Prozac
Treatment of depression. New pharmacologic approaches.

Calabrese JR, Markovitz PJ.

Department of Psychiatry, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Ohio.

Recurrent major depression is an underdiagnosed, undertreated mood disorder that affects approximately 10 million Americans. Although the tricyclic antidepressants are the oldest and best studied class of antidepressant medications available, their use is routinely compromised by unsatisfactory pharmacokinetic and side-effect profiles. The newer antidepressant medications have longer half-lives and are less likely to produce side effects. The prototypes of the newer antidepressants are bupropion (Wellbutrin) and fluoxetine (Prozac). Fluoxetine distinguishes itself in that its half-life is 2 to 3 days, whereas the mean half-life of buproprion and the tricyclics are 10 to 14 hours. For this reason, fluoxetine is routinely administered once daily in the morning. Both of these agents bind to the cholinergic, histaminergic, and alpha-1 adrenergic receptors with minimal affinity, and are less likely to yield clinically significant side effects. The use of the newer antidepressants has led to improved patient compliance and physician acceptance.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1876622&dopt=Abstract fluoxetine Prozac



Prozac
Testing of analgesic effect of fluoxetine.

Begovic A, Zulic I, Becic F.

Bosnalijek, Sarajevo, Bosnia and Herzegovina.

Fluoxetine is used in treatment of depression caused by a variety of different factors and from year to year new indications are being added, especially in conditions followed with strong bouts of pain. Additional fluoxetine based therapy that is known to help in improvement of mental state and mood stabilization can significantly increase analgesic effects. Analgesic effects of fluoxetine as well as of fluoxetine in combination with morphine were analyzed on albino mice of both genders. The sense of pain was induced by thermal stimulus by the method of hot plate. Analgesic effect was measured 30, 60, 90 and 120 minutes after a single i.p. administration of fluoxetine in following dosages: 5, 10 and 20 mg/kg. The control group was treated with 0.1 ml/10 g physiological solution. Test group injected with morphine s.c. (7 mg/kg) was used to observe the effect of fluoxetine in combination with morphine. Fluoxetine applied in 5 mg/kg dosage causes increased pain reaction 60 and 90 minutes (p=0.049 and p=0.002) (t-test) following application when compared with corresponding values of control group. When fluoxetine is applied in 10 mg/kg dosage duration of pain reaction is significantly increased after 30 (p=0.01), 60 (p=0.001) and 90 minutes (p=0.026), when compared to the control group. When fluoxetine is applied in 20 mg/kg dosage duration of pain reaction is increased 60 and 120 minutes (p<0.001) after application when compared to the control group. After application of fluoxetine (5 mg/kg) in combination with morphine, reaction time to pain is significantly extended (p<0.001) 60, 90 and 120 minutes after application when compared to the control group injected exclusively with morphine. Fluoxetine causes analgesic effect in all three applied dosages as well as it significantly increases analgesic effect when applied in 5 mg/kg dosage in combination with morphine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15629002&dopt=Abstract fluoxetine Prozac



Prozac
Effects of long-term administration of nicotine and fluoxetine on sleep in depressed patients.

Haro R, Drucker-Colin R.

Clinica de Trastornos de Sueno, Facultad de Medicina, Instituto de Fisiologia Celular, Universidad Nacional Autonoma de Mexico, Mexico City.

BACKGROUND: The long-term effects of transdermal nicotine and fluoxetine on sleep and major depression were investigated. METHODS: Two independent groups of 12 nonsmoking patients with major depression (Hamilton Rating >/=18) served as subjects. The first group received transdermal nicotine (17.5 mg) while the second group received an oral dose of 20 mg/day of fluoxetine, 5 days weekly for 6 months, 3 days weekly at month 7 and 1 day/week at month 8. From the 9(th) to the 14(th) month, once a week a patch without nicotine and an oral placebo substituted nicotine and fluoxetine. Polysomnographic recordings were conducted and depressive symptoms evaluated at baseline and on a monthly basis during medication and during withdrawal. RESULTS: Nicotine diminished wakefulness and stage 1 and increased REM sleep latency and slow wave sleep throughout the study. A small decrease of REM sleep duration was observed upon nicotine withdrawal. Fluoxetine increased wakefulness, stage 1 duration and REM latency and decreased the sleep efficiency index. Both nicotine and fluoxetine improved mood according to HRS-D scores. CONCLUSIONS: Nicotine and fluoxetine showed equivalent antidepressant efficacy; however, important differences in sleep parameters were observed between nicotine and fluoxetine, both during their administration and following withdrawal.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15631874&dopt=Abstract fluoxetine Prozac



