citalopram escitalopram Lexapro
Citalopram overdose--review of cases treated in Swedish hospitals.

Personne M, Sjoberg G, Persson H.

Swedish Poisons Informaation Centre, Karolinska Hospital, Stockholm, Sweden. gic. gic.ks.se

BACKGROUND: The toxic effects of acute citalopram overdose are reported by the Swedish Poisons Information Centre. DESIGN: Case reports received from Swedish hospitals during 1995 have been analyzed. Forty-four cases of pure citalopram intoxication have been studied in detail. RESULTS: At doses below 600 mg, mild symptoms were observed. Doses above 600 mg caused ECG abnormalities and convulsions in some patients, while doses greater than 1900 mg caused such symptoms in all patients. CONCLUSIONS: The findings are consistent with previous reports claiming that selective serotonin reuptake inhibitors are less toxic compared to tricyclic antidepressants. However, there is a risk of developing serious symptoms when large doses have been ingested.

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An open pilot study of citalopram for behavioral disturbances of dementia. Plasma levels and real-time observations.

Pollock BG, Mulsant BH, Sweet R, Burgio LD, Kirshner MA, Shuster K, Rosen J.

Western Psychiatric Institute and Clinic, Pittsburgh, PA 15213, USA.

Citalopram, in European studies, has shown some early promise for treatment of poststroke depression and behavioral complications of dementia. An open pilot study of citalopram was conducted in 16 patients with dementia and behavioral disturbances. Citalopram was well tolerated by 13 of the patients, and 9 had a clinically impressive response. A significant overall mean reduction in disruptive vocalizations was observed by means of a novel technique of computer-assisted real-time observation. The mean citalopram plasma level-to-dose ratio was found to be twice that previously reported in younger patients. These pilot findings should encourage future placebo concentration-controlled trials.

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Ex vivo inhibitory effect of the 5-HT uptake blocker citalopram on 5-HT synthesis.

Moret C, Briley M.

Pierre Fabre Research Centre, Castres, France.

Serotonin (5-hydroxytryptamine, 5-HT) synthesis was determined in vivo by measuring the accumulation of 5-hydroxytryptophan (5-HTP) in rat frontal cortex after inhibition of aromatic amino acid decarboxylase by administrative of m-hydroxybenzylhydrazine (NSD 1015) (100 mg/kg, i.p.). The selective 5-HT reuptake inhibitor, citalopram, the 5-HT1A agonists, (+/-) 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), ipsapirone, gepirone and the 5-HT1A/B agonist, 7-trifluoromethyl-4(4-methyl-1-piperazinyl-pyrolo[1,2-a]-quinox ali ne (CGS 12066B), the 5-HT1A/B ligands and beta-adrenoceptor antagonists, (+/-) pindolol and (+/-) alprenolol, and the non-selective 5-HT ligands, m-chlorophenylpiperazine (mCPP) and metergoline, all inhibited the synthesis of 5-HT. The 5-HT1A/5-HT2 antagonist, spiperone, alone, had no effect on basal 5-HT synthesis, however it attenuated the effect of 8-OH-DPAT by 56% and CGS 12066B by 39% but only barely that of citalopram by 17%. The selective 5-HT1A antagonist, WAY 100635, which did not modify by itself 5-HT synthesis, had no effect on citalopram-induced reduction of 5-HT synthesis. Neither the 5-HT2 agonist, (+/-)1-(2,5-dimethoxy-4-indophenyl)-2-aminopropane (DOI) nor the 5-HT2 antagonist, ritanserin, had any effect on the synthesis of 5-HT. In addition, ritanserin did not modify the inhibitory effect of citalopram. Methiothepin was the only compound to increase 5-HT synthesis. These results suggest that the effect of citalopram on the synthesis of 5-HT is not mediated by 5-HT1A or 5-HT2 receptors and that other receptors may be involved.

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citalopram escitalopram Lexapro
[11C]-NS 4194 versus [11C]-DASB for PET imaging of serotonin transporters in living porcine brain.

Jensen SB, Smith DF, Bender D, Jakobsen S, Peters D, Nielsen EO, Olsen GM, Scheel-Kruger J, Wilson A, Cumming P.

PET Center, Aarhus University Hospitals, Aarhus, Denmark.

In vitro, the novel diazabicyclononane NS 4194 has several thousand-fold selectivity for blocking the transport into rat brain synaptosomes of [(3)H]-serotonin in comparison to [(3)H]-dopamine or [(3)H]-noradrenaline. We have prepared [(11)C]-NS 4194 in order to test its properties for PET imaging of brain serotonin transporters in comparison with the well-documented tracer [(11)C]-DASB. Both compounds had rapid clearance from blood to brain of living pigs. The apparent equilibrium distribution volumes in cerebellum were 35 ml g(-1) for [(11)C]-NS 4194 and 11 ml g(-1) for [(11)C]-DASB. Pretreatment of pigs with citalopram did not reduce the uptake of either tracer in cerebellum, validating the use of that tissue as a nonbinding reference tissue for kinetic analysis of specific binding. The binding potential (pB) calculated for [(11)C]-NS 4194 using arterial input models was close to 0.5 in the telencephalon, and was 60% displaced by citalopram. However, the reference tissue method of Lammertsma was unsuited to calculate pB for this tracer, apparently due to its excessive nonspecific binding. In contrast to the relatively homogeneous binding of [(11)C]-NS 4194, the pB of [(11)C]-DASB ranged from 0.6 in frontal cortex to 2 in the mesencephalon when calculated by the method of Lammertsma. Parametric maps of the pB of [(11)C]-DASB showed a pattern consistent with the known distribution of serotonin transporters in pig brain in vitro, and there was a uniform displacement of 80% of the specific binding after citalopram treatment in vivo. In conclusion, [(11)C]-DASB is in several respects superior to [(11)C]-NS 4194 for the detection of serotonin uptake sites by PET. Copyright 2003 Wiley-Liss, Inc.

