It hasn’t been that long since ketamine (and its derivative, esketamine) came into common awareness – a phenomenon that seemed to happen almost overnight. Enthusiasm for ketamine, esketamine, and a variety of different psychedelic medications currently under FDA investigation bloomed into our communal experience in just the past few years, garnering media attention, social media posts, conversations among friends, books, and so on. While, certainly, there has been an undercurrent of awareness that ketamine and similar medications can be helpful in the treatment of mental health conditions for quite some time, the growing permissiveness to talk about and explore the medical utility of these kinds of medications combined with some of the very promising outcomes from studies has fueled a tremendous interest. The question then becomes: beyond media hype, beyond lay-publications and social media, what does the provider need to know about these medications to responsibly talk about them with their patients?
What are ketamine and esketamine?
Ketamine is classified as an anesthetic agent. Its anesthetic effects are thought to be mediated by blockade of receptors associated with the excitatory neurotransmitter, glutamate. However, paradoxically, at low doses, due to the more selective activity on the receptors involved in the inhibitory feedback loop related to the release of glutamate, ketamine actually enhances the release of glutamate with a number of downstream effects. Ketamine is a racemic mixture of dextrorotatory and levorotatory enantiomers of the ketamine molecule. The dextrorotatory enantiomer is very poorly orally and transmucosally absorbed. Therefore, when administering ketamine, many prefer to administer parenterally, either intravenously or through intramuscular injection.
Esketamine is the levorotatory enantiomer. This particular conformation of the ketamine molecule is, indeed, transmucosally absorbable, hence its intranasal application as the medicine "Spravato." Both have the same mechanisms of action, and both have the same side effects.
What are the side effects of ketamine and Spravato (esketamine)?
Most side effects occur while the medication is in one’s a system. Headache, sedation, dissociation, double vision, blurry vision, poor coordination, hypertension, tachycardia, nausea, vomiting, dizziness, sialorrhea, and psychedelic-like experiences are very common. Once the medication has left the system, some people report some persistent headache, tiredness, and nausea. This usually resolves throughout the course of the day with a small subset of people continuing to report the side effects even until the next day. With specific regard for ketamine, pain at the injection site can occur. With specific regard to esketamine (Spravato), a bitter taste in the back of one’s throat can also occur.
What Psychiatric Conditions do Ketamine and Esketamine (Spravato) Treat and What are the Costs?
Soon after its FDA approval in the 1970s as an anesthetic agent there were a handful publications that recognized the potential psychiatric application of ketamine. Some of these revolved around changes in drinking habits, and another study recognized its potential role in mood regulation. That said, things "went dry" for almost 30 years. As the apocryphal story goes, in the late 1990s when psychiatrists were looking for novel targets for antidepressant medications, especially glutamate and the NMDA receptor, a chance conversation between an anesthesiologist and a psychiatrist on a train lead to the re-discovery that, at low doses, ketamine can enhance the activity of glutamate. The physician scientist at the time, Dr. Amit Anand, provided a single dose of ketamine to a patient who was having active suicidal thoughts and to everyone's both pleasure and surprise, the individual's suicidality improved! The first paper documenting this renewed interest in ketamine as a novel potential antidepressant was in 2000. Over the past two decades a host of articles have confirmed that, for some, ketamine can provide rapid alleviation of depressive symptoms, including depressive symptoms and those for whom multiple trials of standard antidepressant medications have been insufficient at resolving depression.
Esketamine, being more heavily regulated in some respects because of its FDA-approval, is exclusively approved for the use of the treatment of treatment refractory depression (i.e., depressive episodes occurring in the context of major depressive disorder that has not responded to between 2-4 antidepressant trials of adequate dose and adequate duration - these must be "classic" antidepressants and not medications that have antidepressant-like effect but are not classified as antidepressants, such as lamotrigine). In addition, esketamine is also approved for the treatment of suicidality occurring in the context of major depressive disorder. Esketamine is covered by insurance.
Ketamine's application for the treatment of psychiatric conditions is off-label. There is empirical evidence that ketamine can treat depressive episodes occurring in both the context of major depressive disorder as well as bipolar disorder. There are case reports and reviews of ketamine's potential application in treating OCD, different anxiety disorders, and PTSD. Ketamine is generally not covered by insurance with only very exceptions (i.e., certain methods of administration, especially IV, for certain indications – specifically the same indications as esketamine).
How likely our ketamine and esketamine to work?
While media has focused a lot of attention on the effectiveness of both ketamine and esketamine as well as the rapidity of this effectiveness, an important consideration that has been left out of the conversation is that ketamine and esketamine do not work for everyone. Somewhere between 30 to 50% of people who try ketamine or esketamine will not notice benefit. And while it is true that the majority of people who try ketamine or esketamine do experience some degree of benefit, it is only a subset of those people who experience categorical resolution of symptoms. All conversations about ketamine and esketamine must include a conversation about its potential ineffectiveness. Patients can sometimes approach ketamine and esketamine with so much hope that, if the treatment were ineffective or insufficiently so, patients are doubly injured: Not only do they not feel better, but also something to which they attached hope has let them down. For that reason, a balanced conversation with expectations about how the effectiveness will be assessed should be a part of all ketamine and esketamine conversations and consultations.
When do I recommend ketamine and esketamine to a patient?
If there is a potential indication that ketamine and esketamine can treat and if a person is experiencing a significant burden of illness, it is absolutely worth starting the conversation. A provider thinking about recommending ketamine or esketamine does not be expert in ketamine or esketamine, but should have access to a consulting psychiatrist who is familiar with these treatments to whom the patient can be sent for a consultation and potential medical necessity evaluation. When ketamine and esketamine work, the effect can be profound (for some) and occur quickly, sparing patients long duration of high morbidity illness. Oftentimes, recommendations to explore ketamine and esketamine occur months or even years into the experience of a mental health condition. Trying to reach patients earlier in their disease course, especially when other treatments have been insufficiently effective, to reduce the overall duration of time spent feeling poorly is reasonable. The recommendation to meet with somebody to talk more about ketamine and esketamine is not necessarily recommendation to pursue it, but a recommendation to your patient to learn more about other treatments to which he/she/they might avail themselves.
How do I communicate with ketamine and esketamine providers?
One of the most consistent criticisms of ketamine and esketamine clinics is the general lack of transparency that occurs once the patient begins a treatment program. Communication between the patient's primary psychiatric provider and the ketamine clinic should occur as often as needed. At the very least, a conversation occurring once monthly or once quarterly, coming from the ketamine clinic, describing the patient's progress should occur. Additionally, if the patient's outside providers are making medication changes, that should likewise be communicated to the ketamine/esketamine provider. At Lumin Health, we have a commitment to transparency with our healthcare partners and make a concerted effort across all areas of care to communicate clearly and effectively with primary providers. Please don't hesitate to get in touch with us if you are interested in referring patients for mental health treatment with ketamine therapy or Spravato (Esketamine) by sending us an email — hello@lumin.health — or filling out our patient referral form.
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