citalopram Celexa
In vitro biotransformation of the selective serotonin reuptake inhibitor citalopram, its enantiomers and demethylated metabolites by monoamine oxidase in rat and human brain preparations.

Kosel M, Gnerre C, Voirol P, Amey M, Rochat B, Bouras C, Testa B, Baumann P.

Unite de Biochimie et Psychopharmacologie Clinique, Departement Universitaire de Psychiatrie Adulte, CH-1008 Prilly-Lausanne, Switzerland.

This study was conducted to identify enzyme systems eventually catalysing a local cerebral metabolism of citalopram, a widely used antidepressant of the selective serotonin reuptake inhibitor type. The metabolism of citalopram, of its enantiomers and demethylated metabolites was investigated in rat brain microsomes and in rat and human brain mitochondria. No cytochrome P-450 mediated transformation was observed in rat brain. By analysing H2O2 formation, monoamine oxidase A activity in rat brain mitochondria could be measured. In rat whole brain and in human frontal cortex, putamen, cerebellum and white matter of five brains monoamine oxidase activity was determined by the stereoselective measurement of the production of citalopram propionate. All substrates were metabolised by both forms of MAO, except in rat brain, where monoamine oxidase B activity could not be detected. Apparent Km and Vmax of S-citalopram biotransformation in human frontal cortex by monoamine oxidase B were found to be 266 microM and 6.0 pmol min(-1) mg(-1) protein and by monoamine oxidase A 856 microM and 6.4 pmol min(-1) mg(-1) protein, respectively. These Km values are in the same range as those for serotonin and dopamine metabolism by monoamine oxidases. Thus, the biotransformation of citalopram in the rat and human brain occurs mainly through monoamine oxidases and not, as in the liver, through cytochrome P-450.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11840311&dopt=Abstract citalopram Celexa



citalopram Celexa
Inhibitory actions of the selective serotonin re-uptake inhibitor citalopram on HERG and ventricular L-type calcium currents.

Witchel HJ, Pabbathi VK, Hofmann G, Paul AA, Hancox JC.

Cardiovascular Research Laboratories and Department of Physiology, School of Medical Sciences, Bristol, UK. harry.witchel bris.ac.uk

Using whole-cell patch clamp recording of heterologous HERG-mediated currents in transfected mammalian cells, we observed that the selective serotonin re-uptake inhibitor citalopram blocks HERG with an IC(50) of 3.97 microM. This is slightly less potent than fluoxetine in our system (IC(50) of 1.50 microM). In isolated guinea pig ventricular cardiomyocytes citalopram inhibited L-type calcium current (I(Ca,L)). The voltage dependence of I(Ca,L) inactivation in the presence of 100 microM citalopram was shifted significantly leftward. As a result, the I(Ca,L) 'window' in citalopram was found to be (a) smaller and (b) leftward-shifted compared to control. The effects of citalopram on both calcium current amplitude and the I(Ca,L) 'window' may help to explain citalopram's good cardiac safety profile, given its propensity to block HERG at excessive dosages.

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citalopram Celexa
Behavioural and biochemical studies of citalopram and WAY 100635 in rat chronic mild stress model.

Papp M, Nalepa I, Antkiewicz-Michaluk L, Sanchez C.

Institute of Pharmacology, Polish Academy of Sciences, 31-343 Cracow, Poland.

Reversal of chronic mild stress (CMS)-induced decrease of sucrose consumption has been studied in rats after 2, 7, 14, and 35 days treatment with imipramine, citalopram (both 10 mg/kg per day, i.p.), WAY 100635 (0.2 mg/kg sc, b.i.d.), and citalopram plus WAY 100635. Bmax, Kd, and functional status [cyclic AMP (cAMP) generation] of beta1-adrenoceptors were assessed in cortical tissue at the same time points. Citalopram reversed CMS-induced reduction of sucrose intake at an earlier time point than imipramine. WAY 100635 was not effective and did not potentiate the effect of citalopram. CMS produced increase of Bmax. Imipramine decreased Bmax in controls (Days 2, 7, 14, and 35) and normalised Bmax in stressed animals (Day 35). Citalopram, WAY 100635, and the combination increased Bmax in stressed animals and controls (Days 14 and 35). Inconsistent changes of Kd values and of cAMP responses to noradrenaline (NA) stimulation were observed. Thus stress- and drug-induced effects on beta1-adrenoceptors do not appear to be a common biochemical marker of antidepressant-like activity in the CMS model.

