citalopram Celexa
The S-enantiomer of R,S-citalopram, increases inhibitor binding to the human serotonin transporter by an allosteric mechanism. Comparison with other serotonin transporter inhibitors.

Chen F, Larsen MB, Sanchez C, Wiborg O.

Institute for Basic Psychiatric Research, Department of Biological Psychiatry, Psychiatric Hospital of Aarhus University, Skovagervej 2, DK-8240 Risskov, Denmark.

The interaction of the S- and R-enantiomers (escitalopram and R-citalopram) of citalopram, with high- and low-affinity binding sites in COS-1 cell membranes expressing human SERT (hSERT) were investigated. Escitalopram affinity for hSERT and its 5-HT uptake inhibitory potency was in the nanomolar range and approximately 40-fold more potent than R-citalopram. Escitalopram considerably stabilised the [(3)H]-escitalopram/SERT complex via an allosteric effect at a low-affinity binding site. The stereoselectivity between escitalopram and R-citalopram was approximately 3:1 for the [(3)H]-escitalopram/hSERT complex. The combined effect of escitalopram and R-citalopram was additive. Paroxetine and sertraline mainly stabilised the [(3)H]-paroxetine/hSERT complex. Fluoxetine, duloxetine and venlafaxine have only minor effects. 5-HT stabilised the [(125)I]-RTI-55, [(3)H]-MADAM, [(3)H]-paroxetine, [(3)H]-fluoxetine and [(3)H]-venlafaxine/SERT complex to some extent. Thus, escitalopram shows a unique interaction with the hSERT compared with other 5-HT reuptake inhibitors (SSRIs) and, in addition to its 5-HT reuptake inhibitory properties, displays a pronounced effect via an affinity-modulating allosteric site.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15695064&dopt=Abstract citalopram Celexa



citalopram Celexa
Antinociceptive effects of the antidepressants amitriptyline, duloxetine, mirtazapine and citalopram in animal models of acute, persistent and neuropathic pain.

Bomholt SF, Mikkelsen JD, Blackburn-Munro G.

Department of Pharmacology, NeuroSearch A/S, 93 Pederstrupvej, DK-2750, Ballerup, Denmark; Department of Molecular Anatomy and Physiology, NeuroSearch A/S, 93 Pederstrupvej, DK-2750, Ballerup, Denmark.

The effects of acute, systemic administration of amitriptyline, duloxetine and mirtazapine (antidepressant drugs that variously affect extracellular noradrenaline and serotonin levels) and the selective serotonin reuptake inhibitor (SSRI) citalopram were compared in rat models of experimental pain. None of the drugs (all 3-30 mg/kg, i.p.) affected acute nociceptive responses as measured in the tail flick test. In the hot plate test, duloxetine and mirtazapine significantly increased (P<0.05) the nociceptive response latency, whereas amitriptyline and citalopram were ineffective. In the formalin test, duloxetine and citalopram significantly attenuated, whereas amitriptyline and mirtazapine increased, second phase flinching behaviour (all P<0.05). However, amitriptyline and mirtazapine reduced second phase licking behaviour. In the chronic constriction injury model of neuropathic pain, thermal hyperalgesia of the injured hindpaw was significantly attenuated by all four drugs (P<0.05); only amitriptyline and duloxetine fully reversed thermal hypersensitivity. None of the drugs tested attenuated mechanical allodynia. In contrast amitriptyline, duloxetine and mirtazapine significantly reduced mechanical hyperalgesia (P<0.05); citalopram was ineffective. No drug-related effects on motor performance in the rotarod test were observed. These results (a) highlight the difficulty in correlating antinociceptive effects of drugs from different antidepressant classes across a range of animal pain models and (b) suggest that antidepressants that variously affect both noradrenaline and serotonin levels have more potent and efficacious antinociceptive effects than SSRIs (as exemplified by citalopram), against a range of pain-like behaviours in an animal model of neuropathic pain.

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citalopram Celexa
Effects of Acute and Long-Term Administration of Escitalopram and Citalopram on Serotonin Neurotransmission: an In Vivo Electrophysiological Study in Rat Brain.

El Mansari M, Sanchez C, Chouvet G, Renaud B, Haddjeri N.

1Laboratory of Neuropharmacology and Neurochemistry, Faculty of Pharmacy, University of Claude Bernard Lyon I, Lyon Cedex, France.

