Investigating an in silico approach for prioritizing antidepressant drug prescription based on drug-induced expression profiles and predicted gene expression.

In clinical practice, an antidepressant prescription is a trial and error approach, which is time consuming and discomforting for patients. This study investigated an in silico approach for ranking antidepressants based on their hypothetical likelihood of efficacy. We predicted the transcriptomic profile of citalopram remitters by performing an in silico transcriptomic-wide association study on STAR*D GWAS data (N = 1163). The transcriptional profile of remitters was compared with 21 antidepressant-induced gene expression profiles in five human cell lines available in the connectivity-map database. Spearman correlation, Pearson correlation, and the Kolmogorov-Smirnov test were used to determine the similarity between antidepressant-induced profiles and remitter profiles, subsequently calculating the average rank of antidepressants across the three methods and a p value for each rank by using a permutation procedure. The drugs with the top ranks were those having a high positive correlation with the expression profiles of remitters and that may have higher chances of efficacy in the tested patients. In MCF7 (breast cancer cell line), escitalopram had the highest average rank, with an average rank higher than expected by chance (p = 0.0014). In A375 (human melanoma) and PC3 (prostate cancer) cell lines, escitalopram and citalopram emerged as the second-highest ranked antidepressants, respectively (p = 0.0310 and 0.0276, respectively). In HA1E (kidney) and HT29 (colon cancer) cell types, citalopram and escitalopram did not fall among top antidepressants. The correlation between citalopram remitters' and (es)citalopram-induced expression profiles in three cell lines suggests that our approach may be useful and with future improvements, it can be applicable at the individual level to tailor treatment prescription.

Combinatorial Pharmacogenomic Algorithm is Predictive of Citalopram and Escitalopram Metabolism in Patients with Major Depressive Disorder.

Pharmacogenomic tests used to guide clinical treatment for major depressive disorder (MDD) must be thoroughly validated. One important assessment of validity is the ability to predict medication blood levels, which reflect altered metabolism. Historically, the metabolic impact of individual genes has been evaluated; however, we now know that multiple genes are often involved in medication metabolism. Here, we evaluated the ability of individual pharmacokinetic genes (CYP2C19, CYP2D6, CYP3A4) and a combinatorial pharmacogenomic test (GeneSight Psychotropic®; weighted assessment of all three genes) to predict citalopram/escitalopram blood levels in patients with MDD. Patients from the Genomics Used to Improve DEpression Decisions (GUIDED) trial who were taking citalopram/escitalopram at screening and had available blood level data were included (N=191). In multivariate analysis of the individual genes and combinatorial pharmacogenomic test separately (adjusted for age, smoking status), the F statistic for the combinatorial pharmacogenomic test was 1.7 to 2.9-times higher than the individual genes, showing that it explained more variance in citalopram/escitalopram blood levels. In multivariate analysis of the individual genes and combinatorial pharmacogenomic test together, only the combinatorial pharmacogenomic test remained significant. Overall, this demonstrates that the combinatorial pharmacogenomic test was a superior predictor of citalopram/escitalopram blood levels compared to individual genes.

Dual Roles for the TSPYL Family in Mediating Serotonin Transport and the Metabolism of Selective Serotonin Reuptake Inhibitors in Patients with Major Depressive Disorder.

We previously reported that testis-specific Y-encoded-like protein (TSPYLs) are transcription regulators for CYP3A4, CYP2C9, and CYP2C19. Here, we observed dual roles for TSPYLs in mediating serotonin transport and the metabolism of selective serotonin reuptake inhibitors (SSRIs) in patients with major depressive disorder (MDD). The widely prescribed SSRIs, citalopram, and escitalopram are metabolized mainly by CYP2C19. The TSPYL1 rs3828743 single nucleotide polymorphism (SNP), which decreases its suppression of CYP2C19 expression, was associated with rapid escitalopram metabolism and worse treatment response in the Mayo PGRN-AMPS clinical trial. We also found that TSPYLs can regulate expression of the serotonin transporter protein, SLC6A4, and, in turn, serotonin transport into cells. The SNPs in tight linkage disequilibrium with the TSPYL1 rs10223646 SNP were significantly correlated with baseline severity of depression in patients with MDD in the Sequenced Treatment Alternatives to Relieve Depression and International SSRI Pharmacogenomics Consortium clinical trials. Our findings suggest that genetic variation in TSPYL genes may be novel indicators for baseline severity of depression and SSRI poor response.

