citalopram Celexa
abcb1ab P-glycoprotein is involved in the uptake of citalopram and trimipramine into the brain of mice.

Uhr M, Grauer MT.

Max Planck Institute of Psychiatry, Kraepelinstrasse 10, D-80804, Munich, Germany. uhr mpipsykl.mpg.de

The phenomenon of a heterogeneous response to the same drug in different patients is well-known. An important reason is that, even at equal concentrations, the bioavailability of a drug depends on the interaction of the drug with the blood-brain barrier (BBB). In part, this is due to the drug-transporting P-glycoprotein (P-gp), a product of the multiple drug resistance gene (ABCB1), which can transport drugs against a concentration gradient across the BBB back into the plasma and thereby reduce the bioavailability in the brain. In the present study, we have examined the uptake of the antidepressants citalopram and trimipramine into the brain of abcb1ab knockout mice compared with controls. One hour after s.c. injection of the drugs, concentrations of the two drugs and of the metabolite d-trimipramine in brain, spleen, kidney, liver and plasma were measured with HPLC. Significantly higher brain concentrations in knockout mice, showing that these drugs are substrates of P-gp and that the presence of P-gp reduces the effective bioavailability of these substances in the brain. The results of our study contradict an earlier report that citalopram is not actively transported from endothelial cells. These results were derived from an in vitro study, showing that due to the complexity of the BBB-drug interaction, it is difficult to transfer results from in vitro studies to the in vivo situation. We hypothesize that inter-individual differences in the activity of the ABCB1 gene can account in part for the great variation in clinical response to antidepressants in psychiatric patients, even at comparable plasma levels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12650738&dopt=Abstract citalopram Celexa



citalopram Celexa
Citalopram, a selective serotonin reuptake inhibitor augments harmaline-induced tremor in rats.

Arshaduddin M, Al Kadasah S, Biary N, Al Deeb S, Al Moutaery K, Tariq M.

Armed Forces Hospital, Riyadh 11159, Saudi Arabia.

Citalopram, a serotonin reuptake inhibitor (SSRI) is one of the widely used antidepressants. Apart from its antidepressant activity citalopram is also used for anxiety, panic disorders, obsessive-compulsive disorder and behavioral disturbances of dementia. Tremor is the second most common neurological adverse effect in patients receiving treatment with SSRIs. Use of these agents in depressed patients with essential tremor has not been studied. The present study was undertaken to investigate the effect of chronic citalopram treatment on harmaline-induced tremors in rats. Female Sprague-Dawley rats weighing 70+/-2 g were given citalopram in doses of 0, 10, 20 and 40 mg/kg by gavage for 2 weeks. On the 15th day, the rats were given harmaline (10 mg/kg, i.p.) 30 min after the last dose of citalopram. The latency of onset, intensity and duration of tremor and EMG were recorded. Serotonin (5HT) and 5-hydroxy indole acetic acid (5HIAA) were measured in brain stem. Citalopram dose dependently exacerbated the duration, intensity and amplitude of EMG of harmaline-induced tremor. A significant decrease in 5HT turnover (5HIAA/5HT ratio) in the brain stem was observed suggesting a possible role of serotoninergic impairment in citalopram-induced augmentation of harmaline-induced tremor. Clinical implications of these observations warrant further investigation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15219702&dopt=Abstract citalopram Celexa



citalopram Celexa
Effects of citalopram on worry and brain activation in patients with generalized anxiety disorder.

Hoehn-Saric R, Schlund MW, Wong SH.

Department of Psychiatry, Johns Hopkins School of Medicine, 115 Meyer Building, Johns Hopkins Hospital, Baltimore, MD 21287, USA. rhoehn mail.jhmi.edu

The effects of auditory statements describing a personal worry on brain activation as measured by functional magnetic resonance imaging were examined in patients with generalized anxiety disorder (GAD) before and after anxiety reduction with citalopram. Six patients were imaged while listening to verbal descriptions of a personal worry or a neutral statement before treatment with citalopram and after 7 weeks of treatment. Pre-post drug analyses showed treatment with citalopram reduced self-reported anxiety and reduced BOLD responses to a pathology-specific worry and a neutral stimulus. After treatment, worry sentences, compared to neutral statements, elicit reduced BOLD responses in prefrontal regions, the striatum, insula and paralimbic regions. In addition, contrasts before and after treatment revealed reductions in the differential response that existed between worry and neutral statements. Overall reduction of BOLD response was most prominent during neutral statements, particularly in the left hemisphere. These findings support the clinical impression that GAD patients overreact to both pathology-specific and non-specific cues and that the reduction of anxiety attenuates the response to both types of cues.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15246451&dopt=Abstract citalopram Celexa



citalopram Celexa
The effect of citalopram on gene expression profile of Alzheimer lymphocytes.