Prozac
Fluoxetine-induced up-regulation of 14-3-3zeta and tryptophan hydroxylase levels in RBL-2H3 cells.

Baik SY, Jung KH, Choi MR, Yang BH, Kim SH, Lee JS, Oh DY, Choi IG, Chung H, Chai YG.

Department of Biochemistry, Division of Molecular and Life Sciences, Hanyang University, Ansan 426-791, Republic of Korea.

The primary mechanisms of antidepressants are based on the monoamine depletion hypothesis. However, we do not yet know the full cascade of mechanisms responsible for the therapeutic effect of antidepressants. To identify the genes involved in the therapeutic mechanism of the selective serotonin reuptake inhibitor, fluoxetine, we used a cDNA microarray analysis with RBL-2H3 cells. We observed the transcriptional changes of several tens of genes containing the 14-3-3zeta gene in the fluoxetine-treated RBL-2H3 cells. Real-time RT-PCR and Western blotting confirmed changes in the expression of the gene and protein. The increase of 14-3-3zeta mRNA was observed at 72 h in the fluoxetine-treated RBL-2H3 cells. The increase of 14-3-3zeta protein was observed at 48 and 72 h. In this study, the expressions of the 14-3-3zeta gene and the protein were up-regulated at 72 h. In addition, the increase of TPH mRNA was observed at 12, 24 and 72 h in the fluoxetine-treated RBL-2H3 cells. We conclude that fluoxetine induces increases of 14-3-3zeta mRNA, 14-3-3zeta protein and TPH mRNA at 72 h in the RBL-2H3 cells. This suggests that the 14-3-3zeta and TPH genes may play a role in the molecular mechanism of fluoxetine. To date, no cases of 14-3-3zeta alterations by antidepressants and specifically by fluoxetine have been reported.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15631896&dopt=Abstract fluoxetine Prozac



Prozac
Relative rectal bioavailability of fluoxetine in normal volunteers.

Teter CJ, Phan KL, Cameron OG, Guthrie SK.

College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-1065, USA.

This study was conducted to determine the relative rectal bioavailability of fluoxetine capsules as well as the acceptability of the rectal route of fluoxetine capsule administration. Using a 2-period, crossover design with a 30-day washout between study sessions, 20 mg fluoxetine capsules were administered to 7 healthy, drug-free, nonsmoking volunteers by the oral and rectal routes. Blood samples were collected at baseline, and 1, 2, 4, 6, 8, 10, 12, 24 hours, as well as 2, 3, 4, 5, 7, 14, 21, 28 days following drug administration. Plasma concentrations of fluoxetine and norfluoxetine were determined using high performance liquid chromatography with ultraviolet detection. The area under the plasma concentration versus time curve could not be determined for fluoxetine following rectal administration due to very low fluoxetine plasma levels. The relative rectal bioavailability was determined for norfluoxetine and total (fluoxetine + norfluoxetine) in each individual. Six subjects completed both phases of the study. The relative bioavailability of rectally administered fluoxetine was approximately 15% [norfluoxetine, 95% CI 9-21%, and total (fluoxetine + norfluoxetine), 95% CI 8-22%]. The rectal route of administration was rated as reasonably tolerable by all subjects. Although rectal bioavailability of fluoxetine capsules is considerably less than oral, the rectal route of administration might be an option in patients who cannot take oral medications.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15643102&dopt=Abstract fluoxetine Prozac



Prozac
Suicidality and fluoxetine: is there a relationship?

Fava M, Rosenbaum JF.

Clinical Psychopharmacology Unit, Massachusetts General Hospital, Harvard Medical School, Boston 02114.

