Continuing Education Activity

Escitalopram is a medication used to manage and treat major depressive and generalized anxiety disorders. It is the S-enantiomer of citalopram and is the most selective of SSRIs. It is in the selective serotonin reuptake inhibitor class of drugs. Escitalopram is also used off-label for social anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder, and vasomotor symptoms of menopause. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions, adverse events) pertinent to members of the healthcare team in the management of patients with depression, anxiety, and other related conditions.

Objectives:

• Identify the mechanism of action of escitalopram.
• Describe the potential adverse effects of escitalopram.
• Review the appropriate monitoring for therapy with escitalopram.
• Summarize interprofessional team strategies for improving care coordination and communication when initiating escitalopram to improve patient outcomes.

Indications

Escitalopram is a selective serotonin reuptake inhibitor (SSRI). It is the S-enantiomer of citalopram and is the most selective of SSRIs. Escitalopram is FDA approved for the acute and maintenance treatment of major depressive disorder (unipolar) in adults and adolescents (12 to 17 years of age). It is also FDA- approved for treating generalized anxiety disorder in adults.[1] Escitalopram is also used off-label for social anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder, and vasomotor symptoms of menopause.[2][3][4][5]

Mechanism of Action

SSRIs' mechanism of action is exerted by binding to the sodium-dependant serotonin transporter protein (SERT) located in the presynaptic neuron. SERT works by re-uptaking serotonin from the synaptic cleft to the presynaptic neuron. When SERT is inactivated by escitalopram, this increases the amount of serotonin in the synaptic cleft.[6]

Serotonin or 5-hydroxytryptamine (5-HT) modulates a wide range of human behavioral processes, which include mood, perception, memory, anger, aggression, fear, stress response, appetite, addiction, and sexuality. For these to happen, brain regions like cortical, limbic, midbrain, and hindbrain regions express multiple serotonin receptors.[7] There are five main serotonin receptors, 5-HT1A, 5-HT1B, 5-HT4, 5-HT6, and 5-HT7, in the brain.[8] In total, there are 15 known serotonin receptors, and they are also present outside the central nervous system.[7]

Pharmacokinetics

Absorption: Pharmacokinetics of escitalopram is linear and dose-proportional in a dose range of 10 to 30 mg/day. Absorption is not affected by the presence of food. The time to attain peak plasma concentration is approximately 5 hours. Steady-state plasma concentrations are achieved within 1-2 weeks.[9]

Distribution: Escitalopram has a high volume of distribution(12 L/kg). Escitalopram has low plasma protein binding (56%) and is not likely to cause interactions with highly protein-bound drugs.

Metabolism: Escitalopram is metabolized in the liver by CYP3A4 and CYP2C19 to S-desmethylcitalopram(S-DCT) and S-di-desmethyl citalopram(S-DDCT).

Excretion: The terminal half-life of escitalopram varies from 27 to 33 hours. Escitalopram and its metabolites are exerted in the urine.[10]

Administration

Escitalopram is administered via the oral route. It is available as a 1 mg/mL oral solution and 5 mg, 10 mg, or 20 mg tablets. It is taken once daily, either with or without food. The typical starting dose for escitalopram is 10 mg. After one week, the dose can be increased to achieve proper symptom control.[9] A 4-week dose reduction is recommended when switching escitalopram from another SSRI.

Specific Patients Population 

• Patient with Hepatic Impairment: 10 mg per day dose is recommended for patients with hepatic impairment as oral clearance was reduced by 37%, and half-life was doubled in patients with hepatic dysfunction.

• Patient with Renal Impairment: No dose adjustment is needed for patients with mild or moderate renal impairment. However, it is recommended to use escitalopram with caution in patients with severe renal impairment (creatinine clearance < 20 mL/min).

• Pregnancy Considerations: It is considered pregnancy category C medicine. It is recommended to monitor patients closely and adjust the dose based on individual patient needs, as escitalopram and desmethylcitalopram can cross the placenta and be distributed into the amniotic fluid.[11]

• Breastfeeding Considerations: It is recommended to calculate and use a relatively smaller dose as escitalopram, and its desmethylcitalopram (DCT) metabolite is excreted in breast milk.[12] One case report of necrotizing enterocolitis has been documented in a breastfed infant exposed to escitalopram during lactation and pregnancy, but adverse event causality was not established. A safety scoring system finds the use of escitalopram possibly compatible with breastfeeding.[13] If the mother requires treatment with escitalopram, it is not a reason to discontinue breastfeeding.[14]

• Pediatric Patients: In a single-dose study in adolescent patients (12 to 17 years of age), the AUC of escitalopram decreased by 19%, and Cmax increased by 26% compared to adult patients. There is no adjustment needed in these patients.

• Geriatric Patients: In single and multiple-dose studies, peak plasma concentration remained unchanged while AUC and half-life were increased by approximately 50% in geriatric patients. Per the manufacturer's label, a 10 mg dose of escitalopram is recommended for geriatric patients.

