Esketamine

BRAND NAMES

• Spravato

• Available as nasal spray

• Used under REMS program only

• Indicated for treatment-resistant depression

• Administered in clinics or healthcare settings

MECHANISM OF ACTION

Esketamine is a NMDA receptor antagonist that modulates glutamate neurotransmission in the brain. By enhancing synaptic connectivity and neuroplasticity, it produces a rapid antidepressant effect. Its action is different from traditional antidepressants, as it does not primarily target serotonin or norepinephrine. Esketamine is particularly effective in treatment-resistant depression, where conventional therapies have failed. It helps relieve symptoms within hours to days, offering faster improvement than standard antidepressants.

PHARMACOKINETICS:

Absorption:
Esketamine is absorbed rapidly through the nasal mucosa, reaching peak plasma levels in 20–40 minutes. Its bioavailability is around 48%, contributing to a fast onset of action.

Distribution:
It is widely distributed, moderately protein-bound (43–45%), and crosses the blood-brain barrier efficiently. Volume of distribution is about 3 L/kg, ensuring CNS action.

Metabolism:
Esketamine is metabolized in the liver via CYP2B6 and CYP3A4, forming the less active metabolite S-norketamine. Liver impairment may slow metabolism and clearance.

Excretion:
Excretion is mainly through urine, with a minor portion in feces. The elimination half-life is 7–12 hours, requiring careful dosing in liver or kidney impairment.

PHARMACODYNAMICS

Esketamine produces rapid antidepressant effects, often within hours of administration. It works by enhancing glutamate signaling and synaptic plasticity, restoring neural circuits affected by depression. It can also reduce suicidal thoughts in high-risk patients. Unlike conventional antidepressants, its effects are not primarily mediated by monoamines. The duration of antidepressant activity typically lasts several days, allowing for intermittent dosing schedules.

ADMINISTRATION

Esketamine is administered intranasally under strict medical supervision. Patients are monitored for at least two hours post-dose for adverse effects such as dissociation or elevated blood pressure. Dosing usually starts twice weekly during the induction phase and may taper during maintenance. Each spray delivers a specific dose based on body weight, ensuring precise control. Proper technique and consistent scheduling are essential for efficacy and safety.

DOSAGE AND STRENGTH

Esketamine nasal spray is available in 28 mg, 56 mg, and 84 mg doses per session. Initial induction is typically twice weekly for four weeks, followed by once-weekly or every-other-week maintenance. Dose adjustments may be necessary for elderly patients or those with hepatic impairment. Maximum single-session dose should not exceed 84 mg. Combination with an oral antidepressant is standard practice for optimal effect.

DRUG INTERACTIONS

Esketamine interacts with CYP3A4 inhibitors, which can increase plasma levels and risk of adverse effects. CNS depressants, including benzodiazepines or alcohol, may enhance sedation and dissociation. Co-administration with other antidepressants can produce additive CNS effects. St. John’s Wort may reduce the effectiveness of Esketamine. Careful monitoring is essential when combining Esketamine with multiple medications.

FOOD INTERACTIONS

Esketamine’s absorption is not significantly affected by food, allowing flexibility with meals. Alcohol should be avoided, as it increases the risk of dissociation and impaired judgment. High-fat meals do not alter its pharmacokinetics significantly. Caffeine or other stimulants may temporarily increase blood pressure after dosing. Patients are advised to maintain consistent hydration and diet during treatment.

CONTRAINDICATIONS

Esketamine should not be used in patients with hypersensitivity to ketamine or Esketamine. It is contraindicated in individuals with uncontrolled hypertension, aneurysmal vascular disease, or intracerebral hemorrhage. Pregnancy and lactation are relative contraindications unless the benefit outweighs the risk. Patients with a history of substance abuse require caution due to dissociative and abuse potential. Severe cardiovascular or cerebrovascular disease also precludes its use.

SIDE EFFECTS

• Dissociation

• Dizziness

• Nausea

• Headache

• Elevated blood pressure

• Vertigo

• Sedation

• Anxiety

• Blurred vision

• Feeling of detachment from reality

OVER DOSE

Overdose of Esketamine may result in excessive sedation, severe dissociation, and respiratory depression. Symptoms include confusion, agitation, hallucinations, and elevated blood pressure. Management involves supportive care, including monitoring of vital signs and oxygenation. Activated charcoal is generally not useful due to nasal administration. Severe cases may require hospitalization for close monitoring and stabilization.

TOXICITY

Chronic or excessive use of Esketamine can lead to neurotoxicity, bladder toxicity, and cognitive impairment. There is a risk of dependence or abuse if misused outside clinical supervision. CNS depression can be exacerbated by alcohol or sedatives. Patients with hepatic or renal impairment are at increased risk of toxicity. Strict adherence to dosing schedules and clinical monitoring is essential to prevent adverse outcomes.