What is Ketamine?
Ketamine is a dissociative anesthetic that has been used clinically since the 1970s. It is made up of two enantiomers, S-ketamine and R-ketamine, with S-ketamine being more potent. Originally used as a general anesthetic, ketamine was found to have analgesic and antidepressant effects at subanesthetic doses.
Ketamine works primarily as a noncompetitive N-methyl-D-aspartate receptor (NMDA) antagonist. The NMDA receptor is one of three glutamate receptors; glutamate being the main excitatory neurotransmitter in the central nervous system. By blocking NMDA receptors, ketamine disrupts communication between neurons in the brain, affecting sensory perception, motor coordination, and mood.
Uses of ketamine
Ketamine is used medicinally for the following:
- Anesthetic for minor procedures or as an induction agent for major operations
- Analgesic for acute or chronic pain
- Adjunct for the treatment of depression, bipolar disorder, and post-traumatic stress disorder
Forms of ketamine
Ketamine is available in several forms:
- Tablets (difficult to manufacture)
- Liquid solution for oral use, injection, or infusion
- Powder for injection after mixing with a liquid
- Nasal spray
What is Esketamine?
Esketamine, also known as S-ketamine, is the most potent of two enantiomers that make up the ketamine molecule. Esketamine nasal spray received FDA approval in 2019 for treatment-resistant depression and is marketed under the brand name Spravato by Janssen Pharmaceuticals.
How esketamine works
Like ketamine, esketamine acts primarily as an NMDA receptor antagonist. By blocking NMDA receptors, esketamine increases glutamate production resulting in changes in neurotransmitter release and synaptic connectivity in the brain. This mechanism of action is believed to contribute to the rapid antidepressant effects of the drug.
Delivery methods
Esketamine is only available in a nasal spray form for the following reasons:
- Non-invasive and easy to use
- Avoid first pass metabolism by the liver, increasing bioavailability
- Rapid absorption via the nasal mucosa into the bloodstream
Key Differences Between Ketamine and Esketamine
There are several key differences between ketamine and esketamine to be aware of:
1. Active Enantiomer
The main difference between ketamine and esketamine is that ketamine is a racemic mixture consisting of equal parts S-ketamine and R-ketamine. Esketamine consists of only the S enantiomer and is therefore twice as potent as ketamine.
2. Dosage and Administration
Since esketamine is more potent, the approved dosage and administration differs from that of ketamine. The initial dose of esketamine nasal spray for depression is 56 mg twice per week for 4 weeks, with subsequent doses of 56 mg or 84 mg based on efficacy and tolerability. Ketamine requires much higher doses administered orally, by injection, or infusion to achieve antidepressant effects.
3. Side Effects
Adverse effects are similar between ketamine and esketamine due to their similar mechanisms of action, but there are a few differences. More intense transient dissociation and perception disturbances occur with ketamine use. Blood pressure spikes tend to be higher and more persistent with ketamine as well. Esketamine is associated with transient sedation shortly after dosing. They both carry risks of misuse and dependence.
4. Cost
As a generic drug available for decades, ketamine therapy is much cheaper than esketamine treatment at this time. A full course of esketamine treatment can cost nearly $5,000 or more while intravenous or oral ketamine protocols may range between $350 - $1,000 in some clinics.
5. Approvals
Esketamine has FDA approval specifically for treatment-resistant depression. Ketamine does not have FDA approval for depression but is used off-label for this purpose. Ketamine does have approval in the U.S. for anesthesia and analgesia. Many other countries also approve ketamine as a psychiatric medication.
The Efficacy of Esketamine for Depression
Clinical trials have demonstrated that esketamine nasal spray, in conjunction with an oral antidepressant, is highly effective for rapidly improving depressive symptoms in patients who have not responded to other treatments.
Evidence from Clinical Trials
In a phase 3 trial published in 2018 in the American Journal of Psychiatry, nearly 70% of those in the esketamine group experienced at least a 50% improvement in depression scores compared to just over half in the placebo group. Symptom improvements occurred within hours after the first dose.
Lasting Effects
A study in the journal JAMA Psychiatry showed that, although depression scores initially spike back up after stopping esketamine, relapse of symptoms took 25 days or longer during the maintenance phase. This indicates there is a sustained beneficial after-effect of repeated esketamine dosing on brain function.
Remission Rates
About 24-28% of esketamine-treated patients with highly resistant depression go into full symptom remission based on clinical trial results. This is nearly double the remission rate of commonly used oral antidepressants for similar patients.
So while esketamine may not produce remission for a majority of people, it does appear to be highly and uniquely effective for relieving severe depression in a significant proportion of patients who have failed other therapies.
Potential Risks and Side Effects
While delivering rapid improvement of depression, esketamine treatment also presents some risks requiring monitoring and management. The nature and frequency of side effects are an important consideration regarding the overall safety profile of esketamine.
Common Adverse Effects
The most common side effects occurring during clinical trials include dissociation/perceptual changes, dizziness, nausea, headache, fatigue, anxiety, vertigo, dysgeusia (distortion of sense of taste), hypoesthesia (reduced touch sensation) and vomiting. Most of these transient effects resolving soon after dosing.
Sedation and Dissociation
Due to the temporary dissociation and sedation following an esketamine dose, patients must be monitored by a health professional for at least 2 hours. Patients are also advised not to drive on the day of dosing.
Blood Pressure Changes
Blood pressure typically spikes transiently following an esketamine dose, requiring blood pressure monitoring for 2 hours post-administration. No increase in cardiovascular events has been observed but close monitoring of patients with unstable/uncontrolled blood pressure is advised.
Other rare side effects like bladder injury, psychotic symptoms and suicidal thoughts have been reported with long-term, high-dose recreational ketamine use but have not been observed with short-term, controlled clinical use of esketamine.
Expanding Potential Applications
Currently, FDA approval restricts the use of esketamine to adults with treatment-resistant depression. But esketamine holds promise for beneficiaries beyond this group based on clinical trials.
Rapid Relief of Suicidal Thoughts
In a 2018 randomized trial published in the American Journal of Psychiatry, esketamine demonstrated a significant benefit over placebo at rapidly reducing acute suicidal ideation. Further study regarding esketamine's role for suicide prevention is needed and underway.
Treatment of Other Conditions
Research is ongoing into esketamine as a therapy for conditions like bipolar depression, post-traumatic stress disorder, substance abuse disorder, obsessive-compulsive disorder and alcohol use disorder. Future expansion of esketamine's indications is likely.
Geriatric Patients
Older adults with late-onset depression that has proven refractory to other interventions may benefit from esketamine based on two positive phase 3 trials. For this vulnerable group, esketamine could provide later-in-life relief where few options exist currently.
Expanding access beyond the current restrictions allows broader access to fast relief from suffering that too often ends tragically. But balancing wider availability with safety precautions around a psychoactive substance remains an important consideration moving forward.
Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always consult with a healthcare professional before starting any new treatment regimen.
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