citalopram Celexa
Effect of chronic antidepressant treatment on beta-receptor coupled signal transduction cascade. Which effect matters most?

Holoubek G, Noldner M, Treiber K, Muller WE.

Department of Pharmacology, Biocenter, University of Frankfurt, 60439 Frankfurt, Germany.

BACKGROUND: Beta-receptor down-regulation has been described as a common biochemical effect of chronic treatment with many but not all antidepressant drugs. Beta-receptor activation leads to elevated intracellular levels of cAMP followed by the activation of several protein kinases which in turn activate various transcription factors. One of those, CREP has received increasing interest as an relevant component within the antidepressant drug modulated signal cascade as it represents a down-stream signal not only of the beta-receptor but also of serotonin receptor activation. Chronic treatment with many antidpressant drugs has been shown to alter CREP levels in several brain regions. While beta-receptor down-regulation by chronic antidepressant treatment has been a consistent finding, alterations of CREP levels have been observed in both direction. Similarly divergent findings have been reported for BDNF a major gene targeted of CREB, where most but not all findings suggest up-regulation at least at the message level following chronic antidepressant treatment. METHODS: Because of these rather divergent data, we investigated the possible effects of chronic treatment (9 or 19 days) with three different antidepressant drugs (reboxetine, citalopram, imipramine) on the individual parameters of the beta-receptor coupled signal transduction cascade. All animals were also tested for possible antidepressant effects using the forced swimming test. RESULTS: While beta-receptor density was down-regulated by reboxetine and imipramine but not citalopram, CREB protein was only mildly elevated after 9 days, and not changed or slightly reduced after 19 days. BDNF protein levels were not or only slightly enhanced, but only for the 9 days treatment. Citalopram was most active. Under the conditions chosen, all three drugs were active in the forced swimming test. CONCLUSION: Taken together, the findings reported make it difficult to identify one single component of the beta-receptor coupled signal transduction cascade as common final target of chronic antidepressant treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15546062&dopt=Abstract citalopram Celexa



citalopram Celexa
Anticonvulsant action of GBR-12909 and citalopram against acute experimentally induced limbic seizures.

Clinckers R, Smolders I, Meurs A, Ebinger G, Michotte Y.

Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Research Group Experimental Pharmacology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.

We recently showed that intrahippocampally administered dopamine and serotonin exert concentration-dependent non-protective, protective and proconvulsant effects against limbic seizures in rats. Anticonvulsant action was mediated via, respectively, hippocampal D2 and 5-HT1A receptor stimulation, while proconvulsant effects were associated with concomitant hippocampal glutamate increases. We here examined whether increases in endogenous hippocampal dopamine and serotonin exert similar actions. Initially, dose-response experiments were performed with intrahippocampal perfusions of GBR-12909 and citalopram, respectively, selective dopamine and serotonin re-uptake blockers. Based on their effects on monoaminergic release, a potential non-protective, protective and proconvulsant concentration was selected. The predicted non-protective GBR-12909 (10 microM) and citalopram (0.5 microM) concentrations failed to prevent pilocarpine-induced seizures. The predicted protective GBR-12909 (100 microM) and citalopram (1 microM) perfusions resulted in complete anticonvulsant action, again mediated by D2 and 5-HT1A receptors. Unexpectedly, at predicted proconvulsant concentrations complete anticonvulsant action was obtained and hippocampal Glu remained unaltered. This study shows that selective monoamine re-uptake blockers have important anticonvulsant properties. Based on the previously established anticonvulsant monoamine ranges, anticonvulsant threshold concentrations can be predicted for compounds with endogenous dopamine or serotonin promoting effects. Non-selective actions curtailing glutamatergic activity may further be responsible for the unexpected anticonvulsant effects at predicted proconvulsant concentrations.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15555639&dopt=Abstract citalopram Celexa



citalopram Celexa
Characterization of an allosteric citalopram-binding site at the serotonin transporter.

Chen F, Larsen MB, Neubauer HA, Sanchez C, Plenge P, Wiborg O.

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

The serotonin transporter (SERT), which belongs to a family of sodium/chloride-dependent transporters, is the major pharmacological target in the treatment of several clinical disorders, including depression and anxiety. In the present study we show that the dissociation rate, of [3H]S-citalopram from human SERT, is retarded by the presence of serotonin, as well as by several antidepressants, when present in the dissociation buffer. Dissociation of [3H]S-citalopram from SERT is most potently inhibited by S-citalopram followed by R-citalopram, sertraline, serotonin and paroxetine. EC50 values for S- and R-citalopram are 3.6 +/- 0.4 microm and 19.4 +/- 2.3 microm, respectively. Fluoxetine, venlafaxine and duloxetine have no significant effect on the dissociation of [3H]S-citalopram. Allosteric modulation of dissociation is independent of temperature, or the presence of Na+ in the dissociation buffer. Dissociation of [3H]S-citalopram from a complex with the SERT double-mutant, N208Q/N217Q, which has been suggested to be unable to self-assemble into oligomeric complexes, is retarded to an extent similar to that found with the wild-type, raising the possibility that the allosteric mechanism is mediated within a single subunit. A species-scanning mutagenesis study comparing human and bovine SERT revealed that Met180, Tyr495 and Ser513 are important residues in mediating the allosteric effect, as well as contributing to high-affinity binding at the primary site.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15606893&dopt=Abstract citalopram Celexa



citalopram Celexa
A pharmacoeconomic evaluation of escitalopram, a new selective serotonin reuptake inhibitor Comparison of cost-effectiveness between escitalopram, citalopram, fluoxetine,and venlafaxine for the treatment of depression in Norway.

