Prozac
Does fluoxetine exacerbate Parkinson's disease?

Caley CF, Friedman JH.

University of Rhode Island, Cranston.

BACKGROUND: Because fluoxetine may be associated with an induction or exacerbation of parkinsonism, caution has been suggested when considering fluoxetine as an antidepressant for patients with Parkinson's disease. METHOD: We retrospectively reviewed the medical records of 23 outpatients with Parkinson's disease who were receiving or had received fluoxetine. One author evaluated all patients using the Northwestern University Disability Scale for scoring parkinsonism. Rather than employing a formal depression scale, we assessed depression globally. Concurrent medications were permitted. RESULTS: Twenty of the 23 patients experienced no worsening of parkinsonism while being treated with up to 40 mg of fluoxetine per day. The other 3 patients' parkinsonism worsened to a mild degree: a 74-year-old man experienced an increase in akinesia, tremor, and rigidity; a 77-year-old man experienced a slight worsening in tremor and rigidity; and a 56-year-old man experienced a decline in gait and akinesia. It was unclear if these declines, which were neither acute nor severe, were due to fluoxetine treatment or the progression of the disease. Signs of parkinsonism in 2 patients appeared to improve during fluoxetine treatment. CONCLUSION: Fluoxetine, in doses up to 40 mg/day, does not appear to be associated with exacerbations of parkinsonian signs and symptoms in outpatients with Parkinson's disease. Further investigation of fluoxetine for the treatment of depression in patients with Parkinson's disease is warranted.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1500404&dopt=Abstract fluoxetine Prozac



Prozac
Fluoxetine attenuates the DL-fenfluramine-induced increase in extracellular serotonin as measured by in vivo dialysis.

Sabol KE, Richards JB, Seiden LS.

Department of Pharmacological and Physiological Sciences, University of Chicago, IL 60637.

Rats with hippocampal dialysis probes were treated with DL-fenfluramine (FEN), fluoxetine, or FEN with fluoxetine pre-treatment. FEN (12.5 mg/kg) increased extracellular serotonin (5-HT) from 0.4 +/- 0.04 to 25.2 +/- 4.16 pg/10 microliters. Fluoxetine (10.0 mg/kg) increased extracellular 5-HT levels from 0.4 +/- 0.05 to 2.4 +/- 0.33 pg/10 microliters. FEN-induced increases in extracellular 5-HT were attenuated by 66% with fluoxetine pre-treatment. This result supports the view that the 5-HT releasing properties of FEN are mediated by the 5-HT uptake transporter.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1511330&dopt=Abstract fluoxetine Prozac



Prozac
Fluoxetine in elderly patients: is there cause for concern?

Brymer C, Winograd CH.

Palo Alto Veterans Affairs Medical Center, California.

OBJECTIVE: To assess whether fluoxetine use is associated with significant weight loss or other side effects in depressed elderly patients with concomitant medical illness. DESIGN: A retrospective chart review. SETTING: A tertiary care VA hospital. PATIENTS: Five groups of outpatients were studied: (1) patients greater than 75 years old receiving fluoxetine (n = 15); (2) patients 60 to 71 years old receiving fluoxetine (n = 20); (3) patients greater than 75 years old receiving nortryptiline or desipramine (n = 20); (4) patients greater than 75 years old with a history of depression but on no antidepressant medication (n = 20); and (5) patients greater than 75 years old with no history of depression (n = 28). MEASUREMENTS: Mortality, change in weight, reports of anorexia or nausea, and serum sodium and glucose measurements. MAIN RESULTS: Patients greater than 75 years of age taking fluoxetine experienced significantly greater weight loss (average 4.6 kilograms, P = 0.0062) than the other groups. Both groups of patients taking fluoxetine were significantly more likely to report nausea (P = 0.0095) and anorexia (P = 0.0009). No significant differences were noted in mortality or the frequency of hypoglycemia or hyponatremia between groups. CONCLUSION: The frequency and degree of weight loss noted here in medically ill elderly receiving fluoxetine warrants further investigation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1512386&dopt=Abstract fluoxetine Prozac



Prozac
Fluoxetine-treated male wrasses exhibit low AVT expression.

