citalopram Celexa
Species-scanning mutagenesis of the serotonin transporter reveals residues essential in selective, high-affinity recognition of antidepressants.

Mortensen OV, Kristensen AS, Wiborg O.

Laboratory of Molecular Neurobiology, Department of Biological Psychiatry, Psychiatric University Hospital, Risskov, Denmark.

The serotonin transporter (SERT) is a high-affinity sodium/chloride-dependent neurotransmitter transporter responsible for reuptake of serotonin from the extracellular space. SERT is a selective target of several clinically important antidepressants. In a cross-species analysis comparing human and bovine SERTs, the kinetic parameters for serotonin uptake were found to be similar, however, the pharmacological profiles of the two transporters differ. Following transient expression in COS-1 cells, IC(50) values were determined for several antidepressants and psychostimulants. The potencies of the antidepressants citalopram, fluoxetine, paroxetine and imipramine were several-fold higher at hSERT compared with bSERT. No species selectivity was observed for the antidepressants fluvoxamine, and sertraline or for the psychostimulants cocaine, the cocaine analogue beta-carbomethoxy-3beta-(4-iodophenyl)tropane, or for 3,4-methylenedioxymethamphetamine (MDMA). Analysis of six hSERT/bSERT chimeras and subsequent species-scanning mutagenesis of each isoform revealed methionine-180, tyrosine-495, and phenylalanine-513 to be responsible for the increase in citalopram and paroxetine potencies at hSERT and methionine-180 and phenylalanine-513 to confer species selectivity at hSERT for fluoxetine and imipramine. Results were obtained by doing the forward, bovine to human, mutations and confirmed by doing the reverse mutations. Citalopram analogues were used to define the roles of methionine-180, tyrosine-495, and phenylalanine-513 and to reveal molecular interactions with individual functional groups of citalopram. We suggest that methionine-180 interacts with the heterocyclic nucleus of citalopram or stabilizes the binding pocket and phenylalanine-513 to be a steric blocker of antidepressant recognition.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11677251&dopt=Abstract citalopram Celexa



citalopram Celexa
Chronic antidepressant treatments decrease pro-opiomelanocortin mRNA expression in the pituitary gland: effects of acute stress and 5-HT(1A) receptor activation.

Jensen JB, Mork A, Mikkelsen JD.

Department of Neurobiology, H. Lundbeck A/S, Copenhagen, Denmark. jbj azign.com

Consistent findings in depressed patients are hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis with high plasma concentrations of adrenocorticotropic hormone and cortisol. Long-term antidepressant treatments seem to normalize this hyperactivity, suggesting a link between the HPA axis and the action of antidepressant treatments. The present study was carried out to study the effects of antidepressant treatments on pro-opiomelanocortin (POMC) mRNA expression, with a focus on interaction with acute stress and 5-HT(1A) receptor activation. Male rats were treated for 21 days with saline, citalopram, fluoxetine, moclobemide or desipramine, and the expression of POMC mRNA in the anterior pituitary was analysed by semi-quantitative in situ hybridization. All antidepressants, but not saline, cocaine and haloperidol, reduced POMC mRNA expression. The decrease in POMC mRNA was not observed until 9 days of citalopram treatment. Decreased POMC mRNA levels were also observed after 14 days of repeated electroconvulsive stimulation. The decreased POMC mRNA levels did not affect the stress-induced POMC mRNA increase, measured following swim stress and restraint stress. Finally, using Fos as a marker for neural activity, we showed attenuation of 8-OH-DPAT-stimulated activity in the paraventricular nucleus following 21 days of citalopram treatment. In conclusion, antidepressant treatments decrease basal POMC mRNA expression without affecting the acute stress response, and the reduced POMC mRNA may be related to reduced 5-HT(1A)-stimulated hypothalamic output.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11679057&dopt=Abstract citalopram Celexa



citalopram Celexa
Effect of citalopram and buspirone on the antinociceptive action of analgesic drugs.

Pakulska W, Czarnecka E.

Department of Pharmacodynamics, Medical University of Lodz, Poland.

