Pharmacology

Citalopram hydrobromide is a racemose bicyclical phthalate derivative.

Pharmacodynamics. Citalopram inhibits the reuptake of serotonin with little effect on dopamine and norepinephrine uptake in vitro. It has little or no affinity for muscarinic cholinergic, gamma-aminobutyric acid, benzodiazepine, and 5-HT1A or 5-HT2A receptors. Other molecular mechanisms of action of citalopram are being explored. Citalopram has been shown to inhibit rectifier outward K+ current in mouse cortical neurons, which is independent of G-protein-coupled receptors and might explain its antidepressant effects by enhancement of presynaptic efficiency (28). The findings of a PET study of cerebral glucose metabolism following treatment with citalopram suggest that cortical and limbic serotonin transporter occupancy of greater than 70% may be an underlying mechanism for the regional cerebral metabolic effects of citalopram in geriatric depression (25). A study on patients with major depressive disorder shows that acute change in GABA levels in the pregenual anterior cingulate cortex, as measured by proton magnetic resonance spectroscopy, possibly mediates and predicts clinical response to citalopram treatment (02).

Examination of whole-brain metabolic changes before and after treatment using FDG-PET imaging has shown greater glucose metabolism in the left orbitofrontal cortex before treatment (combined citalopram and placebo subjects) relative to after treatment but did not correlate with clinical recovery (26). Clinical efficacy was similar for citalopram versus placebo. These preliminary results suggest that the orbitofrontal cortex may be a neural substrate for the improvement of depressive symptoms in bipolar depression, regardless of whether they are due to active treatment with citalopram or placebo.

Pharmacokinetics. The pharmacokinetic features are as follows:

Pharmacogenetics/pharmacogenomics. Response to citalopram and subsequent remission from major depressive disorder is influenced by variation in the mu-opioid receptor gene (06). A genome-wide association study has shown that biomarkers within the genes PAPLN (encodes papilin) and IL28RA (encodes an interleukin receptor) may help identify patients at increased risk of suicidal ideation during treatment of depression with citalopram (10). Variations in CYP2C19 are associated with tolerance and remission in white non-Hispanic patients treated with citalopram (14).

In one study, major depressive disorder (MDD) patients treated with citalopram were genotyped for polymorphisms of serotonin-receptor genes in relation to efficacy of the drug (01). The results showed that A allele at TPH1 rs1800532 may be associated with citalopram efficacy only in melancholic and psychotic types of MDD, indicating the usefulness of investigating the effect of genetic variants in conjunction with specific clinical features.

A meta-analysis based on a systematic review of available information has shown that all functional CYP2C19 genotypes have significant effects on pharmacokinetics of citalopram. These findings are likely to help in understanding the interindividual variability in response to citalopram and enable personalization of therapy (03).

Pharmacogenomic tests used to guide treatment of major depressive disorder must be validated for ability to predict medication blood levels, which reflect altered metabolism. A study has shown that a combinatorial pharmacogenomic/ pharmacogenetic test (GeneSight Psychotropic®) with weighted assessment of three genes (CYP2C19, CYP2D6, CYP3A4) is a superior predictor of citalopram/escitalopram blood levels compared to individual genes (24).

Pharmacogenetic testing, particularly genotyping for CYP2C19 and CYP2D6 polymorphisms, prior to initiation of citalopram could be useful in medicolegal settings as the possibility of unintentional drug interactions should be considered in drug poisoning deaths. A pharmacogenetic study found higher incidence of a combined group of genetically predicted poor and ultrarapid metabolizer phenotypes of CYP2C19 among suicide victims compared to controls (18).

Clinical trials

Several controlled clinical trials have been conducted since the end of 20th century to demonstrate the safety and efficacy of citalopram, some comparing it with an older drug of the same category. Some of the clinical trials during the past decade are summarized here.

