Ketamine, a chiral compound, exists as two enantiomers: S-ketamine (esketamine) and R-ketamine (arketamine). These isomers, like mirror images of hands, have distinct effects on the brain and body. While ketamine has been around for a long time, the development and subsequent FDA approval of esketamine nasal spray in early 2019 for treatment-resistant depression (TRD) and acute suicidal ideation has brought renewed attention to the specific effects of the S isomer. This article delves into the various aspects of S-ketamine, comparing it with R-ketamine and racemic ketamine (a mixture of both), and exploring its clinical applications, mechanisms of action, and potential side effects.
Ketamine: A Historical Perspective
Ketamine was first synthesized in 1962 by Calvin L. Stevens and approved for use in the United States in 1970. Initially utilized as a safer anesthetic alternative to phencyclidine (PCP), it found widespread use in veterinary medicine and as a surgical anesthetic during the Vietnam War. In 2000, the discovery of its rapid antidepressant effects marked a major breakthrough in the treatment of depression, leading to its modern application in psychiatric care.
Understanding Ketamine's Isomers: S-Ketamine vs. R-Ketamine
Ketamine is a chiral molecule, meaning it exists in two non-superimposable mirror-image forms: S-ketamine and R-ketamine. These isomers interact differently with the brain, leading to variations in their therapeutic and side effect profiles.
- S-Ketamine (Esketamine): Also known as the left-handed version of ketamine, S-ketamine has a higher affinity for the NMDA receptor, approximately 3-4 times greater than R-ketamine. It is the active ingredient in the FDA-approved nasal spray, Spravato, for treatment-resistant depression.
- R-Ketamine (Arketamine): The right-handed version of ketamine, R-ketamine, has shown more marked and longer-lasting antidepressant-like effects in some studies.
While both isomers have antidepressant potential, S-ketamine is more likely to cause dissociative effects.
Clinical Applications of S-Ketamine
Treatment-Resistant Depression (TRD)
The FDA approved esketamine nasal spray for adults with treatment-resistant depression. TRD is diagnosed when a person doesn't respond to at least two different antidepressant treatments. S-ketamine offers a new approach for these individuals, providing rapid relief from depressive symptoms.
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Acute Suicidal Ideation
Esketamine's FDA-approved uses were later expanded to include patients suffering from acute suicidal ideation. The fast-acting nature of S-ketamine can be life-saving in these critical situations, providing rapid relief from suicidal thoughts and helping to stabilize patients.
How S-Ketamine Works
S-ketamine, like ketamine, primarily acts as an NMDA receptor antagonist. NMDA receptors bind to glutamate, a neurotransmitter. By blocking NMDA receptors, S-ketamine increases glutamate levels in the brain. This increase allows glutamate to connect to AMPA receptors, which can trigger a cascade of events that lead to improved mood and reduced depressive symptoms. S-Ketamine expands BDNF production, thus aiding neuron growth as well as cell survival.
The precise mechanism by which ketamine and its isomers exert their antidepressant effects is still under investigation. However, it is believed that they promote synaptic connectivity in the brain.
S-Ketamine Administration and Monitoring
Esketamine is administered as a nasal spray under strict medical supervision due to its potential for side effects and misuse. The drug warrants strict administration oversight because of its addictive quality, which limits its availability to certified health care facilities.
- REMS Program: Esketamine is only available under a Risk Evaluation and Mitigation Strategy (REMS) and only at certified treatment centers. A REMS protects the patient during treatment.
- Treatment Schedule: During the first four weeks, a patient visits the treatment center twice a week. During weeks five through eight, a patient visits once a week.
- Dosage and Administration: The nasal spray device contains 28 milligrams. The treatment provider will show the patient how to use the nasal spray.
- Post-Treatment Monitoring: After the patient has performed the treatment, they will remain at the treatment center for at least two hours. During that time, the provider will monitor them for dissociation or sedation.
Side Effects of S-Ketamine
At lower sub-anesthetic doses, psychiatric side effects are prominent. The most common psychiatric side effects are dissociation, visual distortions, and numbness. Also common (20-50%) are difficulty speaking, confusion, euphoria, drowsiness, and difficulty concentrating. Hallucinations are described by 6-10% of people. Dizziness, blurred vision, dry mouth, hypertension, nausea, increased or decreased body temperature, or flushing are the common (>10%) non-psychiatric side effects.
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- Dissociation: A sense of detachment from one's body and surroundings.
- Sedation: Drowsiness and a feeling of being out of it.
- Nausea and Vomiting
- Increased Blood Pressure
- Other Psychiatric Effects: Visual distortions, numbness, difficulty speaking, confusion, euphoria, difficulty concentrating, and hallucinations.
- Other Non-Psychiatric Effects: Dizziness, blurred vision, dry mouth, hypertension, nausea, increased or decreased body temperature, or flushing.
S-Ketamine vs. Racemic Ketamine
While S-ketamine is a component of racemic ketamine, there are key differences between the two:
- Composition: Racemic ketamine contains equal parts of S-ketamine and R-ketamine, while esketamine is a modified form of ketamine that only includes one of the molecules found in the substance.
- Administration: Esketamine is available as a nasal spray, while racemic ketamine is most commonly given in IV form. Injections, oral versions and nasal sprays of racemic ketamine are available but are less common.
- FDA Approval: Esketamine is FDA-approved for TRD and acute suicidal ideation, while racemic ketamine is FDA-approved as an anesthetic but is used off-label for depression.
- Insurance Coverage: Esketamine (Spravato) receives insurance coverage; however, patients must cover the costs of racemic ketamine since these treatments are used off-label.
Ketamine and Neuroplasticity
Neuroplasticity defines the brain's capacity to create new connections and make adaptations to external alterations. The brain conducts a structural rearrangement to develop better coping mechanisms against future obstacles. Neuroplasticity develops through essential processes that help heal depression symptoms along with PTSD, while also enhancing people's moods.
R-Ketamine was thought to establish itself through its strong capability to encourage synaptogenesis in both the prefrontal cortex and hippocampus, which could lead to long-term therapeutic results. S-Ketamine expands BDNF production, thus aiding neuron growth as well as cell survival.
Ketamine in Veterinary Medicine
In veterinary anesthesia, ketamine is often used for its anesthetic and analgesic effects on cats, dogs, rabbits, rats, and other small animals. It is frequently used in induction and anesthetic maintenance in horses. Veterinarians often use ketamine with sedative drugs to produce balanced anesthesia and analgesia, and as a constant-rate infusion to help prevent pain wind-up.
Long-Term Effects and Potential Risks
The long-term effects of repeated ketamine use are still being investigated.
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- Urinary Toxicity: Urinary toxicity occurs primarily in people who use large amounts of ketamine routinely, with 20-30% of frequent users having bladder complaints. It includes a range of disorders from cystitis to hydronephrosis to kidney failure.
- Liver Toxicity: Liver toxicity of ketamine involves higher doses and repeated administration.
- Dependence and Tolerance: Although the incidence of ketamine dependence is unknown, some people who regularly use ketamine develop ketamine dependence. Ketamine tolerance rapidly develops, even with repeated medical use, prompting the use of higher doses.