Citalopram

Oral
Depression, Depressive phase of bipolar disorder

Oral
Panic disorder with or without agoraphobia

CYP2C19 poor metabolisers or concurrent use of CYP2C19 inhibitors: Max: 20 mg/day.

Pharmacogenomics:

CYP2C19 is the main enzyme responsible in citalopram metabolism. CYP2C19 polymorphism test can be considered to identify individuals who may require dose adjustment or experience treatment failure. The incidence of CYP2C19 poor metabolizer is markedly higher in Asian (13–23%) than in white populations (2–5%).

Ultrarapid metabolisers (carriers of 2 increased function alleles or 1 normal function allele and 1 increased function allele e.g. *17/*17, *1/*17)
Increased metabolism reduces citalopram plasma concentration which may lead to pharmacotherapy failure. Consider use of alternative drug not predominantly metabolised by CYP2C19 (e.g. fluoxetine, paroxetine).

Extensive metabolisers (carriers of 2 normal function alleles e.g. *1/*1)
Initiate therapy with recommended starting dose.

Intermediate metabolisers (carriers of 1 normal function allele or 1 increased function allele and 1 no function allele e.g. *1/*2, *1/*3, *2/*17)
Reduced metabolism compared to extensive metabolisers. Initiate therapy with recommended starting dose.

Poor metabolisers (carriers of 2 no function alleles e.g. *2/*2, *2/*3, *3/*3)
Greatly reduced metabolism increased citalopram plasma concentration, which may result in arrhythmias caused by QT prolongation. Consider 50% reduction of recommended starting dose and titrate to response (Max: 20 mg daily) or use alternative drug not predominantly metabolised by CYP2C19.

No dosage adjustment needed.

Mild to moderate: 10 mg/day for the 1st 2 wk. Max: 20 mg/day.

May be taken with or without food.

Congenital long QT syndrome or QT interval prolongation; bradycardia, recent acute MI, uncompensated heart failure, hypokalaemia, hypomagnesaemia. Concomitant admin or w/in 14 days of discontinuing MAOI treatment. Concomitant use w/ drug that prolong QT interval. Childn and adolescents <18 yr.

May worsen depression, suicidal ideation and atypical behaviour in patients w/ psychiatric disorder. History of seizure and mania; hepatic impairment. CYP2C19 poor metabolisers. Avoid withdrawal reactions by gradual dose reduction. Pregnancy and lactation.

Hyponatraemia (reversible); syndrome of inappropriate antidiuretic hormone secretion (SIADH); haemorrhage or bleeding; somnolence, insomnia, dizziness, asthenia, anxiety, fatigue, yawning; nausea, dry mouth, diarrhoea, dyspepsia, anorexia, vomiting, abdominal pain; sweating; decreased libido, ejaculation dysfunction, impotence in male patients, dysmenorrhoea; myalgia, arthralgia, fever; upper respiratory tract, rhinitis, sinusitis.
Potentially Fatal: Dose-dependent QT interval prolongation; torsade de pointes; ventricular tachycardia; sudden death. Increased risk of suicidal thinking and behaviour especially in childn and adolescents.

PO: C, Z (Risk of postpartum haemorrhage, persistent pulmonary hypertension in infant and neonatal withdrawal/toxicity in late pregnancy use. Monitor closely.)

Closely monitor for possible depression worsening, suicidality or unusual changes in behaviour and serotonin syndrome or neuroleptic malignant syndrome (NMS)-like signs and symptoms. Periodically monitor serum electrolytes (e.g. K and Mg) before and during therapy. Monitor ECG in at-risk patients.

Symptoms: Dizziness, sweating, nausea, vomiting, tremor, somnolence and sinus tachycardia. Rarely, amnesia, confusion, coma, seizures, hyperventilation, cyanosis, rhabdomyolysis and ECG changes (e.g. QT prolongation, sinus bradycardia, ventricular arrhythmias, nodal rhythm, torsade de pointes and left bundle branch block). Management: Symptomatic and supportive treatment. Maintain and ensure adequate ventilation and oxygenation. Gastric evacuation by lavage and use of activated charcoal should be considered. Frequently monitor cardiac function and vital signs.

May increase anticoagulant effect w/ drugs affecting haemostatis (e.g. warfarin). Increased risk of hypomania w/ sibutramine. Increased lowering seizure threshold w/ TCAs and other SSRIs.
Potentially Fatal: Increased risk of severe adverse effects (e.g. serotonin syndrome) w/ MAOI. QT interval prolongation w/ subsequent risk of torsade de pointes w/ QT-prolonging drugs (e.g. pimozide, quinidine, procainamide, chlorpromazine, thioridazine, amiodarone, sotalol, moxifloxacin, pentamidine, levomethadyl, methadone).

Avoid St John's wort as it may increase CNS depression.

Description:
Mechanism of Action: Citalopram is bicyclic phthalane derivative and a selective serotonin re-uptake inhibitor, w/ little or no effect on noradrenaline, dopamine and GABA re-uptake. The inhibitory activity explains the antidepressant property of citalopram. It has no or very low affinity for 5-HT_1AA, 5-HT_2A, D₁ and D₂ receptors, α₁, α₂, β-adrenergic, histamine H₁, muscarinic, cholinergic, benzodiazepine and opioid receptors.
Pharmacokinetics:
Absorption: Rapidly and well absorbed from the GI tract. Absolute bioavailability: Approx 80%. Time to peak plasma concentration: 2-4 hr.
Distribution: Highly lipophilic, widely distributed; enters breast milk (small amounts), crosses placenta and blood brain barrier. Volume of distribution: Approx 12 L/kg. Plasma protein binding: Approx 80%.
Metabolism: Undergoes demethylation, deamination and oxidation to active and inactive metabolites. Demethylation to its active metabolite (demethylcitalopram) via CYP3A4 and CYP2C19 isoenzymes. Partially metabolised by CYP2D6 isoenzyme.
Excretion: Via liver (85%) and approx 12% of the dose via urine (as unchanged drug). Terminal half- life: Approx 36 hr.

Store at 25°C.

Thuốc chống trầm cảm

Hicks JK, Bishop JR, Sangkuhl K et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clinical Pharmacology and Therapeutics. 2015 Aug;98(2):127-134. doi: 10.1002/cpt.147. Accessed 19/09/2018 . PMID: 25974703

Mrazek DA, Biernacka JM, O'Kaen DJ et al. CYP2C19 Variation and Citalopram Response. Pharmacogenet Genomics. 2011 Jan;21(1):1-9. Accessed 20/09/2018. PMID: 21192344

Yu BN, Chen GL, He N et al. Pharmacokinetics of Citalopram in Relation to Genetic Polymorphism of CYP2C19. The American Society for Pharmacology and Experimental Therapeutics DMD. 2003;31(10):1255-1259. Accessed 20/09/2018

Annotation of CPIC Guideline for Citalopram, Escitalopram and CYP2C19. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 19/09/2018.

Annotation of DPWG Guideline for Citalopram and CYP2C19. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 19/09/2018.

Annotation of FDA Label for Citalopram and CYP2C19, CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 19/09/2018.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org. Accessed 19/09/2018.