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citalopram Celexa
Citalopram in fatal poisoning cases.

Jonasson B, Saldeen T.

Department of Surgical Sciences/Forensic Medicine, University of Uppsala, Dag Hammarskjolds vag 17, S-752 37, Uppsala, Sweden. birgitta.jonasson rfv.sfa.se

Citalopram, a selective serotonin reuptake inhibitor, is the most frequently prescribed antidepressant in Sweden. To investigate the extent to which citalopram in overdose is found in fatal poisoning cases compared with other drugs, all fatal poisonings in one forensic medicine district in Sweden during the years 1994-1999 were examined. Drugs found in overdose in more than 10 cases were included. The ratio between number of cases with each included drug and prescription of defined daily dose/1,000 inhabitants/day (DDD) was determined.Citalopram was the fourth most frequently found drug in overdose, occurring in 22 (6%) of the 358 fatal poisoning cases, after dextropropoxyphene (DXP), flunitrazepam and nitrazepam, which were present in 111 (31%), 56 (16%) and 31 (9%) cases, respectively. When related to the prescription rate, citalopram was significantly less represented than five of the other seven included drugs, namely DXP, flunitrazepam, nitrazepam, amitriptyline and clomipramine. Propiomazine and zopiclone occurred to the same extent as citalopram. According to the assessments of the forensic physicians, citalopram was the cause of death in five cases (1.4%) and contributed to death in another nine cases (2.5%).It is concluded that citalopram, in spite of its high prescription rate, has not become a drug of importance in fatal poisoning cases. Since, this result may not be generalisable to non-fatal poisoning cases, it is recommended that the prevalence of citalopram in these cases be examined separately.

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citalopram Celexa
Carbamazepine augmentation in depressive patients non-responding to citalopram: a pharmacokinetic and clinical pilot study.

Steinacher L, Vandel P, Zullino DF, Eap CB, Brawand-Amey M, Baumann P.

Praxis am Zweierplatz, Badenerstrasse 67, CH-8004 Zurich, Switzerland.

Citalopram is a chiral antidepressant drug. Its eutomer, S-citalopram (escitalopram), has recently been introduced as an antidepressant. In an open pilot study, four outpatients and two inpatients with a major depressive episode (ICD-10), and who were nonresponders to a 4-week pretreatment with 40-60 mg/day citalopram, were comedicated for another 4-week period with carbamazepine (200-400 mg/day). Some of the patients suffered also from comorbidities: Phobic anxiety disorder with panic attacks (n=2), generalised anxiety disorder, alcohol abuse, dependent personality disorder, hypertension (n=1). After a 4-week augmentation therapy with carbamazepine, a significant (P<0.03) decrease of the plasma concentrations of S-citalopram and R-citalopram, by 27 and 31%, respectively, was observed. Apparently, the probable induction of CYP3A4 by carbamazepine results in a nonstereoselective increase in N-demethylation of citalopram. Moreover, there was a significant (P<0.03) decrease of the ratio S/R-citalopram propionic acid derivative, the formation of it being partly regulated by MAO-A and MAO-B. Already, within 1 week after addition of carbamazepine, there was a slight but significant (P<0.03) decrease of the MADRS depression scores, from 27.0+/-7.7 (mean+/-S.D.) to 23.3+/-6.6, and the final score on day 56 was 18.8+/-10.9. The treatment was generally well tolerated. There was no evidence of occurrence of a serotonin syndrome. After augmentation with carbamazepine, treatment related adverse events were: Nausea in one case, diarrhea in one case, and rash in two cases. In conclusion, the results of this pilot study suggest that carbamazepine augmentation of a citalopram treatment in previous nonresponders to citalopram may be clinically useful, but that in addition carbamazepine can lead to a decrease of the plasma concentrations of the active enantiomer escitalopram.

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citalopram Celexa
Citalopram treatment for impulsive aggression in children and adolescents: an open pilot study.

Armenteros JL, Lewis JE.

