citalopram Celexa
Serotonin modulation of cerebral glucose metabolism in normal aging.

Goldberg S, Smith GS, Barnes A, Ma Y, Kramer E, Robeson K, Kirshner M, Pollock BG, Eidelberg D.

Department of Psychiatry Research, The Zucker Hillside Hospital, North Shore-Long Island Jewish Health System, 75-59 263rd Street, Glen Oaks, NY 11004, USA.

Age-related alterations in serotonin function may increase the vulnerability to psychiatric and neurodegenerative disorders in late life. The neuroendocrine and cerebral metabolic response to the acute administration of the selective serotonin reuptake inhibitor, citalopram (40mg, IV), was measured in 17 normal control subjects using positron emission tomography (PET) to evaluate changes in serotonin function with normal aging. The citalopram-induced change in cerebral metabolism was positively correlated with age in the right precuneus, right paracentral lobule, and left middle temporal gyrus and negatively correlated with age in the left anterior cingulate gyrus, right inferior and middle frontal gyri, right insula, and right inferior parietal lobule. The positive correlations in mainly posterior brain regions indicate that normal aging is associated with an increase in metabolism after citalopram administration, whereas the negative correlations in mainly anterior brain regions indicate that normal aging is associated with a greater decrease in metabolism. These results suggest different compensatory processes in anterior compared to posterior brain regions secondary to the age-related loss of serotonin innervation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14749134&dopt=Abstract citalopram Celexa



citalopram Celexa
Frequency of infant adverse events that are associated with citalopram use during breast-feeding.

Lee A, Woo J, Ito S.

Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, and the Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada.

OBJECTIVE: The purpose of this study was to determine the frequency of infantile adverse events from exposure through breast-feeding to maternal citalopram therapy. STUDY DESIGN: This was a prospective, observational cohort study. Women who were breast-feeding were placed in three groups on the basis of citalopram use: group 1 consisted of 31 women who were depressed and were undergoing citalopram therapy, group 2 consisted of 12 women who were depressed but were not undergoing citalopram therapy, and group 3 consisted of 31 healthy women who were matched to group 1 by maternal age and parity. Data collection included infant feeding method, medication use, and adverse events. RESULTS: There was no statistically significant difference in the rate of adverse events in the three groups (3/31 events, 0/12 events, and 1/31 events in groups 1, 2, and 3, respectively). The average dose of citalopram that was used in group 1 was 25.3+/-11.4 mg per day (range, 10-60 mg/d). CONCLUSION: To our knowledge, this is the first prospective, controlled study to examine the safety of citalopram during breast-feeding, which should be continued during maternal citalopram therapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14749663&dopt=Abstract citalopram Celexa



citalopram Celexa
R-citalopram attenuates anxiolytic effects of escitalopram in a rat ultrasonic vocalisation model.

Sanchez C.

Neuropharmacological Research, H. Lundbeck A/S, Ottiliavej 9, DK 2500 Copenhagen-Valby, Denmark. cs lundbeck.com

Escitalopram mediates the serotonin reuptake inhibitory effect of citalopram. To investigate the potential interactive effects between escitalopram and R-citalopram, they were studied at standard and elevated serotonin levels in a model predictive of anxiolytic activity (inhibition of footshock-induced ultrasonic vocalisation in adult rats). At standard levels, citalopram partially inhibited (64%) and escitalopram abolished (97%) vocalisation. Co-treatment with L-5-hydroxytryptophan resulted in complete inhibition with citalopram and a substantially enhanced response to escitalopram, while R-citalopram increased the vocalisation significantly. Furthermore, R-citalopram attenuated the effect of escitalopram. These findings may be relevant to the enhanced clinical efficacy seen with escitalopram compared to citalopram.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12620508&dopt=Abstract citalopram Celexa



citalopram Celexa
R-citalopram inhibits functional and 5-HTP-evoked behavioural responses to the SSRI, escitalopram.

Sanchez C, Kreilgaard M.

Neuropharmacological Research, H. Lundbeck, Ottiliavej 9, DK 2500 -Valby, Copenhagen, Denmark. cs lundbeck.com

Escitalopram mediates the serotonin re-uptake inhibitory and antidepressant effect of citalopram racemate. However, recent studies have shown that R-citalopram inhibits the escitalopram-induced increase of extracellular 5-HT levels in the frontal cortex of rats. Here, we investigated the inhibitory effect of R-citalopram on the escitalopram-induced increase of 5-HT neurotransmission at the behavioural [potentiation of 5-hydroxytryptophan (5-HTP)-induced behavioural changes in mice and rats] and functional (increase in serum corticosterone in rats) levels. The effect of escitalopram was inhibited by R-citalopram in all three models, and R-citalopram, given alone, was inactive. The effects were more pronounced using an escitalopram to R-citalopram ratio of 1:4 than ratios of 1:2 and 1:1, suggesting a dose-dependent effect. The ED(50)-value of escitalopram in mouse 5-HTP potentiation studies corresponded to a serum concentration of approximately 50 ng/ml, which can be considered to be in the range of clinically relevant serum concentrations.In conclusion, R-citalopram inhibited the escitalopram-induced increase of 5-HT activity in functional, as well as behavioural, animal models. The mechanism involved in this interaction is currently unknown, but may be related to an improved clinical effect seen with escitalopram in comparison with citalopram.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14751469&dopt=Abstract citalopram Celexa



citalopram Celexa
Pharmacology of a novel selective 5-hydroxytryptamine1B receptor antagonist, AR-A000002.

