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At least 19 recordsLinked to original sources
PubMed2006

The pharmacology of citalopram enantiomers: the antagonism by R-citalopram on the effect of S-citalopram.

Recent results on the in vivo and in vitro pharmacology of escitalopram are summarised. The exact molecular mechanism by which R-citalopram inhibits the effect of S-citalopram on the serotonin transporter remains to be elucidated. Preliminary evidence indicates an effect of R-citalopram on the association of escitalopram with the high affinity primary site, and on its dissociation from the serotonin transporter, via an allosteric mechanism. Escitalopram can be considered as an allosteric serotonin reuptake inhibitor. This serotonin dual action in binding to two sites on the serotonin transporter (both the primary site and the allosteric site) is hypothesised to be responsible for a longer binding to, and therefore greater inhibition of the serotonin transporter by escitalopram.

Animals↗
PubMed2006

Heterozygous mutation in CYP2C19 significantly increases the concentration/dose ratio of racemic citalopram and escitalopram (S-citalopram).

There is limited documentation of the importance of heterozygous cytochrome P450 (CYP) mutations on drug exposure. This study was designed to evaluate the influence of heterozygous mutations in CYP2C19 on the serum concentration of racemic citalopram and escitalopram (S-citalopram). Eighty-three samples from subjects with determined CYP2C19 and CYP2D6 genotype receiving racemic citalopram or S-citalopram as part of their clinical treatment were collected from a routine therapeutic drug monitoring database. Concentration/dose (C/D) ratios, parent drug/metabolite ratios, and serum concentrations in CYP2C19 homozygous extensive metabolizers (EMs) and heterozygous extensive metabolizers (HEMs) were compared. The median C/D ratio was significantly higher in the HEM group compared with the EM group, both for racemic citalopram (8.0 vs. 4.9, P < 0.01) and S-citalopram (5.3 vs. 2.6, P < 0.01). The median parent drug/metabolite ratio was significantly higher in the HEM group compared with the EM group, both for racemic citalopram (2.9 vs. 1.6, P < 0.01) and for S-citalopram (2.4 vs. 1.2, P < 0.01). A higher median non-dose-corrected serum concentration also was observed in HEMs compared with EMs both for S-citalopram (P < 0.01) and racemic citalopram (P = 0.066). This study shows that the metabolism of racemic citalopram and S-citalopram is significantly impaired in CYP2C19 HEMs. Higher absolute serum concentrations indicate that this is not compensated for by dose reductions in clinical practice.

Adolescent↗
PubMed2000

Efficacy of intravenous citalopram compared with oral citalopram for severe depression. Safety and efficacy data from a double-blind, double-dummy trial.

BACKGROUND: Intravenous administration is often beneficial in the treatment of severely depressed patients. It is mainly the tri- and tetracyclic antidepressant drugs that can be administered intravenously. However, these drugs have a less favourable safety profile than newer antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs). Citalopram is the only SSRI that is available in a formulation for infusion. This double-blind, randomised, multicentre trial was designed to compare the efficacy and tolerability of citalopram infusion (40 mg per day) and citalopram tablet (40 mg per day). METHODS: Patients were randomised to receive either placebo tablet plus citalopram infusion (the infusion group; n=135) or citalopram tablet plus placebo infusion (the tablet group; n=119). After receiving randomised treatment for eight days, all patients entered an open treatment phase, during which they received oral citalopram 40 mg per day for five weeks. RESULTS: Although there was no difference in Montgomery-Asberg Depression Rating Scale (MADRS) scores at the end of the randomised treatment period, by the end of the open treatment phase the reduction in MADRS scores was significantly greater in the infusion group than in the tablet group (p=0.015). The infusion group also showed superior efficacy in Clinical Global Impressions assessments. Citalopram was equally well tolerated in both treatment groups. CONCLUSIONS: This trial confirmed the efficacy of citalopram 40 mg per day, and clearly supports the use of citalopram infusion in the treatment of severely depressed, hospitalised patients.

Administration, Oral↗
PubMed2003

Anxiolytic-like effects of escitalopram, citalopram, and R-citalopram in maternally separated mouse pups.