The influence of citalopram (20 mg/kg i.p.) and buspirone (3 mg/kg i.p.) on analgesic effects of morphine (10 mg/kg i.p.), metamizole (500 mg/kg i.p.) and indomethacin (10 mg/kg) was studied with tail-flick and hot-plate tests on mice. The research studies were further conducted with multiple (14 days) drug dosage. The results indicate that citalopram and buspirone decrease analgesic effects of morphine, metamizole and indomethacin. This mode of action is more pronounced in case of a single dose than after multiple doses.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11693737&dopt=Abstract citalopram Celexa



citalopram Celexa
Differential effects of serotonin reuptake inhibitors on erectile responses, NO-production, and neuronal NO synthase expression in rat corpus cavernosum tissue.

Angulo J, Peiro C, Sanchez-Ferrer CF, Gabancho S, Cuevas P, Gupta S, Saenz de Tejada I.

Fundacion para la Investigacion y el Desarrollo en Andrologia, Department de Investigacion, Hospital Ramon y Cajal, Madrid, Spain.

Increased incidence of impotence is associated with some selective serotonin-reuptake-inhibitors (SSRIs), but the pathophysiological mechanism is unknown. Paroxetine and citalopram are extensively used SSRIs, but only paroxetine has been shown to inhibit nitric oxide synthase (NOS) activity. NO is a key mediator of penile erection. Thus, the aim of this study was to determine the effects of paroxetine and citalopram on erectile function and NO production, in a rat model. Application of cavernosal nerve electrical stimulation produced frequency-related intracavernosal pressure (ICP) increases, which were inhibited by the NOS inhibitor, N(G)-nitro-L-arginine (0.3 mg x kg(-1)). Acute or chronic (2 weeks) paroxetine-treatment (10 mg x kg(-1)) reduced ICP-responses, while citalopram did not. Paroxetine, but not citalopram, significantly reduced nitrite+nitrate plasma levels by 61.4% and inhibited penile neuronal NOS (nNOS) protein expression by 31.2% after chronic treatment. The results show that paroxetine inhibits erectile responses in rats. We propose that this effect is due to reduced NO production and nNOS expression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11704638&dopt=Abstract citalopram Celexa



citalopram Celexa
Long-term treatment with citalopram in patients with highly recurrent forms of unipolar depression.

Franchini L, Spagnolo C, Rampoldi R, Zanardi R, Smeraldi E.

Department of Neuropsychiatric Sciences, School of Medicine, University of Milan, Universita Vita e Salute, Via Luigi Prinetti, 29, 20127, Milan, Italy. franchini.linda hsr.it

The authors evaluated the efficacy and safety of citalopram in a 28-month study in 48 inpatients with highly recurrent forms of unipolar depression. The patients, who each had at least one depressive episode during the 18 months preceding the index episode, were openly treated with citalopram, 40 mg/day. Thirty-six of the patients had a stable response to citalopram and continued treatment as outpatients for 4 months. No relapses were observed. At the time of recovery, 32/36 subjects received maintenance treatment with citalopram (40 mg) for an additional 24 months. At the end of the study, 11/32 patients experienced a single new recurrence.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11740983&dopt=Abstract citalopram Celexa



citalopram Celexa
Citalopram as adjunctive therapy in bipolar depression.

Kupfer DJ, Chengappa KN, Gelenberg AJ, Hirschfeld RM, Goldberg JF, Sachs GS, Grochocinski VJ, Houck PR, Kolar AB.