Stenfors C, Hallerback T, Larsson LG, Wallsten C, Ross SB.

AstraZeneca R&D Sodertalje, 151 85 Sodertalje, Sweden. carina.stenfors astrazeneca.com

The terminal 5-HT(1B) autoreceptors have attracted great pharmacological interest since they are potential targets for compounds modifying serotonergic neurotransmission. In the present work the in vivo biochemical properties of AR-A000002 ((R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide), a novel selective 5-HT(1B) receptor antagonist, are reported. The effects of AR-A000002 on: 5-HT metabolism was measured as the ratio between 5-HIAA and 5-HT concentrations in different brain regions; 5-HT synthesis was measured as the accumulation of 5-HTP after inhibition of the aromatic amino acid decarboxylase activity with m-hydroxybenzylhydrazine (NSD1015); 5-HT release was measured using the microdialysis technique. 5-HT, 5-HIAA and 5-HTP concentrations were analyzed using high power liquid chromatography (HPLC) with electrochemical detection. AR-A000002 significantly enhanced 5-HT metabolism (5-HIAA/5-HT ratio) and 5-HT synthesis in guinea pig brain in the dose range 0.9-18 mg/kg s.c. (ED(50)=1 mg/kg s.c. in the four brain regions examined) with maximal effect seen after 2-4 h. AR-A000002 (9 mg/kg s.c.) significantly increased the extracellular concentrations of 5-HT and 5-HIAA by 20% in the guinea pig frontal cortex, measured with the in vivo microdialysis technique in freely moving guinea pigs. AR-A000002 (9 mg/kg s.c.) in combination with the 5-HT uptake inhibitor citalopram (5 mg/kg s.c.) increased the extracellular 5-HT concentration in guinea pig frontal cortex from 250 to 400% of the basal level. Citalopram alone decreased the extracellular 5-HIAA levels to 70% of the basal value. AR-A000002 counteracted the citalopram-induced decrease in 5-HIAA. Since the basal level of extracellular 5-HIAA was 160 times higher than that of 5-HT the 20% increase in 5-HIAA concentrations indicates that only a few percent of the exocytotically released 5-HT from the nerve terminals reached the extracellular space when the re-uptake mechanism was intact. The results also show that the terminal 5-HT(1B) autoreceptors are tonically activated under drug-free as well as citalopram conditions. The increase in plasma level of cortisol after AR-A000002 administration may indicate stimulation of post-synaptic 5-HT receptors. AR-A000002 also blocked 5-HT(1B) agonist-induced (CP-135,807) decrease in 5-HT metabolism and hypothermia (ED(50)=1 mg/kg s.c.), thus indicating competition between these two drugs. It is concluded that AR-A000002 is a 5-HT(1B) receptor antagonist that enhances the serotonergic neurotransmission in guinea pig brain.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14758468&dopt=Abstract citalopram Celexa



citalopram Celexa
Synthesis, radiosynthesis, and biological evaluation of carbon-11 and iodine-123 labeled 2beta-carbomethoxy-3beta-[4'-((Z)-2-haloethenyl)phenyl]tropanes: candidate radioligands for in vivo imaging of the serotonin transporter.

Plisson C, McConathy J, Martarello L, Malveaux EJ, Camp VM, Williams L, Votaw JR, Goodman MM.

Department of Radiology, Emory University, Atlanta, Georgia 30320, USA.

2beta-Carbomethoxy-3beta-[4'-((Z)-2-iodoethenyl)phenyl]tropane (ZIET) and 2beta-carbomethoxy-3beta-[4'-((Z)-2-bromoethenyl)phenyl]tropane (ZBrET) were synthesized as well as their nortropane congeners ZIENT and ZBrENT. Binding affinities of these compounds were determined in cells transfected to express human SERT, DAT, and NET using [3H]citalopram, [125I]RTI-55, and [3H]nisoxetine, respectively. Both ZIET and ZBrET displayed high affinity for the SERT (Ki = 0.11 and 0.08 nM, respectively).The affinities of ZIET and ZBrET for the DAT were 200 and 38-fold lower, respectively, than for the SERT. [11C]ZIET and [11C]ZBrET were prepared by alkylation of their corresponding nortropanes with [11C]methyl iodide in approximately 30% radiochemical yield (decay-corrected to end of bombardment, EOB). High specific activity [123I]ZIET was synthesized in 33% radiochemical yield (decay-corrected) by treating the 2beta-carbomethoxy-3beta-[4'-((Z)-2-trimethylstannylethenyl)phenyl]tropane (3) with no carrier-added sodium [123I]iodide and hydrogen peroxide in ethanolic HCl. Biodistribution studies in rats indicated that [123I]ZIET enters the brain readily and accumulates in SERT-rich regions. Blocking studies performed in rats demonstrated that [123I]ZIET was selective and specific for SERT-rich regions (e.g. thalamus, brainstem, and striatum). MicroPET brain imaging studies in monkeys demonstrated that [11C]ZIET and [11C]ZBrET uptakes were selectivity localized in the putamen, midbrain, caudate, thalamus, pons, and medulla. Radioactivity in the regions of high SERT density of monkey brain was displaceable with citalopram except in the putamen and caudate. Radioactivity uptake in these DAT-rich regions was significantly displaceable either by preadministration of citalopram followed by injection of RTI-113 (or vice-versa) or by administration of a mixture of DAT and SERT ligands. In conclusion, the high yield, high specific activity, one-step radiolabeling method, high selectivity and favorable kinetics, and the good results obtained with [123I]ZIET in rats support the candidacy of [11C]ZIET for in vivo visualization and quantification of brain SERT.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14971892&dopt=Abstract citalopram Celexa



