citalopram Celexa
Escitalopram: A New SSRI for the Treatment of Depression in Primary Care.

Culpepper L.

Department of Family Medicine, Boston University Medical Center, Boston, Mass.

Escitalopram is the S-enantiomer of the racemic compound citalopram, a selective serotonin reuptake inhibitor (SSRI) widely used for the treatment of depression. This review describes the current body of pharmacologic and clinical evidence supporting the use of escitalopram for the treatment of depression and anxiety. Preclinical studies have confirmed that it is primarily this molecule that provides the inhibition of serotonin reuptake responsible for the antidepressant effect of citalopram, with minimal-to-nonexistent affinity for other receptor sites. Clinical trials of escitalopram in depressed patients indicate that escitalopram, 10 mg/day, is as effective as 40 mg/day of its parent compound, citalopram, with an excellent safety and tolerability profile. Because of its increased selectivity, escitalopram represents a refinement in SSRI therapy for symptoms of depression and anxiety. This article also explores the implications of a more selective SSRI on the management of depressed patients in the primary care clinical practice.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15014711&dopt=Abstract citalopram Celexa



citalopram Celexa
Stereoisomers in Psychiatry: The Case of Escitalopram.

Burke WJ, Kratochvil CJ.

Department of Psychiatry, University of Nebraska, Omaha.

Many medications in common clinical use consist of "mirror image" isomers that differ only in the direction in which they rotate plane-polarized light. These stereoisomers exist as mixtures of "right" and "left" handed molecules that are the product of chemical syntheses. However, the biochemical milieu of the human body is a highly stereospecific environment where the fit of medication and receptor may depend on the shape of the molecule in 3-dimensional space. Recent advances in chemistry have allowed the more ready preparation of single isomers of various drugs that were previously available only as racemic mixtures. For those compounds in which the isomers differ in stereospecificity, this separation into single isomers can result in significant changes in potency, tolerability, and efficacy. This article reviews some basic information about stereochemistry and describes the development of a new single isomer antidepressant, escitalopram, which is one of the components of the widely used selective serotonin uptake inhibitor citalopram.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15014731&dopt=Abstract citalopram Celexa



citalopram Celexa
Effect of combined administration of 5-HT1A or 5-HT1B/1D receptor antagonists and antidepressants in the forced swimming test.

Tatarczynska E, Klodzinska A, Stachowicz K, Chojnacka-Wojcik E.

Department of New Drug Research, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, Cracow PL 31-343, Poland.

In the present study, we examined effects of the selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor citalopram, the 5-HT/noradrenaline reuptake inhibitor imipramine, the selective noradrenaline reuptake inhibitor desipramine or the monoamine oxidase-A inhibitor moclobemide, administered in combination with the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridynyl)cyclohexanecarboxamide (WAY 100635) or the 5-HT(1B/1D) receptor antagonist N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)1,1'-biphenyl-4-carboxamide (GR 127935) and the 5-HT(1B) receptor antagonist N-[3-(2-dimethylamino) ethoxy-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide (SB 216641) in the forced swimming test in rats. When given alone, citalopram (20 and 30 mg/kg), imipramine (20 mg/kg), desipramine (20 mg/kg), moclobemide (20 mg/kg), WAY 100635 (0.1 and 1 mg/kg), GR 127935 (10 and 20 mg/kg) or SB 216641 (2 mg/kg) did not shorten the immobility time of rats. Co-administration of WAY 100635 (0.1 and 1 mg/kg) and citalopram (20 mg/kg), or imipramine (20 mg/kg), or moclobemide (20 mg/kg) did not affect the immobility time of rats, whereas WAY 100635 given jointly with desipramine (20 mg/kg) induced a weak anti-immobility effect. GR 127935 (10 and 20 mg/kg) or SB 216641 (2 mg/kg) co-administered with imipramine, desipramine or moclobemide, but not citalopram, produced a significant anti-immobility action in the forced swimming test in rats. These results indicate that the blockade of 5-HT(1B) rather than 5-HT(1A) receptors may facilitate the anti-immobility effect of imipramine, desipramine or moclobemide in the forced swimming test. No interaction was observed between 5-HT(1A) or 5-HT(1B/1D) receptor antagonists and citalopram.

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citalopram Celexa
R-citalopram functionally antagonises escitalopram in vivo and in vitro: evidence for kinetic interaction at the serotonin transporter.

Storustovu S, Sanchez C, Porzgen P, Brennum LT, Larsen AK, Pulis M, Ebert B.

Department of Electrophysiology, H. Lundbeck A/S, 9 Ottiliavej, Valby DK-2500, Denmark.

