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Citalopram

A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Potential in Depressive Illness

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Summary

Synopsis

Citalopram is an antidepressant belonging to a new class of drugs which enhance serotoninergic neurotransmission through potent and selective inhibition of serotonin reuptake. Preliminary trials suggest that its short term therapeutic efficacy is significantly greater than that of placebo and mianserin, and comparable to that of amitriptyline, maprotiline and imipramine. It appears to be a weaker antidepressant agent than clomipramine, but better tolerated. Its elimination half life of 33 hours permits once daily oral administration

Symptomatic improvement obtained with short term treatment has been maintained when therapy has been extended for up to 1 year; in the few patients studied for this extended period, the relapse rate was lower than with fluvoxamine, fluoxetine or imipramine

Compared to standard antidepressant agents, citalopram is well tolerated. It does not appear to be cardiotoxic, has not been associated with seizures in humans, and is relatively nonsedating. Unlike the tricyclic antidepressants, citalopram has minimal anticholinergic effects. Mild and transient nausea, with or without vomiting, is the most frequent adverse effect — occurring in 20% of patients — and increased perspiration, headache, dry mouth, tremor and insomnia are experienced by 15 to 18% of patients

Citalopram thus offers similar therapeutic efficacy and a more favourable tolerability profile than the tricyclic antidepressants. Preliminary data suggest that it may be particularly useful in patients who cannot tolerate the anticholinergic or cardiovascular side effects of tricyclic antidepressants and in those for whom sedation is not indicated

Pharmacodynamic Properties

Citalopram, like the other ‘second generation’ antidepressant agents fluvoxamine, fluoxetine and paroxetine, enhances serotoninergic neurotransmission through selective and potent inhibition of neuronal serotonin reuptake. Its major metabolites are weaker and less selective serotonin uptake blockers. In vitro, citalopram blocks serotonin uptake in platelets, synaptosomal preparations, and brain slices, and it competes with serotonin and imipramine for a common binding site. Citalopram has low affinity for a range of receptors including 5-HT1A, 5-HT1B, 5-HT2, dopamine1, dopamine2, α1-, α2-, β1-, β2-adreno, histamine1, benzodiazepine, opioid, muscarinic and monoamine oxidase inhibitor receptors

Pronounced inhibition of serotonin reuptake has been demonstrated in various species of animals at plasma citalopram concentrations less than 100 nmol/L. In vivo, citalopram and its main metabolite, demethyl-citalopram, antagonise displacement of serotonin, but not noradrenaline, by 4, α-dimethyl-metatyramine in the central nervous system, confirming citalopram’s selectivity for serotonin. In several animal models citalopram reduces serotonin turnover, presumably secondary to the increased intrasynaptic serotonin levels resulting from reuptake inhibition. The therapeutic effects of all antidepressants, including citalopram, develop over several weeks (see Therapeutic Use), possibly as a result of adaptive changes in receptors. Long term administration of citalopram ‘up-regulates’ α1-receptors and ‘down-regulates’ β2-receptors in rat cerebral cortex but not in thalamus or hippocampus. Unlike many other antidepressants, citalopram does not down-regulate the β-adrenoreceptor-coupled adenylate cyclase system

Like other antidepressants, citalopram prevents the immobility (‘behavioural despair’) induced by enforced swimming in rodents. In screening tests for central effects on monoaminergic mechanisms, citalopram prevents the hyperthermia induced by depletion of serotoninergic nerve terminals and enhances behaviours induced by administration of the serotonin precursor, 1-5-hydroxytryptophan. Citalopram potentiates morphine analgesia in rats probably via its effects on the serotoninergic component of morphine’s action. Unlike tricyclic antidepressants, citalopram does not reduce exploratory activity in rodents, and has little sedative effect in humans

At doses in dogs approximating usual clinical doses, citalopram is considered to have little convulsant potential. In contrast with tricyclic antidepressants, citalopram does not affect indices of cardiac conduction in dogs or cats, and does not induce orthostatic hypotension in humans. Neurohormonal effects of citalopram are largely uninvestigated

