Vice Chair of Research at the Baylor College of Medicine, Sanjay Mathew, MD, talks about how ketamine is treating treatment-resistant depression.
Interview conducted by Ivanhoe Broadcast News in 2023.
When does depression termed “treatment-resistant”?
Mathew: Treatment resistant depression signifies when a patient has not responded optimally to at least two conventional treatments. By conventional treatments, we usually mean SSRI medications which are very commonly used antidepressants, but there’s a whole host of other antidepressants that a patient cannot respond optimally to. Once they have reached the level of two trials of medications, then we generally term that as treatment resistant depression.
I want to make sure I understand that, two conventional trials, but you’re talking about that could be a combination of medications?
Mathew: Yes, that’s exactly right. It could be two separate trials of medications, or it could be adding one medication on top of another. Medications are commonly used together. If you have a situation where you’re adding an SSRI plus a commonly used antidepressant like grupprion, that would be another way of administering it.
How did you guys determine that two conventional courses of treatment were the outer limit, so to speak?
Mathew: The field has done research looking at how you define treatment-resistant depression. What has been found is that if you fail to respond to more than two consecutive treatments, the odds of responding to a third standard antidepressant become exceedingly low. At the first trial, you have about a 30 to 40 percent chance of achieving remission, which is a virtual absence of symptoms following that trial. In the second trial, the remission rates are also similar. Once you get to trial number three, the rates of remission are extremely low. It can be less than 20 percent. It could be 15 percent. The field has concluded that in treatment-resistant depression, by the time you get to the third level, the odds of just doing more of the same will result in improvement of a very small percentage of the time.
Could you give us an idea of why some people are treatment-resistant?
Mathew: There’s any number of reasons. One of the challenges we face in major depression is we don’t have a full understanding of the biology and what is going on in the brain and the body in a person who has a major depressive disorder. Major depression is still a diagnosis based on symptoms. If a patient reports depressed or low mood, a loss of interest, a loss of motivation, impaired sleep, or impaired concentration for a period of at least two weeks, that’s pervasive and debilitating, they get the diagnosis. We don’t have an MRI scan that can definitively tell us a patient has the diagnosis. It makes it a very challenging diagnosis but also a challenging way of monitoring and tracking treatment.
Let’s say you get 100 patients that come in with depression, do people exhibit, after a while, the same repeated symptoms so that you can make more of an educated diagnosis?
Mathew: One of the challenges in the diagnosis of depression is heterogeneity. Meaning no two patients with the diagnosis of depression are exactly alike. That goes for many other illnesses as well, but it’s particularly marked and notable in depression. You can have a patient who oversleeps and over eats and has low energy and make the diagnosis. You could also have a patient who sleeps two hours a night and doesn’t have any appetite and has lost 20 pounds in the last month. They could also have the diagnosis and the heterogeneity of the symptom presentation of depression makes it very challenging.
At the root of depression is there a chemical issue?
Mathew: It’s more complex than a chemical issue. We know there are neurotransmitters in the brain that are important in the control and regulation of mood, anxiety, emotional states, sleep, and so on. Some of these chemicals include serotonin, norepinephrine, and dopamine, and all of the major antidepressants impact those chemicals. Over the last 20 years, we’ve also learned that depression and emotional states are disorders of brain circuits. Specific parts of the brain circuits are not functioning properly. We’ve thought of this as much more than a neurochemical issue, but it’s a neurochemical and neurocircuitry abnormality or dysfunction.
This may be too convoluted, but the nature versus nurture argument is part of how kids are, and what their environment is. As a very young child, say zero to three?
Mathew: There’s definitely a natural component to depression. There is a familial inheritance of depression. It’s a disorder that involves multiple genes, hundreds of genes. In contrast to some conditions where there’s a specific gene and variance of the gene that causes a disease. Here it’s a chronic illness, much like hypertension and diabetes with complex genetic determinants. However, genetics only plays a part in the expression of depression. Early life stress is a major risk factor for depression, so individuals, and children who’ve been exposed to trauma, they’re much more likely to experience depression in adolescence and adulthood than those who have not. There are other lifestyle factors, stress, and other complicating factors that can make a person susceptible to recurrence of depression.
Why has ECT gold standard in treating?
Mathew: Yes, ECT is electroconvulsive therapy and it’s the administration of an electrical shock to patients to induce a seizure. It’s been a treatment that’s been available in psychiatry for many decades, and in fact, was one of the first biological treatments in psychiatry. How it works and how it improves a patient’s depression is still not 100 percent clear. There are some theories and some evidence that the brain’s seizure and the brain’s response to having that seizure is what is therapeutic. That could involve upregulation of specific neurotransmitters, reshaping of certain neural circuits, and so on. It’s still not entirely clear. What we do know is that for serious depression, it remains the gold standard therapy. It’s usually a treatment that is given three days a week, Monday, Wednesday, and Friday, for at least three to four weeks in duration not just a one-time treatment. It is a three to four, several-days-a-week type treatment.
One of the questions I always ask the experts is, how did you get onto this course of treatment, the ag, ketamine? What led you to that if you will?
