citalopram escitalopram Lexapro
Stereoselective biotransformation of the selective serotonin reuptake inhibitor citalopram and its demethylated metabolites by monoamine oxidases in human liver.

Rochat B, Kosel M, Boss G, Testa B, Gillet M, Baumann P.

Unite de Biochimie et Psychopharmacologie Clinique, Departement Universitaire de Psychiatrie Adulte, Prilly-Lausanne, Switzerland.

Citalopram (CIT) is an antidepressive drug of the group of selective serotonin reuptake inhibitors (SSRIs). The tertiary amine CIT is given as a racemic drug, but its pharmacological activity resides mainly in S-CIT. CIT is metabolised by cytochrome P450 (CYP) to N-demethylcitalopram (DCIT) and N-didemethylcitalopram (DDCIT). The citalopram propionic acid derivative (CIT-PROP) is another, but pharmacologically inactive, metabolite, the formation of which has been poorly characterised but is postulated to occur by deamination of CIT, DCIT and/or DDCIT. The aim of the present investigation was to study the formation of the enantiomers of CIT-PROP from CIT and its two N-demethylated metabolites, DCIT and DDCIT, in an in vitro incubation system (microsomal and cytosolic fractions) obtained from human livers. The production of CIT-PROP was measured by a stereospecific HPLC method. Incubation of rac-CIT, rac-DCIT and rac-DDCIT (500 microM each, separately) in the presence (or absence) of NADP showed that CIT-PROP formation was substrate-dependent and essentially NADP-independent. Monoamine oxidases (MAO) type A and B and aldehyde oxidase were identified as the probable enzymes involved in the formation of CIT-PROP from CIT, DCIT and DDCIT. Indeed, the irreversible monoamine oxidase type A inhibitor clorgyline and the irreversible monoamine oxidase type B inhibitor selegiline (both at 0.5 microM in the incubation mixture) inhibited CIT-PROP formation, depending on the substrate, up to 70% and 88%, respectively. The participation of aldehyde oxidase in the subsequent step is suggested by the inhibition caused by menadione (50 microM) in CIT-PROP formation. Preliminary experiments suggest the presence of four unknown metabolites, probably products of deamination, which were detected in plasma and urine samples of patients treated with CIT as well as in in vitro biotransformations. Their presence confirms the importance of deamination in the biotransformation of CIT and its demethylated metabolites, especially in the brain where, in contrast to the liver, the role of cytochrome P450 appears to be low.

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citalopram escitalopram Lexapro
Evidence from microdialysis and synaptosomal studies of rat cortex for noradrenaline uptake sites with different sensitivities to SSRIs.

Hughes ZA, Stanford SC.

Department of Pharmacology, University College London.

1. Microdialysis of the frontal cortex of freely-moving rats and uptake of [3H]noradrenaline into cortical synaptosomes were used to evaluate changes in efflux of noradrenaline in vivo and uptake of [3H]noradrenaline in vitro, respectively, induced by the selective serotonin reuptake inhibitors (SSRIs), fluoxetine and citalopram, and the tricyclic antidepressant, desipramine. 2. Noradrenaline efflux was increased during local infusion into the cortex of each of these drugs. All three agents also inhibited synaptosomal uptake of [3H]noradrenaline; this inhibition was unaffected by a substantial (50%) lesion of central 5-hydroxytrytaminergic neurones induced by intracerebroventricular infusion of 5,7-DHT (150 microg). 3. A noradrenergic lesion (70%), induced by pretreatment with the selective neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, 40 mg kg(-1) i.p.), 5 days earlier, abolished the increase in noradrenaline efflux caused by local infusion of fluoxetine. In contrast, the desipramine-induced increase in efflux was greater than in non-lesioned rats whereas the effect of citalopram on noradrenaline efflux was unaffected by DSP-4 pretreatment. 4. The combined results of all these experiments suggest that there could be more than one, functionally distinct, noradrenaline uptake site in rat frontal cortex which can be distinguished by their different sensitivities to desipramine and the SSRIs, fluoxetine and citalopram.

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citalopram escitalopram Lexapro
Use of the selective serotonin reuptake inhibitor citalopram in a possible animal analogue of obsessive-compulsive disorder.

