citalopram Celexa
Autoreceptors remain functional after prolonged treatment with a serotonin reuptake inhibitor.

Hjorth S, Auerbach SB.

Department of Pharmacology, University of Goteborg, Goteborg, Sweden.

Serotonin (5-hydroxytryptamine, 5-HT) autoreceptors may desensitize during prolonged administration of antidepressant drugs. If autoreceptors desensitize, their inhibitory influence on extracellular 5-HT should be attenuated. To test this hypothesis, the selective serotonin reuptake inhibitor (SSRI) citalopram (10 mg kg(-1), s.c., b.i.d.) or saline was administered for 14 days to rats. After a 24-h washout period, rats were anesthetized, and implanted with dialysis probes for determination of 5-HT in the frontal cortex (FCx) and dorsal hippocampus (DH). In response to citalopram (5 mg kg(-1), s.c.) challenge, there were moderate increases in 5-HT in the FCx and DH of both the chronic citalopram and saline pretreatment groups. After subsequent administration of the 5-HT(1A/1B) autoreceptor antagonist, (-)-penbutolol, there were further increases in 5-HT in the FCx and DH of the saline pretreatment group. Moreover, contrary to the expected effect if autoreceptors were desensitized, the potentiation produced by (-)-penbutolol was greater in the FCx and DH of the chronic citalopram group as compared to rats pretreated with saline. These results suggest that autoreceptors still restrain the increase in 5-HT produced by an SSRI after prolonged administration. Copyright 1999 Elsevier Science B.V.

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citalopram Celexa
[Citalopram in forensic samples. Citalopram concentrations in samples from legal autopsies and from living persons in connection with traffic accidents or cases of violence in Denmark 1989-1996]

[Article in Danish]

Worm K, Dragsholt C, Simonsen KW, Kringsholm B.

Retskemisk afdeling, Kobenhavns Universitet.

Citalopram was found in 92 autopsy cases and 27 cases from living persons and the concentrations are described. A range of 6.2-19 mumol/kg whole blood was found in cases where citalopram alone was the cause of death and a range of 1.9-16 mumol/kg whole blood in cases, where citalopram together with other compounds were considered to be the cause of death. In autopsy cases toxic concentrations were in the range 1.2-2.8 mumol/kg whole blood and concentrations between 0:09 and 1.9 mumol/kg were considered therapeutic. In cases from living persons the citalopram concentrations in whole blood were 0.06-0.9 mumol/kg.

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citalopram Celexa
Fluoxetine increases extracellular dopamine in the prefrontal cortex by a mechanism not dependent on serotonin: a comparison with citalopram.

Pozzi L, Invernizzi R, Garavaglia C, Samanin R.

Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.

Fluoxetine at 10 and 25 mg/kg increased (167 and 205%, respectively) the extracellular dopamine concentration in the prefrontal cortex, whereas 25 (but not 10) mg/kg citalopram raised (216%) dialysate dopamine. No compound modified dialysate dopamine in the nucleus accumbens. The effect of 25 mg/kg of both compounds on cortical extracellular dopamine was not significantly affected by 300 mg/kg p-chlorophenylalanine (PCPA) (fluoxetine, saline, 235%; PCPA, 230%; citalopram, saline, 179%; PCPA, 181%). PCPA depleted tissue and dialysate serotonin by approximately 90 and 50%, respectively, and prevented the effect of fluoxetine and citalopram on dialysate serotonin (fluoxetine, saline, 246%; PCPA, 110%; citalopram, saline, 155%; PCPA, 96%). Citalopram significantly raised extracellular serotonin from 0.1 to 100 microM (251-520%), whereas only 10 and 100 microM increased dialysate dopamine (143-231%). Fluoxetine similarly increased extracellular serotonin (98-336%) and dopamine (117-318%). PCPA significantly reduced basal serotonin and the effects of 100 microM fluoxetine (saline, 272%; PCPA, 203%) and citalopram (saline, 345%; PCPA, 258%) on dialysate serotonin but did not modify their effect on dopamine (fluoxetine, saline, 220%; PCPA, 202%; citalopram, saline, 191%; PCPA, 211%). The results clearly show that the effects of fluoxetine and of high concentrations of citalopram on extracellular dopamine do not depend on their effects on serotonin.

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citalopram Celexa
The antidepressants imipramine, clomipramine, and citalopram induce apoptosis in human acute myeloid leukemia HL-60 cells via caspase-3 activation.