Semsar K, Perreault HA, Godwin J.

Department of Zoology, Center of Behavioral Biology, North Carolina State University, Box 7617, Raleigh, NC 27695-7617, USA.

In many species, increasing serotonergic activity can reduce aggression and reverse dominance relationships. These effects may in part be mediated through interactions with the arginine vasotocin/vasopressin (AVT/AVP) system. We tested this hypothesis in a territorial coral reef fish, the bluehead wrasse (Thalassoma bifasciatum), by experimentally enhancing serotonergic neurotransmission, using the selective serotonin re-uptake inhibitor (SSRI) fluoxetine. Terminal phase (TP) males received 2 weeks of nightly intraperitoneal fluoxetine injections (6 microg/g body weight) and were then tested for their aggressive response to an intruder and killed to examine AVT phenotype in the preoptic area of the hypothalamus (POA), an area important to social behavior in fishes. Our previously published study demonstrated that fluoxetine-treated males are less aggressive [H.A.N. Perreault, K. Semsar, J. Godwin, Fluoxetine treatment decreases territorial aggression in a coral reef fish, Physiol. and Behav. 79 (2003) 719-724.]. Here, further study of these same fluoxetine-treated males shows approximately twofold lower AVT mRNA expression relative to saline-treated controls in all regions of the POA (all p< or =0.05) without any changes in AVT-ir soma size (all p>0.4). This study experimentally supports the hypothesis that behavioral effects of SSRIs may be mediated in part through interactions with the AVT/AVP system. These results parallel findings from rodents and humans and are consistent with an indirect neurosteroidogenic rather than a solely direct serotonergic mechanism for SSRI effects on the AVT/AVP system. Furthermore, they suggest that SSRI effects on neuroendocrine function may be best modeled in animals with sensitive stress responses such as those found in nondomesticated animals.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15542067&dopt=Abstract fluoxetine Prozac



Prozac
Sensitive and selective liquid-chromatographic assay of fluoxetine and norfluoxetine in plasma with fluorescence detection after precolumn derivatization.

Suckow RF, Zhang MF, Cooper TB.

Analytical Psychopharmacology Division, New York State Psychiatric Institute, NY 10032.

We determined fluoxetine (Prozac) and its major metabolite norfluoxetine in plasma by liquid chromatography with fluorescence detection. After liquid-liquid extraction from 1 mL of plasma, the extract was derivatized at room temperature with dansyl chloride, and the highly fluorescent derivatives were chromatographed with a reversed-phase C18 column and a mobile phase of phosphate buffer and acetonitrile. Dansylated fluoxetine, norfluoxetine, and the internal standard were eluted in less than 14 min with no interference from endogenous material. The calibration curve was linear over the concentration range 25-800 micrograms/L with inter- and intra-assay imprecision (CV) of less than 10%. Validity of the assay was checked by comparing results for 110 patients' samples with those by a liquid-chromatographic method with ultraviolet detection (r = 0.993 for fluoxetine, 0.957 for norfluoxetine). The identity of the dansylated derivatives was verified by positive chemical ionization mass spectroscopy. The lower limit of detection was approximately 3 micrograms/L. Because no major antidepressant, neuroleptic, or respective drug metabolites interfere with the quantification of fluoxetine and norfluoxetine, this is a useful procedure for pharmacokinetic studies and in clinical settings.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1526010&dopt=Abstract fluoxetine Prozac



Prozac
Role of serotonin and catecholamines in brain in the feeding suppressant effect of fluoxetine.

Grignaschi G, Samanin R.

Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.