Smoking Is Associated With Lower Dose-Corrected Serum Concentrations of Escitalopram.

BACKGROUND: Tobacco smoking rates in depressive patients are higher compared with the general population. Smoking was demonstrated to accelerate the metabolism of different drugs metabolized by CYP1A2, but possibly also by CYP2C19 and CYP3A4. The principle aim of the present investigation from 2015 to 2018 was to determine the differences in the pharmacokinetics of escitalopram between smokers and nonsmokers. METHODS: A group of nonsmokers (n = 88) was compared with smokers (n = 36), both receiving escitalopram, using the Mann-Whitney U test. Linear regression analysis was used to account for the impact of escitalopram dose, age, and sex in addition to smoking on the steady-state serum concentration of escitalopram. RESULTS: Smokers received by mean 17.6% higher doses of escitalopram (P = 0.026) but showed 31.9% lower serum concentrations (P = 0.031). To control for confounders, linear regression analysis showed that dose (P < 0.001), sex (P = 0.03), and smoking tobacco (P = 0.027) did significantly influence serum concentrations of escitalopram with higher levels in women and nonsmokers. CONCLUSIONS: Notwithstanding higher daily doses, smokers had significantly lower serum concentrations of escitalopram. In concordance with previous results, besides CYP1A2, a possible induction of CYP2C19 and CYP3A4 by tobacco smoke, resulting in lower serum concentrations of escitalopram in smokers than in nonsmokers, is suggested. Therefore, to provide personalized therapy, clinicians should consider smoking status and inform patients on the interactions of smoking and escitalopram metabolism.

DPCPX, a selective adenosine A1 receptor antagonist, enhances the antidepressant-like effects of imipramine, escitalopram, and reboxetine in mice behavioral tests.

The main goal of the present study was to evaluate the influence of the adenosine A1 receptor (A1R) antagonist - DPCPX - on depressive-like behavior in mice, as well as the effect of DPCPX on the activity of imipramine, escitalopram, and reboxetine, each at non-effective doses. The influence of DPCPX on behavior and its influence on the activity of selected antidepressants was evaluated in the forced swim test (FST) and the tail suspension test (TST) in mice. Locomotor activity was measured to verify and exclude false-positive data obtained in the FST and TST. Moreover, serum and brain concentrations of tested antidepressants were determined using HPLC. DPCPX, at doses of 2 and 4 mg/kg, exhibited antidepressant activity in the FST and TST, which was not related to changes in the spontaneous locomotor activity. Co-administration of DPCPX with imipramine, escitalopram, or reboxetine, each at non-active doses, significantly reduced the immobilization period in the FST and TST in mice, which was not due to the increase in locomotor activity. Both antagonists of 5-HT receptors (WAY 100635 and ritanserin) completely antagonized the effect elicited by DPCPX in the behavioral tests. Results of assessment of the nature of the interaction between DPCPX and test drugs show that in the case of DPCPX and imipramine or reboxetine, there were pharmacodynamic interactions, whereas the DPCPX-escitalopram interaction is at least partially pharmacokinetic in nature. Presented outcomes indicate that an inhibition of A1Rs and an increase of monoaminergic transduction in the CNS may offer a novel strategy for the development of antidepressant drugs.

Chronic treatment with caffeine and its withdrawal modify the antidepressant-like activity of selective serotonin reuptake inhibitors in the forced swim and tail suspension tests in mice. Effects on Comt, Slc6a15 and Adora1 gene expression.