The present study was undertaken to compare the acute and long-term effects of escitalopram and citalopram on rat brain 5-HT neurotransmission, using electrophysiological techniques. In hippocampus, after 2 weeks of treatment with escitalopram (10 mg/kg/day, s.c.) or citalopram (20 mg/kg/day, s.c.), the administration of the selective 5-HT(1A) receptor antagonist WAY-100,635 (20-100 mug/kg, i.v.) dose-dependently induced a similar increase in the firing activity of dorsal hippocampus CA(3) pyramidal neurons, thus revealing direct functional evidence of an enhanced tonic activation of postsynaptic 5-HT(1A) receptors. In dorsal raphe nucleus, escitalopram was four times more potent than citalopram in suppressing the firing activity of presumed 5-HT neurons (ED(50)=58 and 254 mug/kg, i.v., respectively). Interestingly, the suppressant effect of escitalopram (100 mug/kg, i.v.) was significantly prevented, but not reversed by R-citalopram (250 mug/kg, i.v.). Sustained administration of escitalopram and citalopram significantly decreased the spontaneous firing activity of presumed 5-HT neurons. This firing activity returned to control rate after 2 weeks in rats treated with escitalopram, but only after 3 weeks using citalopram, and was associated with a desensitization of somatodendritic 5-HT(1A) autoreceptors. These results suggest that the time course of the gradual return of presumed 5-HT neuronal firing activity, which was reported to account for the delayed effect of SSRI on 5-HT transmission, is congruent with the earlier onset of action of escitalopram vs citalopram in validated animal models of depression and anxiety.Neuropsychopharmacology advance online publication, 9 February 2005; doi:10.1038/sj.npp.1300686.

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citalopram Celexa
Simultaneous analysis of citalopram and desmethylcitalopram by liquid chromatography with fluorescence detection after solid-phase extraction.

Meng QH, Gauthier D.

Department of Pathology and Molecular Medicine, McMaster University, Ontario, Canada L8N 4A6.

OBJECTIVES:: To develop a HPLC method for the determination of citalopram (CIT) and desmethylcitalopram (DCIT). METHODS:: Solid-phase extraction followed by fluorescence detection was used to measure CIT and DCIT in deproteinized plasma. RESULTS:: The extraction recovery for both analytes was 104 +/- 3%. The calibration was linear over the concentration range of 12-1600 ng/mL for CIT and 6-800 ng/mL for DCIT. The within-run CVs were 2.5% for CIT (400 ng/mL) and 2.9% for DCIT (200 ng/mL) and the between-run CVs were 5.2% for CIT and 2.9% for DCIT, respectively. With low concentrations of CIT (50 ng/mL) and DCIT (25 ng/mL), the within-run CVs were 3.1% and 1.1% and the between-run CVs were 7.4% and 8.8%, respectively. The lower limit of quantification was 12 ng/mL for CIT and 6 ng/mL for DCIT. CONCLUSIONS:: This method allows for the simultaneous determination of CIT and DCIT in plasma at therapeutic and toxic drug concentrations.

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citalopram Celexa
Citalopram combined with WAY 100635 inhibits ejaculation and ejaculation-related Fos immunoreactivity.

R de Jong T, Pattij T, Veening JG, Dederen PJ, Waldinger MD, Cools AR, Olivier B.

Department of Anatomy, University Medical Centre St. Radboud, Nijmegen, The Netherlands; Department of Psychoneuropharmacology, University Medical Centre St. Radboud, Nijmegen, The Netherlands; Department of Psychopharmacology, Utrecht Institute of Pharmacological Sciences and Rudolf Magnus Institute of Neuroscience, Utrecht University, Utrecht, The Netherlands.

The role of 5-HT (5-hydroxytryptamine, 5-HT)(1A) receptor activation in the sexual side-effects, in particular delayed ejaculation, of selective serotonin reuptake inhibitors (SSRIs) was studied. Male Wistar rats were treated for 15 days with vehicle, the SSRI citalopram (10 mg/kg/day p.o.), the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl) cyclohexane carboxamide 3HCL (WAY 100635, 0.1 mg/kg/ day s.c.), or both drugs combined. Sexual behavior was assessed weekly. One h after the last sexual behavior test, rat brains were processed for Fos-immunohistochemistry. Acute and chronic citalopram mildly inhibited ejaculation, which was strongly augmented by co-administration of WAY 100635. WAY 100635 alone did not alter sexual behavior. Brain sites associated with ejaculation showed reduced Fos-immunoreactivity in rats treated with both citalopram and WAY 100635. Citalopram reduced Fos-immunoreactivity in the arcuate hypothalamic nucleus, an area that might link serotonergic neurotransmission to ejaculation.

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citalopram Celexa
Evidence for a combined genetic effect of the 5-HT1A receptor and serotonin transporter genes in the clinical outcome of major depressive patients treated with citalopram.

Arias B, Catalan R, Gasto C, Gutierrez B, Fananas L.