Xia Z, Bergstrand A, DePierre JW, Nassberger L.

Department of Biochemistry, Wallenberg Laboratory, Stockholm University, Sweden. xia tuborg.biokemi.su.se

Some widely used antidepressants such as imipramine, clomipramine, and citalopram have been found to possess antineoplastic effects. In the present study, these compounds were found to induce apoptotic cell death in human acute myeloid leukemia HL-60 cells. Apoptosis induced by the antidepressants was identified by electron microscopy and conventional agarose gel electrophoresis and was quantitated by propodium iodide staining and the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) via flow cytometry. Treatment with apoptosis-inducing concentrations of the antidepressants (80 microM imipramine, 35 microM clomipramine, or 220 microM citalopram) caused induction of caspase-3/caspase-3-like activity, which was monitored by the cleavage of poly(ADP-ribose) polymerase (PARP), the loss of the 32 kD caspase-3 (CPP32) precursor, and the cleavage of the fluorescent CPP32-like substrate PhiPhiLux. Pretreatment with a potent caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl-ketone (zVAD-fmk) inhibited antidepressant-induced CPP32/CPP32-like activity and apoptosis. Furthermore, activation of caspase induced by the antidepressants was preceded by the hypergeneration of intracellular reactive oxygen species (ROS). These results suggested that the antidepressants may induce apoptosis via a caspase-3-dependent pathway, and induction of apoptosis by the antidepressants may provide a clue for the mechanism of their antineoplastic effects.

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citalopram Celexa
Citalopram and desmethylcitalopram in vitro: human cytochromes mediating transformation, and cytochrome inhibitory effects.

von Moltke LL, Greenblatt DJ, Grassi JM, Granda BW, Venkatakrishnan K, Duan SX, Fogelman SM, Harmatz JS, Shader RI.

Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.

BACKGROUND: Biotransformation of citalopram (CT), a newly available selective serotonin reuptake inhibitor antidepressant, to its principal metabolite, desmethycitalopram (DCT), and the capacity of CT and DCT to inhibit human cytochromes P450, were studied in vitro. METHODS: Formation of DCT from CT was evaluated using human liver microsomes and microsomes from cDNA-transfected human lymphoblastoid cells. Cytochrome inhibition by CT and DCT in liver microsomes was studied using isoform-specific index reactions. RESULTS: Formation of DCT from CT in liver microsomes had a mean apparent K(m) of 174 mumol/L. Coincubation with 1 mumol/L ketoconazole reduced reaction velocity to 46 to 58% of control values, while omeprazole, 10 mumol/L, reduced velocity to 80% of control. Quinidine produced minimal inhibition. DCT was formed from CT by heterologously expressed human P450-2D6, -2C19, -3A4. After accounting for the relative abundance of individual cytochromes, 3A4 and 2C19 were estimated to make major contributions to net reaction velocity, with a possible contribution of 2D6 at therapeutic CT concentrations. CT and DCT themselves produced negligible inhibition of 2C9, 2E1, and 3A, and only weak inhibition of 1A2, 2C19, and 2D6. CONCLUSIONS: Formation of DCT from CT is mediated mainly by P450-3A4 and 2C19, with an additional contribution of 2D6. CT at therapeutic doses in humans may produce a small degree of inhibition of P450-1A2, -2C19, and -2D6, but negligible inhibition of P450-2C9, -2E1, and -3A.

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citalopram Celexa
Synergistic actions of the 5-HT1A receptor antagonist WAY-100635 and citalopram on male rat ejaculatory behavior.

Ahlenius S, Larsson K.

Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden. sven.ahlenius fyfa.ki.se

The selective serotonin re-uptake inhibitor citalopram (0-40 mg kg(-1), s.c., - 60 min) did not affect the male rat ejaculatory behavior, and there were no statistically significant effects of the 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide 3HCl (WAY-100635) (0.04-0.08 mg kg(-1), s.c., - 30 min). When combined, there was a marked, and statistically significant, prolongation of the ejaculation latency in comparison with saline treated controls, as well as in comparison with either drug by itself. This citalopram (10.0)/WAY-100635 (0.04)-induced effect was fully antagonized by the administration of the 5-HT1B receptor antagonist isamoltane (4.0 mg kg(-1)). There were no consistent effects on other aspects of the male rat sexual behavior, i.e., number of mounts and intromissions preceding ejaculation and the post-ejaculatory interval. Finally, the intromission latency was also markedly enhanced in animals receiving both citalopram and WAY-100635, and at the higher dose of WAY-100635 (0.08 mg kg(-1)) 7 out of 18 animals failed to initiate copulation. It is suggested that blockade of inhibitory 5-HT1A autoreceptors discloses inhibitory effects of the selective serotonin re-uptake inhibitor citalopram on male rat ejaculatory behavior mediated via stimulation of 5-HT1B receptors.