Recent preclinical and clinical data suggest that low dose of caffeine enhances the effects of common antidepressants. Here we investigated the effects of chronic administration of caffeine (5mg/kg, twice daily for 14days) and its withdrawal on day 15th on the activity of per se ineffective doses of fluoxetine (5mg/kg) and escitalopram (2mg/kg) given on day 15th. We found decreased immobility time in the forced swim and tail suspension tests in mice in which caffeine was administered simultaneously with antidepressants on day 15th following a 14-day caffeine treatment and no alterations in the spontaneous locomotor activity. A decrease in the level of escitalopram and an increase in the level of caffeine in serum were observed after concomitant administration of these compounds, while the joint administration of caffeine and fluoxetine was not associated with changes in their levels in serum or brain. Caffeine withdrawal caused a decrease in Adora1 mRNA level in the cerebral cortex (Cx). Administration of escitalopram or fluoxetine followed by caffeine withdrawal caused an increase in this gene expression, whereas administration of escitalopram, but not fluoxetine, on day 15th together with caffeine caused a decrease in Adora1 mRNA level in the Cx. Furthermore, antidepressant-like activity observed after joint administration of the tested drugs with caffeine was associated with decreased Slc6a15 mRNA level in the Cx. The results show that withdrawal of caffeine after its chronic intake may change activity of antidepressants with concomitant alterations within monoamine, adenosine and glutamate systems.

Investigate the control release effect of ion-pair in the development of escitalopram transdermal patch using FT-IR spectroscopy, molecular modeling and thermal analysis.

The aim of this study was to develop a controlled release drug-in-adhesive patch containing escitalopram (ESP) using ion-pair technique. Special attention was paid on the mechanism of how counter ion controlled the release of ESP. Five organic acids were chosen as the counter ions. Formulation factors including adhesive matrix, drug loading and permeation enhancers were investigated through in vitro experiments using rat skin and the optimized patch was evaluated using in vivo pharmacokinetic study. Drug-counter ion-PSA interactions were characterized by FT-IR, molecular modeling and DSC at molecular level. The optimized patch prepared with ESP-BA showed zero-order skin permeation profile and a satisfied permeation amount of three days (1059±104.9µg/cm2) in vitro, which also showed a steady-state drug plasma concentration lasting 36h in vivo and the Cmax was significantly controlled compared with the control group. The controlled release of ESP was attributed to the interactions among ESP-counter ion-PSA by hydrogen bonding, and counter ion enhanced the interaction between ESP and PSA molecule, which acted as a "bridge" between them. In conclusion, a controlled release ESP transdermal patch was developed and a novel insight of ion-pair controlled release was proposed at molecular level.

Chronic citalopram administration desensitizes prefrontal cortex but not somatodendritic α2-adrenoceptors in rat brain.

Selective serotonin reuptake inhibitors (SSRIs) regulate brain noradrenergic neurotransmission both at somatodendritic and nerve terminal areas. Previous studies have demonstrated that noradrenaline (NA) reuptake inhibitors are able to desensitize α2-adrenoceptor-mediated responses. The present study was undertaken to elucidate the effects of repeated treatment with the SSRI citalopram on the α2-adrenoceptor sensitivity in locus coeruleus (LC) and prefrontal cortex (PFC), by using in vivo microdialysis and electrophysiological techniques, and in vitro stimulation of [35S]GTPγS binding autoradiography. Repeated, but not acute, treatment with citalopram (5 mg/kg, i.p., 14 days) increased extracellular NA concentration selectively in PFC. The α2-adrenoceptor agonist clonidine (0.3 mg/kg, i.p.), administered to saline-treated animals (1 ml/kg i.p., 14 days) induced NA decrease in LC (Emax = -44 ± 4%; p < 0.001) and in PFC (Emax = -61 ± 5%, p < 0.001). In citalopram chronically-treated rats, clonidine administration exerted a lower decrease of NA (Emax = -25 ± 7%; p < 0.001) in PFC whereas the effect in LC was not different to controls (Emax = -36 ± 4%). Clonidine administration (0.625-20 µg/kg, i.v.) evoked a dose-dependent decrease of the firing activity of LC noradrenergic neurons in both citalopram- (ED50 = 3.2 ± 0.4 µg/kg) and saline-treated groups (ED50 = 2.6 ± 0.5 µg/kg). No significant differences between groups were found in ED50 values. The α2-adrenoceptor agonist UK14304 stimulated specific [35S]GTPγS binding in brain sections containing LC (144 ± 14%) and PFC (194 ± 32%) of saline-treated animals. In citalopram-treated animals, this increase did not differ from controls in LC (146 ± 22%) but was lower in PFC (141 ± 8%; p < 0.05). Taken together, long-term citalopram treatment induces a desensitization of α2-adrenoceptors acting as axon terminal autoreceptors in PFC without changes in somatodendritic α2-adrenoceptor sensitivity.