Francois C, Toumi M, Aakhus AM, Hansen K.

International Department of Health-Economics, Epidemiology and Pricing, Lundbeck A/S,Paris, France.

This study compared the cost-effectiveness of escitalopram to that of citalopram,fluoxetine, and venlafaxine in the treatment of depression in Norway.A two-path decision analytic model with a 6-month horizon was used.Patients start at the primary path and are referred to specialist care in the secondary care path. Model inputs included drugspecific probabilities from comparative trial data, literature, and a panel of experts.The main outcome measure is success (remission), and costs of treatment (total and drug costs).Treatment with escitalopram yielded lower expected cost and greater effectiveness than citalopram,fluoxetine, and venlafaxine. The expected success rate was 64.2% with escitalopram,58.7% with citalopram, 58.7% with fluoxetine, and 62.1% with venlafaxine.Average expected total costs per patient were similar with escitalopram (19,661 Norwegian crowns) and venlafaxine (20,989) and somewhat higher with citalopram (22,379) and fluoxetine (22,558).Budgetary impact estimates a decrease in total health care budget of 72 million crowns.Escitalopram is therefore the most cost-effective alternative and its use would significantly reduce health care costs for the treatment of depression in Norway.

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citalopram Celexa
Serotonergic influence on the potentiation of D-amphetamine and apomorphine-induced rotational behavior by the alpha(2)-adrenoceptor antagonist 2-methoxy idazoxan in hemiparkinsonian rats.

Srinivasan J, Schmidt WJ.

Zoological Institute, Neuropharmacology, University of Tuebingen, Tuebingen, Germany.

The alpha(2)-adrenoceptor antagonists potentiate both ipsilateral and contralateral rotations induced by amphetamine and apomorphine respectively in hemiparkinsonian rats. The present study investigated the role of serotonergic transmission in this potentiation in unilaterally 6-hydroxydopamine nigral lesioned rats. D-amphetamine (0.5 mg/kg, i.p.) produced ipsilateral rotations, which were decreased by the dopamine receptor antagonist haloperidol (0.2 mg/kg, i.p.) and the alpha(1)-receptor antagonist prazosin (1 mg/kg, i.p.). The selective alpha(2)-antagonist 2-methoxy idazoxan (0.2 mg/kg, i.p.) potentiated the amphetamine-induced ipsilateral rotations, that were attenuated by haloperidol and prazosin. The selective serotonin re-uptake inhibitor citalopram (10 mg/kg, i.p.) and selective serotonin synthesis inhibitor p-chlorophenylalanine (150 mg/kg, i.p., 3 days) decreased and increased the observed potentiation respectively. Apomorphine (0.2 mg/kg, s.c.) produced contralateral rotations, which were decreased by haloperidol but not by prazosin. 2-methoxy idazoxan potentiated these rotations which were attenuated by haloperidol but not by prazosin. Citalopram and p-chlorophenylalanine increased and decreased the observed potentiation respectively. Citalopram and p-chlorophenylalanine had no effect by per se on D-amphetamine and apomorphine-induced rotations. 2-methoxy idazoxan alone increased both ipsilateral and contralateral spontaneous rotations. Taken together, these findings indicate that an increase in noradrenergic tone by 2-methoxy idazoxan potentiates both D-amphetamine-induced ipsilateral and apomorphine induced contralateral rotations. alpha(1)-Antagonism attenuates D-amphetamine induced ipsilateral rotations and its potentiation by 2-methoxy idazoxan but not apomorphine rotations or its potentiation. Increasing and decreasing the serotonergic transmission decreases and increases D-amphetamine potentiation, whereas increases and decreases apomorphine potentiation respectively. The possible mechanisms for these findings are discussed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15614426&dopt=Abstract citalopram Celexa



citalopram Celexa
Chronic administration of citalopram in olfactory bulbectomy rats restores brain 5-HT synthesis rates: an autoradiographic study.

Hasegawa S, Watanabe A, Nguyen KQ, Debonnel G, Diksic M.

Cone Neurosurgical Research Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, Montreal, Quebec, Canada.

