Unlocking the Mysteries of the Glutamate System
Ketamine, Similar Compounds Emerging as Mood Disorder Treatments
Sanjay J. Mathew, MD, vice chair for research at Baylor College of Medicine and staff physician at the Michael E. Debakey VA Medical Center in Houston, Texas, has long been interested in the brain’s glutamate system and how it could be manipulated with substances such as ketamine to treat conditions including depression and suicidal ideation.
At this year’s Psych Congress, Dr. Mathew, who is also director of Baylor’s mood and anxiety disorders program, will share the top 5 things that mental health clinicians should know about therapy with ketamine and the esketamine nasal spray newly approved by the US Food and Drug Administration (FDA). Below, he discusses his research into ketamine, how it works in the body, ongoing research into the compound, and similar agents that are in development.
Q: How did you first become involved with research into glutamatergic agents such as ketamine?
A: I've been involved ever since my faculty position at Mount Sinai [School of Medicine], where we were interested in the glutamate system broadly for its potential impact in neuroplasticity and we were studying agents such as riluzole, which is approved in amyotrophic lateral sclerosis (ALS), and repurposing it for depression and generalized anxiety disorder. And then in 2006, we noted the work by [Carlos A.] Zarate, and prior to that John Krystal and Dennis Charney at Yale [School of Medicine] had done initial studies with IV ketamine. Dennis Charney, who was my mentor at Mount Sinai, influenced us to try to replicate and extend some of the work of Zarate. And so we've been involved since that early time testing ketamine as an antidepressant but also looking at it in suicide and looking at it from a mechanistic point of view, trying to understand how it may be working in patients.
Q: What did you find exciting? Why did you think it was something you wanted to spend time working on?
A: It was really a paradigm shift, in that it was a way to rapidly potentially get a patient better, get them out of a depression. Many of these patients had been depressed for several decades and they report that they'd been on multiple trials and even if the trials of selective serotonin reuptake inhibitors (SSRIs) or other medications worked, they would lose effectiveness, and they would relapse. So it was an almost sort of endless cycle of partial hope and then despair. Some of these patients had had electroconvulsive therapy (ECT). Some of them had had multiple hospitalizations and suicide attempts and so they were really seeking alternatives. They were exploring neurostimulation. Around that time, transcranial magnetic stimulation (TMS) had become FDA-approved. And there was clinical trials in deep brain stimulation. Ketamine offered this hope that you could get out of the despair or hole of depression and get better quickly and so that was what was exciting, I think, for patients. And then for me, as a clinician, to actually see that awakening, if you will, of patients for several hours after the infusion, that would persist in some patients for several days—and we've had patients even with several week responses—was very gratifying to see. The challenge of course is how did you maintain that wellness as inevitably the ketamine effect wears off and patients would relapse. And so that's where we've been devoting a lot of our efforts to identify the best ways to maintain the benefit.
Q: In your research, what have you found most striking about ketamine and similar agents?
A: Well, it seems that across different clinical programs, different research programs in the US and internationally, ketamine no matter what the formulation—be it IV, intranasal, subcutaneous, and so on— does appear to have this rapid onset of benefit within 50% plus of patients, even with resistant depression, and it also appears to have antisuicidal properties that may be independent of depression. And that's been a replicable finding. Now with the FDA approval of intranasal esketamine, we've seen data even in very large numbers supporting that notion, that you can get a patient better, quicker, and get them out of the suicidal state. So that research over the last 10 to 15 years has now matured to the point where we actually now have an FDA-approved variant of ketamine that will now be available to potentially many more thousands of patients.
Q: Can you explain how ketamine works in the body and how it is different from other antidepressants?
A: It's different, most fundamentally, in that it does not impact the monoamine systems directly. So it doesn't impact serotonin, norepinephrine, and dopamine directly. I mean certainly there are indirect effects on multiple systems. How ketamine is actually working as an antidepressant is part of the talk I'll be giving at Psych Congress, and it's a complex story and it's an evolving story. We know its initial target is on the glutamate N-methyl-D-aspartate (NMDA) receptor and it's a channel blocker, so it works within the ion channel and binds to the phencyclidine (PCP) site within the channel pore. So it's a channel blocker but at the same time it may potentiate the activity of other glutamate receptors, namely the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. We know the AMPA receptor is critical for a whole host of processes involving learning, memory, and mood. And AMPA receptor potentiation is critical to neuroplasticity and the growth of synaptic connections, or so-called synaptic connectivity. So the pathways involve enhancement of brain-derived neurotrophic factor (BDNF) and other neurotrophic factors and proteins that are involved in this process that makes synapses or spaces between neurons connect better with each other. So that's sort of a long-winded explanation of a very exciting area in basic science.