Sodium channel blockade with QRS widening after an escitalopram overdose.

INTRODUCTION: Escitalopram is rarely associated with prolongation of the QTc interval; however, there are no reported cases of QRS complex widening associated with escitalopram overdose. We report a case of a patient who presented with both QRS complex widening and QTc interval prolongation after an escitalopram overdose. CASE: A 16-year-old girl presented to the emergency department after ingestion of escitalopram, tramadol/acetaminophen, and hydrocodone/acetaminophen. Laboratory results were significant for 4-hour acetaminophen 21.1 µg/mL. Serum electrolytes including potassium, magnesium, and calcium were all normal. Initial electrocardiogram (ECG) revealed a widened QRS with an incomplete right bundle branch pattern. After administration of 100-mEq sodium bicarbonate, a repeat ECG revealed narrowing of the QRS complex and a prolonged QTc interval. Magnesium sulfate 2 g intravenous and sodium bicarbonate drip were initiated. A repeat ECG, 1 hour after the second, revealed normalization of the QRS complex and QTc interval. DISCUSSION: Prolongation of the QTc interval is an expected effect of escitalopram. Both escitalopram and citalopram are metabolized to the cardiotoxic metabolite S-didesmethylcitalopram and didesmethylcitalopram, respectively, which have been implicated in numerous cardiac abnormalities including widening of the QRS complex. Although never previously described with escitalopram, this mechanism provides a reasonable explanation for the QRS complex widening and incomplete right bundle branch block that occurred in our patient. CONCLUSIONS: Both QRS complex widening and QTc interval prolongation should be monitored in cases of escitalopram and citalopram overdoses.

How to combine non-compartmental analysis with the population pharmacokinetics? A study of tobacco smoke's influence on the bioavailability of racemic citalopram in rats.

BACKGROUND: Citalopram (CIT) is an antidepressant drug from the group of selective serotonin reuptake inhibitors in which it is the most potent selective inhibitor of serotonin uptake currently available. Patients treated with CIT are often heavy cigarette smokers. Individual pharmacokinetic parameters cannot be directly estimated if full pharmacokinetic profiles are not available for each subject. Sparse sampling is common to experiments using small animals, such as the case that our study is concerned with. METHODS: The aim of the study was to demonstrate how the two (non-compartmental analysis (NCA) and nonlinear mixed-effect (NLME)) approaches, used simultaneously, can help overcome specific limitations of these separate methods whilst at the same time preserve their respective benefits. RESULTS: Despite the ultra-sparse design, the NLME approach enabled us to develop a pharmacostatistic model with the required covariate--exposition to the tobacco smoke. CONCLUSIONS: A tobacco smoke slows down the absorption of the CIT and at the same time makes it more effective. The consistency of results obtained both with NCA and NLME decreased the risk of model misspecification and increased confidence in the final conclusions. Combining NLME with NCA may therefore be recommended for investigating pharmacokinetic properties of the drug in the sparse designs.

Prenatal exposure to escitalopram and/or stress in rats: a prenatal stress model of maternal depression and its treatment.

