Continuing Education Activity
Escitalopram is a medication used to manage and treat the major depressive disorder and generalized anxiety disorder. It is in the selective serotonin reuptake inhibitor class of drugs. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions, adverse events) pertinent for members of the healthcare team in the management of patients with depression, anxiety, and other related conditions.
- 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.
Escitalopram is a selective serotonin reuptake inhibitor (SSRI). It is the S-enantiomer of citalopram and is the most selective of SSRIs. SSRIs are widely known for their use in the treatment of depression, anxiety, and other related disorders. Escitalopram (and SSRIs) are also known for their off-label use for the treatment of social anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder, and vasomotor symptoms of menopause.
Mechanism of Action
SSRI's mechanism of action is exerted by binding to the sodium-dependant serotonin transporter protein (SERT), also known as 5-HTT, which is located in the presynaptic neuron. SERT works by re-uptaking serotonin from the synaptic cleft to the presynaptic neuron and thus increasing the amount of serotonin in the synaptic cleft. This activity potentiates the effect of serotonin in the central nervous system. Serotonin or 5-hydroxytryptamine (5-HT) modulates a wide range of human behavioral processes, which includes 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. There are five main serotonin receptors; 5-HT1A, 5-HT1B, 5-HT4, 5-HT6, 5-HT7 located in the brain. In total, there are 15 known serotonin receptors, and all of them can also be found outside the central nervous system.
Absorption: Dose linear and dose-proportional l in a dose range of 10 to 30 mg/day; absorption is not affected by the presence of food.
Time of peak plasma concentration: 5 hours
Volume of distribution: 12 L/kg
Plasma Protein binding: 56 %
Metabolism: Metabolized to S-demethylcitalopram (S-DCT) and S-didemethylcitalopram (S-DDCT) in the liver.
Terminal half-life: 27 to 32 hours, and it takes 7 to 10 days for it to reach a steady-state in the blood.
Excretion: 8% of unchanged escitalopram and 10% of S-DCT are excreted in the urine.
Escitalopram is administered via the oral route. It is available as a 1 mg/mL oral solution as well as 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, and after one week, the dose can be increased to achieve proper symptoms control. A 4-week dose reduction is recommended when trying to switch escitalopram for 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).
- Pregnant Women: It is considered as pregnancy category C medicine. It is recommended to monitor patients closely and adjust the dose based on individual patient need as escitalopram and desmethylcitalopram can cross the placenta and can be distributed into the amniotic fluid.
- Breastfeeding Women: It is recommended to calculate and use relative infant dose below 10% as escitalopram, and its desmethylcitalopram (DCT) metabolite are excreted in breast milk.
- Pediatric Patients: In a single-dose study in adolescent patients (12 to 17 years of age), 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. As per the manufacturer label, a 10 mg dose of escitalopram is recommended for geriatric patients.
Escitalopram and SSRIs have a lower toxicity profile than older antidepressants. Despite this, they have been associated with significant adverse effects. 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.
Escitalopram can potentially cause withdrawal symptoms like dizziness, nausea, and lethargy if abruptly stopped.
Escitalopram can cause SSRI-induced syndrome of inappropriate antidiuretic hormone secretion (SSRI-induced SIADH), leading to hyponatremia, especially in elderly patients. Depending on the severity of hyponatremia, symptoms can range from anorexia, nausea, vomiting, fatigue, headache to more severe conditions like; altered mental status, seizures, and even coma.
QT prolongation and serotonin syndrome are amongst the rare but serious adverse effects caused by escitalopram. QT prolongation is defined as a corrected QT interval on an EKG of greater than 500 ms or an increase from a baseline interval of more than 60 ms. QT prolongation can cause potentially fatal cardiac arrhythmias, including torsade de pointes. The mechanism by which escitalopram causes QT prolongation is a poorly understood phenomenon. However, it is known to be a dose-dependent relationship.
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). Symptoms of serotonin syndrome may include autonomic instability such as tachycardia, hypertension, dizziness, diaphoresis, flushing, mydriasis, and increased temperature (above 38 degrees celsius). It can also include nausea, vomiting, diarrhea, and mental status changes like agitation, delirium, hallucinations, somnolence, and coma. Neuromuscular symptoms can also present, including incoordination, rigidity, clonus, hyperreflexia, tremors, and hypertonicity. There are reports of severe cases presenting with EKG changes and seizures. Before trying another antidepressant therapy, a four-week weaning-off is advised to avoid causing serotonin syndrome.
In order to prescribe 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 who have a prior history of hypersensitivity reactions to escitalopram or citalopram.
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. Other medications contraindicated due to the possibility of inducing serotonin syndrome include; antidepressants, triptans, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, St. John's Wort. Drugs that impair the metabolism of serotonin, such as intravenous methylene blue, linezolid, MAOIs, and other psychiatric medications, are also contraindicated.
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.
In recent years, liver enzyme CYP2C19 activity has been evaluated in pharmacogenetics as a determinant in contraindicating escitalopram use. CYP2C19 metabolizes escitalopram, and it is now possible to assess an individual patient's activity of this enzyme 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. 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.
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 in the past.
Electrolyte disturbances (SSRI-induced SIADH), 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. 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 baseline of more than 60 ms should merit consideration of changing to another antidepressant.
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 close conjunction with a local poison control center.
In an overdose of escitalopram, the most concerning clinical aspect is QT prolongation and a subsequent torsade de pointes arrhythmia, as this 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. In the event of the development of torsade de pointes, administer magnesium sulfate.
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. 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.
Enhancing Healthcare Team Outcomes
Management of depression and anxiety requires an interprofessional team, including physicians, 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 a thorough review of 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 be necessary to monitor for disturbances. These coordinated activities and open communication strategies will result in more effective therapeutic outcomes when using escitalopram while minimizing adverse effects. [Level 5]