Neuropsychopharmacology. 1996 Jun;14(6):437-42.
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.

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




Pharmacol Biochem Behav. 1996 May;54(1):143-7.
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




Neuroscience. 1996 May;72(2):557-66.
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 arc




J Clin Psychopharmacol. 1995 Dec;15(6):417-20.
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.

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




Therapie. 1996 Jan-Feb;51(1):19-25.
[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.

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




Encephale. 1996 May-Jun;22(3):221-7.
[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 toleran




Clin Sci (Lond). 1996 Jul;91(1):87-92.
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.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8774265&dopt=Abstract fluoxetine




N Engl J Med. 1996 Oct 3;335(14):1010-5.
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 complica




Synapse. 1996 Jul;23(3):125-31.
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.

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