A recent report of six depressed patients who developed intense, violent suicidal preoccupation after 2 to 7 weeks of fluoxetine treatment prompted the authors to survey 27 psychiatrists who treated 1017 depressed outpatient with antidepressants during 1989: 3.5% (8/231) of those treated with fluoxetine alone, 6.5% (4/62) of those treated with fluoxetine and tricyclics, 1.3% (5/385) of those treated with tricyclics alone or with lithium, and 3.0% (3/101) of those treated with other antidepressants became suicidal only after treatment with these antidepressants was initiated. None of these patients, however, reported intense suicidal thoughts of the degree described in the previously reported six cases. The difference in incidence of suicidal ideation occurring only after initiation of treatment was not significant between patients treated with fluoxetine alone and those receiving the other antidepressant treatments.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2005073&dopt=Abstract fluoxetine Prozac



Prozac
In vitro and in vivo effect of fluoxetine on the permeability of 3H-serotonin across rat intestine.

Martel F, Monteiro R, Lemos C, Vieira-Coelho MA.

Department of Biochemistry, Faculty of Medicine, University of Porto, Portugal. fmartel med.up.pt

The aim of this work was to characterize the mucosal-to-serosal (apical to basolateral; AP-BL) and serosal-to-mucosal (basolateral to apical; BL-AP) transport of serotonin (5-HT) across rat jejunum, ileum, and colon, and to determine the influence of serotonin neuronal transporter inhibitors on this transport. The AP-BL apparent permeability (Papp) of 3H-5-HT increased in the order colon = jejunum < ileum, and the BL-AP Papp of 3H-5-HT increased in the order colon < jejunum = ileum. In vitro, neither fluoxetine (0.02 or 0.2 micromol/L) nor desipramine (0.4 or 4 micromol/L) had a significant effect upon the AP-BL or BL-AP Papp of 3H-5-HT in any of the intestinal regions. However, fluoxetine (0.2 micromol/L) decreased the accumulation of 3H-5-HT in the ileum (to 65% of control) in the BL-AP experiments. In vivo, chronic fluoxetine (10 mg/kg daily administered orally for 15 days), as assessed in the ileum, significantly increased (to +/-180% of control levels) the BL-AP Papp of 3H-5-HT and tended to increase the AP-BL Papp of 3H-5-HT. In conclusion, the increase in the Papp of 3H-5-HT after chronic administration of fluoxetine suggests that this treatment is able to increase the extracellular concentration of 3H-5-HT at the intestinal level.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15644933&dopt=Abstract fluoxetine Prozac



Prozac
A preliminary, open study of the combination of fluoxetine and desipramine for rapid treatment of major depression.

Nelson JC, Mazure CM, Bowers MB Jr, Jatlow PI.

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

Prompted by a recent study suggesting that the combination of desipramine hydrochloride and fluoxetine down-regulates beta-adrenergic receptors more rapidly than either drug alone, we administered both desipramine and fluoxetine to 14 inpatients with major depression in an open, 4-week trial. Desipramine plasma levels drawn 24 hours after an initial standardized dose were used to rapidly adjust desipramine dosage and compensate for the interactive effects of fluoxetine on desipramine levels in the blood. Responses were retrospectively compared with those of 52 inpatients who were descriptively similar and previously treated in the same setting with desipramine alone. Response was significantly more rapid in the group that received both drugs. One week after treatment began, the mean change in Hamilton Depression Rating Scale scores was 42% in the group that received both drugs and 20% in the group that received desipramine alone (Mann-Whitney U test, P = .007). Two weeks after administration of the drugs, the mean change in scores of the group that received both drugs was 60%, while a 30% change was noted in the patients treated with desipramine alone (P = .001). Ten (71%) of the 14 patients in the group that received both drugs completely remitted (change in Hamilton Depression Rating Scale score of greater than 75%, and final score of less than 7) within 4 weeks, while few patients treated with desipramine alone met these criteria within 4 weeks. This preliminary study suggests that treatment with both desipramine and fluoxetine is a rapid and effective strategy for treatment of major depression, and supports recent hypotheses of noradrenergic-serotonergic synergism.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2009031&dopt=Abstract fluoxetine Prozac