Prozac
Fluoxetine in depressed patients with renal failure and in depressed patients with normal kidney function.

Levy NB, Blumenfield M, Beasley CM Jr, Dubey AK, Solomon RJ, Todd R, Goodman A, Bergstrom RR.

Department of Psychiatry and Medicine, Westchester County Medical Center, Valhalla, NY, USA.

Nine depressed patients with normal kidney function and seven depressed patients with renal failure undergoing hemodialysis were treated with open-label fluoxetine 20 mg/day in an 8-week study. The study was designed to evaluate the pharmacokinetics of fluoxetine during repeated administration and to acquire preliminary data regarding the effectiveness of this antidepressant in a population undergoing hemodialysis. Six patients in each group completed the study. Of these, five patients undergoing hemodialysis and five patients with normal renal function experienced moderate to marked improvement in their depression. Side effects were equal and minor in both groups, indicating that fluoxetine is safe in patients with renal impairment. The mean +/- standard deviation steady-state plasma concentrations of the sum of fluoxetine plus its metabolite norfluoxetine for patients completing 8 weeks (N = 6, both groups) were comparable for the patients undergoing hemodialysis (253 +/- 61 ng/ml) and those with normal kidney function (218 +/- 122 ng/ml; t = 1.5, df = 70, p > 0.13). These data suggest that the efficacy of fluoxetine in patients with renal failure undergoing hemodialysis is comparable to that in patients with normal kidney function. These data further suggest that renal failure and the process of hemodialysis do not materially alter the pharmacokinetics of fluoxetine or its major metabolite norfluoxetine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8666216&dopt=Abstract fluoxetine Prozac



Prozac
Adverse events and tolerability of the combination of fluoxetine/lithium compared with fluoxetine.

Bauer M, Linden M, Schaaf B, Weber HJ.

Department of Psychiatry, Free University of Berlin, Germany.

Data from an intensive observational drug utilization study were analyzed to determine whether patients who received the combination of fluoxetine and lithium had more and different adverse events as compared with those receiving fluoxetine alone. In a matched cohort control design, we compared 110 patients per group. Results showed no significant difference in side effects between groups. Also, the incidence of "serotonergic" adverse events showed no significant differences between groups during the 7-week study period. In conclusion, the results show that the combination of fluoxetine/lithium is generally well tolerated in spite of a somewhat increased rate of minor side effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8690828&dopt=Abstract fluoxetine Prozac



Prozac
The effects of selective serotonin reuptake inhibitors and their metabolites on S-mephenytoin 4'-hydroxylase activity in human liver microsomes.

Kobayashi K, Yamamoto T, Chiba K, Tani M, Ishizaki T, Kuroiwa Y.

Department of Clinical Pharmacy, Showa University, Tokyo, Japan.

The inhibitory effects of four selective serotonin reuptake inhibitors (SSRIs), fluoxetine, sertraline, paroxetine and citalopram, and three metabolites (norfluoxetine, demethylcitalopram and didemethylcitalopram), on S-mephenytoin 4'-hydroxylation activities in human liver microsomes were studied. The 4'-hydroxylation of S-mephenytoin, a representative substrate toward CYP2C19, was competitively inhibited by all the SSRIs and their metabolites studied. The mean Ki values of fluoxetine, norfluoxetine, sertraline, paroxetine, citalopram, demethylcitalopram and didemethylcitalopram were 5.2, 1.1, 2.0, 7.5, 87.3, 55.8 and 7.7 microM, respectively. The findings suggest that some SSRIs and their metabolites with a low Ki value (e.g., fluoxetine, norfluoxetine) may reduce the clearance of drugs metabolized by this isoform of P450, thereby resulting in a possible drug-drug interaction, when administered simultaneously. In addition, SSRIs and their metabolites examined herein may be substrates toward CYP2C19.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8703653&dopt=Abstract fluoxetine Prozac



Prozac
Modification of acoustic startle reactivity by cocaine administration during the postnatal period: comparison with a specific serotonin reuptake inhibitor.

Dow-Edwards DL.

Department of Pharmacology, State University of New York Health Science Center, Brooklyn 11203, USA.

