Prozac
[Pharmaco-clinical correlations during fluoxetine administration in patients with depressive schizophrenia treated with haloperidol decanoate]

[Article in French]

Viala A, Aymard N, Leyris A, Caroli F.

Unite de Pharmacologie, Centre Hospitalier Sainte-Anne, Paris, France.

The study concerned 7 patients suffering from schizophrenic disorder according to the DSM III R criteria, treated with a stable dose of haloperidol decanoate (Haldol decanoas) added with fluoxetine (Prozac) from 20 mg to 40 mg/day because of major depression. Patients were assessed at baseline and weekly during the first cycle, and then once a month before each haloperidol decanoate injection, using the brief psychiatric rating scale (BPRS), the general clinical impression scale (CGI) and the Montgomery and Asberg depression rating scale (MADRS). Extrapyramidal and anticholinergic side-effects, blood pressure and pulse were noted. Determinations of plasma and red blood cells concentrations of haloperidol and reduced haloperidol, and of fluoxetine and norfluoxetine, were conducted at the same time than clinical evaluations. For all patients, we observed an improvement by the end of the first week, which became significant at the end of the second week, and continued in subsequent weeks (more than 30 per cent). Two weeks after the addition of fluoxetine, a very significant increase in haloperidol concentrations (more than 100 per cent) was noted; fluoxetine seems to have pharmacokinetic interactions with haloperidol, either by inhibiting its hepatic metabolism (inhibition of cytochrome P450 isoenzyme) or/and by displacing it from protein binding sites.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8762216&dopt=Abstract fluoxetine Prozac



Prozac
[Pharmaco-epidemiologic study of the use of antidepressant drugs in the general population]

[Article in French]

Rouillon F, Blachier C, Dreyfus JP, Bouhassira M, Allicar MP.

Service de Psychiatrie du Pr Ades, Hopital Louis-Mourier, Colombes.

The objective of this study was to evaluate the mode of prescription and the users of antidepressant agents. It consisted of an initial phase (survey of the general population), aimed at selecting a representative sample of antidepressants users by a mail questionnaire, without asking prescribers in order to avoid the bias inherent to such an approach. Results showed a current incidence of use of 2.75 % for the 8 main antidepressants, i.e. more than one million adults in France. The distribution of antidepressants showed Prozac in first place, followed by Anafranil, and Laroxyl, then Stablon, Athymil, Survector and Ludiomil. In more than 50 % of cases, antidepressants have been taken for a year or more, continuously of intermittently. They were prescribed by a general practitioner in 60 % of cases and a psychiatrist in 30 %. A second survey phase (telephone) undertaken by psychiatrists and involving a sample of this population enabled determination of the pathophysiological profile of consumers at the time of prescription of antidepressant treatment, using a validated diagnostic tool, the MINI. Taking all drugs together, results showed that prescription was within Marketing Authorization approved indications in about 65 % of cases (existence of depression 61 %, dysthymia 3 %, OCD 1 %). This study shows that, in 23 % of cases, antidepressants are not used in patients with one of the psychiatric diseases identified by the MINI but nevertheless suffering from pathophysiological symptoms (subsyndronic syndrome). It can be concluded that, in some subjects, antidepressants are used in non-identified disorders. It must also be recognized that, with 3 % of users, the population of individuals treated by antidepressants is less than that of patients suffering, in the general population, from depression (5 to 10 % per year, according to studies).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8767026&dopt=Abstract fluoxetine Prozac



Prozac
[Fluoxetine and tricyclic antidepressants: clinical tolerance in short-term combined administration]

[Article in French]

Bonin B, Bertschy G, Baumann P, Francois T, Vandel P, Vandel S, Sechter D, Bizouard P.

Service de Psychiatrie et Psychologie Medicale, CHU, Besancon.

