Celexa (Citalopram)
Citalopram - Celexa®
Classification:
Psychotropic Agents
- Antidepressants
- Selective serotonin reuptake inhibitors (SSRIs)
Description: Citalopram is an oral selective serotonin reuptake inhibitor (SSRI) used to treat depression; thus, it is similar to fluoxetine, sertraline, and paroxetine. Citalopram is structurally unrelated to the other SSRIs or to any other available antidepressant agent (i.e., tricyclics, MAOIs). Citalopram is a relatively weak inhibitor of the hepatic CYP2D6 isoenzyme in vitro, when compared to SSRI medications like fluoxetine and paroxetine, which are potent inhibitors of this pathway. While citalopram may be less likely to inhibit the metabolism of other drugs versus these other SSRIs, the potential for clinically significant drug interactions is still present. When compared to other SSRIs available in the US, clinical studies have shown citalopram to be as effective as either sertraline or fluvoxamine for the treatment of depression. In one study, citalopram was tolerated better than fluvoxamine, which was associated with a greater incidence of gastrointestinal adverse events. The tolerability of sertraline and citalopram appear to be comparable. Other uses for citalopram have included obsessive-compulsive disorder (OCD), panic disorder, and premenstrual dysphoric disorder (PMDD). Citalopram was approved by the FDA for the treatment of depression in adults in July 1998; citalopram is not approved for use in children with depression. The FDA approved Celexa™ oral solution in December 1999. Citalopram is approved in about 50 countries and has been used by more than 4 million patients worldwide. On October 15, 2004 the FDA directed manufacturers of all antidepressants to include a Black Box warning, expanded warning statements, and clinical trial results detailing the increased risk of suicidality in children and adolescents. A Patient Medication Guide (MedGuide) will also accompany all prescriptions for antidepressants. British regulators have banned the use of some SSRIs in children in the UK. The FDA is currently assessing the risk of suicidality in adults taking antidepressants and a final report is expected by mid- to late 2006.
Mechanism of Action: Citalopram potentiates the pharmacological effects of serotonin (5-HT) in the CNS. Like other SSRIs, citalopram is a potent and highly selective reuptake inhibitor of serotonin and has little or no effect on other neurotransmitters. Although the precise mechanism of antidepressant action of SSRIs is not fully understood, it is believed that citalopram and related agents inhibit reuptake of serotonin at the neuronal membrane. SSRIs have less sedative, anticholinergic, and cardiovascular effects than the tricyclic antidepressant drugs due to their dramatically lower affinity for histamine, acetylcholine, and norepinephrine receptors. Monoamine oxidase is not inhibited by any SSRIs. Anticholinergic activity is virtually absent.
Pharmacokinetics: Citalopram is administered orally. Absolute bioavailablity following a single oral dose is about 80% and is not affected by the presence of food. Peak plasma concentrations are attained about 4 hours after dosing. Steady state plasma concentrations are achieved within approximately one week and are expected to be 2.5 times the plasma concentrations observed after a single dose. Citalopram exhibits linear and dose-proportional pharmacokinetics over the therapeutic dosage range. Protein binding of citalopram and its metabolites are about 80%.
The parent drug is metabolized via N-demethylation primarily by the CYP3A4 and CYP2C19 isoenzymes. In humans, unchanged citalopram is the predominant compound in plasma. In vitro studies show that citalopram is at least 8 times more potent than its metabolites in the inhibition of serotonin reuptake, suggesting that the metabolites evaluated do not likely contribute significantly to the antidepressant actions of citalopram. Twenty percent of the systemic clearance of citalopram is due to renal clearance. The half-life of citalopram in a healthy individual is 35 hours.
Pharmacokinetic parameters of citalopram can vary significantly among the elderly and patients with liver and severe renal impairment. In a multiple dose study, citalopram AUC and half-life were increased in the elderly by 23% and 30%, respectively. Citalopram oral clearance was reduced by 37% and half-life was doubled in patients with reduced hepatic function but changes in clearance did not correlate with the Child-Pugh classification. Although no information is available about the pharmacokinetics in patients with severely reduced renal function (CrCl < 20 ml/min), oral clearance of citalopram was reduced by 17% in patients with mild to moderate renal function impairment. Citalopram is unlikely to be significantly removed by hemodialysis given its large volume of distribution. Based on the pharmacokinetic variability demonstrated among these patient populations, appropriate dosage adjustments may be necessary.
References
Haffmans PM, Timmerman L, Hoogduin CA. Efficacy and tolerability of citalopram in comparison with fluvoxamine in depressed outpatients: a double-blind, multicentre study. The LUCIFER Group. Int Clin Psychopharmacol 1996;11:157-64.
Ekselius L, von Knorring L, Eberhard G. A double-blind multicenter trial comparing sertraline and citalopram in patients with major depression treated in general practice. Int Clin Psychopharmacol 1997;12:323-31.
[ Revised 8/31/2005 3:01:00 PM ]
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