1. Clinical observations with the selective serotonin reuptake inhibitor (SSRI), S-citalopram, indicate that S-citalopram is more efficacious and produces earlier symptom relief than RS-citalopram. Since R-citalopram is at least 20-fold weaker than S-citalopram as inhibitor of the 5-HT transporter (SERT) in preclinical studies, the clinical data suggest an unexpected antagonistic interaction between the two enantiomers. We therefore characterised the interaction of R- and S-citalopram with the SERT in in vivo and in vitro assays. 2. In both behavioural (potentiation of 5-hydroxytryptophan (5-HTP)-induced behaviour) and electrophysiological studies (inhibition of 5-HT-elicited ion currents in Xenopus oocytes expressing the human SERT (hSERT) R-citalopram inhibited the effects of S-citalopram in a dose-dependent manner. With S-citalopram : R-citalopram ratios of 1 : 2 and 1 : 4, 5-HTP potentiation was significantly smaller than with S-citalopram alone. 3. R-citalopram did not antagonise the effects of another SSRI (fluoxetine) in either behavioural or electrophysiological studies. 4. In oocytes, inhibition of hSERT-mediated currents by R-citalopram was almost completely reversible and characterised by fast on- and off-sets of action. In contrast, the off-set for S-citalopram was 35-fold slower than for R-citalopram. 5. Kinetic analysis of the oocyte experiments suggests that S-citalopram binding to SERT induces a long-lasting, inhibited state of the transporter and that coapplication of R-citalopram partially relieves SERT of this persistent inhibition. 6. We propose that the kinetic interaction of R- and S-citalopram with SERT is a critical factor contributing to the antagonistic effects of R-citalopram on S-citalopram in vitro and in vivo.

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citalopram Celexa
Enantioselective analysis of citalopram and its metabolites in postmortem blood and genotyping for CYD2D6 and CYP2C19.

Holmgren P, Carlsson B, Zackrisson AL, Lindblom B, Dahl ML, Scordo MG, Druid H, Ahlner J.

National Board of Forensic Medicine, Department of Forensic Chemistry, Faculty of Health Science, Linkoping University, S-581 85 Linkoping, Sweden. per.holmgren rmv.se

Citalopram, a selective serotonin reuptake inhibitor, is one of the most commonly found drugs in Swedish forensic autopsy cases. Citalopram is a racemic drug with 50:50 of the S- and R- enantiomers. Enantioselective analysis of citalopram and its metabolites desmethylcitalopram and didesmethylcitalopram were performed in femoral blood from 53 autopsy cases by a chiral high-performance liquid chromatography (HPLC) method. The mean (+/- standard deviation) S/R ratio for citalopram was 0.67 +/- 0.25 and for desmethylcitalopram, 0.68 +/- 0.20. We found increasing S/R ratios with increasing concentrations of citalopram. We also found that high citalopram S/R ratios were associated with a high parent drug-to-metabolite ratio and may be an indicator of recent intake. Citalopram is metabolized by cytochrome P450 (CYP) 3A4, 2C19, and 2D6. Genotyping for the polymorphic CYP2C19 and CYP2D6 revealed no poor metabolizers regarding CYP2C19 and only 2 (3.8%) poor metabolizers regarding CYP2D6. The presence of drugs metabolized by and/or inhibiting these enzymes in several of the cases suggests that such pharmacokinetic interactions are a more important (practical) problem than metabolic deficiency. Enantioselective analysis of citalopram and its metabolites can provide additional information when interpreting forensic toxicology results and might be a necessity in the future.

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citalopram Celexa
5-HT 1A/1B receptor-mediated effects of the selective serotonin reuptake inhibitor, citalopram, on sleep: studies in 5-HT 1A and 5-HT 1B knockout mice.

Monaca C, Boutrel B, Hen R, Hamon M, Adrien J.

INSERM U288, NeuroPsychoPharmacologie Moleculaire Cellulaire et Fonctionnelle, CHU Pitie-Salpetriere-91, Boulevard de l'Hopital, 75013 Paris, France.

Selective serotonin reuptake inhibitors (SSRIs) are extensively used for the treatment of depression. Aside from their antidepressant properties, they provoke a deficit in paradoxical sleep (PS) that is most probably mediated by the transporter blockade-induced increase in serotonin concentration in the extracellular space. Such an effect can be accounted for by the action of serotonin at various types of serotonergic receptors involved in PS regulation, among which the 5-HT(1A) and 5-HT(1B) types are the best candidates. According to this hypothesis, we examined the effects of citalopram, the most selective SSRI available to date, on sleep in the mouse after inactivation of 5-HT(1A) or 5-HT(1B) receptors, either by homologous recombination of their encoding genes, or pharmacological blockade with selective antagonists. For this purpose, sleep parameters of knockout mice that do not express these receptors and their wild-type counterparts were monitored during 8 h after injection of citalopram alone or in association with 5-HT(1A) or 5-HT(1B) receptor antagonists. Citalopram induced mainly a dose-dependent inhibition of PS during 2-6 h after injection, which was observed in wild-type and 5-HT(1B)-/- mice, but not in 5-HT(1A)-/- mutants. This PS inhibition was fully antagonized by pretreatment with the 5-HT(1A) antagonist WAY 100635, but only partially with the 5-HT(1B) antagonist GR 127935. These data indicate that the action of the SSRI citalopram on sleep in the mouse is essentially mediated by 5-HT(1A) receptors. Such a mechanism of action provides further support to the clinical strategy of antidepressant augmentation by 5-HT(1A) antagonists, because the latter would also counteract the direct sleep-inhibitory side-effects of SSRIs.