This study investigated whether exposure to cocaine during postnatal period affects the acoustic startle response (ASR) following administration of the serotonin (5-HT) agonists, 8-OH-DPAT and mCPP, in adulthood. To test the hypothesis that alterations in reactivity may be due to cocaine's effects at the 5-HT carrier, another group of rats was given fluoxetine, a specific 5-HT uptake inhibitor, during the same postnatal period and tested along with the cocaine-treated rats. Male and female rats received 25 mg/kg/day cocaine HCl, fluoxetine HCl, or vehicle SC during postnatal days 11-20. At 75 days of age, subjects were ASR tested for 30 min on 2 consecutive days. On the first test day, there was a significant effect of treatment and gender with post hoc analysis indicating that, overall, the males were more reactive than the females and that the fluoxetine-treated males showed a pattern of reactivity resembling sensitization. On the second test day, subjects received a dose of the 5-HT1A agonist 8-OH-DPAT, the 5-HT1B/2C agonist, mCPP, or saline prior to being placed in the startle chamber. Cocaine-exposed males showed an enhanced response to 8-OH-DPAT and a reduction in the depression produced by mCPP administration compared to their response to saline. Fluoxetine exposed males showed a significant increase in startle response following saline administration compared to the rats receiving vehicle during the postnatal period and 8-OH-DPAT produced an insignificant enhancement of that startle response. mCPP reduced startle in fluoxetine-treated males as it did in the postnatal vehicle-treated controls. In females, the postnatal cocaine and fluoxetine treatments did not alter the response to 8-OH-DPAT or mCPP compared to females receiving vehicle during the postnatal period. Together these data indicate that, in males, whereas postnatal cocaine alters the development of the 5-HT system as evidenced by an altered startle response to 5-HT agonists, cocaine does not produce the same alteration as that produced by the administration of a specific 5-HT uptake inhibitor during the same period of development.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8725641&dopt=Abstract fluoxetine Prozac



Prozac
Fluoxetine-induced sleep disturbance in depressed patients.

Dorsey CM, Lukas SE, Cunningham SL.

Sleep Disorders Center, McLean Hospital, Harvard Medical School, Belmont, MA 02178, USA.

Abnormal polysomnographic (PSG) features, most notably increased electromyographic (EMG) tone and eye movements during non-REM sleep have been observed during sleep in fluoxetine-treated depressed patients. However, the relationship between these PSG features and sleep disruption is unclear. Nine depressed patients treated with 10 to 80 mg of fluoxetine and six unmedicated, depressed patients were studied polysomnographically on two consecutive nights during which sleep parameters, transient arousals, and eye movements were measured. The fluoxetine group experienced a lower-average sleep efficiency index (SEI) and significantly more eye movements and arousals during non-REM sleep than the control group. Eye movement and arousal counts were significantly correlated. In addition, clinically significant periodic limb movement disorder (PLMD) was observed in 44% of the fluoxetine-treated group versus none of the control group. We conclude that a higher incidence of PLMD and frequent transient arousals associated with eye movements may be responsible in part for the complaint of insomnia made by patients treated with fluoxetine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8726754&dopt=Abstract fluoxetine Prozac



Prozac
Role of 5-HT1A receptors in the effects of acute chronic fluoxetine on extracellular serotonin in the frontal cortex.

Invernizzi R, Bramante M, Samanin R.

Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.