Department of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, PA 15213, USA. kupferdj msx.upmc.edu

BACKGROUND: The treatment of bipolar depression remains a major clinical challenge. The effectiveness and safety of adjunctive citalopram were evaluated in DSM-IV-diagnosed bipolar depressed patients in a 5-site study. METHOD: The treatment strategy consisted of an open-label add-on design in which patients received 8 weeks of acute treatment with citalopram adjunctive to their ongoing treatment with mood stabilizers. Ongoing treatment with 1 antipsychotic, 1 anxiolytic, and 1 hypnotic agent was permitted. Responders to the 8-week trial then received 16 weeks of additional treatment with citalopram. RESULTS: Forty-five subjects entered the trial; 12 dropped out before the end of the acute treatment phase. Of the 33 patients who completed the acute treatment phase, 64% (N = 21) were responders and 36% (N = 12) were nonresponders. In the continuation phase of the study, 14 patients achieved sustained remission, 3 patients did not achieve remission before completing 16 weeks of continuation treatment, 2 patients experienced a relapse, and 2 patients dropped out of the study and did not have a chance to remit. In spite of the extensive concomitant medication usage allowed in this study, citalopram treatment was well tolerated and the level of reported adverse events (including headache, nausea, diarrhea, and sexual dysfunction) relatively low. CONCLUSION: The high response rate, the high rate of sustained remission, and the low rate of adverse events strongly support the use of citalopram as a treatment for bipolar I or II depression. These findings should stimulate a controlled double-blind trial to demonstrate even more clearly the usefulness of this drug in the therapeutic regimen for bipolar disorder.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11780881&dopt=Abstract citalopram Celexa



citalopram Celexa
Enantioselective analysis of citalopram and metabolites in adolescents.

Carlsson B, Olsson G, Reis M, Walinder J, Nordin C, Lundmark J, Scordo MG, Dahl ML, Bengtsson F, Ahlner J.

Division of Clinical Pharmacology, Department of Medicine and Care, Faculty of Health Sciences, Linkoping University, Sweden. bjorn.carlsson.lio.se

Studies of the antidepressant effect and pharmacokinetics of citalopram have been performed in adults, but the effects on children and adolescents have only been studied to a minor extent despite its increasing use in these age groups. The aim of this study was to investigate a group of adolescents treated for depression, with respect to the steady-state plasma concentrations of the enantiomers of citalopram and its demethylated metabolites desmethylcitalopram and didesmethylcitalopram. Moreover, the authors studied the genotypes for the polymorphic cytochrome P450 enzymes CYP2D6 and CYP2C19 in relation to the different enantiomers. The S/R ratios of citalopram and desmethylcitalopram found in this study of 19 adolescents were similar to studies involving older patients. The concentrations of the R-(-)- and S-(+)-enantiomers of citalopram and desmethylcitalopram were also in agreement with values from earlier studies, the R-(-)-enantiomer (distomer) being the major enantiomer. The results indicate that the use of oral contraceptives may have some influence on the metabolism of citalopram. This might be because of an interaction of the contraceptive hormones with the CYP2C19 enzyme.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11802100&dopt=Abstract citalopram Celexa



citalopram Celexa
Role of 5-HT1A receptors in the mediation of acute citalopram effects: a 8-OH-DPAT challenge study.

Pruus K, Vaarmann A, Rudissaar R, Allikmets L, Matto V.

Department of Pharmacology, University of Tartu, Estonia.

(1) The study was aimed to investigate the effects of the minimal effective doses of acute citalopram (5 mg/kg), (+/-)-8-hydroxydipropylaminotetralin HBr (8-OH-DPAT; 0.1 mg/kg), and their combined treatment on the rat open field and forced swimming behaviour and post-mortem monoamine content. (2) The animals were prospectively divided into the vehicle- and para-chlorophenylalanine (p-CPA)-pretreated (350 mg/kg) groups. (3) Acute citalopram (5 mg/kg), 8-OH-DPAT (0.1 mg/kg), or their combined treatment had no major effect on the rat open field and forced swimming behaviour. (4) The post-mortem catecholamine content in four brain regions studied was unchanged in all treatment groups. (5) The combined 8-OH-DPAT (0.1 mg/kg) and citalopram (5 mg/kg) treatment partially reversed the p-CPA-induced decrease of serotonin (5-HT) and 5-hydroxy-indolacetic acid (5-HIAA) content. (6) The present experiments demonstrate that the 5-HT1A receptors mediate some of the selective serotonin reuptake inhibitor (SSRI)-induced biochemical phenomena.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11817498&dopt=Abstract citalopram Celexa