Division of Child and Adolescent Psychiatry, University of Miami School of Medicine, FL 33136, USA. j.armenteros miami.edu

OBJECTIVE: To assess the short-term effect and safety of citalopram in the reduction of impulsive aggression in children and adolescents. METHOD: Twelve subjects, aged 7 to 15 years, were attending a psychiatric outpatient clinic and had a profile of impulsive aggression. Subjects were treated in an open trial with citalopram for 6 weeks after a 1-week washout period. Dosage was regulated individually over a period of 4 weeks. The starting dose was 10 mg/day followed by 10 mg increments on a weekly basis. The maximum dose was not to exceed 40 mg/day. Outcome measures included the Modified Overt Aggression Scale (MOAS), the Child Behavioral Checklist (CBCL), and the Clinical Global Impressions (CGI). RESULTS: Eleven subjects completed the study Citalopram produced clinically and statistically significant reductions on target symptoms of impulsive aggression, independent of other behavioral problems, as measured by the MOAS, the CBCL, and the CGI at doses ranging from 20 to 40 mg/day (mean = 27 mg). No major adverse reactions were associated with citalopram use. CONCLUSION: Citalopram appears to be effective and well tolerated in this sample of children and adolescents with impulsive aggression.

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citalopram Celexa
Early malnourished rats are not affected by anorexia induced by a selective serotonin reuptake inhibitor in adult life.

Barreto Medeiros JM, Cabral Filho JE, De Souza SL, Freitas Silva SR, Mendes Da Silva C, Deiro TC, Monteiro JM, Guedes RC, De Castro CM, Manhaes De Castro R.

Departamento Ciencias de la Nutricao, Universidade Federal da Bahia, Salvador, Brazil.

The effect of early postnatal malnutrition upon food intake and its modulation by the selective serotonin reuptake inhibitor (SSRI) citalopram, was investigated in adult rats. Sixty four Wistar rats were allocated to two groups, according to their mother's diet during lactation. Mothers receiving a 23% protein diet fed the well-nourished group; mothers receiving 8% protein diet fed the malnourished. After weaning, all rats received the 23% protein diet ad libitum. On the 120th day after birth, each nutritional group was divided in two subgroups (each one, n = 16) which received a single daily injection of citalopram (10 mg/kg) or saline (0.9% NaCl) for 14 days. Chronic treatment with citalopram decreased both the food intake and weight gain in the well-nourished rats, but not in the malnourished ones. These data are consistent with findings concerning the nutritional manipulation of the nervous system during its higher vulnerable phase, suggesting that early malnutrition alters the effect of treatment of SSRI in adult rats, and that malnutrition during the critical period of brain development affects the serotoninergic system.

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citalopram Celexa
The selective serotonin reuptake inhibitor citalopram induces the storage of serotonin in catecholaminergic terminals.

Suarez-Roca H, Cubeddu LX.

Pharmacology Section, Instituto de Investigaciones Clinicas, School of Medicine, University of Zulia, Maracaibo, Venezuela.

We investigated whether selective inhibition of serotonin (5-hydroxytryptamine; 5-HT) transporter with citalopram leads to accumulation of 5-HT in catecholaminergic neurons. In the rabbit olfactory tubercle, citalopram (1-10 microM) inhibited [(3)H]5-HT uptake; however, the maximal degree of inhibition achieved was 70%. Addition of nomifensine (1-10 microM) was required for complete inhibition of [(3)H]5-HT uptake. In slices labeled with 0.1 microM [(3)H]5-HT, cold 5-HT (0.03-1 microM) induced a large increase in the efflux (release) of stored [(3)H]5-HT, an effect blocked by coperfusion with 1 microM citalopram. Similar concentrations (0.03-1 microM) of norepinephrine (NE) or dopamine (DA) failed to release [(3)H]5-HT. When labeling with 0.1 microM [(3)H]5-HT was carried out in the presence of citalopram, 1) low concentrations of 5-HT failed to release [(3)H]5-HT; 2) DA and NE were more potent and effective in releasing [(3)H]5-HT than in control slices; 3) coperfusion of NE, DA, or 5-HT with citalopram enhanced the release of [(3)H]5-HT induced by the catecholamines but not by 5-HT; and 4) coperfusion of NE or DA with nomifensine antagonized NE- and DA-evoked [(3)H]5-HT release, with a greater effect on NE than on DA. These results suggest that in the rabbit olfactory tubercle, where there is coexistence of 5-HT, NE, and DA neurons, inhibition of the 5-HT transporter led to accumulation of 5-HT in catecholaminergic terminals. Thus, during treatment with selective serotonin uptake inhibitors (SSRIs), 5-HT may be stored in catecholaminergic neurons acting as a false neurotransmitter and/or affecting the disposition of DA and/or NE. Transmitter relocation may be involved in the antidepressant action of SSRIs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12065714&dopt=Abstract citalopram Celexa