RATIONALE: A rigorously investigated model of stress and antidepressant administration during pregnancy is needed to evaluate possible effects on the mother. OBJECTIVE: The objective of this study was to develop a model of clinically relevant prenatal exposure to an antidepressant and stress during pregnancy to evaluate the effects on maternal care behavior. RESULTS: Female rats implanted with 28-day osmotic minipumps delivering the SSRI escitalopram throughout pregnancy had serum escitalopram concentrations in a clinically observed range (17-65 ng/ml). A separate cohort of pregnant females exposed to a chronic unpredictable mild stress paradigm on gestational days 10-20 showed elevated baseline (305 ng/ml), and acute stress-induced (463 ng/ml), plasma corticosterone concentrations compared to unstressed controls (109 ng/ml). A final cohort of pregnant dams were exposed to saline (control), escitalopram, stress, or stress and escitalopram to determine the effects on maternal care. Maternal behavior was continuously monitored over the first 10 days after parturition. A reduction of 35 % in maternal contact and 11 % in nursing behavior was observed due to stress during the light cycle. Licking and grooming behavior was unaffected by stress or drug exposure in either the light or dark cycle. CONCLUSIONS: These data indicate that: (1) clinically relevant antidepressant treatment during human pregnancy can be modeled in rats using escitalopram; (2) chronic mild stress can be delivered in a manner that does not compromise fetal viability; and (3) neither of these prenatal treatments substantially altered maternal care post parturition.

Influence of tobacco smoke on the pharmacokinetics of citalopram and its enantiomers.

The purpose of this study was to evaluate the influence of tobacco smoke on the pharmacokinetics of citalopram (CIT) and desmethylcitalopram (DCIT) and its enantiomers on an animal model. High performance liquid chromatography (HPLC) with a diode array detector (DAD) was used for the identification and quantification of the studied compounds. The HPLC quantification of racemic mixtures of CIT was performed on a C18 column. The limits of detection (LOD) and quantification (LOQ) were: 7 and 10 ng/ml respectively. HPLC separation of citalopram enantiomers (S- and R-CIT) was performed on a Chirobiotic V column. The limits of detection (LOD) and quantification (LOQ) were: 6 and 15 ng/ml for R- and S-CIT respectively. The experiment was carried out on male Wistar rats. The rats were exposed to tobacco smoke for five days (6 hours per day). After the exposure, citalopram was administered in a dose of 10 mg/kg intragastrically. In the control group (non-exposed animals), citalopram was administered in the same way and at an equal dose. The blood of the animals was collected at nine time points. It was found that tobacco smoke exposure inhibits the biotransformation of citalopram. The half-life of the racemic mixture of citalopram after intragastric administration was increased by about 287%. Changes in the pharmacokinetic parameters of S-citalopram (active isomer) show a similar tendency to those of the racemic mixture. The pharmacokinetics of R-citalopram showed no statistically important differences after tobacco smoke exposure. Alterations in the pharmacological parameters of desmethylcitalopram presented an opposite trend to the parent drug. After exposure to tobacco smoke, the induction of metabolism of this compound was observed.

The extraction of pharmacogenetic and pharmacogenomic relations--a case study using PharmGKB.

In this paper, we report on adapting the JREX relation extraction engine, originally developed For the elicitation of protein-protein interaction relations, to the domains of pharmacogenetics and pharmacogenomics. We propose an intrinsic and an extrinsic evaluation scenario which is based on knowledge contained in the PharmGKB knowledge base. Porting JREX yields favorable results in the range of 80% F-score for Gene-Disease, Gene-Drug, and Drug-Disease relations.

Pharmacogenetics of escitalopram and mental adaptation to cancer in palliative care: report of 18 cases.