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citalopram Celexa
Economic appraisal of citalopram in the management of single-episode depression.

Sclar DA, Skaer TL, Robison LM, Galin RS.

Pharmacoeconomics and Pharmacoepidemiology Research Unit, College of Pharmacy, Washington State University, Pullman 99164-6510, USA. sclar mail.wsu.edu

A retrospective intent-to-treat analysis (N = 1,339) was conducted to discern the natural course of antidepressant use and direct health service expenditures for the treatment of single-episode depression (DSM-IV code 296.20) among patients initiating antidepressant pharmacotherapy with either a tricyclic antidepressant (TCA) (amitriptyline, N = 237) or a selective serotonin reuptake inhibitor (SSRI) (citalopram, N = 71; fluoxetine, N = 411; paroxetine, N = 334; or sertraline, N = 286). Data were derived from the computer archive of a network-model health maintenance organization for the period of January 1, 1996, through April 30, 1999. Comparisons at the end of the 6-month post-period (180 days) were undertaken between cohorts initiating antidepressant pharmacotherapy with citalopram and each SSRI or TCA. Consistent with the intent-to-treat design, all accrued health service expenditures were assigned to the pharmacotherapeutic option initially prescribed. Multivariate models were adjusted for patient's age, gender, number of concomitant disease state processes, use of health services in the 6-month time frame (180 days) before initiating antidepressant pharmacotherapy, specialty of physician recording a diagnosis of single-episode depression, and the presence or absence of a previous diagnosis of single-episode depression and receipt of antidepressant pharmacotherapy. Patients initiating antidepressant pharmacotherapy with citalopram were far more likely to (1) have been diagnosed by a psychiatrist (37%; p < or = 0.05); (2) continue with the original pharmacotherapeutic option (79%) compared with patients originally prescribed amitriptyline (51%; chi2 = 17.29, df = 1, p < or = 0.05) or sertraline (65%; chi2 = 36.91, df = 1, p < or = 0.05); no significant difference was found compared with patients initiating antidepressant pharmacotherapy with paroxetine (72%; p = not significant [NS]) or fluoxetine (83%; p = NS); (3) obtain 90 days or more of antidepressant pharmacotherapy (86%) compared with those prescribed amitriptyline (69%; chi2 = 8.09, df = 1, p < or = 0.05); no significant difference was found compared with sertraline (77%), paroxetine (81%), or fluoxetine (84%); and (4) obtain 6 months (180 days) of antidepressant pharmacotherapy (68%) compared with those prescribed amitriptyline (39%; chi2 = 18.26, df = 1, p < or = 0.05) or sertraline (51%; chi2 = 6.02, df = 1, p < or = 0.05); no significant difference was found compared with paroxetine (56%) or fluoxetine (59%). Receipt of amitriptyline or sertraline as initial medication was associated with a per capita increase (p < or = 0.05) in health service utilization (17% and 9%, respectively) relative to citalopram. No significant difference (p > 0.05) in health service utilization was discerned between citalopram and either fluoxetine or paroxetine. Multivariate models adjusted for nonrandom assignment to the initial pharmacotherapeutic option confirmed these findings. Further research over a longer time course is warranted.

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citalopram Celexa
Citalopram: new indication. No advantage.

[No authors listed]

(1) Citalopram, a serotonin reuptake inhibitor antidepressant, now has a new licensed indication, in the preventive treatment of panic attacks. In France, clomipramine, a tricyclic antidepressant, and paroxetine, another serotonin reuptake inhibitor, are already approved for this use. (2) In the only available comparative trial the efficacy of citalopram (20-60 mg/day) was similar to that of clomipramine (60-90 mg/day). (3) The safety profile of citalopram is different from that of clomipramine. (4) There are no data clearly comparing citalopram with paroxetine in terms of efficacy, safety, drug interactions, or convenience. (5) Clomipramine is much cheaper than citalopram.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10557570&dopt=Abstract citalopram Celexa