Pharmacokinetic Properties

Following oral administration of citalopram 50mg, peak plasma concentrations of 120 to 150 nmol/L are reached within 3 hours. Upon repeated daily oral administration, steady-state conditions are achieved in about 1 week. Doses in the range 30 to 60mg daily give rise to steady-state plasma concentrations of 120 to 600 nmol/L. About 50% of citalopram is bound to plasma proteins. In humans, the volume of distribution of citalopram is relatively large (14 L/kg). The elimination half-life of citalopram in healthy subjects is about 33 hours, thus once-daily administration is adequate to maintain steady-state concentrations

After a single oral dose of citalopram, about 12% is excreted unchanged in the urine. The major metabolite, demethyl-citalopram, is found in plasma in concentrations one-half to one-third that of the parent compound. Since this metabolite is 4 times less potent as a serotonin reuptake inhibitor, and less selective for serotonin than citalopram, it is unlikely to contribute substantially to the therapeutic effect of citalopram

Although pharmacokinetic data are not yet available for patients with known hepatic or renal impairment, in elderly patients daily doses of 20mg yielded plasma drug concentrations as much as 4 times higher than those expected for younger patients administered the same dose, implying lower clearance rates. Phenothiazines may impair hepatic metabolism of citalopram, and thereby raise plasma concentrations

Therapeutic Use

Citalopram is an effective antidepressant when administered in single daily doses of 40 to 60mg, usually orally, to patients with major depressive disorder. Noncomparative studies over 4 to 6 weeks have shown that citalopram produces marked improvement in 30 to 70% of patients, and moderate improvement in another 10 to 50%, using the Hamilton Depression, Montgomery-Asberg Depression Rating or Clinical Global Impression Scales. Small comparative studies indicate that it is more effective than placebo, and similar in efficacy to amitriptyline and maprotiline in alleviating symptoms of depressive illness, but possibly weaker than clomipramine and less effective in normalising sleep patterns. Therapeutic effects can be apparent within 1 week but the full effects take 4 to 6 weeks to develop. The therapeutic effects of citalopram appear more rapidly than those of mianserin but may develop more slowly than those of clomipramine. Controlled comparisons with other serotonin reuptake inhibitors such as paroxetine, fluvoxamine and fluoxetine are required to establish the relative efficacies

Tolerability

Compared with the standard tricyclics, citalopram is a relatively well tolerated antidepressant agent. It has not been associated with seizures or changes in pulse or blood pressure, and does not cause orthostatic hypotension. Citalopram is largely nonsedating and does not appear to stimulate appetite. Anticholinergic effects (dry mouth, constipation, difficulties in visual accommodation) are less common than with tricyclic antidepressants. The most commonly reported adverse effects associated with short term treatment are nausea and vomiting in 20% of patients, increased perspiration, headache and dry mouth (17% each), and tremor and insomnia (about 15% each). All adverse symptoms tend to reduce in frequency during medium to long term administration of citalopram

Dosage and Administration

The usual starting dose of citalopram in patients with depression is 20 or 40mg orally once daily. This may be titrated against efficacy and adverse events to 60mg over the first 1 to 3 weeks. In geriatric patients a steady-state dose of 20 to 30mg daily is more appropriate, and a correspondingly lower starting dose should be used. Citalopram may be administered in conjunction with a benzodiazepine if required to reduce anxiety or improve sleep. Lower starting doses of citalopram may be required when phenothiazines are coadministered

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    Richard J. Milne & Karen L. Goa

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  1. Richard J. Milne
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Various sections of the manuscript reviewed by: G.D. Burrows, University of Melbourne, Melbourne, Victoria, Australia; L.F. Gram, Odense University Hospital, Odense, Denmark; T.M. Itil, New York Medical College, New York, New York, USA; P. Kragh- Sørensen, Odense University Hospital, Odense, Denmark; R.R. Kydd, School of Medicine, University of Auckland, Auckland, New Zealand; G. Lees, School of Medicine, University of Auckland, Auckland, New Zealand; T.R. Norman, University of Melbourne, Victoria, Australia; M.V. Rudorfer, Clinical Neuroscience Branch, National Institute of Mental Health, Bethesda, Maryland, USA; D.M. Shaw, University of Wales, College of Medicine, Whitchurch Hospital, Whitchurch, Cardiff, Wales

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Milne, R.J., Goa, K.L. Citalopram. Drugs 41, 450–477 (1991). https://doi.org/10.2165/00003495-199141030-00008

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