The S-enantiomer of citalopram, escitalopram, is a selective serotonin reuptake inhibitor (SSRI) that appears to be responsible for citalopram's antidepressant and anxiolytic effects. Clinically, escitalopram is reported to have fewer adverse side effects than do other SSRIs. This study compared escitalopram to other antidepressants in a preclinical procedure predicting anxiolytic-like effects of drugs. Carworth Farms Webster (CFW) mouse pups (7 days old) were separated from the dam and maintained at a temperature of 34 degrees C. Forty-five minutes after administering citalopram (0.56-10 mg/kg), escitalopram (0.0056-3 mg/kg), R-citalopram (1-10 mg/kg), paroxetine (0.3-3 mg/kg), fluoxetine (1-30 mg/kg), or venlafaxine (3-56 mg/kg) subcutaneously, the pups were placed individually on a 19.5 degrees C surface for 4 min. Ultrasonic vocalizations (USVs) (30-80 kHz), grid crossing, rolling (i.e., the pup turned on one side or its back), and colonic temperature were recorded. All the drugs reduced USV emission; escitalopram was the most potent (ED(50) 0.05 mg/kg), followed by paroxetine (0.17 mg/kg), citalopram (1.2 mg/kg), fluoxetine (4.3 mg/kg), R-citalopram (6 mg/kg), and venlafaxine (7 mg/kg). The doses that decreased USVs differed from those that increased motor activity. Increased grid crossing occurred after low doses of paroxetine (0.03 or 0.1 mg/kg) and fluoxetine (1 mg/kg), but only after the highest doses of the citalopram enantiomers and venlafaxine (0.3, 10, and 56 mg/kg, respectively). Except for escitalopram and venlafaxine, high doses of the treatments increased rolling. R-Citalopram caused a 10-fold rightward shift in escitalopram's dose-effect curve, suggesting that R-citalopram inhibits escitalopram's anxiolytic-like effects. These data support clinical findings that escitalopram is a potent, well tolerated SSRI with anxiolytic-like effects.

Animals↗
PubMed2002

Citalopram dose-response revisited using an alternative psychometric approach to evaluate clinical effects of four fixed citalopram doses compared to placebo in patients with major depression.

RATIONALE: Among the many problems in interpreting dose-response studies with antidepressants are the psychometric problems in the identification of true antidepressive effect versus true adverse drug effect. OBJECTIVES: This study is a re-examination of a dose-response trial with citalopram in order to examine the explanatory ability of using strict psychometric dimensions to measure the wanted and unwanted drug effects of different doses compared to placebo. METHODS: The antidepressive response was measured after 2 and 6 weeks of therapy with the depression subscales of the HAM-D and on the Montgomery-Asberg Depression Scale (MADRS). The patient-reported Symptom Checklist (SCL) sub-scales for depression and anxiety were also examined. Subjective side-effects were measured on serotonin-specific items of the SCL. Effect size statistics were used to measure the antidepressive effect (an effect size of 0.30 equals a drug superiority over placebo of 15-20%). Side effects were statistically analysed using baseline-adjusted scores of the individual symptoms. RESULTS: The psychometric analysis of the outcome scales showed that the full HAM-D(17), the SCL-56 and the SCL side-effect subscale were multidimensional scales, while the HAM-D and MADRS subscales as well as the SCL-anxiety subscale were most homogeneous, indicating that their total scores are sufficient statistics. When the scales were used as well as the individual serotonin-specific SCL side-effect symptoms, the results showed that after 2 weeks of therapy a clinical response (effect side over 0.30) was only seen for the SCL-anxiety subscale in the citalopram doses of 40 mg and 60 mg daily. After 6 weeks of therapy response to even 10 mg and 20 mg was seen in the HAM-D and MADRS subscales and in the SCL-anxiety subscale, however, with lower effect sizes than found for 40 mg and 60 mg citalopram daily. The dose of 20 mg citalopram induced side-effects comparable with those seen for 40 mg and 60 mg, while 10 mg was not different from placebo. This was further confirmed by the fact that more patients dropped out on 20 mg than on 10 mg citalopram daily, due to adverse events. CONCLUSION: This psychometric re-examination of a citalopram dose-response trial has shown that the pure antidepressive or antianxiety effects can be observed after 6 weeks of therapy even in a dose of 10 mg daily. However, both 10 mg and 20 mg daily had lower effect sizes than 40 mg and 60 mg daily. At a dose level of 20 mg daily, side effects are more pronounced initially than at 10 mg daily; this should be taken into account clinically when evaluating the overall benefit of the drug. For a highly serotonin-specific drug such as citalopram, both wanted and unwanted effects are dose-related.

Antidepressive Agents↗
PubMed1993

A 24-week study of 20 mg citalopram, 40 mg citalopram, and placebo in the prevention of relapse of major depression.

A total of 147 patients who had responded in a placebo-controlled study to 6 weeks treatment of an episode of DSM-III-R major depression with either 20 mg or 40 mg citalopram were randomized double-blind to continue on the same dose of citalopram or to receive placebo during a 24-week study of the efficacy of citalopram in the prevention of relapse. The citalopram 20 and 40 mg groups showed a significant advantage compared with placebo both in relapses (p < 0.05) and in the survival analysis of time to relapse (p = 0.01 and p = 0.02, respectively). Both 20 and 40 mg citalopram appeared similarly safe and well tolerated with little difference in side effects from placebo. The results demonstrate that citalopram, at a dose of both 20 and 40 mg is effective and well tolerated in continuation treatment to consolidate response. The relapse rate in patients who had responded to placebo during the 6-week acute treatment study, who were continued double-blind with placebo but not included in the efficacy analysis, was similar to the rate in the formal placebo control group, suggesting that patients who respond to placebo in a short treatment course may nonetheless require long-term active treatment to prevent relapse.