There's been recent work by Conor Liston at Weill Cornell Medicine in New York, and then building on work from Ron Duman and others from Yale, showing that the enhancement of spines, so-called dendritic spines, is required for sustaining the antidepressant activity of ketamine. And it explains why, when ketamine's out of your system in several hours, there are effects longer term, well beyond the time the drug has left your body. And it may be because, what's been shown in animals, is the formation of these newly formed dendritic spines. Very exciting work.
Now it should be mentioned that there's controversy regarding the role of glutamate and NMDA in ketamine's activity. Work by Alan Schatzberg most recently, and his colleagues at Stanford, including Carolyn Rodriguez and Nolan Williams, they've shown that if you give naltrexone, which is a mu-opioid receptor blocker, you can attenuate the antidepressant activity of ketamine. So they've argued that ketamine acts by an opioid mechanism, either directly as a mu receptor agonist, or through an endogenous opiate mechanism, which remains to be determined. And so that's very intriguing data in a small group of patients, and there have been arguments back and forth, both clinically and preclinically, suggesting that ketamine's opiate activity is not a critical aspect. So I think that argument remains in progress and it's an interesting one, particularly as this is a Schedule III agent, a potential agent of abuse. We know it's misused in regions in the country and internationally, and so the last thing we want to do as clinicians is start another opiate abuse epidemic, and so we need to be very careful and mindful about this product and its mechanism of action. I think we just need to learn a lot more about it.
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Q: Has ketamine shown promise in treating any conditions other than depression and suicidal ideation?
A: Post-traumatic stress disorder (PTSD) is probably been the other main indication that's under study. There's initial pilot reports with a single infusion showing rapid reductions in broad PTSD symptoms across multiple dimensions of the illness, including the hyperarousal that we experience in the mood and cognitive symptoms associated with PTSD. There's now an ongoing trial funded by United States Department of Veterans Affairs (VA) and Department of Defense, run by John Krystal at Yale and John Roache in San Antonio, studying two doses of ketamine vs placebo in almost 200 patients with PTSD. So I think that'll be the definitive largest trial of ketamine.
There's also been some other smaller studies of obsessive-compulsive disorder (OCD) based on some initial work that there could be reductions in obsessions and compulsions associated with this illness. There's also been some interesting work from Elias Dakwar, at Columbia University and the New York State Psychiatric Institute, where he's combining ketamine with a mindfulness-based group psychotherapy. And he's using that as a means to enhance the effectiveness of this mindfulness therapy to decrease relapse for cocaine use disorder patients. And so this is a study that I think soon will be published in the American Journal of Psychiatry, showing remarkable persistence of the benefit of coadministration of ketamine with this group psychotherapy. So there's a number of potential applications beyond major depression, but I think the most promising, certainly have been the suicide and the PTSD indication. I should also mention there's been work in bipolar depression, which would be a natural sort of extension of the work in treatment-resistant depression.
Q: What risks or possible side effects do patients face when taking ketamine?
A: The most commonly observed side effects would be dissociation, and dissociation can entail feelings of unreality, feeling outside of yourself, feeling outside of your body, like you're looking outside yourself from above, and feelings of floating, levitation, feelings that your body parts are unusually big or unusually small, an altered sense of time.So these are strange experiences, some have called it a K-hole type experience. Users of ketamine get into this sort of altered state and for some it can be a scary experience, but for many, it's not unpleasant. And these are transient effects that generally normalize within an hour and one of the reasons that there is a 2-hour recommended monitoring period is to make sure patients, after their treatments, are no longer having dissociation or sedation. Sedation is another commonly observed side effect. Dizziness you see as a transient effect. You see nausea, some patients may have vomiting. For some patients we may premedicate with ondansetron to help mitigate that. There could be elevations in blood pressure, and in small proportions of patients, you may see more dramatic elevations of systolic or diastolic blood pressure, so blood pressure is something we regularly check at several time points during the treatment. For patients with uncontrolled hypertension, this is not something we would recommend. And ketamine is also contraindicated in patients with aneurysmal vascular disease, arteriovenous malformation, or history of intracerebral hemorrhage. So there are some absolute contraindications, but what I've mentioned are the most common side effects: the sedation, dissociation, the increase in blood pressure. And we recommend patients don't drive or operate heavy machinery on the day that they're receiving the ketamine.
Q: Now that esketamine is on the market, how do you expect it to impact the overall treatment of depression?
