Citalopram

Citalopram belongs to the selective serotonin reuptake inhibitor class of antidepressants, the group that has become the usual first-line drug treatment for depression. It is prescribed chiefly for major depressive disorder and is sometimes used for anxiety-related conditions. Chemically it is a racemate, an equal mixture of two mirror-image molecules, and only the S form is responsible for the wanted antidepressant activity; Lundbeck later isolated that half and sells it separately as escitalopram.

The compound was first synthesized in 1972 by the chemist Klaus Bogeso at Lundbeck and was approved for medical use in the United States in 1998. It has since become a widely prescribed, inexpensive generic medicine.

Evidence for its effectiveness comes from both controlled trials and pragmatic studies. A large network meta-analysis of antidepressants found that all of the studied drugs, including citalopram, were more effective than placebo for acute depression, and it ranked citalopram among the better-tolerated options ^[1]. In the large real-world STAR*D program, citalopram given with measurement-based dose adjustment produced remission in roughly a quarter to a third of outpatients and a response in nearly half, with results in primary care similar to those in psychiatric settings ^[2].

Citalopram's most distinctive safety issue is its effect on the heart's electrical cycle. In 2011 the United States Food and Drug Administration restricted the maximum dose after evidence that citalopram lengthens the QT interval in a dose-dependent way, with lower limits advised for older adults and for people taking drugs that slow its metabolism; an analysis of electronic health records confirmed a modest but real prolongation of the QT interval with citalopram ^[3]. Like other SSRIs, it can also cause discontinuation symptoms if stopped abruptly. It is a prescription-only medicine.

A hard dose ceiling is what separates citalopram from the rest of the SSRI class, and the reason is cardiac. The FDA capped it at 40 mg a day in 2011 after QTc lengthened by roughly 8.5 ms at 20 mg and 18.5 ms at 60 mg, with a 20 mg ceiling for anyone over 60, anyone with hepatic impairment, CYP2C19 poor metabolisers and anyone on a CYP2C19 inhibitor. It is not recommended with congenital long QT syndrome, bradycardia, low potassium or magnesium, recent heart attack or uncompensated heart failure. Like every antidepressant it carries a boxed warning for suicidal thinking in adolescents and young adults, and it is tapered rather than stopped.

Citalopram prolongs the QT interval in a dose-dependent way, and that single property drives most of its interaction profile. It is metabolized partly by CYP2C19, so inhibitors of that enzyme raise its concentrations and with them the arrhythmia risk. Cimetidine increased citalopram AUC by 43 percent and Cmax by 39 percent; omeprazole, esomeprazole, fluconazole and ticlopidine act the same way, and poor CYP2C19 metabolizers reach higher levels for the same intake. Pairing citalopram with other QT-prolonging drugs such as amiodarone, sotalol, methadone or certain antipsychotics compounds the effect, and uncorrected hypokalemia or hypomagnesemia makes torsade de pointes likelier still.

Monoamine oxidase inhibitors are contraindicated, linezolid and intravenous methylene blue included, because the combination can cause serotonin syndrome; a fourteen-day gap on either side is standard. Triptans, tramadol, fentanyl and St John's wort raise the same risk more modestly.

By depleting platelet serotonin, citalopram increases bleeding when combined with NSAIDs, aspirin, warfarin or direct oral anticoagulants.

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