Stein DJ, Mendelsohn I, Potocnik F, Van Kradenberg J, Wessels C.

Department of Psychiatry, University of Stellenbosch, Tygerberg, South Africa.

Canine acral lick dermatitis (ALD) has been suggested as an animal analogue of obsessive-compulsive disorder (OCD). A series of dogs with ALD or similar conditions were treated with citalopram, the most selective of the selective serotonin reuptake inhibitors. Six of nine (66.7%) dogs showed significant improvement. Given the apparent efficacy of citalopram in the treatment of OCD and related disorders, these data provide further evidence that ALD is a useful animal analogue of OCD.

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citalopram escitalopram Lexapro
Citalopram-induced hypophagia is enhanced by blockade of 5-HT(1A) receptors: role of 5-HT(2C) receptors.

Grignaschi G, Invernizzi RW, Fanelli E, Fracasso C, Caccia S, Samanin R.

Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.

The selective 5-hydroxytryptamine reuptake inhibitor citalopram (10 and 20 mg kg(-1), i.p.) significantly reduced food intake in male rats (CD-COBS) habituated to eat their daily food during a 4-h period. The 5-HT1A receptor antagonist WAY100635 (0.3 mg kg(-1)) administered systemically did not modify feeding but significantly potentiated the reduction in food intake caused by 10 mg kg(-1) i.p. citalopram. The dose of 5 mg kg(-1) i.p. citalopram was not active in animals pretreated with vehicle but significantly reduced feeding in animals pretreated with WAY100635. WAY100635 (0.1 microg 0.5 microl(-1)) injected into the dorsal raphe significantly potentiated the hypophagic effect of 10 mg kg(-1) citalopram. WAY100635 (1.0 microg 0.5 microl(-1)) injected into the median raphe did not modify feeding or the hypophagic effect of 10 mg kg(-1) citalopram. The 5-HT2B/2C receptor antagonist SB206553 (10 mg kg(-1), p.o.) slightly reduced feeding by itself but partially antagonized the effect of WAY100635 administered systemically (0.3 mg kg(-1), s.c.) or into the dorsal raphe (0.1 microg 0.5 microl(-1)) in combination with 10 mg kg(-1) i.p. citalopram. The hypophagic effect of 10 mg kg(-1) i.p. citalopram alone was not significantly modified by SB206553. Brain concentrations of citalopram and its metabolite desmethylcitalopram in rats pretreated with SB206553, WAY100635 and their combination were comparable to those of vehicle-pretreated rats, 90 min after citalopram injection. The hypophagic effect of citalopram was potentiated by blocking 5-HT1A receptors. Only the effect of the WAY100635/citalopram combination seemed to be partially mediated by central 5-HT2C receptors.

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citalopram escitalopram Lexapro
Chronic administration of imipramine and citalopram alters the expression of NMDA receptor subunit mRNAs in mouse brain. A quantitative in situ hybridization study.

Boyer PA, Skolnick P, Fossom LH.

Laboratory of Neuroscience, NIDDK, National Institutes of Health, Bethesda, MD, USA.

Chronic administration of antidepressants produces region-specific adaptive changes in the radioligand binding properties of N-methyl-D-aspartate (NMDA) receptors. We hypothesized that this effect of chronic antidepressant administration was owing to an alteration in NMDA receptor subunit composition. This hypothesis was examined using in situ hybridization with [35S]-labeled riboprobes to quantify the impact of chronic (16 d) injection with either imipramine (15 mg/kg) or citalopram (20 mg/kg) on the levels of transcripts encoding NMDA receptor subunits in mouse brain. These antidepressants altered the levels of mRNA encoding the zeta-subunit in a parallel fashion, with both drugs either reducing transcript levels (e.g., in the cortex, cerebellum, thalamus, and striatum) or producing no substantial effects (e.g., hippocampus). In contrast, these antidepressants often produced distinct, region-specific effects on mRNA levels encoding the epsilon family of subunits. For example, citalopram treatment produced widespread reductions in epsilon 1-subunit mRNA levels (e.g., in frontal cortex, CA2 of hippocampus, and amygdala), whereas imipramine reduced levels of this transcript only in the amygdala. Conversely, imipramine treatment produced widespread reductions in epsilon 2-subunit mRNA levels (e.g., in cortex, CA1-4 of hippocampus, and amygdala), whereas the effects of citalopram on levels of this transcript were largely restricted to amygdala. These findings indicate that long-term antidepressant treatment produces region-specific changes in expression of transcripts for NMDA receptor subunits, presumably altering NMDA receptor composition. Because subunit composition determines the physiological and pharmacological properties of NMDA receptors, these changes may play a critical role in the therapeutic actions of structurally diverse antidepressants.

