Continuing Education Activity

Citalopram hydrobromide is a selective serotonin reuptake inhibitor. The primary FDA-approved clinical use for citalopram hydrobromide is for the treatment of depression in adults. Non-FDA-approved uses include alcohol use disorder, coronary arteriosclerosis, obsessive-compulsive disorder, panic disorder, postmenopausal flushing, and premenstrual dysphoric disorder. This activity reviews indications, mechanism of action, administration, contraindications, monitoring, and toxicity associated with citalopram and the interprofessional team's role in caring for patients with conditions that indicate therapy with citalopram.

Objectives:

• Describe the mechanism of action of citalopram.
• Identify the approved and off-label indications of citalopram.
• Summarize the potential adverse effects of citalopram, and indicate measures to take should they appear during the course of therapy.
• Review the importance of improving care coordination among interprofessional team members to improve outcomes for patients on citalopram therapy.

Indications

Citalopram hydrobromide got FDA approval in 1998 and is the most selective serotonin reuptake inhibitor.[1] It is listed in the WHO model list of essential medicines to treat depressive disorders.

FDA-approved Indication

• Citalopram hydrobromide is for the treatment of depression in adults 18 years or older[2]
• Recommendation: Adult, class IIa
• Strength of Evidence: Adult, category B

Off-label Use[3]

• Obsessive-compulsive disorder (OCD)[4]
• Panic disorder[5]
• Generalized anxiety disorder (GAD)[6]
• Social anxiety disorder (SAD)
• Separation anxiety disorder
• Premenstrual dysphoric disorder (PMDD)[7]
• Binge eating disorder[8]
• Post-traumatic stress disorder (PTSD)[9]

The advantages and disadvantages of using this drug in non-FDA-approved conditions have their basis on the patient's condition and the clinician's judgment.

Mechanism of Action

Citalopram hydrobromide acts as an antidepressant by potentiating serotonergic activity in the central nervous system (CNS). Multiple studies confirmed that citalopram hydrobromide is a selective serotonin reuptake inhibitor (SSRI) and that it has minimal effects on norepinephrine (NE) and dopamine (DA) neuronal reuptake.[10] It has a low affinity for muscarinic acetylcholine receptors, mild antagonist actions at histamine (H1), but no significant effect on alpha- or beta-adrenergic receptors or dopamine-1, dopamine-2, gamma-aminobutyric acid, opioid, or benzodiazepine receptors.[11][12]

Administration

Citalopram is available as 10 mg, 20 mg, and 40 mg oral tablets and  10 mg/5 mL oral solution. It is administered by oral route for adults younger than 60 years. 

• An initial dose of 20 mg once daily (morning or evening, with or without food)
• Increase the dose to 40 mg after one week (maximum dose of 40 mg daily)
• The maximum dose is 20 mg daily for patients older than 60 years of age or poor metabolizers of CYP2C19.

Patients at risk of significant side effects or overstimulation using citalopram should be started on a lower-end dose. The dose should be increased gradually in 10 mg increments to optimize therapy. Currently, anecdotal reports suggest that higher doses may benefit those afflicted with OCD; however, doses of more than 40 mg daily are not recommended due to the risk of QT prolongation.[13][14][15]

Specific Population

Pregnant Women: It is FDA pregnancy category C medicine. Not an absolute contraindication in pregnancy but is not generally recommended, especially during the first trimester. Clinicians treating women with psychiatric conditions must inform whether these medicines are needed during pregnancy.[16] Manufactures reports neonates exposed to SSRIs or SNRIs, citalopram late in the third trimester have developed complications requiring respiratory support, tube feeding, and prolonged hospitalization.

Breastfeeding Women: According to the safety scoring system, citalopram is acceptable during breastfeeding. If the mother used citalopram while pregnant or other psychotropic drugs have been a therapeutic failure, most experts recommend against changing medicines while breastfeeding. Drugs with lower excretion into breastmilk are generally preferred, especially while nursing preterm infant or newborns. Monitor breastfed newborns for poor feeding, excess drowsiness, restlessness, agitation, and poor weight gain. Extra care should be exercised in a younger and exclusively breastfed infant when a breastfeeding woman is on psychotropic drugs.[17]

Hepatic Impairment: According to product labeling dose needs to be reduced to 20 mg per day for patients with hepatic impairment.