Adverse Effects

Escitalopram and SSRIs have a lower toxicity profile than older antidepressants. Despite this, they have been associated with significant adverse effects.[15] The most commonly observed adverse effects reported are; insomnia, sexual dysfunction (primarily decreased libido, anorgasmia, and male ejaculatory delay), nausea, increased sweating, fatigue, and somnolence.[16] QT prolongation and serotonin syndrome are amongst the rare but serious adverse effects caused by escitalopram. 

Escitalopram can cause a syndrome of inappropriate antidiuretic hormone secretion (SSRI-induced SIADH), leading to hyponatremia, especially in elderly patients.[17] Depending on the severity of hyponatremia, symptoms can range from anorexia, nausea, vomiting, fatigue, and headache to more severe conditions like; altered mental status, seizures, and even coma.[17][18]

QT prolongation is defined as a corrected QT interval on an EKG greater than 500 ms or an increase from a baseline interval of more than 60 ms.[19] QT prolongation can cause potentially fatal cardiac arrhythmias, including torsades de pointes (TdP).[20] The mechanism of QT prolongation involves the blockage of the inward rectifier current, prolonging phase 3 of cardiac repolarization.[19] QTc prolongation is a dose-dependent relationship.[21] According to AHA (American Heart Association), risk factors for drug-induced Tdp are age >65 years, female sex, acute coronary syndrome, electrolyte disturbances (hypokalemia, hypocalcemia, hypomagnesemia), and HFrEF. Escitalopram can also exacerbate sinus bradycardia/AV block by inhibiting sodium and calcium channels.[22]

Serotonin syndrome, a potentially life-threatening side effect, results from excess serotonin in the peripheral and central nervous systems. This medical condition can lead to symptoms of neuromuscular excitation and autonomic stimulation. Serotonin syndrome is more likely to occur in patients taking high-dose SSRIs, who have overdosed, or patients taking more than one serotonergic drug, especially if they work by different mechanisms (an SSRI plus a monoamine oxidase inhibitor, for example).[23] Symptoms of serotonin syndrome may include autonomic instability such as tachycardia, hypertension, dizziness, diaphoresis, flushing, mydriasis, and increased temperature (above 38 degrees Celsius). Clinical features are nausea, vomiting, diarrhea, and mental status changes like agitation, delirium, hallucinations, somnolence, and coma. Neuromuscular signs can also be present, including incoordination, rigidity, clonus, hyperreflexia, tremors, and hypertonicity.[23] There are reports of severe cases presenting with EKG changes and seizures.[24][23] Before trying another antidepressant therapy, a four-week weaning-off is advised to avoid causing serotonin syndrome.[25]

Drug Withdrawal: Escitalopram can cause withdrawal symptoms like dizziness, nausea, and lethargy if abruptly stopped.[10]

Drug-Drug Interactions

• A combination of escitalopram and rasagiline should be avoided due to the risk of serotonin syndrome.[26]
• SSRIs, including escitalopram, inhibit platelet function, risk of bleeding increases when given antiplatelet agents.[27] Bleeding tendency increases when administered with LWMH (low molecular weight heparin).[27][28]
• The risk of bleeding also increases when escitalopram is administered with NSAIDs.[29] SSRI may increase the risk of UGIB (Upper gastrointestinal bleeding) when administered with NSAIDs.[30]
• A study reported that patients administered an SSRI with aspirin or dual antiplatelet therapy(DAPT) after acute myocardial infarction had an increased risk of bleeding.[31]
• Increased risk of QT prolongation exists when escitalopram is given with other agents that can prolong QTc intervals, such as amiodarone, especially in patients with chronic kidney disease.[32]

Contraindications

Before prescribing escitalopram, a proper risk assessment for hypersensitivity reactions to other medications (especially antidepressants and SSRIs), possible QT prolongation, and serotonin syndrome is indicated for all patients. This drug is contraindicated for patients with a history of hypersensitivity reactions to escitalopram or citalopram.[15]

Co-administration of a monoamine oxidase inhibitor (MAOI) is also contraindicated with escitalopram due to the risk of causing serotonin syndrome. MAOIs include phenelzine, selegiline, isocarboxazid, and selegiline.[33] Other medications contraindicated due to the possibility of inducing serotonin syndrome include; antidepressants, triptans, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's wort. Drugs that impair serotonin metabolism, such as intravenous methylene blue, linezolid, MAOIs, and other psychiatric medications, are also contraindicated.[23][34]

Although it is a relative contraindication, the risk of QT prolongation is another consideration when starting escitalopram. A family history of long QT syndrome, or sudden, premature cardiac death, should be evaluated. Concomitant use of other drugs that can cause prolonged QT syndrome, including antipsychotics (especially older typical antipsychotics), should also be carefully assessed.[20]

