The Clinical Pharmacokinetics of Escitalopram

Kyowa Pharmaceutical, Inc., Princeton, New Jersey 08540, USA.
Clinical Pharmacokinetics (Impact Factor: 5.05). 02/2007; 46(4):281-90. DOI: 10.2165/00003088-200746040-00002
Source: PubMed


Escitalopram is the (S)-enantiomer of the racemic selective serotonin reuptake inhibitor antidepressant citalopram. Clinical studies have shown that escitalopram is effective and well tolerated in the treatment of depression and anxiety disorders. Following oral administration, escitalopram is rapidly absorbed and reaches maximum plasma concentrations in approximately 3-4 hours after either single- or multiple-dose administration. The absorption of escitalopram is not affected by food. The elimination half-life of escitalopram is about 27-33 hours and is consistent with once-daily administration. Steady-state concentrations are achieved within 7-10 days of administration. Escitalopram has low protein binding (56%) and is not likely to cause interactions with highly protein-bound drugs. It is widely distributed throughout tissues, with an apparent volume of distribution during the terminal phase after oral administration (V(z)/F) of about 1100L. Unmetabolised escitalopram is the major compound in plasma. S-demethylcitalopram (S-DCT), the principal metabolite, is present at approximately one-third the level of escitalopram; however, S-DCT is a weak inhibitor of serotonin reuptake and does not contribute appreciably to the therapeutic activity of escitalopram. The didemethyl metabolite of escitalopram (S-DDCT) is typically present at or below quantifiable concentrations. Escitalopram and S-DCT exhibit linear and dose-proportional pharmacokinetics following single or multiple doses in the 10-30 mg/day dose range. Adolescents, elderly individuals and patients with hepatic impairment do not have clinically relevant differences in pharmacokinetics compared with healthy young adults, implying that adjustment of the dosage is not necessary in these patient groups. Escitalopram is metabolised by the cytochrome P450 (CYP) isoenzymes CYP2C19, CYP2D6 and CYP3A4. However, ritonavir, a potent inhibitor of CYP3A4, does not affect the pharmacokinetics of escitalopram. Coadministration of escitalopram 20mg following steady-state administration of cimetidine or omeprazole led to a 72% and 51% increase, respectively, in escitalopram exposure compared with administration alone. These changes were not considered clinically relevant. In vitro studies have shown that escitalopram has negligible inhibitory effects on CYP isoenzymes and P-glycoprotein, suggesting that escitalopram is unlikely to cause clinically significant drug-drug interactions. The favourable pharmacokinetic profile of escitalopram suggests clinical utility in a broad range of patients.