AIMS AND BACKGROUND: In palliative care, few data are available on the diagnosis and treatment of mood disorders and of difficulties of mental adaptation to cancer for patients in the advanced phases of the disease. SSRI antidepressants are the treatment of choice; the 5-HTTLPR genetic polymorphism of the serotonin transporter (SERT) has been shown in psychiatry to significantly determine the therapeutic response and the incidence of adverse effects. The aim of the present investigation has been therefore to examine the effects of the SSRI antidepressant escitalopram, also considering 5-HTTLPR, on depression, anxiety and mental adaptation to cancer in palliative care. METHODS AND STUDY DESIGN: Eighteen consecutive depressed patients with different forms of advanced cancer admitted to the Hospice Ass 6 of S. Vito al Tagliamento (Pordenone, Italy) were genotyped for the "s" and "l" variants of 5-HTTLPR and were treated with escitalopram. Their response after two weeks of treatment was psychometrically evaluated. RESULTS: Treatment with escitalopram significantly decreased anxiety scores on the Hospital Anxiety and Depression Scale (HADS) (P = 0.006) as well as anxious preoccupation (P = 0.007) and hopelessness-helplessness (P = 0.017) scores on the Mini Mental Adjustment to Cancer (Mini-MAC) scale. When patients were stratified by SERT genotype, HADS anxiety was significantly decreased in patients carrying the "s/s" and "s/l" variants (P = 0.024), whereas those with an "l/l" genotype displayed a significant reduction of Mini-MAC anxious preoccupation (P = 0.018). CONCLUSIONS: The results of this study indicate that the use of SSRI antidepressants is effective in the palliative care of cancer patients, and their action affects not only depression but also the patients' mental adaptation to the disease. These results encourage further examination of these drugs in a larger cohort of patients. The significant contribution of pharmacogenetics indicates the possibility of personalized treatment with SSRIs in palliative care.

Plaque deposition dependent decrease in 5-HT2A serotonin receptor in AbetaPPswe/PS1dE9 amyloid overexpressing mice.

Intrahippocampal injections of aggregated amyloid-beta (Abeta)1-42 in rats result in memory impairment and in reduction of hippocampal 5-HT2A receptor levels. In order to investigate how changes in 5-HT2A levels and functionality relate to the progressive accumulation of Abeta protein, we studied 5-HT2A receptor regulation in double transgenic AbetaPPswe/PS1dE9 mice which display excess production of Abeta and age-dependent increase in amyloid plaques. Three different age-groups, 4-month-old, 8- month-old, and 11-month-old were included in the study. [3H]-MDL100907, [3H]-escitalopram, and [11C]-PIB autoradiography was performed for measuring 5-HT2A receptor, serotonin transporter (SERT), and Abeta plaque levels in medial prefrontal cortex (mPFC), prefrontal cortex (PFC), frontoparietal cortex (FPC), dorsal and ventral hippocampus, and somatosensory cortex. To investigate 5-HT2A receptor functionality, animals were treated with the 5-HT2A receptor agonist DOI and head-twitch response (HTR) subsequently recorded. Expression level of the immediate early gene c-fos was measured by in situ hybridization. We found that the age-related increase in Abeta plaque burden was accompanied by a significant decrease in 5-HT2A receptor binding in mPFC in the 11-month-old group. The changes in 5-HT2A receptor binding correlated negatively with [11C]-PIB binding and were not accompanied by decreases in SERT binding. Correspondingly, 11-month-old transgenic mice showed diminished DOI-induced HTR and reduced increase in expression of c-fos mRNA in mPFC and FPC. These observations point towards a direct association between Abeta accumulation and changes in 5-HT2A receptor expression that is independent of upstream changes in the serotonergic system.

Therapeutic drug monitoring of escitalopram in an outpatient setting.

The main objectives of this study were to outline the inter- and intraindividual and overall pharmacokinetic variability of S-citalopram, S-desmethylcitalopram, and S-didesmethylcitalopram in serum by means of therapeutic drug monitoring; and to investigate potential correlations between the serum concentration and simultaneously collected clinical data. The study was conducted on outpatients in Sweden in 2002 to 2005. Included in the pharmacokinetic evaluation were 155 patients (68% women and 32% men) aged 17 to 95 years (average, 51 years). One serum sample per patient, taken as a trough value in steady state, was assessed. For the inter- and intraindividual variation calculation, 16 patients were included with two eligible samples each. The median daily dose was 20 mg/day (range, 5-40 mg). Extensive overall serum concentration variability was seen for all dose levels. The interindividual coefficient of variation for dose-normalized concentrations was 71% for S-citalopram, 36% for S-desmethylcitalopram, and 50% for S-didesmethylcitalopram. The intraindividual variations over time for the same parameters were approximately 30%, except for the ratio S-desmethylcitalopram/S-citalopram, which was 23%. The median S-desmethylcitalopram level was approximately 60% of the parent substance and the S-didesmethylcitalopram level approximately 9%. Higher age was correlated with higher serum concentrations, but no gender-related concentration differences were found. A majority (76%) of the patients took one or more drugs in addition to escitalopram, but concomitant medication did not seem to interact with escitalopram. However, women taking oral contraceptives showed a lower metabolic ratio compared with age-matched women. As a result of the wide range of the ratio in this population, these findings are not considered of clinical relevance.