In recent years, liver enzyme CYP2C19 activity has been assessed by pharmacogenetics as a determinant for contraindicating escitalopram use. CYP2C19 metabolizes escitalopram, and it is now possible to assess an individual patient's enzyme activity via genetic testing. Poor metabolizers, or those with decreased activity of this enzyme, are shown to have higher concentrations of escitalopram in their bloodstream and are, therefore, at higher risk of adverse drug reactions.[21] If the status of the CYP2C19 enzyme is known and is weak, it is reasonable to evaluate whether escitalopram use is necessary or whether adjustments should be made to the dose to avoid serious adverse drug reactions.[35]

Box Warning

Patients taking escitalopram should be monitored for mood or behavioral changes, including suicidality. An increase in suicidal thoughts and self-destructive behavior in pediatric and adolescent patients taking SSRIs have been documented.[1]

Monitoring

Monitor the effect of pharmacotherapy over time using GAD-7 (generalized anxiety disorder-7) and the HAM-A (Hamilton Anxiety Scale) for anxiety disorders.[36]

Monitor and quantify depression severity using PHQ-9 (Patient Health Questionnaire-9).[37]

Electrolyte disturbances (SSRI-induced SIADH) and EKG changes (QT prolongation) should also be assessed in subsequent visits with a basic metabolic panel and EKG, especially in patients 65 years or older or with a family history of arrhythmias.[15] In patients with a history of arrhythmias, follow-up EKGs after escitalopram has reached therapeutic levels are also recommended to evaluate for prolongation of the QT interval. A QT interval greater than 500 ms or a change from a baseline of more than 60 ms should consider changing to another antidepressant.[38] RISQ-PATH score can be used to monitor patients with a low risk of QT prolongation with a negative predictive value of 98.0%.[39]

Toxicity

Currently, the highest recommended dose of escitalopram is 20 mg PO daily. Management for out-of-hospital isolated SSRI overdose in patients who are experiencing minor symptoms (regularly less than five times their treatment dosage) is recommended at-home observation and in close conjunction with a local poison control center.[24]

In an overdose of escitalopram, the most concerning clinical aspect is QT prolongation and a subsequent torsade de pointes arrhythmia, which could be fatal. In reported ingestions of 300 mg or more of escitalopram, single-dose activated charcoal demonstrably decreased the fraction of absorption by 31% and decreased the risk of abnormal QT interval by 35%. Therefore, the recommendation is to administer a single dose of activated charcoal to patients who have ingested at least 300 mg of escitalopram in an attempted overdose. Cardiac monitoring of patients who receive activated charcoal (overdose of 300 mg or greater) is recommended for 12 hours.[40] In the event of the development of torsade de pointes, administer magnesium sulfate.[41] Patients with hemodynamically unstable TdP should undergo defibrillation.[22]

In patients with more severe hyperexcitability symptoms, supportive treatment is the mainstay. Besides discontinuing all serotonergic drugs, measures for adequate temperature and blood pressure control should be initiated; agitation control can be achieved with benzodiazepines. In severe cases of serotonin toxicity, patients may require endotracheal intubation and ventilatory support.[24] For refractory cases to supportive care, medications that are known to have anti-serotonergic properties, like cyproheptadine, a histamine-1 receptor antagonist, and nonspecific 5-HT1A and 5-HT2A antagonists, can be used. Despite this antagonistic effect, its effect on patient clinical outcomes is still unclear.[42] Hemodialysis is likely ineffective due to the large volume of distribution of escitalopram.[9][43]

Enhancing Healthcare Team Outcomes

Management of depression and anxiety requires an interprofessional team, including clinicians (MD, DO, NP, PA), psychiatrists, nurses, therapists, and pharmacists. When treating depression and anxiety with escitalopram, the interprofessional healthcare team should communicate and collaborate to achieve the best outcome for the patient. This collaboration can include thoroughly reviewing the patient’s medications to avoid drug interactions and adverse events. Furthermore, pharmacists may monitor the drug level in the blood in cases of overdose, and serum electrolyte levels will require monitoring for disturbances. Emergency physicians, medical toxicologists, and intensivists consultation are necessary in case of overdose. Any member of the interprofessional team who notes any issues or has a concern should contact other team members as appropriate for potential corrective action. In escitalopram overdose, these coordinated activities and open communication strategies will result in more effective therapeutic outcomes when using escitalopram while minimizing adverse effects. [Level 5]

A randomized controlled trial in which clinical care was provided by an interprofessional team of registered nurses, PSW (personal support workers), home care case manager, the client’s primary care providers, psychiatrists, occupational therapists, physical therapists, and social workers has demonstrated that interprofessional nurse-led mental health intervention effectively decreased healthcare utilization and improved patient outcomes under real-world conditions related to antidepressant therapy.[44] [Level 2]