The hypophagic effect of fluoxetine was studied in rats, injected intracerebroventricularly with 150 micrograms/20 microliters 5,7-dihydroxytryptamine, to destroy serotonin-containing neurones or 250 micrograms/20 microliters 6-hydroxydopamine, to destroy catecholamine-containing neurones. The effect of various serotonin receptor antagonists was assessed as well. Neither neurotoxin significantly modified the effect of 20 mg/kg (i.p.) fluoxetine on food intake. Metergoline (1-5 mg/kg), (-)-propranolol (16 mg/kg) and ICS 205-930 (0.1 and 1 mg/kg) did not modify the hypophagic effect of fluoxetine, while mianserin (1 and 5 mg/kg), ritanserin (0.5 and 1 mg/kg) and xylamidine (3 mg/kg) slightly but significantly reduced it. While the mechanism by which some 5-HT receptor antagonists modify the effect of fluoxetine remains to be elucidated, it seems clear that 5-HT receptors hardly have any significant role in the ability of the drug to suppress food intake.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1528396&dopt=Abstract fluoxetine Prozac



Prozac
Fluoxetine, a selective serotonin-uptake inhibitor, enhances the anticonvulsant effects of phenytoin, carbamazepine, and ameltolide (LY201116).

Leander JD.

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

Dose-response curves for the prototypical anticonvulsants phenytoin (PHT) and carbamazepine (CBZ), and a novel anticonvulsant, ameltolide (LY201116), were determined with and without pretreatment with the selective serotonin-uptake inhibitor fluoxetine by maximal electroshock seizure (MES) test in mice. Fluoxetine (2.5, 5, and 10 mg/kg intraperitoneally, i.p.) produced a dose-related decrease in the ED50 values for the anticonvulsants (i.p. administration) to protect against MES-induced tonic-extensor seizures. Fluoxetine (10 mg/kg i.p.) also decreased the intravenous (i.v.) ED50 doses of the three anticonvulsants by a factor of approximately 2. These data suggest that fluoxetine, through its selective inhibition of serotonergic reuptake, may have beneficial advantages as compared with common antidepressant drugs in treatment of depressed patients with epilepsy and may also enhance the seizure control of prototypical anticonvulsants in treatment of epilepsy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1534297&dopt=Abstract fluoxetine Prozac



Prozac
Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction.

Bergstrom RF, Peyton AL, Lemberger L.

Lilly Laboratory for Clinical Research, Eli Lilly and Company, Indianapolis, IN 46285.

Clinical reports of concurrent use of fluoxetine and tricyclic antidepressant agents suggest that tricyclic concentrations increase upon coadministration with fluoxetine. This study was conducted to confirm the clinical reports, to quantify the degree of change in tricyclic kinetics, and to establish the mechanism of interaction. Twelve male subjects were given 50 mg desipramine (six subjects) or 50 mg imipramine (six subjects) on three occasions: alone, after a 60 mg dose of fluoxetine, and after eight daily 60 mg doses of fluoxetine. Fluoxetine significantly reduced oral clearance of both imipramine and desipramine as much as tenfold and prolonged half-life as much as fourfold. Desipramine oral clearance values were 289, 112, and 27 L/hr alone, after a single fluoxetine dose, and after multiple fluoxetine doses, respectively. Correspondingly, imipramine oral clearance values were 181, 87, and 51 L/hr. These kinetic changes resulted in significantly higher plasma tricyclic concentrations after fluoxetine administration. The amount of parent drug excreted unchanged in urine increased and imipramine or desipramine clearance to their respective 2-hydroxy metabolites decreased. Metabolic conversion of imipramine to desipramine appeared to be unaffected. The findings indicate that fluoxetine causes an inhibition of tricyclic 2-hydroxylation and may decrease first-pass and systemic metabolism. When imipramine or desipramine are to be coadministered with fluoxetine, a lower dosage may be needed to maintain steady-state concentrations and to avoid undesirable side effects caused by excessive tricyclic concentrations.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1544284&dopt=Abstract fluoxetine Prozac