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Stereoselective single-dose kinetics of citalopram and its metabolites in rats.

Kugelberg FC, Carlsson B, Ahlner J, Bengtsson F.

Division of Clinical Pharmacology, Department of Medicine and Care, Faculty of Health Sciences, Linkoping University, Linkoping, Sweden. frederik.kugelberg imv.liu.se

The single-dose kinetics of the enantiomers of citalopram (CIT) and its metabolites, demethylcitalopram (DCIT) and didemethylcitalopram (DDCIT), were investigated after administration of 10, 20, or 100 mg/kg (s.c.) rac-CIT to rats. Samples from serum and two brain regions were collected 1, 3, 10, or 20 h postdose for HPLC analysis. In the 100 mg/kg rats, the enantiomeric (S/R) serum concentration ratios of CIT decreased during the study period (0.93 at 1 h vs. 0.59 at 20 h; P < 0.001). In the 10 and 20 mg/kg rats, the decrease in serum S/R CIT ratios was not so evident as in the 100 mg/kg rats. In all three groups the S/R CIT ratio was almost the same in the brain as in serum, although both CIT enantiomer levels in the brain were found to be 5-10 times higher than the levels in serum. The serum and brain metabolite levels were low in the 10 and 20 mg/kg rats, whereas the levels increased during the study period in the 100 mg/kg rats. In conclusion, the CIT enantiomers were shown for the first time to be stereoselectively metabolized after single-dose administration to rats, as previously shown in steady-state dosing studies in humans and rats. Copyright 2003 Wiley-Liss, Inc.

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The R-enantiomer of citalopram counteracts escitalopram-induced increase in extracellular 5-HT in the frontal cortex of freely moving rats.

Mork A, Kreilgaard M, Sanchez C.

Department of Neurochemistry and Discovery ADME, H. Lundbeck A/S, Copenhagen, Denmark. arm lundbeck.com

The selective serotonin (5-HT) reuptake inhibitor, citalopram, is a racemic mixture of an S(+)- and R(-)-enantiomer, escitalopram and R-citalopram, respectively. The present study compares the effects of escitalopram, R-citalopram and citalopram on extracellular levels of 5-HT in the frontal cortex of freely moving rats. In addition, co-injection of escitalopram and R-citalopram (ratios 1:2 and 1:4) were assessed. In some experiments escitalopram and R-citalopram were infused into the frontal cortex by reverse microdialysis. Finally, the extracellular level of escitalopram in the frontal cortex was studied after administration of escitalopram alone or in combination with R-citalopram. Escitalopram (1.0-3.9 mg/kg, s.c.) produced a greater maximal increase in extracellular 5-HT than citalopram (2.0-8.0 mg/kg, s.c.). R-citalopram (15.6 mg/kg s.c.) did not affect the 5-HT levels. When co-injected, R-citalopram counteracted the escitalopram-induced increase in extracellular 5-HT levels. Local infusion of the two enantiomers into the frontal cortex produced a similar inhibitory response. R-citalopram did not influence the extracellular levels of escitalopram and therefore does not exert its effect via a pharmacokinetic interaction with escitalopram. In conclusion, the 5-HT-reuptake inhibitory activity of citalopram resides in escitalopram, and the R-enantiomer counteracts this effect. This observation would predict an improved clinical profile of escitalopram compared to citalopram.

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Nicotine and nicotinic receptor antagonists potentiate the antidepressant-like effects of imipramine and citalopram.

Popik P, Kozela E, Krawczyk M.

Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna street, 31-343 Krakow, Poland. nfpopik cyf-kr.edu.pl

1. Epidemiological and clinical observations suggest the involvement of nicotinic acetylcholine receptors (nAChRs) in depressive illness. Nonetheless, there is no clearcut evidence that nicotine and/or nAChR antagonists produce an antidepressant effect. 2. In the tail-suspension test (C57/Bl male mice), nicotine (0.8-1.2 mg kg(-1) s.c. or i.p.) given 15-60 min before the measurement exerted no effect on immobility. 3. Given 30 min before the measurement, citalopram (2 mg kg(-1)) produced a slight decrease in immobility; coadministration of nicotine (0.8 mg kg(-1), 15 but not 40 min before the test) to citalopram-treated mice resulted in a robust decrease in immobility. Imipramine (4 mg kg(-1)) did not affect immobility, but given in combination with 0.8 mg kg(-1) of nicotine (15 but not 40 min before the test), a decrease in immobility was observed. Nicotine (0.8 and 1.2 mg kg(-1)) also produced an enhancement in the anti-immobility effect of imipramine (20 mg kg(-1)). 4. We further investigated if nAChR antagonists would influence the antidepressant-like effects of imipramine and citalopram. Unexpectedly, mecamylamine (1-2.5 mg kg(-1)) and dihydro-beta-erythroidine (2 mg kg(-1)) potentiated the antidepressant-like effect of imipramine (4-20 mg kg(-1)). Mecamylamine (2.5 mg kg(-1)) but not dihydro-beta-erythroidine also increased the antidepressant-like effect produced by 2 mg kg(-1) of citalopram. 5. The interaction between nAChR antagonists and antidepressants appeared synergistic. 6. Neither nAChR ligands, antidepressants nor combinations of the two, affected locomotor activity. 7. The present results demonstrate an unexpected interaction between nAChR ligands and imipramine and citalopram in the tail-suspension test.

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