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Weight loss dynamics during combined fluoxetine and olanzapine treatment.

Perrone JA, Chabla JM, Hallas BH, Horowitz JM, Torres G.

Department of Neuroscience, New York College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, New York 11568, USA. perronejennifer hotmail.com <perronejennifer hotmail.com>

BACKGROUND: Fluoxetine and olanzapine combination therapy is rapidly becoming an effective strategy for managing symptoms of treatment-resistant depression. Determining drug-drug interactions, drug metabolism and pharmacokinetics is of particular interest for revealing potential liabilities associated with drug augmentation in special patient populations. In the current studies, we chronically administered fluoxetine and olanzapine in non-stressed rats to extend our previous findings regarding body weight dynamics. RESULTS: Chronic fluoxetine (10 mg/kg) and olanzapine (5 mg/kg and 0.5 mg/kg) treatment decreased weight gain irrespective of olanzapine dosing. At the 10 mg/kg and 5 mg/kg dose, respectively, fluoxetine and olanzapine also significantly reduced food and water consumption. This pharmacodynamic event-related effect, however, was not observed at the 10 mg/kg and 0.5 mg/kg dosing paradigm suggesting differences in tolerability rates as a function of olanzapine dose. The decrease in weight gain was not associated with apparent changes in glucose metabolism as vehicle- and drug-treated rats showed undistinguishable serum glucose levels. The combination of fluoxetine and olanzapine in rats yielded drug plasma concentrations that fell within an expected therapeutic range for these drugs in psychiatric patients. CONCLUSIONS: These data suggest that fluoxetine and olanzapine treatment decreases weight gain in rats; a pharmacodynamic event-related effect that differs considerably from what is observed in the clinical condition. The possibility of mismatched models regarding body weight changes during drug augmentation therapy should be seriously considered.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15498104&dopt=Abstract fluoxetine Prozac



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Fluoxetine potentiates nitrazepam-induced behavioral sleep in young chicks.

Hussaini IM, Musa MH.

Department of Pharmacology and Clinical Pharmacy, Ahmadu Bello University, Zaria, Nigeria.

Nitrazepam (0.5-10 mg/kg, IP) dose dependently induced behavioral sleep in day-old chicks. Fluoxetine (0.1-1 mg/kg) did not produce sleep in the young birds, but the 5-HT reuptake inhibitor (0.1 and 0.5 mg/kg) potentiated nitrazepam (0.5 and 1.0 mg/kg)-induced hypnosis. Doses (0.5 and 1 mg/kg) of the benzodiazepine that did not produce sleep in any or all the chicks, when administered alone, induced sleep in some or all the chicks in the presence of fluoxetine (0.1 and 0.5 mg/kg). Ketanserin (0.5 and 2.5 mg/kg) effectively antagonized the effect of fluoxetine on nitrazepam-induced behavioral sleep. These results suggest that enhancement of 5-HT level by fluoxetine may be the mechanism involved in the potentiation of nitrazepam-induced sleep in the young chicks.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8153184&dopt=Abstract fluoxetine Prozac



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Fluoxetine and violent death in Maryland.

Frankenfield DL, Baker SP, Lange WR, Caplan YH, Smialek JE.

Johns Hopkins University, School of Public Health, Baltimore, MD.

A retrospective Medical Examiner case review of all deaths in Maryland where either fluoxetine or tricyclic antidepressant (TCA) use was forensically detected was conducted for the time period January 1987-July 1991. Case records and toxicology reports from the Office of the Chief Medical Examiner were reviewed to determine cause and manner of death, circumstances of death, demographic information on the decedent, prior medical history of the decedent, and presence and level of either fluoxetine or TCA in various body fluids/tissues. Suicide was the manner of death most frequently associated with TCA and fluoxetine detection. Violent methods were more often associated with fluoxetine suicides than with TCA suicides (65% v. 23%, P < 0.001). Demographic characteristics of antidepressant-related deaths in Maryland were similar to those of the entire USA. Possible explanations for the results obtained include the inherent lower lethality of fluoxetine compared to the TCAs, necessitating the use of additional means to complete the act of suicide; that physicians may have switched more impulsive, high risk patients to this new agent as it became available, thus creating a selection bias for more violence-prone individuals in the fluoxetine group; or that fluoxetine may be associated with induction of violence and/or suicidal ideation. Further research examining the possible association of these agents with violent acts is warranted.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8175081&dopt=Abstract fluoxetine Prozac



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Delayed decreases in brain 5-hydroxytryptamine2A/2C receptor density and function in male rat progeny following prenatal fluoxetine.

Cabrera TM, Battaglia G.

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

The present study investigated the consequences of prenatal exposure to the 5-hydroxytryptamine (serotonin; 5-HT) uptake inhibitor fluoxetine on central 5-HT2A/2C receptors and receptor-mediated function in male and female progeny. Pregnant rats were administered saline or fluoxetine (10 mg/kg s.c.) daily from gestational day 13 through 20. All litters were fostered to non-treated lactating dams. Fluoxetine did not alter weight gain during pregnancy but did significantly decrease progeny weight at birth (-8%) and at postnatal day (PD) 70 (-14%). Progeny were tested at PD28 (males and females) and PD70 (males) by measuring: 1) (+/-)-[125I]4-iodo,2,5-dimethoxyphenylisopropylamine ([125I]DOI)-labeled 5-HT2A/2C receptors; 2) [3H]paroxetine-labeled 5-HT uptake sites; and 3) the stimulation of adrenocorticotropin, corticosterone and renin after a single injection of the 5-HT2A/2C agonist DOI (2 mg/kg s.c.) to provide an index of 5-HT2A/2C receptor function. At PD28, neither 5-HT2A/2C receptor density nor 5-HT2A/2C receptor-mediated endocrine responses were altered by prenatal exposure to fluoxetine. In contrast, at PD70, the maximal density of hypothalamic 5-HT2A/2C receptors was reduced significantly (-35%) in male progeny of fluoxetine-treated dams. Consistent with the reduction of 5-HT2A/2C receptors, the adrenocorticotropin response to DOI was attenuated markedly and selectively (-58%; P < .05) in PD70 progeny following prenatal exposure to fluoxetine. Basal levels of all hormones measured were unaffected by prenatal fluoxetine. Likewise, fluoxetine did not alter the number of hypothalamic 5-HT uptake sites or the binding of [125I]DOI to cortical 5-HT2A/2C receptors.

