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:
| • Citalopram is rapidly absorbed, and absorption is not affected by food intake.
• Citalopram reaches peak serum concentrations within a few hours after oral intake.
• Half-life is about 35 hours.
• Pharmacokinetics is linear and dose-proportional in a dose range of 10 to 60 mg/day.
• Repeated administrations lead to steady state levels in about one week.
• Citalopram is metabolized in the liver, and 20% of the dose is excreted in the urine.
• CYP3A4 and CYP2C19 are the primary isoenzymes involved in the N-methylation of citalopram. |
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).