Fluoxetine 10 mg/kg i.p. significantly increased the extracellular concentrations of serotonin (5-HT) in the frontal cortex as assessed by in vivo microdialysis. This effect was significantly potentiated when 0.3 mg/kg s.c. WAY-100635, a 5-HT1A receptor antagonist, was administered 30 min before. WAY-100635 by itself had no effect on extracellular 5-HT. Twenty-four hours after chronic fluoxetine schedule (10 mg/kg/day i.p. x 14 days), basal extracellular 5-HT concentrations in the frontal cortex were higher than those of animals that had received the vehicle chronically. At 24 h after the last dose, a challenge dose of fluoxetine (10 mg/kg i.p.) raised extracellular 5-HT similarly in chronically vehicle or fluoxetine treated rats. At this same interval 25 micrograms/kg s.c. 8-OH-DPAT, a 5-HT1A receptor agonist, significantly reduced extracellular 5-HT only in the frontal cortex of rats treated chronically with the vehicle. Examining basal extracellular 5-HT, the effect of a challenge dose of fluoxetine and the effect of 25 micrograms/kg 8-OH-DPAT after 96 h washout, no differences were found between chronically fluoxetine and vehicle-treated rats. The results confirm that the ability of fluoxetine to stimulate 5-HT1A autoreceptors through an increase of endogenous 5-HT attenuates its effect on cortical dialysate 5-HT. Chronic fluoxetine increased the basal concentrations of extracellular 5-HT only when a substantial amount of its metabolite was present in the brain and during the desensitization of presynaptic 5-HT1A autoreceptors (24 h after the last dose). These effects, in fact, disappeared after 96 h washout. The continuous presence of the drug may, therefore, be necessary to maintain extracellular 5-HT at concentrations high enough to produce a therapeutic effect.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8728551&dopt=Abstract fluoxetine Prozac



Prozac
The serotonergic agent fluoxetine reduces neuropeptide Y levels and neuropeptide Y secretion in the hypothalamus of lean and obese rats.

Dryden S, Frankish HM, Wang Q, Pickavance L, Williams G.

Department of Medicine, University of Liverpool, U.K.

Evidence suggests that serotonin and neuropeptide Y neurons in the hypothalamus, which respectively inhibit and stimulate food intake, may interact to control energy homoeostasis. We therefore investigated the effects of fluoxetine, which inhibits serotonin reuptake, on food intake and the activity of the neuropeptide Yergic arcuato-paraventricular projection in lean Wistar and Zucker rats. We also studied its effects in obese Zucker rats, in which obesity is postulated to be due to overactivity of the arcuato-paraventricular projection. Fluoxetine significantly reduced food intake in lean and obese rats, both during continuous subcutaneous infusion and (10 mg/kg/day for seven days) and acutely after a single injection (10 mg/kg). Fluoxetine also significantly reduced neuropeptide Y levels in the paraventricular nucleus, a major site of neuropeptide Y release which is highly sensitive to the appetite-stimulating actions of neuropeptide Y. Push-pull sampling in lean and fatty Zucker rats showed that neuropeptide Y secretion in the paraventricular nucleus was significantly reduced after acute fluoxetine treatment. Furthermore, seven days fluoxetine treatment prevented the significant increases in hypothalamic neuropeptide Y messenger RNA which were induced in lean rats by food restriction which precisely matched the hypophagia induced by the drug. We conclude that fluoxetine inhibits various aspects of the activity of the neuropeptide Yergic arcuato-paraventricular neurons, and suggest that reduced neuropeptide Y release in the paraventricular nucleus may mediate, at least in part, the drug's hypophagic action. We further suggest that serotonin may influence food intake and energy balance by inhibiting the arcuato-paraventricular projection, and that the two neurotransmitters may act together to regulate feeding and energy homoeostasis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8737424&dopt=Abstract fluoxetine Prozac



Prozac
Effects of third trimester fluoxetine exposure on the newborn.

Goldstein DJ.

Lilly Research Laboratories, Eli Lilly and Company, Department of Pediatrics, Methodist Hospital of Indiana, Indianapolis, USA.

Prospectively identified fluoxetine-exposed pregnancies were evaluated to determine whether fluoxetine, a serotonin reuptake inhibitor commonly used for the treatment of depression and obsessive-compulsive disorder, might be associated with neonatal complications after maternal fluoxetine exposure during the third trimester through delivery. The outcomes of all prospectively identified, spontaneously reported pregnancies with confirmed fluoxetine exposure during the third trimester through delivery were evaluated. Postnatal complications unrelated to malformations were reported in 15 of the 112 identified pregnancies (115 infants), but there was neither a consistent or recurring pattern nor a dose relationship. On the basis of this survey and comparison with reported rates from the National Hospital Discharge Survey, it is unlikely that maternal fluoxetine use during the third trimester results in significant postnatal complications.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8748430&dopt=Abstract fluoxetine Prozac