indication

For the treatment of depression. Unlabeled indications include: treatment of mild dementia-associated agitation in nonpsychotic patients, smoking cessation, ethanol abuse, obsessive-compulsive disorder (OCD) in children, and diabetic neuropathy.

pharmacology

Citalopram is one of a class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs). It is used to treat the depression associated with mood disorders. It is also used on occassion in the treatment of body dysmorphic disorder and anxiety. The antidepressant, antiobsessive-compulsive, and antibulimic actions of citalopram are presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. In vitro studies show that citalopram is a potent and selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. Citalopram has no significant affinity for adrenergic (α₁, α₂, β), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT_1A, 5HT_1B, 5HT₂), or benzodiazepine receptors; antagonism of such receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. The chronic administration of citalopram was found to downregulate brain norepinephrine receptors, as has been observed with other drugs effective in the treatment of major depressive disorder. Citalopram does not inhibit monoamine oxidase.

mechanism of action

The antidepressant, antiobsessive-compulsive, and antibulimic actions of citalopram are presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Citalopram blocks the reuptake of serotonin at the serotonin reuptake pump of the neuronal membrane, enhancing the actions of serotonin on 5HT_1A autoreceptors. SSRIs bind with significantly less affinity to histamine, acetylcholine, and norepinephrine receptors than tricyclic antidepressant drugs.

toxicity

Symptoms most often accompanying citalopram overdose, alone or in combination with other drugs and/or alcohol, included dizziness, sweating, nausea, vomiting, tremor, somnolence, and sinus tachycardia. In more rare cases, observed symptoms included amnesia, confusion, coma, convulsions, hyperventilation, cyanosis, rhabdomyolysis, and ECG changes (including QTc prolongation, nodal rhythm, ventricular arrhythmia, and very rare cases of torsade de pointes). Acute renal failure has been very rarely reported accompanying overdose. Withdrawal symptoms include flu-like symptoms, insomnia, nausea, imbalance, sensory changes and hyperactivity.

biotransformation

Citalopram is metabolized mainly in the liver via N-demethylation to its principle metabolite, demethylcitalopram. Other metabolites include didemethylcitalopram, citalopram N-oxide, and a deaminated propionic acid derivative. Cytochrome P450 (CYP) 3A4 and 2C19 isozymes appear to be principally involved in producing demethylcitalopram. Demethylcitalopram appears to be further N-demethylated by CYP2D6 to didemethylcitalopram. Citalopram metabolites possess little pharmacologic activity in comparison to their parent compound and do not likely contribute to the clinical effect of the drug.

absorption

Rapidly and well absorbed from the GI tract. Peak plasma concentrations occur within 4 hours of a single orally administered dose. Bioavailability is 80% following oral administration. Food does not affect absorption.

half life

35 hours

route of elimination

The systemic clearance of citalopram was 330 mL/min, with approximately 20% of that due to renal clearance. Citalopram is metabolized to demethylcitalopram (DCT), didemethylcitalopram (DDCT), citalopram-N-oxide, and a deaminated propionic acid derivative.

drug interactions

Acenocoumarol: The SSRI, citalopram, increases the effect of anticoagulant, acenocoumarol.

Almotriptan: Increased risk of CNS adverse effects

Anisindione: The SSRI, citalopram, increases the effect of anticoagulant, anisindione.

Artemether: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Carvedilol: The SSRI, citalopram, may increase the bradycardic effect of the beta-blocker, carvedilol.

Clarithromycin: Possible serotoninergic syndrome with this combination

Clozapine: The antidepressant increases the effect of clozapine

Desvenlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Dicumarol: The SSRI, citalopram, increases the effect of anticoagulant, dicumarol.

Eletriptan: Increased risk of CNS adverse effects

Erythromycin: Possible serotoninergic syndrome with this combination

Frovatriptan: Increased risk of CNS adverse effects

Ginkgo biloba: Additive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.

Isocarboxazid: Possible severe adverse reaction with this combination

Josamycin: Possible serotoninergic sydrome with this combination

Ketoprofen: Concomitant therapy may result in additive antiplatelet effects and increase the risk of bleeding. Monitor for increased risk of bleeding during concomitant therapy.

Linezolid: Combination associated with possible serotoninergic syndrome

Lumefantrine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Metoprolol: The SSRI, citalopram, may increase the bradycardic effect of the beta-blocker, metoprolol.

Moclobemide: Possible serotoninergic syndrome

Naratriptan: Increased risk of CNS adverse effects

Oxycodone: Increased risk of serotonin syndrome

Phenelzine: Possible severe adverse reaction with this combination

Pimozide: The SSRI, citalopram, may increase the effect and toxicity of pimozide.

Propranolol: The SSRI, citalopram, may increase the bradycardic effect of the beta-blocker, propranolol.

Rasagiline: Possible severe adverse reaction with this combination

Rizatriptan: Increased risk of CNS adverse effects

Selegiline: Possible severe adverse reaction with this combination

Sibutramine: Risk of serotoninergic syndrome

St. John's Wort: St. John's Wort increases the effect and toxicity of the SSRI, citalopram.

Sumatriptan: Increased risk of CNS adverse effects

Telithromycin: Telithromycin may reduce clearance of Citalopram. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Citalopram if Telithromycin is initiated, discontinued or dose changed.

Tiaprofenic acid: Additive antiplatelet effects increase the risk of bleeding. Consider alternate therapy or monitor for increased bleeding.

Ticlopidine: Ticlopidine may decrease the metabolism and clearance of Citalopram. Consider alternate therapy or monitor for adverse/toxic effects of Citalopram if Ticlopidine is initiated, discontinued or dose changed.

Tolmetin: Increased antiplatelet effects may enhance the risk of bleeding. Alternate therapy may be considered or monitor for inreased bleeding during concomitant therapy.

Tramadol: The use of two serotonin modulators, such as citalopram and tramadol, may increase the risk of serotonin syndrome. Consider alternate therapy or monitor for serotonin syndrome during concomitant therapy.

Tranylcypromine: Increased risk of serotonin syndrome. Concomitant therapy should be avoided. A significant washout period, dependent on the half-lives of the agents, should be employed between therapies.

Trazodone: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Treprostinil: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the antiplatelet agent, Citalopram. Monitor for increased bleeding during concomitant thearpy.

Trimipramine: The SSRI, Citalopram, may decrease the metabolism and clearance of Trimipramine. Increased risk of serotonin syndrome. Monitor for changes in Trimipramine efficacy and toxicity if Citalopram is initiated, discontinued or dose changed.

Triprolidine: The CNS depressants, Triprolidine and Citalopram, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.

Troleandomycin: Possible serotoninergic syndrome with this combination

Venlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of citalopram by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of citalopram if voriconazole is initiated, discontinued or dose changed.

Warfarin: The SSRI, citalopram, increases the effect of anticoagulant, warfarin.

Ziprasidone: Additive QTc-prolongation may occur increasing the risk of life-threatening ventricular arrhythmias and torsade de pointes. Concomitant therapy should be avoided.

Zolmitriptan: The use of two serotonin modulators, such as zolmitriptan and citalopram, may increase the risk of serotonin syndrome. Consider alternate therapy or monitor for serotonin syndrome during concomitant therapy.

Zuclopenthixol: Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).