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    • "Since the half lives of substances applied for moclobemide, milnacipran, reboxetine, and imipramine are 4 h, 8 h, 12 h and 18 h respectively (Bonnet, 2003; Ciraulo et al., 1987; Pae et al., 2009; Edwards et al., 1995) compounds were eliminated after 24 h. In the case of escitalopram with its half life 27e33 (Rao, 2007), however the extensive washing of the membranes during the binding studies, make the possibility of residual drug unlikely. Brain structures (hippocampus and cerebral cortex) were dissected, immediately frozen and stored in À80 C. "
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    ABSTRACT: Metabotropic glutamate 5 (mGlu5) receptors are functionally connected with NMDA receptors. The antidepressant activity of the NMDA receptor antagonist ketamine in both preclinical and clinical studies, along with the antidepressant-like activities of negative allosteric modulators (NAMs) of mGlu5, led us to investigate if prolonged administration of various antidepressant drugs or the mGlu5 NAM, MTEP, causes changes in mGlu5 receptor availability or protein expression or in expression of Homer proteins in the rat brain. Our results clearly show that prolonged treatment with antidepressants with various mechanisms of action (such as escitalopram, reboxetine, milnacipran, moclobemide and imipramine) or with MTEP led to significant increases in [(3)H]MPEP binding in homogenates of the hippocampus and/or cerebral cortex. Increases in mGlu5 expression were also observed, though they did not always parallel the increase in binding. The results indicate that adaptive up-regulation of mGlu5 receptors may be a common change induced by antidepressant drugs.
    Neuropharmacology 05/2014; 84. DOI:10.1016/j.neuropharm.2014.04.016 · 5.11 Impact Factor
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    • "In general, the three antidepressants produce good absorption, distribution, and clearance profiles at their therapeutic doses. Escitalopram is approved at clinical dosages of 10 and 20 mg (with 5 mg in certain subpopulations or as starting dose), and when taken orally reaches Tmax in 5 h, is 56% protein bound, and reaches steady-state concentration in the blood within 1–2 weeks (Sogaard et al., 2005; Rao, 2007; Spina et al., 2012). Paroxetine is approved at clinical dosages of 12.5, 25, 37.5, and 50 mg daily, and when taken orally reaches Tmax in 6–10 h, is 95% protein bound, and reaches steady-state concentration in the blood within two weeks (Hiemke and Hartter, 2000; Bourin et al., 2001). "
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    ABSTRACT: It is known that newer antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs), provide advantages in tolerability over antidepressants such as the tricyclics. However, even within the SSRI class, differences in efficacy or tolerability exist between the individual drugs. Among the three most widely prescribed SSRIs are paroxetine, sertraline, and escitalopram. Escitalopram is commonly referred to as an SSRI, but also has well-documented allosteric properties, and thus can be further classed as an allosteric serotonin reuptake inhibitor. All three antidepressants are efficacious compared with placebo, but there is evidence that escitalopram is more effective than a range of other antidepressants. There are no direct data to regard either paroxetine or sertraline as a superior antidepressant. Escitalopram is superior compared with paroxetine, which has a less favorable tolerability profile. Paroxetine is associated with cholinergic muscarinic antagonism and potent inhibition of CYP2D6, and sertraline has moderate drug interaction issues in comparison with escitalopram. Overall, as an allosteric serotonin reuptake inhibitor that is somewhat different from classical SSRIs, escitalopram is the first choice judged by combined efficacy and tolerability, and nonclinical data have offered possible mechanisms through which escitalopram could be more efficacious, based on its interaction with orthosteric and allosteric binding sites at the serotonin transporter.
    International clinical psychopharmacology 01/2014; 29(4). DOI:10.1097/YIC.0000000000000023 · 2.46 Impact Factor
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    • "Participants were randomized to treatment order and administered either a saccharin placebo or 20 mg of escitalopram on their first visit and the alternate treatment on their second visit. The pharmacokinetic profiles of escitalopram do not differ between adolescents and young adults, indicating that dosage adjustment according to age is not required (Rao 2007). A 1-week interval separated visits in order to ensure sufficient washout of at least five half-lives (Anonymous 2012; Sogaard 2005). "
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    ABSTRACT: Rationale Black box warnings for young adults under the age of 25 years indicate that antidepressants may increase risk of suicide. While underlying mechanisms for age-related treatment effects remain unclear, vagally mediated cardiovascular function may play a key role. Decreased heart rate (HR) and an increase in its variability (HRV) improve one’s capacity to adapt to environmental stress and attenuate risk for suicide. Objectives Using a double blind, randomized, placebo-controlled, crossover, experimental study, we examine whether a single dose of escitalopram (20 mg) attenuates cardiovascular responses to stress under experimental conditions and determine whether age moderates these effects. Methods Forty-four healthy females received a single dose of escitalopram (20 mg) and placebo treatment separated by a 1-week interval (>5 half-lives). HR and high frequency HRV (HF HRV normalized units; 0.15–0.40 Hz) were measured during resting state and stress. Results While escitalopram attenuated the increase in HR and increased HF HRV, these moderate to large effects were only significant in participants over 25 years of age. No beneficial cardiovascular effects of escitalopram were observed in those under the age of 25. Conclusions Maturational differences in the development of the prefrontal cortex—a critical region in the central network of autonomic control—may underpin these differential findings. This study provides a theoretical framework on which future research on treatment-emergent suicidality in clinical populations could be based.
    Psychopharmacology 12/2013; DOI:10.1007/s00213-013-3374-4 · 3.88 Impact Factor
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