A: Ketamine has been used off-label, particularly in the last several years, at numerous clinics all over the country. By now there's several hundred freestanding ketamine centers that we know about that advertise their services. What the approval of Spravato, or intranasal esketamine spray, will do will increase access in that now it would be covered by private insurances, presumably, and by other government-run insurances. The VA is starting a pilot program for the use of intranasal esketamine sometime this year.
So it'll expand access because up until now there's been very little insurance coverage. Many patients have had to pay out of pocket, which could be very expensive. The prices, several hundred dollars, up to $600, $800 even per infusion. So if you're thinking about 6 to 8 infusions over 3 to 4 weeks, that can be very expensive and well outside the range of financial feasibility for many patients. And so having an FDA-approved insurance covered approach is critical for many, many patients who would just not otherwise have access to the drugs if they were not in a clinical trial or did not have the means to pay out of pocket.
Q: What are the main differences between getting ketamine infusions and taking the intranasal spray, and can patients do both?
A: With the intranasal spray, you spare yourself an IV line, and a stick at each treatment, and for some patients that's a big deal. They simply do not like IVs and may have concerns about that, so for them it's a huge advantage. For other patients, they certainly don't mind the IV, and it's a nonissue for them. And I should mention that for the intranasal there are some patients who would not be good candidates for that. If they have history of nasal polyps, or if they have nasal deviated septums, or have chronic rhinitis or chronic sinusitis, it may be more problematic for them to have an intranasal approach due to that. So at this point, we would want to take the patient's preferences into account, their financial situation, their insurance coverage, there's a number of factors I think that would guide us to think about the intranasal versus other forms. Each have their advantages and potential disadvantages.
Q: Are there any misconceptions about ketamine that you would like to address?
A: People throw out the term 'party drug' and so on, and certainly I'm not minimizing the abuse liability. It's a scheduled agent that certainly has been misused and abused. I should say that for the intranasal approved version, there's a very stringent
Risk Evaluation and Mitigation Strategy (REMS) program that is absolutely mandated and that requires due diligence and careful control of the supply and the distribution such that there would be minimal potential for diversion. You have to have a certified health care setting. The patient doesn't take it home, but they administer the drug under direct observation of the health care provider. There's 2 hours post-treatment monitoring. Every patient has to be enrolled and registered and the data sent to the company. So it's a very carefully thought-out program, which I think will really minimize the risk for serious diversion, although certainly clinicians should be keeping alert and vigilant to that potential.
Q: Are there any other glutamate modulating agents that you think clinicians should be watching?
My Psych Congress talk will cover a few of those. Since the ketamine story has emerged, it's been a really hot area for drug development. There are drugs that are orally administered in development in phase 3. There's a drug by Axsome Therapeutics called AXS-05, which is a combination of dextromethorphan, which is one of the active ingredients in Robitussin, and bupropion, sort of a well-known antidepressant. That's a combination drug that's orally administered and that's being pursued for depression right now, which is exciting because it's an oral drug, and if it has rapid onset of antidepressant efficacy and minimal abuse liability, that will be a huge advance.
There's also a drug called rapastinel that's being studied in adjunctive treatment of major depression, and as an IV drug also being studied in suicide, and so those studies are underway. There were some negative phase 3 studies but there are additional studies that are ongoing. And there's a number of other drugs including AV-101. It's an oral drug as well that's being studied as an adjunctive treatment in depression that works on a modulatory site on the NMDA receptor, the glycine site. So it's a different mechanism than ketamine and it's not a channel blocker within NMDA, but by modulating the glycine site, the hope is that it would provide a safe, relatively minimal side effect profile with some of the same efficacy.
So that's the hope for these drugs. So the glutamate NMDA story continues to evolve, and so the hope is over the next 5 years we'll have additional compounds that are approved.
Q: Is there anything else you'd like to add about what you're going to be talking about at Psych Congress?
A: One thing I will be talking about at the end of the talk is, what are the unknowns and where do we really need to focus our research efforts, and clinical efforts, to try and understand? And one of them is, how does the drug do in late-life depression? We don't have much data in patients older than 65. There was some suggestion from the esketamine data that the effects may not be as robust in that population. This is a critically unserved population, because they may be more susceptible to some of the side effects, they have multiple medical comorbidities, there may be mild cognitive impairment, so we have very few good alternatives for them. So we need to know much more about that population. We need to know much more about the clinical predictors or mediators of efficacy. Who are the types of patients who do well? So I'll be talking a little bit about that as well in the talk. What are the unmet needs and where do we need more data?
—Terri Airov