Unitat d'Antropologia, Departament de Biologia Animal, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.

In the context of a long-term follow-up study, we analysed the possible implication of the 5-HT(1A) receptor gene (HTR1A) -1018C/G polymorphism in the clinical outcome of major depressive patients treated with citalopram. We had previously reported an association between variation on the SERT gene (SLC6A4) and clinical remission after citalopram treatment. In the present 12-week follow-up study, the combined effect of HTR1A and SLC6A4 genes in clinical outcome and response to citalopram was also evaluated. The sample consisted of 130 patients, all of Spanish origin, who were diagnosed as having a current major depressive episode according to DSM-IV criteria. A 21-item Hamilton Depression Rating Scale was used to assess severity of symptoms at the beginning and during the follow-up to determine the outcome and remission status at week 12. Patients were genotyped for HTR1A gene and, in addition, for two polymorphisms at the CYP2C19 gene, which together account for the 87% of the Caucasian poor metabolizer phenotype. Data were analysed adjusting for the effect of poor metabolizers in clinical response. No independent effect was found for the 5-HT(1A) receptor gene in relation to clinical outcome or remission after citalopram treatment. However, a combined genetic effect of HTR1A and SLC6A4 genes was found to influence the clinical outcome of patients [F(4,102) = 2.89, p= 0.02]. When considering the remission status, an increase of patients carrying the risk genotype combination (S/S-G/G) was found among those subjects who did not reach remission (Fisher's exact test = 0.009). Our results suggest that the combined effect of the serotonin transporter and the 5-HT(1A) receptor genes could be related to the clinical outcome of depressive patients treated with citalopram.

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citalopram Celexa
The effect of citalopram hydrobromide on 5-HT(2A) receptors in the impulsive-aggressive dog, as measured with (123)I-5-I-R91150 SPECT.

Peremans K, Audenaert K, Hoybergs Y, Otte A, Goethals I, Gielen I, Blankaert P, Vervaet M, van Heeringen C, Dierckx R.

Department of Medical Imaging, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820, Merelbeke, Belgium, kathelijne.peremans ugent.be.

PURPOSE: Involvement of the serotonergic system in impulsive aggression has been demonstrated in both human and animal studies. The purpose of the present study was to investigate the effect of citalopram hydrobromide (a selective serotonin re-uptake inhibitor) on the 5-HT(2A) receptor and brain perfusion in impulsive-aggressive dogs by means of single-photon emission computed tomography. METHODS: The binding index of the radioligand (123)I-5-I-R91150 was measured before and after treatment with citalopram hydrobromide in nine impulsive-aggressive dogs. Regional perfusion was measured with (99m)Tc-ethyl cysteinate dimer (ECD). Behaviour was assessed before treatment and again after 6 weeks of treatment. RESULTS: A correlation was found between decreased binding and behavioural improvement in eight out of nine dogs. The 5-HT(2A) receptor binding index was significantly reduced after citalopram hydrobromide treatment in all cortical regions but not in the subcortical area. None of the dogs displayed alterations in perfusion on the post-treatment scans. CONCLUSION: This study supports previous findings regarding the involvement of the serotonergic system in impulsive aggression in dogs in general. More specifically, the effect of treatment on the 5-HT(2A) receptor binding index could be demonstrated and the decreased binding index correlated with behavioural improvement.

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citalopram Celexa
Basal Prolactin Values Correlate with Response to Reboxetine Treatment in Major Depression, but Not with Response to Citalopram.

Moeller O, Hetzel G, Michael N, Rothermundt M, Arolt V, Erfurth A.

Affective Disorders Research Unit, Department of Psychiatry, University of Munster, Munster, Germany.

Little is known about variables that might predict outcome in major depression. Recently, basal prolactin values (BPV) have been suggested to predict response to treatment with tricyclic antidepressive drugs. In order to examine whether BPV predict response to selective mono-aminergic therapy, 24 in-patients with major depression were treated in a single-masked, randomised study using the most selective noradrenergic or serotonergic reuptake inhibitors available for antidepressant treatment, i.e. reboxetine and citalopram. A significant correlation between BPV and treatment response to reboxetine was found, but not between BPV and response to citalopram. As BPV are influenced by noradrenergic activity, it can be hypothesized that depressed patients with comparatively high BPV have a relatively high noradrenergic function. This might explain why in our study depressed patients with the highest BPV responded strongest to selective noradrenergic treatment with reboxetine. As measurement of BPV is simple, further studies are suggested to examine the possible clinical value of the link between prolactin, noradrenergic function in major depression and treatment response. Copyright (c) 2005 S. Karger AG, Basel.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15741746&dopt=Abstract citalopram Celexa