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Fluoxetine efficacy in treatment resistant depression.

Amsterdam JD, Maislin G, Potter L.

Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia.

1. As many as 30% of depressed patients fail to respond to antidepressant drug therapy, and at least 60%-75% will not achieve complete recovery. Recently, several studies have suggested that newer, "second generation" antidepressants might be beneficial in treatment resistant depression (TRD). In the present study the authors examined the potential utility of fluoxetine in TRD by comparing its efficacy in patients with and without a prior history of antidepressant response. 2. 149 patients with MDD received fluoxetine 20mg daily for a minimum of 5 weeks: 43 (29%) had never responded to drug therapy (TRD patients), 41 (28%) did have a prior drug response (non-TRD patients) and 65 (44%) had never received any antidepressant treatment. Clinical response was defined as a > or = 50% reduction in baseline Hamilton Depression Rating score plus a final score < 7. 3. Compared to non-TRD patients, the TRD patients were more likely to have unipolar depression (p = 0.002), a chronic episode of > 2 years duration (p < 0.0001), a later age of illness onset (p < 0.0001), fewer prior episodes (p < 0.0001) and fewer prior drug treatments (p = 0.04). Overall, the response rate to fluoxetine was slightly greater in the non-TRD patients (76%) compared to the TRD patients (56%); however, this difference did not achieve statistical significance. 4. The present observations suggest that fluoxetine treatment of adequate duration may be beneficial for some patients with a prior history of refractory depression.

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Changes in dopamine metabolism in rat forebrain regions after cessation of long-term fluoxetine treatment: relationship with brain concentrations of fluoxetine and norfluoxetine.

Gardier AM, Lepoul E, Trouvin JH, Chanut E, Dessalles MC, Jacquot C.

Fac. Pharmacie, Lab. Pharmacol., JE DRED 1992-372, Chatenay-Malabry, France.

We examined the effects of repeated administration of the selective serotonin uptake inhibitor (SSRI) fluoxetine (Flx) (5, 10, or 15 mg/kg i.p., twice daily for 21 days) on brain and plasma concentrations of the parent drug and its active desmethyl metabolite, norfluoxetine (NFlx), in rats during the 21-day regimen as well as after cessation of drug treatment. We also measured dopamine (DA) levels in 2 midbrain regions (the striatum, St and nucleus accumbens, NAc) in rats killed 1-14 days after the last dose. NFlx concentrations in plasma and brain were ten times higher than those of Flx during the period of drug treatment. Although Flx accumulated more markedly in the rat brain than NFlx, it disappeared completely from plasma and brain after treatment stopped, while NFlx persisted up to Day P7. Chronic Flx treatment caused a persistent decrease in brain DA levels of -60% to -70% in St and NAc; this lasted for 7-14 days after cessation of treatment, depending on the dose used. The levels of DA metabolites decreased by 20-40%, and, except for 3-MT, tended to overshoot during the recovery period. Our data suggest that the long-term inhibition of DA neurons after cessation of Flx treatment parallels the inhibition previously observed for 5-HT neurons. Thus, besides blocking 5-HT uptake, Flx is likely to also inhibit in vivo DA uptake in forebrain regions, following prolonged administration.

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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.

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[The effect of fluoxetine on insulin resistance in non diabetic obese patients]

[Article in Spanish]

Araya V, Contreras P, Aguirre C, Depix MS, Zura ML.

Seccion Endocrinologia del Hospital Clinico de la Universidad de Chile, Santiago de Chile.

Fluoxetine, a serotonin re-uptake inhibitor with antidepressive and appetite reduction effects, could improve insulin sensitivity. The aim of this work was to assess this effect of fluoxetine in obese subjects. We studied 12 subjects with a body mass index over 30, with a normal oral glucose tolerance test and not subjected to dietary restrictions. Insulin sensitivity using Bergman's minimal model, sex hormone binding globulin (SHBG) and insulin like growth factor binding protein 1 (BP 1) were evaluated before and after three weeks of treatment with 60 mg OD of fluoxetine. During treatment, subjects lost a mean of 1.9 kg. When compared with basal values, insulin sensitivity index (S1) improved significantly at the end of treatment (1.71 +/- 0.44 and 2.72 +/- 0.63 respectively), SHBG increased (28.9 +/- 5.1 and 18.2 +/- 3.4 nM/ml respectively) and BP 1 did not change (2.8 +/- 0.9 and 1.5 +/- 0.3 ng/ml respectively). The changes in insulin sensitivity did not correlate with weight changes (r = 0.4 NS). Weight or insulin sensitivity changes did not correlate with initial degree of insulin resistance. We conclude that the improvement in insulin sensitivity elicited by Fluoxetine is not related to weight changes and may be useful in the treatment of insulin resistant obese subjects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8657961&dopt=Abstract fluoxetine Prozac