citalopram Celexa
A claims analysis comparing citalopram with sertraline as initial pharmacotherapy for a new episode of depression: impact on depression-related treatment charges.

McLaughlin TP, Eaddy MT, Grudzinski AN.

NDCHealth, Phoenix, Arizona 85016, USA. Trent.McLaughlin ndchealth.com

BACKGROUND: Citalopram, a selective serotonin reuptake inhibitor (SSRI) recently approved in the United States for treatment of depression, has similar efficacy to and a lower acquisition cost than other SSRIs. The impact of using citalopram (instead of other SSRIs) on total treatment costs has not been studied extensively. OBJECTIVE: The aim of this study was to compare depression-related treatment charges for the first 6 months of treatment among patients with newly diagnosed depression who received sertraline or citalopram. METHODS: This was a retrospective analysis of medical and pharmaceutical claims from 20 managed care organizations across the United States. This study population can be considered representative of a commercially insured US population. Patients aged >or= 18 years with newly diagnosed depression (ie, major depressive disorder, dysthymia, or depressive disorder not otherwise specified) who had a prescription claim for sertraline or citalopram (within 30 days of initial diagnosis) from July 1, 1998, through June 30, 1999, were included in the study. Patients with previous mental disorders and/or treatment with an SSRI (including patients diagnosed with an anxiety disorder before the first SSRI prescription) were excluded from the analysis. Log-transformed depression-related treatment charges for the first 6 months of therapy were compared across the 2 treatment cohorts with use of multivariate regression. Other outcomes measures included medication compliance and use of other antidepressant medications during the 6-month study period. Costs were measured in year-1999 US dollars. RESULTS: A total of 15222 sertraline and 3175 citalopram patients met the inclusion criteria. Mean disease-related medical charges were US dollars 931 per patient in the setraline group and US dollars 1035 in the citalopram group ( [P<0.001). The difference between groups may have been due to higher mean outpatient charges in the citalopram group (US dollars 414 vs US dollars 360; P<0.001). Citalopram patients had lower mean pharmacy charges than did sertraline patients (US dollars 255 vs Us dollars 267; 0.036). After the data were controlled for differences in age, sex, managed care plan, pretreatment history of resource use, physician specialty type, index prescription year, and switching/augmentation of the treatment drug, depression-related charges for the citalopram patients were 22% higher than those for the sertraline cohort (beta coefficient, -0.21925; P<0.001). CONCLUSION: Despite potential cost savings due to a lower acquisition cost, initial treatment of depression with citalopram was associated with higher depression-related charges than was sertraline in the population studied.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14996524&dopt=Abstract citalopram Celexa



citalopram Celexa
A comparison of d, l-fenfluramine and citalopram challenges in healthy adults.

Flory JD, Manuck SB, Perel JM, Muldoon MF.

Behavioral Physiology Laboratory 506 OEH, University of Pittsburgh, 4015 O'Hara Street, Pittsburgh, PA 15260, USA. janine.flory mssm.edu

Dimensional personality characteristics (e.g. impulsivity) and related behaviors and psychiatric disorders are linked to abnormalities of central nervous system (CNS) serotonergic functioning. Although neuroendocrine [e.g. plasma prolactin (PRL)] responses to the serotonin agonist, fenfluramine, have been used widely to index CNS serotonergic responsivity, safety concerns constrain continued use of fenfluramine. Citalopram, which inhibits serotonin reuptake, may serve as an alternative pre-synaptic neuropharmacologic challenge agent, due to its high selectivity and absence of intrinsic activity at serotonin or other receptor families. Twenty-two healthy adults who had been administered a fenfluramine challenge before May 1996 completed a 5-h oral citalopram challenge 3-6 years later. PRL responsivity to citalopram correlated significantly with PRL response to fenfluramine for baseline-corrected maximal and area-under-the-curve (AUC) indices ( r's > or =0.49, P's< or =0.02). The magnitude of the correlations is notable given the length of time between challenges. The results support the use of citalopram as an alternate neuroendocrine challenge to index CNS serotonergic responsivity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14997271&dopt=Abstract citalopram Celexa