Citalopram↗
PubMed1996

Neuroendocrine effects of a 20-mg citalopram infusion in healthy males. A placebo-controlled evaluation of citalopram as 5-HT function probe.

Pharmacokinetic measurements, neuroendocrine responses, and side effects profiles of intravenous infusions of 20 mg citalopram over 30 minutes during the early afternoon have been studied. Eight healthy male volunteers were enrolled in a placebo- (saline) controlled, single-blind, cross-over protocol. Plasma concentrations of the parent compound showed a double exponential decay. Demethyl and didemethyl metabolites were not detectable, but low concentrations of the propionic acid derivative of citalopram were found. Determination of the citalopram enantiomers yielded a balanced S(+)/R(-) ratio of 0.9 to 1.2. The endocrine response to the drug was characterized by significant increases in plasma prolactin and cortisol. Except for one subject, who developed pronounced side effects, human growth hormone showed a surge following saline that was inhibited following citalopram. Rectal temperature and heart rate were not affected and tolerability was favorable. Because of citalopram's extremely high selectivity for the presynaptic 5-hydroxytryptamine nerve terminals, the present data suggest that it might be a promising tool for the investigation of serotonergic function in the human brain in vivo.

Citalopram↗
PubMed2003

Repeated citalopram treatment but not stress exposure attenuates hypothalamic-pituitary-adrenocortical axis response to acute citalopram injection.

Many experimental, clinical and epidemiological studies have shown a direct connection between exposure to stress or adverse life events and disease, but little is known about the effect of stress on the action of drugs. The aim of this study was to test the hypothesis that previous exposure to stress changes the action of the antidepressant drug citalopram (10 mg/kg, i.p.) on hypothalamic-pituitary-adrenocortical (HPA) axis function, gene expression of selected neuropeptides and serotonin reuptake. Three different stress models were used, which included immobilization, restraint and unpredictable stress stimuli. Samples of plasma for hormone measurement were taken from conscious cannulated animals. Changes in corticotropin-releasing hormone (CRH) and proopiomelanocortin (POMC) gene expression in the paraventricular nucleus of the hypothalamus and the anterior pituitary, respectively, and the ability of citalopram to inhibit serotonin reuptake were investigated. The exposure to three different stress models did not influence citalopram action on individual parameters of HPA axis and on serotonin reuptake. On the other hand, repeated administration of the drug led to significant attenuation of ACTH and CRH mRNA responses. The present results allow to suggest that the stressors used did not influence serotonergic neurotransmission to the extent that would modify HPA axis response to citalopram challenge. Activation of HPA axis by acute citalopram treatment was found to be accompanied by increased CRH gene expression in the hypothalamus. Repeated administration of the drug led to the development of tolerance to activation of central and peripheral components of HPA axis, but not to serotonin reuptake inhibition.

Adrenal Cortex↗
PubMedDate not supplied

Autoreceptor antagonists enhance the effect of the reuptake inhibitor citalopram on extracellular 5-HT: this effect persists after repeated citalopram treatment.

The effect of repeated administration of the reuptake inhibitor citalopram (10 mg/kg s.c., b.i.d. for 14 days) or saline on extracellular 5-hydroxytryptamine (5-HT) and autoreceptor sensitivity was assessed using microdialysis in the frontal cortex (FCx) and dorsal hippocampus (DH) of unanesthetized rats. Acute citalopram (5 mg/kg s.c.) challenge produced significant increases in DH and FCx 5-HT. The nonselective 5-HT1A/1B receptor antagonist (-)+penbutolol (8 mg/kg s.c.), administered 2 hr after citalopram challenge, significantly enhanced 5-HT in FCx and DH of both the chronic citalopram and saline pretreatment groups. Administration of the selective 5-HT1A receptor antagonist WAY 100635 (0.3 mg/kg s.c.) after citalopram challenge significantly enhanced 5-HT in FCx but not DH of both pretreatment groups. This suggests that there may be differences between DH and FCx in regulation of 5-HT release. Nevertheless, these results provide evidence that 5-HT autoreceptors are still active in restraining 5-HT release. Nevertheless, these results provide evidence that 5-HT autoreceptors are still active in restraining 5-HT release even after repeated administration of an antidepressant drug.

Animals↗
PubMed2006

Determination of citalopram and escitalopram together with their active main metabolites desmethyl(es-)citalopram in human serum by column-switching high performance liquid chromatography (HPLC) and spectrophotometric detection.

