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Citalopram

A Review of its Pharmacology, Clinical Efficacy and Tolerability in the Treatment of Depression

Abstract

Synopsis

Citalopram is a selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI) which has been evaluated primarily in the treatment of major depression. In well controlled short term studies, Citalopram had efficacy similar to that of a number of but not all, tricyclic or tetracyclic antidepressants and was as effective as fluoxetine and fluvoxamine. There is some evidence of a faster onset of action for Citalopram compared with fluoxetine. Initial data suggest that Citalopram is effective in the prevention of depressive relapse and in the treatment of post-stroke depression.

The anticholinergic and cardiovascular adverse events often seen with tricyclic antidepressants generally occur less frequently or are infrequent with Citalopram, as with other SSRIs. Citalopram has been well tolerated in the elderly and in patients with existing cardiovascular disease. In vitro and in vivo pharmacodynamic studies suggest that Citalopram is a weak inhibitor of cytochrome P450 (CYP) 2D6, and data from several interaction studies in patients and healthy volunteers are consistent with this finding.

Thus, Citalopram is an effective and well tolerated SSRI which, like the other members of its class, represents a suitable first-line therapy for major depression. Additional efficacy data would be beneficial in clarifying the potential of Citalopram in the elderly and in patients with post-stroke depression or preexisting cardiovascular disorders, for whom anticholinergic or cardiovascular adverse events (caused by tricyclic antidepressants) are a serious concern. The main distinguishing feature of Citalopram within its class is its apparent low propensity to cause problematic drug interactions with CYP2D6 substrates; these include a number of commonly prescribed drug classes, such as antipsychotics, tricyclic antidepressants, antiarrhythmics and β-blockers. Thus, Citalopram may prove useful in the many patients with depression who require one or more such agents for treatment of additional psychiatric or general disorders.

Pharmacodynamic Properties

Citalopram is a potent in vitro inhibitor of serotonin (5-hydroxytryptamine; 5-HT) uptake. Its activity in this respect is more than 3000 times greater than that against noradrenaline (norepinephrine) uptake, making it the most serotonin-selective agent in its class. Citalopram has low affinity in vitro for adrenergic, muscarinic, dopaminergic and serotonergic receptors. Evidence from behavioural studies in animals supports a selective facilitatory effect of Citalopram on serotonergic neurotransmission.

Citalopram is a weaker in vitro and in vivo inhibitor of the hepatic cytochrome P450 (CYP) 2D6 isozyme than paroxetine and fluoxetine and therefore has a lower potential for pharmacokinetic interactions with cytochrome CYP2D6 substrates such as tricyclic antidepressants and antipsychotic agents.

Pharmacokinetic Properties

Peak plasma concentrations of Citalopram are observed 2 to 4 hours after single or multiple oral doses and steady-state plasma concentrations are reached after about 1 week of daily administration. The plasma concentration-dose relationship for Citalopram is linear for doses of 10 to 60mg.

Citalopram is converted by hepatic CYP isozymes to the metabolites demethyl- and didemethyl-citalopram which are less lipophilic than the parent molecule (and are weaker serotonin reuptake inhibitors).

Preliminary indications suggest that Citalopram may cause only moderate pharmacokinetic interactions or have no effect when coadministered with tricyclic antidepressants which are metabolised by CYP2D6, although formal studies of such interactions are limited. Available data suggest that coadministration of Citalopram and antipsychotic agents does not cause any significant pharmacokinetic interactions.

The elimination half-life of Citalopram following oral administration is about 30 hours, with an estimated clearance of 26 to 28 L/h. Approximately 12% of an oral dose of Citalopram is excreted unchanged into the urine.

Aging appears to be associated with increased plasma concentrations and decreased clearance of Citalopram. Similar effects are seen in patients with renal or hepatic dysfunction.

Clinical Efficacy

In well controlled clinical studies, score reductions for the Hamilton Depression Rating Scale (HDRS) or Montgomery-Åsberg Depression Rating Scale (MADRS) ranged from about 43 to 81% with Citalopram and from about 56 to 71 % with tricyclic or tetracyclic antidepressants. In the largest comparative study published to date, reductions in HDRS scores after 6 weeks were similar for Citalopram and imipramine in more than 400 patients from general practice. Furthermore, the proportions of patients whose HDRS score was reduced by ≥50% were similar for Citalopram and imipramine. In smaller studies, Citalopram had end-point efficacy similar to that of amitriptyline or maprotiline (2 studies each), although comparisons with mianserin have produced somewhat contradictory findings. Citalopram was less effective than clomipramine in a single study. Results from meta-analyses indicate that Citalopram is broadly similar to tricyclic agents (amitriptyline, clomipramine, nortriptyline and imipramine) in its antidepressant efficacy in clinical trials.