The tricyclic SSRI antidepressant association is often used in the treatment of resistant depressive illness. The pharmacokinetic interaction existing between these two types of drugs is well known, with as result, an increase of tricyclic antidepressant plasma levels. The aim of this work was to assess the clinical tolerance of the association of fluoxetine and tricyclic antidepressants, prescribed at usual doses. In 10 patients, having a bad response to a tricyclic antidepressant treatment, with in the therapeutic window adjusted plasma levels since 3 weeks, an association of fluoxetine (20 mg/d) to the tricyclic was prescribed. The other associated treatments were unmodified. The clinical evolution was recorded with the MADRS and the UKU scale for side effects, before the tricyclic antidepressant treatment adjustment (D-21) and just before the fluoxetine association (D1) and every 7 days after this association too. The tricyclic plasma levels (amitriptyline and clomipramine) and the patient phenotype CYP 2D6 and 2C19 were determined before and 7 days after the fluoxetine addition. A good clinical evolution was noted since the 7th day after the fluoxetine association to tricyclic (mean MADRS scores on D-21, D1, D7 and D14; 35.4, 33.1, 23.9, 16.8 respectively). In 3 patients, an anxiety increase on day 6, 14 and 16 respectively, after fluoxetine addition, induces a stop of the serotonergic antidepressant. In one patient all the treatment was stopped due to the appearance of a mood inversion. In another patient, after 14 days of antidepressant association, EC were prescribed as asked by the patient, due to an insufficient mood improvement, with a good clinical result and tolerance. The evolution of the side effects was surprising. There was no increase of the UKU score mean during the associated treatment, despite an increase of the tricyclic plasma levels that reached, in three patients, the toxic level (510, 605 and 860 ng/ml of amitriptyline + nortriptyline or clomipramine + demethylclomipramine). The UKU psychic score mean significatively decreased (7.7, 6.8, 5.3, 4 on D-21, D1, D7, D14 respectively). The fluoxetine association did not modify the neurological, neuro-endocrinologic and the skin side effects. None increase of headheck was noted. The increase of anxiety, observed in 3 patients, was not considered as a side effect of the antidepressant association, but an effect of the stimulant potency of fluoxetine in anxious patients. The pharmacogenetic results confirmed the strong inhibition potenty of fluoxetine on the CYP 2D6 isoenzyme. In 5 patients indeed, the extensive metabolizer phenotype was modified in a poor metabolizer phenotype, seven days after the association of fluoxetine. The CYP 2C19 phenotype was unchanged after this association. The patient phenotype did not seem to interfere with the clinical results. In conclusion, in this group of patients, the short-term clinical tolerance of the tricyclic antidepressant and fluoxetine association was very good, despite the pharmacokinetic interaction existing between these two types of drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8767051&dopt=Abstract fluoxetine Prozac



Prozac
Platelet 5-hydroxytryptamine is decreased in a preliminary group of depressed patients receiving the 5-hydroxytryptamine re-uptake inhibiting drug fluoxetine.

Menys VC, Smith CC, Lewins P, Farmer RD, Noble MI.

Department of Biological Sciences, Manchester Metropolitan University, U.K.

1. In view of the importance of 5-hydroxytryptamine in coronary thrombosis, we wanted to know whether a potentially protective decrease in platelet 5-hydroxytryptamine could be achieved by treatment with an inhibitor of 5-hydroxytryptamine uptake, fluoxetine. 2. We studied 15 patients treated for psychiatric indications with fluoxetine, and compared the findings with those obtained with blood from 18 patients treated with amitriptyline and 13 controls previously treated for affective disorders. 3. Platelet-rich plasma 5-hydroxytryptamine levels were significantly decreased in the fluoxetine group (P < 0.005) but not in the amitriptyline group compared with the control group. 4. Collagen-induced aggregation in whole blood anticoagulated with hirudin was measured by sequential single platelet counting. The contribution of 5-hydroxytryptamine was assessed from the effect of adding the 5-hydroxytryptamine specific antagonist ICI 170809. This contribution was significantly decreased in the fluoxetine group but not in the amitriptyline group compared with the control group. 5. It is concluded that platelet 5-hydroxytryptamine is indeed decreased by fluoxetine, and we would predict a protective effect of fluoxetine against coronary thrombosis.

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Prozac
A study of the brain structures involved in the acute effects of fluoxetine on REM sleep in the rat.

Monti JM, Jantos H.

Department of Pharmacology and Therapeutics, Clinics Hospital, Montevideo, Uruguay.

The effects of acute administration of fluoxetine, a selective serotonin reuptake inhibitor on spontaneous sleep, were studied in adult rats implanted for chronic sleep recordings. Fluoxetine was administered systemically or infused directly into the dorsal raphe nucleus (DRN), the right laterodorsal tegmental nucleus (LDT) or the medial pontine reticular formation (mPRF). Systemic administration of fluoxetine (3.0-12.0 mumol/kg) significantly reduced rapid-eye-movement sleep (REMS) and the number of REM periods; REMS latency was augmented. Direct infusion of fluoxetine (1.0 nmol) into the DRN induced a significant increment of REMS and of the number of REM periods whereas REMS latency was reduced. Microinjection of fluoxetine into the LDT (1.0 nmol) or the mPRF (0.8 nmol) decreased REMS and the number of REM periods whereas REMS latency was augmented. Pre-treatment with the selective 5-HT1A receptor antagonist WAY 100635 prevented the reduction of REMS induced by the microinjection of fluoxetine into the LDT. Our results indicate that the fluoxetine-induced suppression of REMS is related to the inhibition of brainstem structures involved in the promotion and the induction of REMS. The decrease of REMS would be dependent upon the activation of several 5-HT receptor subtypes, including the 5-HT1A receptor.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15327697&dopt=Abstract fluoxetine Prozac



Prozac
Birth outcomes in pregnant women taking fluoxetine.

Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL.

Department of Pediatrics, University of California-San Diego, La Jolla, 92103, USA.