We established a method for automated quantitative analysis of (es-)citalopram and desmethyl(es-)citalopram in serum using column-switching high performance liquid chromatography (HPLC). For sample clean-up serum was injected onto a LiChrospher CN 20 microm precolumn using 8% acetonitrile in deionized water. Drugs were eluted by back-flush flow onto the analytical column (LiChrospher CN 5 microm) at a flow rate of 1.5 ml/min with phosphate buffer 8 mmol/l pH 6.4/acetonitrile (50/50, v/v). Haloperidol was used as internal standard. Analytes were detected by ultraviolet spectrophotometry at 210 nm. Detection limit of (es-)citalopram was 6 ng/ml. The method was found to be suitable for therapeutic drug monitoring of patients treated with citalopram or escitalopram.

Chromatography, High Pressure Liquid↗
PubMed1999

[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].

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.

Accidents, Traffic↗
PubMed2005

Long-term citalopram administration reduces responsiveness of HPA axis in patients with major depression: relationship with S-citalopram concentrations in plasma and cerebrospinal fluid (CSF) and clinical response.

RATIONALE: A dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a well-documented neurobiological finding in major depression. Moreover, clinically effective therapy with antidepressant drugs may normalize the HPA axis activity. OBJECTIVE: The aim of this study was to test whether citalopram (R/S-CIT) affects the function of the HPA axis in patients with major depression (DSM IV). METHODS: Twenty depressed patients (11 women and 9 men) were challenged with a combined dexamethasone (DEX) suppression and corticotropin-releasing hormone (CRH) stimulation test (DEX/CRH test) following a placebo week and after 2, 4, and 16 weeks of 40 mg/day R/S-CIT treatment. RESULTS: The results show a time-dependent reduction of adrenocorticotrophic hormone (ACTH) and cortisol response during the DEX/CRH test both in treatment responders and nonresponders within 16 weeks. There was a significant relationship between post-DEX baseline cortisol levels (measured before administration of CRH) and severity of depression at pretreatment baseline. Multiple linear regression analyses were performed to identify the impact of psychopathology and hormonal stress responsiveness and R/S-CIT concentrations in plasma and cerebrospinal fluid (CSF). The magnitude of decrease in cortisol responsivity from pretreatment baseline to week 4 on drug [delta-area under the curve (AUC) cortisol] was a significant predictor (p<0.0001) of the degree of symptom improvement following 16 weeks on drug (i.e., decrease in HAM-D21 total score). The model demonstrated that the interaction of CSF S-CIT concentrations and clinical improvement was the most powerful predictor of AUC cortisol responsiveness. CONCLUSION: The present study shows that decreased AUC cortisol was highly associated with S-CIT concentrations in plasma and CSF. Therefore, our data suggest that the CSF or plasma S-CIT concentrations rather than the R/S-CIT dose should be considered as an indicator of the selective serotonergic reuptake inhibitors (SSRIs) effect on HPA axis responsiveness as measured by AUC cortisol response.

Adrenocorticotropic Hormone↗
PubMed2001

Escitalopram (S-citalopram) and its metabolites in vitro: cytochromes mediating biotransformation, inhibitory effects, and comparison to R-citalopram.

Transformation of escitalopram (S-CT), the pharmacologically active S-enantiometer of citalopram, to S-desmethyl-CT (S-DCT), and of S-DCT to S-didesmethyl-CT (S-DDCT), was studied in human liver microsomes and in expressed cytochromes (CYPs). Biotransformation of the R-enantiomer (R-CT) was studied in parallel. S-CT was transformed to S-DCT by CYP2C19 (K(m) = 69 microM), CYP2D6 (K(m) = 29 microM), and CYP3A4 (K(m) = 588 microM). After normalization for hepatic abundance, relative contributions to net intrinsic clearance were 37% for CYP2C19, 28% for CYP2D6, and 35% for CYP3A4. At 10 microM S-CT in liver microsomes, S-DCT formation was reduced to 60% of control by 1 microM ketoconazole, and to 80 to 85% of control by 5 microM quinidine or 25 microM omeprazole. S-DDCT was formed from S-DCT only by CYP2D6; incomplete inhibition by quinidine in liver microsomes indicated participation of a non-CYP pathway. Based on established index reactions, S-CT and S-DCT were negligible inhibitors (IC(50) > 100 microM) of CYP1A2, -2C9, -2C19, -2E1, and -3A, and weakly inhibited CYP2D6 (IC(50) = 70-80 microM). R-CT and its metabolites, studied using the same procedures, had properties very similar to those of the corresponding S-enantiomers. Thus S-CT, biotransformed by three CYP isoforms in parallel, is unlikely to be affected by drug interactions or genetic polymorphisms. S-CT and S-DCT are also unlikely to cause clinically important drug interactions via CYP inhibition.

Algorithms↗