RATIONALE: The olfactory bulbectomized (OBX) rat model is widely accepted as an animal model of depression with a proposed serotonergic imbalance in the brain. OBJECTIVE: To study the effects of chronic administration of citalopram on serotonin (5-HT) synthesis rates. METHOD: Serotonin synthesis was evaluated using the alpha-[(14)C]methyl-L: -tryptophan (alpha-MTrp) autoradiographic method in OBX rats. Citalopram was administered continuously (10 mg kg(-1) day(-1)) for 14 days using a subcutaneous osmotic minipump. RESULTS: The OBX rats treated with citalopram (OBX-CTP) have the same 5-HT synthesis rates as the sham-operated rats treated with citalopram (Sham-CTP). The OBX-CTP rats, relative to the OBX rats treated with saline (OBX-SAL), showed a reduction in the majority of the terminal brain structures, suggesting a normalization of 5-HT synthesis in the OBX-CTP rats following treatment. The OBX-SAL rats have significantly greater synthesis than the Sham-SAL rats in a majority of the terminal structures, but lower rates in the dorsal raphe. A few structures in the OBX-CTP group have lower synthesis than in the Sham-SAL group (e.g., dorsal raphe, hippocampus, amygdala). The data suggest that receptors in some brain areas are likely still responsive to the elevated levels of the extracellular 5-HT produced by citalopram. CONCLUSION: There is no significant global or individual structure difference in the synthesis between the Sham-CTP and OBX-CTP groups. The similarity in the synthesis between the OBX-CTP, Sham-CTP and Sham-SAL groups is likely a result of changes in the sensitivity of the receptors through which 5-HT synthesis is controlled. Because of some of the differences in the synthesis between the Sham-CTP and Sham-SAL groups, the data suggest that receptors throughout the brain are not fully desensitized.

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citalopram Celexa
Randomized double-blind comparison of serotonergic (Citalopram) versus noradrenergic (Reboxetine) reuptake inhibitors in outpatients with somatoform, DSM-IV-TR pain disorder.

Aragona M, Bancheri L, Perinelli D, Tarsitani L, Pizzimenti A, Conte A, Inghilleri M.

Department of Psychiatry, University of Rome La Sapienza, V.le Universita 30 00185 Rome, Italy.

OBJECTIVES: Whether the effect of tricyclic antidepressants on Pain Disorder arises from their noradrenergic or serotonergic actions or both remains unclear. We compared the selective serotonin reuptake inhibitor (SSRI) citalopram and the noradrenergic reuptake inhibitor (NARI) reboxetine in outpatients with Pain Disorder. We also distinguished the drugs' analgesic and antidepressant effects. METHODS: In this 8-week, randomized double-blind study, 35 patients with a DSM-IV-TR diagnosis of Pain Disorder were randomly assigned to receive either citalopram 40 mg/day (N=17 patients) or reboxetine 8 mg/day (N=18). The Present Pain Intensity (PPI) scale and the Total Pain Rating Index (tPRI) of the McGill Pain Questionnaire were used to measure the effect on pain symptoms. Changes in the Zung Self-Rating Depression Scale (Zung-D) scores were evaluated to monitor a possible antidepressant effect. For all patients who had at least one assessment, an intent-to-treat analysis was performed. RESULTS: No significant differences were found in the demographic variables or clinical characteristics of the two treatment groups. In the citalopram group, PPI and tPRI scores measured at baseline decreased after treatment (tPRI: 41.9 vs. 30.0, p=.004; PPI: 3.5 vs. 2.8, p=.045) whereas in the reboxetine group differences were not statistically significant (tPRI: 35.2 vs. 31.5; PPI: 3.7 vs. 3.1). The Zung-D showed no significant changes between baseline and endpoint assessment in either group. CONCLUSIONS: Our study suggests that the SSRI citalopram may have a moderate analgesic effect in patients with Pain Disorder, and that this analgesic activity appears to be not correlated to changes in depressive scores. If confirmed in a larger sample, this evidence suggests that patients who are intolerant or resistant to tricyclic antidepressants, may be treated with SSRIs.

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citalopram Celexa
Age-related differences in the side effect profile of citalopram.

Barak Y, Swartz M, Levy D, Weizman R.

Psychogeriatric Department, Abarbanel Mental Health Center, 15 KKL Street, Bat-Yam 59100, Israel. mdybarak netvision.net.il

The authors evaluated the autonomic and cardiovascular side effects of citalopram with particular emphasis on their relation to the age of treated patients. The data that formed the basis for the U.S. Food and Drug Administration approval of citalopram were provided by Lundbeck (Copenhagen, Denmark). This database included placebo-controlled short- and long-term studies in major depressed patients. The list of side effects comprised all "heart rate and rhythm disorders" as well as "autonomic nervous system disorders" that had been reported by at least 5% more than that reported for the placebo group of subjects. The database encompassed 1344 subjects treated with citalopram (20-60 mg/day) for a period of no less than 6 weeks. Statistically significant age-related distribution was found for five side effects: bradycardia, nausea, diarrhea, sweating and headache. Bradycardia was more prevalent in elderly (>65 years) patients as compared to the younger population (2.4% vs. 0.2%, P<.05), whereas gastrointestinal side effects, sweating and headache were less prevalent in the elderly. The age-related differences in the side effect profile may be attributable to altered sensitivity of the serotonergic system.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12691792&dopt=Abstract citalopram Celexa