BACKGROUND: Although fluoxetine is the most frequently prescribed antidepressant drug in the United States, its safety in pregnant women has not been established. METHODS: From 1989 through 1995, we prospectively identified 228 pregnant women taking fluoxetine. We compared the outcomes of their pregnancies with those of 254 women identified in a similar manner who were not taking fluoxetine. RESULTS: The rate of spontaneous pregnancy loss did not differ significantly between the women treated with fluoxetine and the control women (10.5 percent and 9.1 percent, respectively), nor was the rate of major structural anomalies significantly different (5.5 percent vs. 4.0 percent). Among the 97 infants exposed to fluoxetine who were evaluated for minor anomalies, the incidence of three or more minor anomalies was significantly higher than among 153 similarly examined control infants (15.5 percent vs. 6.5 percent, P=0.03). As compared with the 101 infants exposed to fluoxetine only during the first and second trimesters, the 73 infants exposed during the third trimester had higher rates of premature delivery (relative risk, 4.8; 95 percent confidence interval, 1.1 to 20.8), admission to special-care nurseries (relative risk, 2.6; 95 percent confidence interval, 1.1 to 6.9), and poor neonatal adaptation, including respiratory difficulty, cyanosis on feeding, and jitteriness (relative risk, 8.7; 95 percent confidence interval, 2.9 to 26.6). Birth weight was also lower and birth length shorter in infants exposed fluoxetine late in gestation. CONCLUSION: Women who take fluoxetine during pregnancy do not have an increased risk of spontaneous pregnancy loss or major fetal anomalies, but women who take fluoxetine in the third trimester are at increased risk for perinatal complications.

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Prozac
Effect of acute and chronic fluoxetine on extracellular dopamine levels in the caudate-putamen and nucleus accumbens of rat.

Clark RN, Ashby CR Jr, Dewey SL, Ramachandran PV, Strecker RE.

Department of Psychiatry and Behavioral Sciences, State University of New York at Stony Brook 11794, USA.

Recent studies indicate that an increase in serotonergic (5-HT) activity in the nucleus accumbens (NAc) produces an increase in dopamine (DA) release, providing a possible mechanism for the involvement of DA in the therapeutic action of selective serotonin reuptake inhibitor (SSRI) antidepressants. However, acutely administered fluoxetine (2.5, 5.0, or 10.0 mg/kg, i.p.) failed to elevate extracellular levels of DA, or its metabolites in the NAc or caudate-putamen (CP). In fact, the highest dose produced a small (20%) decrease in DA levels in the NAc. Extracellular levels of the 5-HT metabolite 5HIAA were consistently decreased at all doses of fluoxetine in both structures. Since SSRIs generally require several weeks of treatment to be effective clinically, a second experiment examined the effect of chronic administration of fluoxetine. Chronic (21 day) daily treatment with 5 mg/kg had no effect on NAc basal levels of DA, DA metabolites, or 5HIAA, relative to a saline-treated control group. Finally, pretreatment with fluoxetine appeared to slightly enhance the elevation of NAc DA induced by an injection of cocaine (10 mg/kg, i.p.), an effect that was not quite significant (P < .06). In conclusion, the 5-HT-induced facilitation of NAc DA neurotransmission described in the literature may not be relevant to the therapeutic action of fluoxetine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8807740&dopt=Abstract fluoxetine Prozac



Prozac
The anticonvulsant action of fluoxetine in substantia nigra is dependent upon endogenous serotonin.

Pasini A, Tortorella A, Gale K.

Georgetown University, Department of Pharmacology, Washington, DC 20007, USA.

Fluoxetine, a serotonin (5-HT) reuptake inhibitor, has been documented to exert a protective action against convulsive seizures in animal models, when administered either systemically, or focally into substantia nigra. It is likely that the mechanism of anticonvulsant action of fluoxetine is due to an enhancement of endogenous 5-HT transmission. To evaluate this possibility in the context of the anticonvulsant action of intranigral fluoxetine, we examined the influence of 5-HT-mediated transmission in substantia nigra on seizure susceptibility in a rat model of focally evoked complex partial seizures. In addition to fluoxetine (3.5 nmol), we found that the directly acting 5-HT receptor agonists, 1-[3-(trifluoromethyl)phenyl]piperazine (TFMPP) (10 nmol), 1-(3-chlorophenyl)piperazine (m-CPP) (7.4 nmol), gepirone (70 nmol) and 2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide (8-OH-DPAT) (10 nmol), when microinjected bilaterally into substantia nigra, protected rats from limbic motor seizures evoked focally from area tempestas, an epileptogenic site in the deep rostral piriform cortex. This indicates that multiple 5-HT receptor subtypes in substantia nigra may contribute to seizure regulation. Consistent with this, the 5-HT antagonist, metergoline, partially reversed the anticonvulsant action of intranigral fluoxetine. Depletion of endogenous 5-HT, by pretreatment with parachlorophenylalanine (PCPA), completely prevented the anticonvulsant action of intranigral fluoxetine, without modifying the anticonvulsant effect of intranigral TFMPP. These findings support the proposal that the anticonvulsant action of fluoxetine in substantia nigra is due to an enhancement of the synaptic action of endogenous 5-HT in substantia nigra which in turn is mediated via multiple 5-HT receptors. Endogenous 5-HT transmission in substantia nigra is therefore capable of limiting the development and propagation of seizure activity generated in limbic circuits.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8816259&dopt=Abstract fluoxetine Prozac