A double-blind, multicenter trial compared citalopram with amitriptyline in elderly depressed patients with or without mild cognitive dysfunction (22). Both drugs were equally effective, but adverse effects were significantly less with citalopram.

Results of a randomized controlled trial show that subsyndromal symptoms of depression in middle-aged and older patients with schizophrenia are lessened with citalopram treatment (29).

A randomized, double-blind, placebo-controlled trial on patients in the acute and maintenance phases of bipolar depression showed that citalopram, added to standard mood stabilizers, did not have a clinically meaningful benefit versus placebo (07).

Indications

Citalopram is indicated for the treatment of depression.

Off-label uses

Several studies have shown that citalopram is useful in the management of patients with illnesses other than depression that are related in some way to serotonergic dysfunction. These include anxiety, panic disorder, obsessive-compulsive disorder, premenstrual dysphoria, alcohol dependence, and the behavioral disturbances of dementia.

Contraindications

Citalopram is contraindicated in patients with hypersensitivity to citalopram or any of the constituents. Its concomitant use is contraindicated in patients who are on monoamine oxidase inhibitor therapy.

Goals and duration of treatment

Citalopram, like other antidepressants, takes two to eight weeks to start having an effect. The goal of treatment is rapid resolution during the acute phase of depression followed by maintenance treatment for six months to reduce chances of recurrence. A study has shown that reduction of prescribed citalopram dosages to a new safety limit of 40 mg/day was associated with a higher rate of hospitalization in a large patient population who had been treated with substantially higher dosages (20).

Dosing

Initial dose is 20 mg/day with increment by 20 mg over an interval of not less than a week. Usual recommended dose is 40 mg/day, and no advantage has been demonstrated for the 60 mg/day dose. The FDA recommends not using doses higher than 40 mg/d because of potential QT prolongation and abnormal heart rhythm (23).

Special considerations

Pediatric. Safety and efficacy in pediatric patients have not been demonstrated.

Geriatric. There are no special precautions for the elderly except those with hepatic or renal insufficiency in whom the dose should not exceed 20 mg/day. However, sodium serum levels should be monitored closely in elderly patients during treatment with citalopram because of a risk of hyponatremia.

Pregnancy. Citalopram administered to the mother reaches the fetus via amniotic fluid, and there is a high correlation between maternal serum concentrations of citalopram and umbilical cord blood concentrations (15). These findings support the use of therapeutic drug monitoring in maintaining the safety of pregnant women on citalopram therapy as well as the exposed infants. Prenatal exposure to citalopram during the last six months of pregnancy may cause neonatal abstinence syndrome with symptoms such as abnormal crying, feeding problems, respiratory distress, and convulsions, which can be managed with phenobarbital; breastfeeding need not be discontinued (05).

Anesthesia. No relevant information.

Interactions

Interactions have been reported with alcohol, monoamine oxidase inhibitors, cimetidine, lithium, sumatriptan, carbamazepine, warfarin, tricyclic antidepressants, and metoprolol.

Adverse effects

Significant adverse effects include serotonin syndrome, osteoporosis, and hyponatremia (21). Citalopram-induced jaw tremor may be due to an inhibitory effect on central dopaminergic activity. Restless legs syndrome is aggravated by citalopram as a possible "dopamine-dependent side effect," and switching to bupropion could potentially correct this dopaminergic dysfunction (16). Parkinsonism has been reported as an adverse reaction in a patient taking citalopram, and full recovery followed discontinuation of the drug (12). Cases of acute dystonia due to citalopram treatment have been reported (13).

For details of other adverse effects see the Physicians’ Desk Reference.

Management. Management of serotonin syndrome is described in a separate clinical summary. Recognition of adverse effect and discontinuation of citalopram can be combined with symptomatic treatment of adverse effects. Electrolytes should be monitored when starting citalopram, and fluid/electrolyte balance should be restored if hyponatremia is severe. Citalopram-induced parkinsonism may be managed with dopamine agonists (04).