Palotas A, Puskas LG, Kitajka K, Palotas M, Molnar J, Pakaski M, Janka Z, Penke B, Kalman J.

Department of Psychiatry, Albert Szent-Gyorgyi Medical and Pharmaceutical Center, Faculty of Medicine, University of Szeged, H-6721 Szeged, Hungary. palotas nepsy.szote.u-szeged.hu

Antidepressants are widely used in the treatment of mood disorders associated with dementia, however little information is available on their effect at the molecular level. In certain neurodegenerative disorders, such as in Alzheimer's disease, lymphocytes have been used to assess mirror changes that thought to occur in the brain. Gene expression profiles of lymphocytes from Alzheimer patients have been shown to differ from that seen with controls. To address this issue in light of antidepressant treatment, we used lymphocytes derived from Alzheimer's disease patients and control individuals to assess the impact of the selective serotonine reuptake inhibitor citalopram on gene expression using a cDNA microarray representing 3200 distinct human genes. Sequences that are differentially regulated after treatment with citalopram were identified and categorized based on similarities in biological functions. This analysis revealed that the overexpression of genes in control and Alzheimer white blood cells by citalopram are implicated in cell survival. Apart from this, citalopram did not markedly alter genes involved in other molecular functions in control cells. In contrast, alteration of genes implicated in ionic currents, cell-adhesion, immune mechanism, and adrenergic functions, were also observed in Alzheimer lymphocytes. The expression of genes of Alzheimer lymphocytes by citalopram is modulated differently which may correlate with the pathology.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15260135&dopt=Abstract citalopram Celexa



citalopram Celexa
Therapeutic drug monitoring of racemic citalopram: a 5-year experience in Sweden, 1992-1997.

Reis M, Lundmark J, Bengtsson F.

Division of Psychiatry, Department of Neuroscience and Locomotion, Faculty of Health Sciences, Linkoping, Sweden. margareta.reis klinfarm.lu.se

Racemic citalopram (CIT) was introduced in Sweden in 1992 for management of major depression. During a 5-year period, 1992 to 1997, serum samples of CIT and desmethylcitalopram (DCIT) were collected for therapeutic drug monitoring (TDM) from patients from all over Sweden. These samples were accompanied by clinical information on a specially designed TDM request form. They represented men and women of various ages (11-94 years) usually on multiple concomitant medications and treated in a naturalistic setting. The TDM samples eligible for evaluation (n = 749), all trough values at steady state, were studied with respect to inter- and intraindividual pharmacokinetic variability. Extensive, interindividual serum concentration variability was seen on all dose levels. For dose-corrected concentrations (C/D) and for clearance (Cl) we found the coefficient of variation (CV) to be approximately 55% for all variables (C/D CIT, C/D DCIT, the ratio DCIT to CIT, and for Cl CIT). The intraindividual variations over time for the same parameters were 30% to 35%. On a population level, signs of a possible saturation of CYP2D6 associated with increasing DCIT-to-CIT ratios with increasing daily doses was observed. Age and gender affected the pharmacokinetics of CIT and DCIT. Women showed significantly higher C/D CIT and C/D DCIT and lower Cl CIT values compared with men, and patients aged more than 65 years had higher C/D CIT and C/D DCIT and lower Cl CIT values compared with younger patients. Finally, concomitant medication affected the outcome of serum concentrations by a general increase in C/D CIT and C/D DCIT but without alteration in the DCIT-to-CIT ratio. Thus, this tendency of changes in the CIT disposition when multiple drugs are used (and multiple diseases are prevailing?) seems more general in character than specific for a certain drug or type of drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12657912&dopt=Abstract citalopram Celexa



citalopram Celexa
Gene expression profile analysis of the rat cortex following treatment with imipramine and citalopram.

Palotas M, Palotas A, Puskas LG, Kitajka K, Pakaski M, Janka Z, Molnar J, Penke B, Kalman J.

Department of Psychiatry, Albert Szent-Gyorgyi Medical and Pharmaceutical Centre, Faculty of Medicine, University of Szeged, H-6721 Szeged, Semmelweis u. 6, Hungary.