Sustained citalopram treatment in experimental hepatic encephalopathy: effects on entrainment to the light-dark cycle and melatonin.

Patients with chronic hepatic encephalopathy often display altered diurnal rhythm as well as other affective disturbances which motivate treatment with antidepressants. We investigated the effects of sustained treatment with citalopram (10 mg/kg daily, 10 days) on 24-hr behavioural open-field activities in portacaval-shunted (PCS) rats and sham-operated control rats. In addition, the daytime and nighttime serum melatonin levels, as well as the serum concentrations of the enantiomers of citalopram and its metabolites, were analyzed. Untreated PCS rats showed reduced locomotor and rearing activities during nighttime. Citalopram treatment resulted in elevated behavioural activity in the PCS rats during night, indicative of an improved entrainment to the light-dark cycle, whereas no behavioural effect could be observed in sham rats. Higher melatonin levels in both PCS and sham rats were observed during nighttime compared with daytime, but the untreated PCS rats also showed higher daytime melatonin level than the corresponding sham group. Citalopram treatment seemed not to have any major effect on the melatonin levels. Higher serum levels of both citalopram and metabolites were observed in PCS rats as compared to sham rats. An altered ratio between the S- and R-enantiomers could also be observed in the PCS rats. In conclusion, the present data support the contention of a disturbed diurnal rhythm, and that the melatonin activity may be altered, in chronic hepatic encephalopathy. The citalopram treatment resulted in similar behavioural performances and daytime serum melatonin levels in PCS rats and controls, although pharmacokinetic differences were present between the groups.

Screening of citalopram, fluoxetine and their metabolites in human urine samples by gas chromatography-mass spectrometry. A global robustness/ruggedness study.

Capillary gas chromatography with mass spectrometry detection in SIM mode (GC-MS-SIM) has been used for the analysis of citalopram (CIT), fluoxetine (FLX), and all of their metabolites in urine samples. The instrumental parameters affecting GC separation and MS-SIM detection were investigated. A validation procedure was performed on urine matrix and a simultaneous robustness/ruggedness evaluation is also presented in this paper. An optimized solid-phase extraction (SPE) has been applied, reaching in this way to limits of detection (LODs) between 0.7 ng L(-1) (CIT) and 33.6 microg L(-1) (CIT-PA). A pharmacokinetic screening in clinical urine samples has been also carried out.

Bioequivalence of two brands of citalopram 40 mg tablets after single oral administration to healthy volunteers.

A randomized, two-way, crossover, bioequivalence study was conducted in 26 fasting, healthy, male volunteers to compare two brands of citalopram 40 mg tablets, Citol (Abdi Ibrahim Ilaç San. ve Tic A.S., Istanbul, Turkey) as a test and Cipramil (H. Lundbeck A/S, Copenhagen, Denmark) as a reference product. One tablet of either formulation was administered with low-carbonate water after 10 h of overnight fasting. After dosing, serial blood samples were collected during a period of 24 hours. Plasma samples were analysed for citalopram by a validated HPLC method. The pharmacokinetic parameters AUC0-24, AUC(0-alpha), Cmax, Tmax, K(el), T(1/2), and CL were determined from plasma concentration-time profiles for both formulations and were compared statistically to evaluate bioequivalence between the two brands of citalopram, using the statistical modules recommended by FDA. The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals (CI) fell within the acceptable range for bioequivalence. Based on these statistical inferences it was concluded that the two brands exhibited comparable pharmacokinetics profiles and that Abdi Ibrahim's Citol is equivalent to Cipramil of H. Lundbeck, Copenhagen, Denmark.

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

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.