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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Citalopram

Last Update: October 12, 2017.

OVERVIEW

Introduction

Citalopram and escitalopram are selective serotonin reuptake inhibitors (SSRIs) and widely used antidepressants. Citalopram is a racemic mixture, whereas escitalopram is its S-enantiomer. Both agents have similar profiles of clinical efficacy and side effects. Both have been associated with rare instances of clinically apparent acute liver injury.

Background

Citalopram (sye tal' o pram) and escitalopram (es" sye tal' oh pram) are antidepressants that belong to the class of selective serotonin reuptake inhibitors (SSRIs). By blocking the reuptake of serotonin in CNS synaptic clefts, SSRIs increase serotonin levels and serotonin activity which results in antidepressant effects. Citalopram was approved for use in the United States in 1998 and it has become one of the most widely used antidepressant medications, with more than 16 million prescriptions being written yearly. Citalopram is available as tablets of 10, 20 and 40 mg and in an oral solution of 10 mg/5 mL in several generic forms and under the brand name of Celexa. The recommended dosage of citalopram in adults is 20 mg once daily, increasing to 40 mg daily if necessary. Escitalopram was approved for use in the United States in 2002 and is available in tablets of 5, 10, and 20 mg under the brand name Lexapro. The recommended dosage of escitalopram is 10 mg once daily, increasing to 20 mg daily if necessary. Both citalopram and escitalopram are approved for treatment of major depression; escitalopram is also used for generalized anxiety disorder. Side effects of citalopram and escitalopram are similar; common side effects are drowsiness, dyspepsia, nausea, headache, increased sweating and sexual dysfunction. Rare, but potentially severe adverse events include suicidal ideation and behavior, prolongation of the QTc interval, serotonin syndrome, precipitation of acute mania and acute glaucoma.

Hepatotoxicity

Liver test abnormalities have been reported to occur in less than 1% of patients on citalopram, and elevations are usually modest and rarely require dose modification or discontinuation. Rare instances of acute, clinically apparent episodes of liver injury with marked liver enzyme elevations with or without jaundice have been reported in patients on citalopram and escitalopram. The typical presentation is with fatigue, nausea and abdominal pain 2 to 10 weeks after starting the medication, followed by dark urine and mild jaundice. Both cholestatic and hepatocellular patterns of serum enzyme elevations have been described. Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) are uncommon. Recovery is usually rapid once the agent is stopped.

Likelihood score: C (probable cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which citalopram and escitalopram cause liver injury is not known. Citalopram and escitalopram are extensively metabolized by the liver, mainly via the cytochrome P450 system (CYP 3A4, 2D6 and 2C19) and hepatotoxicity may be mediated by toxic intermediates of their metabolism.

Outcome and Management

The serum aminotransferase elevations that occur on citalopram therapy are usually self-limited and do not require dose modification or discontinuation of therapy. No instances of acute liver failure or chronic vanishing bile duct syndrome have been attributed to citalopram or escitalopram. Persons with intolerance to citalopram may have similar reactions to other SSRIs and careful monitoring is warranted if other such agents are used.

Drug Class: Antidepressant Agents

Other Drugs in the Subclass, SNRIs/SSRIs: Duloxetine, Fluoxetine, Fluvoxamine, Levomilnacipran, Paroxetine, Sertraline, Venlafaxine, Vilazodone, Vortioxetine

CASE REPORT

Case 1. Acute cholestatic liver injury due to citalopram.

[Modified from: Milkiewicz P, Chilton AP, Hubscher SG, Elias E. Antidepressant induced cholestasis: hepatocellular redistribution of multidrug resistant protein (MRP2). Gut 2003; 52: 300-3. PubMed Citation]

A 30 year old woman developed jaundice and pruritus 2 months after starting citalopram for depression (10 mg daily for 1 month, followed by 20 mg daily). She had chronic depression and had been treated in the past with fluoxetine for a year without complications, but with inadequate control of her symptoms. She was taking no other medications. She had a history of cholestasis managed with ursodiol during two pregnancies. Blood tests showed a bilirubin of 4.4 mg/dL and prominent elevations in alkaline phosphatase, with minimal increase in aminotransferase levels (Table). Tests for hepatitis A, B and C and for autoimmune liver disease were negative. An abdominal ultrasound showed no evidence of biliary obstruction. A liver biopsy showed intrahepatic cholestasis without bile duct loss, fat or fibrosis. Citalopram was stopped and her jaundice and pruritus resolved over the next two months. When seen 6 months after stopping citalopram, she was asymptomatic of liver disease and serum enzymes were normal.

Key Points

Medication:Citalopram (20 mg daily)
Pattern:Cholestatic (R=~0.6)
Severity:3+ (jaundice, hospitalization)
Latency:2 months
Recovery:2-3 months
Other medications:None

Laboratory Values

Time After StartingTime After StoppingAST
(U/L)		Alk P (U/L)Bilirubin (mg/dL)Other
8 weeks0336374.4Citalopram stopped
12 weeks4 weeks6102.5Estimated from Figure 1
32 weeks24 weeks132770.4
Normal Values <35 <360 <1.2

Comment

The abrupt onset of jaundice and pruritus suggests a cholestatic form of drug induced liver disease, which was confirmed in this case by both the pattern of serum enzyme elevations (an R value of less than 2.0) and liver histology. While usually benign, cholestatic hepatitis from medications can be prolonged. The liver biopsy showing a lack of bile duct loss and the history of cholestasis of pregnancy suggest that interference with bile secretion rather than frank injury to bile ducts was the cause.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Citalopram – Celexa®

Escitalopram – Lexapro®

DRUG CLASS

Antidepressant Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULAS AND STRUCTURES

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Citalopram 59729-33-8 C20-H21-F-N2-O
Image of Citalopram Chemical Structure
Escitalopram 128196-01-0 C20-H21-F-N2-O
Image of Escitalopram Chemical Structure

ANNOTATED BIBLIOGRAPHY

References updated: 12 October 2017

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