The effect of antidepressants is the culmination of a series of molecular actions occurring in the brain. These events are thought to lead to changes in the expression level of numerous, but as yet unknown genes that result in different cellular functions. In our present study we addressed this issue by establishing gene expression profiles of the rat brain after treatment with imipramine and citalopram at therapeutic doses. After 96 h and 4 wk, fronto-temporal cortices from controls and each treated strain were prepared and total RNA was isolated, and assessed using a cDNA microarray system containing 3200 clones. The expression of 6 genes was decreased and 8 were over-expressed by imipramine, whereas 27 were repressed and 7 were up-regulated by citalopram. Members of signal transduction (e.g. phosphatidylinositol transfer protein), structural elements (e.g. tubulin, fibronectin), factors related to protein metabolism in general (e.g. proteasomal subunits, ubiquitin-like proteins, polyadenylation sites), components involved in cell survival (e.g. midkine, stress-inducible protein), and determinants of membrane conductance and ion transport (e.g. vacuolar H+-ATPase), and basics of nuclear functions (e.g. translin, basal transcription factor 3), were some of the genes with altered expression. These data demonstrate that antidepressants interfere with the expression of a large array of genes involved in signalling, survival and protein metabolism. Our results demonstrate for the first time that antidepressants specifically regulate neuronal plasticity through induction of a highly specific transcriptional programme in brain cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15315716&dopt=Abstract citalopram Celexa



citalopram Celexa
Differential effects of reboxetine and citalopram on hand-motor function in patients suffering from major depression.

Hegerl U, Mergl R, Henkel V, Pogarell O, Muller-Siecheneder F, Frodl T, Juckel G.

Laboratory of Clinical Neurophysiology, Department of Psychiatry, Ludwig-Maximilians-Universitat Munchen, Nussbaumstr. 7, 80336, Munich, Germany, uhegerl psy.med.uni-muenchen.de.

RATIONALE: Motor dysfunctions might be a more common side effect of serotonergic than noradrenergic antidepressants. However, the effects of antidepressants on motor function in depression have rarely been analyzed systematically. Computerized methods allow the objective registration of drug-induced motor dysfunction and were applied in this study.OBJECTIVES: To examine the effects of a selective noradrenaline re-uptake inhibitor (NARI) (reboxetine) and a selective serotonin re-uptake inhibitor (SSRI) (citalopram) on hand-motor function in patients with major depression.METHODS: Different types of hand movements (drawing of circles and handwriting probes) were recorded and analyzed in 16 acutely depressed inpatients receiving citalopram (30-60 mg/day) and 12 acutely depressed inpatients treated with reboxetine (4-8 mg/day), using a digitizing tablet for the analysis of movement dynamics. Both groups were comparable regarding mean age (42-43 years), gender, handedness (preponderance of right-handers) and the mean baseline HAMD score (about 27). Five kinematical parameters reflecting velocity, regularity and degree of automation of hand movements have been computed.RESULTS: Reboxetine had significantly more favorable effects on fine motor function (increased velocity of rapid hand movements) in depressed patients than citalopram. These differences became obvious when patients conducted more complex tasks and are not explained by differential antidepressant effects.CONCLUSIONS: Our findings are in line with the hypothesis that SSRI tend to have small, but more pronounced negative effects on motor function than NARI.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15316714&dopt=Abstract citalopram Celexa



citalopram Celexa
Postmortem citalopram concentrations: alone or along with other compounds.

Segura LJ, Bravo B.

Toxicology Laboratory, Instituto Anatomico Forense of Madrid, Ciudad Universitaria, Madrid, Spain. lseguraa meditex.es

Citalopram, an antidepressant whose use has become more widespread in Spain in recent years participates directly and indirectly in the lethal mechanism in voluntary and involuntary poisonings. There were 30 cases of autopsies in the Madrid region where citalopram and other psychoactive substances (psychotropic drugs, alcohol, opiates) were detected in the corpses. The postmortem citalopram levels in relation to the manner and mechanism of death were evaluated, and a significant difference between the toxic and nontoxic cases (p < 0.01) was found. We studied the citalopram blood levels alone and along with other psychoactive products, and these cases were then further divided into those where the compounds were at deadly levels and those which were not. We found a range of citalopram levels between 0.37 and 0.83 microg/mL in which some cases were associated with citalopram toxicity and others were not. Citalopram blood levels of less than 0.35 microg/mL did not lead to fatal poisoning when it was the sole substance detected.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15317201&dopt=Abstract citalopram Celexa