Renal Impairment: No dose adjustment is required in patients with mild to moderate renal impairment. Closely monitor patients with severe renal impairment for possible adverse reactions.

Elderly Population: Citalopram is listed in Beers Criteria as potentially inappropriate medicine and should be used with caution in patients 65 years and older as it can cause or worsen hyponatremia or SIADH.[18]

Pharmacokinetics

• The onset of action for depression is about 1 to 4 weeks. However, the complete response may take 8 to 12 weeks after initiation of treatment.
• Bioavailability is 80%. Tablets and oral solutions are bioequivalent.
• Half-life is 24 to 48 hours (average: 35 hours); however, half-life significantly increases in patients with hepatic impairment, mild-to-moderate renal impairment, in elderly patients (60 years or older), and poor CYP2C19 metabolizers.
• Metabolized by CYP450 3A4 and 2C19; a weak inhibitor of CYP450 2D6.

Adverse Effects

Reports suggest that adverse reactions occur in up to 10% of patients.[3][19][20]

Most Common Adverse Effects[21]

• CNS: Drowsiness, insomnia, dizziness, headache (dose dependant)
• Dermatologic: Diaphoresis
• Gastrointestinal (GI): Nausea, vomiting, xerostomia, constipation, diarrhea
• Sexual: Ejaculation disorder (dose dependant)

Less Common Adverse Effects

• Cardiovascular: Myocardial infarction, prolonged QT interval, Torsades de pointes
• Hematologic: Hemorrhage, abnormal
• Neurologic: Cerebrovascular accident
• Psychiatric: Suicidal ideation, suicide, induction of mania
• Other: Serotonin syndrome 

A rare adverse effect is a hyponatremia resulting from SIADH (syndrome of inappropriate antidiuretic hormone secretion). Citalopram has been shown to induce hyponatremia in case reports involving elderly patients. In addition to advanced age, other factors such as female gender, concurrent diuretic use, low body weight, and recent pneumonia may increase the likelihood of hyponatremia.

There are suggestions that there is a direct correlation between dose and symptom severity for the following adverse effects: impotence, fatigue, somnolence, insomnia, sweating, and yawning.

Abrupt Discontinuation of antidepressant (Discontinuation Syndrome)

Discontinuation syndrome is common in patients who suddenly stop antidepressant therapy. The most common symptoms include nausea, vomiting, diarrhea, headaches, light-headedness, dizziness, diminished appetite, sweating, chills, tremors, fatigue, somnolence, and sleep disturbances.  Less common symptoms include electric shock-like sensations, cardiac arrhythmias, myalgia, arthralgia, and balance difficulties. Due to these side effects, gradual tapering of the antidepressant over several weeks to several months (based on the treatment duration) is strongly recommended. The half-life of drugs and duration of the therapy should factor in these decisions, as antidepressants with a shorter half-life may need to be tapered more conservatively.

Black Box Warning

Citalopram hydrobromide has correlated with suicidality and worsening depression, especially in children, adolescents, and young adults (younger than 24 years old). Antidepressants increased the risk of suicidal thinking compared to placebo in children, adolescents, and young adults. The advantages and disadvantages of using citalopram hydrobromide or any other antidepressant in these populations depend on the patient's condition and the clinician's judgment.[22]

Patients of any age who start antidepressant therapy should be monitored and observed closely for clinical worsening, suicidality, or unusual behavior changes. Citalopram hydrobromide does not have approval for use in pediatric patients.