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citalopram Celexa
Comparative toxicity of citalopram and the newer antidepressants after overdose.

Kelly CA, Dhaun N, Laing WJ, Strachan FE, Good AM, Bateman DN.

Scottish Poisons Information Bureau, Royal Infirmary, Little France Crescent, Edinburgh, Scotland, UK. cathy.kelly luht.scot.nhs.uk

OBJECTIVE: To compare the toxicity of citalopram, venlafaxine, mirtazapine, and nefazadone after overdose. METHODS: Two-year retrospective review of consecutive patients admitted to the toxicology unit of Edinburgh Royal Infirmary. Outcome measure included physiological variables, ECG recordings, peak creatine kinase, development of arrhythmias, seizure, tremor or agitation, and the need for admission to a critical care facility. RESULTS: A total of 225 patients were studied. Venlafaxine was associated with a significantly higher pulse rate (p < 0.0001) and tremor (p = 0.007) than other antidepressants. Citalopram was associated with a significantly longer QT interval on ECG recording (p < 0.0001) but mean QTc durations were not significantly different between all drugs studied. No arrhythmias were recorded. Only venlafaxine and citalopram caused seizures and were associated with the need for admission to Intensive Care, but there was no significant difference between them. CONCLUSIONS: Mirtazapine and nefazadone appear safe in overdose and were associated with minimal features of neurological or cardiovascular toxicity. Citalopram is more likely to cause QT prolongation but other features of cardiovascular toxicity were uncommon. Both citalopram and venlafaxine are proconvulsants. Venlafaxine also causes more frequent features of the serotonin syndrome.

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citalopram Celexa
Citalopram concentrations and response in obsessive-compulsive disorder. Preliminary results.

Bareggi SR, Bianchi L, Cavallaro R, Gervasoni M, Siliprandi F, Bellodi L.

Department of Pharmacology, University of Milan School of Medicine, Via Vanvitelli 32, I-20129 Milan, Italy. silvio.bareggi unimi.it

OBJECTIVE: Citalopram, a highly potent SSRI, is effective in the treatment of depressive disorders and obsessive-compulsive disorder (OCD); however, very few studies have reported concentration-effect relationships for SSRIs. The aim of this study was to investigate the relationship between citalopram concentrations and clinical response in patients with OCD. METHODS AND STUDY DESIGN: Fifteen patients (aged 18-65 years) with a DSM-IV diagnosis of OCD were included in this open-label, single-blind study. Citalopram was started at a dosage of 20 mg/day; the dosage was increased to a maximum of 60 mg/day by the third week, on the basis of clinical need and tolerability. The dosage then remained unchanged until the end of the 10-week study. Clinical assessments were made at baseline, weekly for the first four weeks and then at weeks 6, 8 and 10. The assessment scales used were the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the Clinical Global Impression Scale (CGI) and the Hamilton Depression Rating Scale (HDRS). Plasma citalopram concentrations were determined using a high performance liquid chromatography method after solid phase extraction. RESULTS: One patient was withdrawn from the study because of poor compliance. Of the 14 patients who completed the study, nine did not meet the treatment response criterion of an improvement of >25% from the baseline total Y-BOCS score and a score of < or =3 for the global improvement item of the CGI (these patients were termed non-responders), while five did (responders). There were no differences in the main demographic and baseline clinical variables between responders and non-responders. Steady-state citalopram concentrations were similar in the two groups, suggesting that the anti-obsessional effects of citalopram were not related to pharmacokinetic differences between responders and non-responders. There was no linear relationship between steady-state citalopram concentrations and response. The citalopram concentrations and Y-BOCS scores of individual responders obtained at baseline and various study timepoints showed a sigmoid relationship when analysed using the E(max) (maximum change in Y-BOCS score) model, with a mean EC(50) value (drug concentration that elicits 50% of the E(max)) of 152 microg/L, whereas a similar analysis of the non-responders generated a flat line. CONCLUSION: The results of this preliminary study suggest that plasma citalopram concentrations may be related to the clinical response in responders, but do not seem to account for the lack of clinical effect in non-responders. These data, as well as the usefulness of the model in relating plasma concentrations to response, even after repeated administration, need to be validated by further investigations.

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