Citalopram had overall efficacy similar to that of fluoxetine in general practice patients and in psychiatrie inpatients and outpatients. However, analysis of 3 different clinical parameters after 2 weeks indicated that the effects of Citalopram were achieved significantly faster than those of fluoxetine in the general practice study; no significant difference between the two treatment groups was apparent at subsequent timepoints. A comparison of Citalopram with fluvoxamine in patients with major depression demonstrated equivalent efficacy for the 2 drugs.

Tolerability

Data from clinical trials and meta-analyses suggest that nausea and vomiting (20% incidence in a meta-analysis of 746 patients), increased sweating, dry mouth and headache were the most common adverse events experienced by Citalopram recipients. The anticholinergic and cardiovascular adverse events often seen with tricyclic antidepressants (dry mouth, constipation, tachycardia, orthostatic hypotension) appear to occur less frequently or to be infrequent with Citalopram in most large studies. Data from 2 comparative studies suggest that there are no major differences in tolerability between Citalopram and fluoxetine, although vomiting during the first week of treatment was significantly more common in Citalopram recipients (3.8%) than in fluoxetine recipients (0%) in one study (the Citalopram dosage in this trial was twice that recommended for initial treatment). Nausea and diarrhoea were significantly more common in patients receiving fluvoxamine 100 to 200 mg/day than in those receiving Citalopram 20 to 40 mg/day in a single study (the starting dosage of fluvoxamine was twice that normally recommended). This difference was apparent at all timepoints for nausea, but had disappeared by week 6 for diarrhoea.

Clinical and postmarketing experience with Citalopram suggests that it is not associated with serious cardiovascular toxicity, and is well tolerated in patients with existing cardiovascular conditions, in those who are receiving drugs that may cause ECG abnormalities and in the elderly. Like the other SSRIs, Citalopram appears to be less toxic than tricyclic antidepressants when taken in overdose during suicide attempts.

Dosage and Administration

The recommended oral treatment regimen for Citalopram in depressed patients is 20 to 60mg once daily, titrated to therapeutic effect, with a minimum treatment period of 6 months to prevent relapse. Citalopram 20 to 30mg once daily is currently recommended for elderly patients. Dosage adjustments are not necessary in patients with mild or moderate renal impairment; information on the use of Citalopram in patients with severe renal dysfunction is lacking. Citalopram 20 to 30mg is recommended as the maximum dose in patients with impaired hepatic function. Citalopram should not be given to patients who are taking monoamine oxidase inhibitors.

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Correspondence to Stuart Noble.

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Various sections of the manuscript reviewed by: U.G. Ahlfors, Hesperia Hospital, Helsinki, Finland; G. Andersen, Department of Neurology, Aarhus Kommunehospital, Aarhus, Denmark; P. Baumann, Unité de Biochimie et Psychopharmacologie Clinique, Département Universitaire de Psychiatrie Adulte, Prilly-Lausanne, Switzerland; P. Bech, Department of Psychiatry, Frederiksborg General Hospital, Hillerød, Denmark; K. Brøsen, Department of Clinical Pharmacology, Odense University, Odense, Denmark; G.D. Burrows, Department of Psychiatry, University of Melbourne, Heidelberg, Victoria, Australia; F. de Jonghe, Psychiatrisch Ziekenhuis, Amsterdam, The Netherlands; R.R. Kydd, Department of Psychiatry and Behavioural Science, School of Medicine, University of Auckland, Auckland, New Zealand; S.A. Montgomery, Department of Psychiatry, St Mary’s Hospital Medical School, London, England; W.Z. Potter, Section on Clinical Pharmacology, National Institute of Mental Health, Bethesda, Maryland, USA; E. Richelson, Departments of Psychiatry and Pharmacology, Mayo Clinic and Foundation, Rochester, Minnesota, USA.

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Noble, S., Benfield, P. Citalopram. CNS Drugs 8, 410–431 (1997). https://doi.org/10.2165/00023210-199708050-00009

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Keywords

  • Fluoxetine
  • Fluvoxamine
  • Clomipramine
  • Hamilton Depression Rate Scale
  • Maprotiline