What’s the Deal with Esketamine?
Esketamine, the newest drug for treating depression, has captured headlines since it was approved by US’s Food and Drug Administration last week. Esketamine is particularly notable due to its close similarity to ketamine, an anesthetic and popular street drug also known as ‘Special K’. Today, I’m going to address some questions about esketamine. What is this antidepressant, how does it work, and how is it different from ketamine?
What is esketamine?
Esketamine, which will be sold as Spravato, was produced by Janssen Pharmaceuticals of Johnson & Johnson. It was developed as an option for treatment-resistant patients suffering from clinical depression; it stands out from standard oral antidepressants particularly because it is a nasal spray. Five Phase 3** studies showed that treatment with esketamine, alongside a newly initiated oral antidepressant, led to a significant reduction of symptoms (this was compared to a second group with a placebo and a newly initiated oral antidepressant to confirm that the esketamine actually made a difference).
**Phase 3 trials are the last step before submitting a drug for FDA approval. They provide insight about the benefit-risk relationship of the drug, and expand on safety and effectiveness data previously acquired in Phase 1 and Phase 2 trials. After FDA approval, Phase 4 continues to investigate long-term safety of the drug, while it is available to the general population.
How is it different from current antidepressants?
Currently, there are five standard classes of antidepressant medications: selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, and atypical antidepressants. SSRIs and SNRIs are usually taken orally, and are the least likely to cause major side effects so are usually prescribed first. For example, the SSRI escitalopram, marketed as Cipralex or Lexapro, is commonly prescribed first to treat major depressive disorder or general anxiety disorder — you probably know someone who is taking escitalopram, even if you don’t know they are taking it. Other common SSRIs include Prozac, Zoloft, and Celexa, and SNRIs include Effexor and Pristiq. MAOIs are known for being strong antidepressants but are prescribed less frequently, as they have a significant number of dangerous drug interactions: anything from St. John’s wort to some anesthetics to amphetamines (including ADHD drugs like Adderall) can react negatively with MAOIs. Tricyclic antidepressants also run a risk of side effects so they are also more likely to be prescribed after SSRIs and SNRIs have been tried. Atypical antidepressants include anything else that doesn’t fit in the other four categorizations. You may have heard of Wellbutrin, which is an atypical antidepressant.
Esketamine would currently fall into the atypical antidepressant category, since it works as an NMDA receptor antagonist. The NMDA receptor is a glutamate receptor, which means that it interacts with glutamate to induce postsynaptic excitation and increase the likelihood of a specific neuron firing. The NMDA receptor requires both glutamate and glycine (or NMDA acting as glutamate). It is sensitive to zinc and magnesium ions, which block the flow of positively-charged ions upon binding. Since it is an uncompetative antagonist, esketamine stops this process from happening by physically blocking the channel.
Q. How does any of this relate to clinical depression?
A. ¯\_(ツ)_/¯. Studies have already begun to link the glutamatergic system, of which the NMDA receptor is a part of, to major depressive disorder (MDD). This is an area that researchers are investigating to understand etiology and mechanisms of MDD. There is a hypothesis that esketamine may work as an antidepressant by blocking NMDA receptors on GABA neurons and eventually leading to an increase in dopamine released in the brain, but it’s still pretty unclear exactly how NDMA receptors and MDD are related.
How is it different from ketamine?
This one made me laugh — esketamine gets its name because it is actually (S)-ketamine, the S enantiomer of ketamine, and opposite of arketamine/(R)-ketamine. What does that mean? Think of it like your two hands — they are mirror images of each other that can’t be superimposed (when your palms are both facing you, your fingers do not line up, and when your fingers line up, your palms are facing opposite directions). This is the difference between esketamine and arketamine. They have the same chemical formula, and all of the atoms that make up the molecule are bonded to each other in the same way when you look at it from a two-dimensional perspective, but they exist in different three-dimensional orientations. The ketamine we are referring to when we talk about the horse tranquilizer is what is known as a racemic mixture — it has both (R)-ketamine and(S)-ketamine mixed together 50/50.
And yes, taking esketamine can cause the same effects as taking ketamine. This is one of the reasons that it is probably not going to become a mainstream option for treating MDD. Because of its potential for abuse, and the possibility of it causing side effects like hallucinations, extreme drowsiness, taste disturbances, dissociation, and numbness, saying that esketamine is going to be administered in an unusual fashion is an understatement. Patients are not going to be allowed to take esketamine home — they will self-administer at a clinic under supervision by a doctor. They will also not be allowed to drive or use heavy machinery on days of administration, and will be required to remain in the clinic for at least two hours until the doctor determines that they are ready to go home. It also can cause problems with pregnancy by hurting the fetus, and women are not advised to breastfeed while undergoing treatment. So, esketamine may be used to treat depression in those who do not respond to other treatments, but treatment is definitely inconvenient and may be considered inaccessable to a percentage of the population who can’t work around the above listed requirements. For some, the inability to drive for the day may be a dealbreaker alone. Practitioners could also face an ethical dilemma when deciding whether to administer the treatment to someone with a history of addiction (ketamine is not an opioid, but it is addictive, and some parallels may be seen in the future between esketamine treatment for severe depression and use of oxycodone and other opioids in treatment of pain).
Summary
Treatment with esketamine, the S enantiomer of ketamine, is impractical for most patients suffering from major depressive disorder. However, under the right circumstances, when the patient is not responding to other types of medication including SSRIs, SNRIs, tricyclic antidepressants, or MAOIs, esketamine may provide the relief of symptoms needed for a patient to live a functional life free of depression, which is the most important goal. In the future, perhaps research will uncover a way to block NMDA receptors in a way that is more convenient and accessible and create a new class of antidepressants (NMDARAs for NMDA receptor antagonists? Maybe NRAs? …never mind). Until then, don’t expect to be prescribed esketamine except in severe, treatment-resistant cases of clinical depression.