Increased risk of suicidal ideation and treatment-emergent suicidal ideation (TESI) is a concern in younger patients at the onset of therapy. However, an analysis of 17 controlled clinical trials involving 5000 patients treated with either citalopram, a tricyclic antidepressant, another SSRI, or a placebo indicated that the group receiving citalopram had the lowest incidence of suicide. In addition, family and twin studies provide evidence of a genetic influence on suicidal behavior, and some postulate that genetic influences may play a role in TESI.

Drug-Drug Interactions

Citalopram has significant drug interactions and clinicians should monitor patients closely who are on medicines with potential for drug interactions. Limit the dose of citalopram to maximum 20 mg per day if patient is using bupropion, omeprazole, esomeprazole, cimetidine, fexinidazole, fluconazole, voriconazole fluoxetine, and fluvoxamine.

Contraindications

Citalopram is contraindicated with the concomitant use of monoamine oxidase inhibitors (MAOIs). Evidence suggests that concurrent use of citalopram alongside an MAOI can result in serotonin syndrome (serotonergic hyperactivity). Symptoms of serotonin syndrome include rigidity, hyperthermia, autonomic instability, mental status changes, and coma. Similar adverse reactions are possible in patients who had abruptly switched from an SSRI to an MAOI; therefore, recommendations are to wait 14 days after discontinuing citalopram to initiate an MAOI.[23]

Citalopram is also contraindicated in patients with a history of hypersensitivity to the drug.

Secondary to its inhibitory effects on CYP 2D6, it could hypothetically increase thioridazine concentrations, inducing dangerous arrhythmias.[24]

Canadian labeling includes additional contraindications not included in United States labeling: known QT interval prolongation or congenital long QT syndrome.

Do not administer citalopram in patients using urokinase, pimozide, methylene Blue, linezolid, or dapoxetine.

Monitoring

Before Treatment

• Monitor and evaluate the electrolytes, especially potassium and sodium. Reevaluating electrolytes in patients at risk for electrolyte disturbances during the treatment is recommended.  
• Monitor patients for QT-prolongation.  ECG is necessary for patients with congenital long QT syndrome, bradycardia, hypokalemia or hypomagnesemia, recent acute myocardial infarction, uncompensated heart failure, or concomitant use of other QT-prolonging drugs.[25]

During Treatment

• Patients need to be assessed and monitored for worsening depression, suicidality, or unusual changes in behavior during the initial few months of therapy or when the dose increases or decreases. Weekly face-to-face contact with patients during the initial first month of treatment, followed by visits every other week for the next month and ultimately at three-month intervals, is recommended.
• Weight and growth should be monitored regularly by a physician during treatment in children and adolescents.
• According to Beers Criteria monitor sodium level closely when starting or adjusting the dose of citalopram in patients age 65 and above.[18]

Toxicity

Studies reveal that toxicity is not common even at doses up to 100 mg. However, there is a chance of developing serotonin hyperactivity at therapeutic doses, primarily if using another serotonergic medication concomitantly.

In the event of an intentional overdose, the ingestion of more than 600 mg of citalopram requires 8 hours of cardiac monitoring. At the end of the observation period, if the patient is asymptomatic and QTc is less than 450 milliseconds, the patient can be discharged. However, in patients with QTc of greater than 450 milliseconds at the end of the observation period, inpatient continued cardiac monitoring is necessary.[26]

Enhancing Healthcare Team Outcomes

Citalopram hydrobromide is a widely prescribed antidepressant by nurse practitioners, primary care providers, psychiatrists, internists, and neurologists. While the drug is effective for depression, its use requires monitoring. Prescibers should be careful as citalopram has correlations with suicidality and worsening depression, especially in children, adolescents, and young adults (younger than 24 years old).  Also, clinicians should monitor electrolytes and obtain an ECG before starting treatment because of the risk of prolonged QT syndrome. Nurses and pharmacists should counsel and educate patients not to combine the drug with alcohol, sedatives, and other antidepressants. Thus, an interprofessional approach that includes prescribers, nurses, and pharmacists who operate as an integrated team with open communication and information sharing will be optimal for employing citalopram therapy and driving better patient outcomes with fewer adverse events. [Level 5]