. Fluoxetine HCl-exposed offspring showed a statistically higher frequency of skin hematomas when compared to water controls. This result is consistent with known adverse effects of fluoxetine and lends support to a recently published report that attempted to link fluoxetine HCl use to bleeding episodes in eight patients being treated for obsessive-compulsive disorder. The results of this study suggest caution in the prolonged use of this medication during pregnancy and in patients with predisposing conditions that may increase the chances of bleeding.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8415836&dopt=Abstract fluoxetine




J Clin Psychopharmacol. 1993 Apr;13(2):107-13.
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