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citalopram escitalopram Lexapro
Regional distribution of 5-HT transporters in the brain of wild type and 'Purkinje cell degeneration' mutant mice: a quantitative autoradiographic study with [3H]citalopram.

Le Marec N, Hebert C, Amdiss F, Botez MI, Reader TA.

Centre de Recherche en Sciences Neurologiques, Departement de Physiologie, Faculte de Medecine, Universite de Montreal, Que., Canada.

The neurological mutant 'Purkinje cell degeneration' (pcd) is characterized by a primary degeneration of Purkinje cells, as well as by retrograde and secondary partial degeneration of cerebellar granule cells and inferior olivary neurons, and can be considered as an animal model of human degenerative ataxias. The serotonin (5-HT) innervation was examined in wild type and pcd mice, by quantifying 5-HT uptake sites, or transporters, using [3H]citalopram binding autoradiography. In both wild type and pcd mutants, the highest densities of 5-HT transporters were in mesencephalic and rostral pontine regions, in limbic structures, in hypothalamus and in discrete thalamic divisions, while the lowest labelling was found in cerebellum and brainstem reticular formation. In pcd mice, although [3H]citalopram labelling was higher in cerebellar cortex and deep cerebellar nuclei, when binding densities were corrected for surface area, the up-regulation of 5-HT transporters was present only in deep cerebellar nuclei. Also, higher labelling was found in nuclei raphe dorsalis and medialis, in ventral divisions of rostral neostriatum, caudal neostriatum, rostral globus pallidus, posteromedial amygdaloid nucleus, septum, olfactory tubercles, vertical limb of Broca's diagonal band, periventricular, latero-ventral and medio-ventral thalamic nuclei, medial geniculate nucleus, anterior hypothalamus and entorhinal cortex. The results indicate a relative integrity of the 5-HT innervation, but with a reorganization of serotoninergic terminals in the cerebellum, in particular in the deep cerebellar nuclei. This suggests that in progressive cerebellar degeneration, as found in the pcd mutant, the modified 5-HT system may still participate in motor functions by exerting an overall modulation of excitatory amino acid neurotransmission, but the availability of 5-HT may be altered in defined brain targets, as is the case for other spontaneous cerebellar mutants, in particular for the 'Lurcher' mutant mouse, a model of human olivopontocerebellar atrophy.

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citalopram escitalopram Lexapro
Antidepressant drugs and heart electrical field.

Slavicek J, Paclt I, Hamplova J, Kittnar O, Trefny Z, Horacek BM.

Department of Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic.

Some antidepressant drugs, especially tricyclic ones--(TCA), have cardiovascular side effects. To compare the effects of antidepressant drugs, the electrocardiogram (ECG), vectorcardiogram (VCG), and body surface maps (BSM) were recorded in psychiatric patients without cardiovascular diseases treated by a) TCA amitriptyline or dosulepin (daily dose 50-200 mg, 22 patients), b) lithium (serum level 0.66 +/- 0.08 meq/l, 21 patients), c) selective serotonine reuptake inhibitor citalopram (daily doses 20-60 mg, 30 patients), and in 23 control patients. In the TCA-treated patients, the heart rate was increased, QT and RR intervals shortened (p < 0.01, antimuscarinic effect). This was not observed in lithium- and citalopram-treated patients. All antidepressants decreased the absolute maximum values of depolarization isointegral maps, lithium and TCA reduced the initial and citalopram the later phase of depolarization. Citalopram slightly diminished the amplitude of the R wave. The results confirm the antimuscarinic effects of TCA in therapeutic doses and specify the intraventricular effects of antidepressants.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9803478&dopt=Abstract citalopram escitalopram Lexapro