Mathew: Ketamine is an anesthetic agent that was approved in the early 1970s for anesthesia. It remains a drug that’s used every day in operating room settings or emergency room settings in the context of short surgical procedures, orthopedic procedures, and sometimes other short interventions. It’s a safe anesthetic. It has a long history of use. About 20 years ago, researchers at Yale University discovered that a low dose, so a dose that’s about a fourth to a sixth of the dose you use anesthesia can have rapid antidepressant properties. Since then, there’s been a host of studies suggesting that a 40 to 45-minute infusion of what’s called a sub-anesthetic dose can be rapidly antidepressant in patients with treatment-resistant depression. Now, it’s been common for most communities to have ketamine clinics and the FDA several years ago approved a form of ketamine called Esketamine as a nasal spray that received the FDA approval for treatment-resistant depression back in 2019. Now it’s become an approved intervention.
How about the IV ketamine? Is that where is that in the approval process?
Mathew: IV ketamine in psychiatry remains off-label. Meaning it’s not approved by the FDA for depression or any other indication. Its only approved indication remains in anesthesia. However, physicians and others can use and can prescribe any medication they deem fit. It’s called off-label prescribing, and there is a rich evidence base at this point for the use of ketamine, IV ketamine in particular in depression and so that’s prompted practitioners in the community to adopt this approach for their patients.
It seems like the off-label prescribing has really picked up over the past couple of years. Is that primarily because the FDA approval process is usually about 20 years?
Mathew: It can take many years for a drug to go through the necessary steps for FDA approval. Which starts with animal testing, then testing in healthy volunteers, then so-called phase two studies in small groups of patients, and then the large phase three studies. By some estimates, it’s a decade plus and a billion dollars to bring a drug to market and that’s a long-involved process and incredibly expensive. Off-label use is something that doctors frequently do because just not enough evidence for the use of drugs for a specific FDA-approved indication. Although clinicians may note that this drug has certain effects and properties and could be beneficial for a specific disorder. A good example in psychiatry is we often get our best ideas from our colleagues in neurology, so a lot of the anti-epileptics or anti-seizure drugs used in neurology are also used in psychiatry to help with depression or related conditions. That’s an example of off-label use that has a reasonable evidence base.
Can you talk briefly about that process? Let’s say you’re talking to a neurosurgeon who’s a friend of yours and he or she offers the fact that this worked for them. You get the idea that IV ketamine can work for your patients, how long does it take you to get to the point where you can run the trial like you did?
Mathew: To run a trial, like a comparison of that. The trial of comparing IV ketamine to ECT started in 2016 and the leg work for that took several years to really get through the regulatory approvals and get all the set up and start. It took a while to even develop the evidence base such that IV ketamine could be considered a viable alternative to ECT. Because much of the work had only looked at single infusions as opposed to a chronic series of infusions as we did in the study, which was six infusions over a three-week period. By mid-2010, there was sufficient evidence to support the notion that repeated ketamine can be beneficial. What we didn’t know was how beneficial it would be in a very refractory ill population where ECT is the gold standard and so that was the impetus for this comparative trial.
Can you talk about this trial, is it the largest? How many people are involved? Just the mechanics of what you went through?
Mathew: Yes. It is the largest trial in the U.S. that has ever, and worldwide at this point, to compare the two treatments in treatment-resistant unipolar depression. The reason I say unipolar depression, is another variant of depression is bipolar disorder and bipolar depression. Those patients were not included in this trial. Also, patients who had psychosis, or so-called psychotic depression, were excluded from the trial. This was a narrower group of patients with so-called treatment-resistant depression, who were then randomized to electroconvulsive therapy or IV ketamine, and the study was conducted at five centers in the U.S. of which Baylor College of Medicine in Houston was one of the sites and it enrolled more than 400 patients, about 200 patients in each arm.
How far away is this from reaching the mainstream? Say somebody’s watching this in Kansas City. How can they go about getting us to make their depression better?
Mathew: Yes. Most major cities in the U.S. have treatment centers offering ketamine. Either the FDA-approved version, the intranasal ketamine spray, or the IV ketamine regimen. It would be something that a patient in most cities would be able to access via their mental health provider, their psychiatrist, or their mental health clinician who could make the referral to a center that performs these treatments.
If someone is undergoing ECT and they want to try this, what is detrimental about the ECT and why is the IV ketamine preferable?
Mathew: One of the challenges with ECT is it is often associated with memory loss. That is what has held ECT back in some respects from more broad acceptance from patients, in that there is a risk of memory loss. For many patients, it’s transient memory loss and they’re completely fine after a period. But that’s enough of a deterrent that it’s a motivated field to develop either a form of ECT that may be better for cognition and memory or to develop different brain interventions that don’t have this liability at all. ECT while powerfully effective, seems to be the major limitation of the approach.
Out of 400 involved in the trial, how many remained on it? What is the course of treatment over the long run?
Mathew: The overall results at the end of the three to four week treatment period suggested ketamine had a slightly elevated rate of response compared to ECT. This means that patients improved their depression scores by about 50 percent. Ketamine performed at a level that’s deemed not to be superior to ECT because that’s not what the study was testing, but a term called non-inferior, which would give the clinician confidence that if a patient for some reason was not eligible for ECT, did not want ECT, did not have access to ECT, they could give this alternative treatment with a reasonable probability of benefit for the patient.
Do they stay on this treatment in the long run?
Mathew: That’s highly variable in what happens in real-world practice. Generally, the point of the IV ketamine is to get a patient out of the depressive episode as quickly as possible and that’s generally done in three to four weeks. Now one thing we know about ketamine, if you stop giving it, there’s a relapse. Patients may do well for a month, and some patients may do well for a little longer than that, but without further treatment, most patients will relapse. What is done in community practice is a maintenance schedule of ketamine, which could be individualized according to a patient’s need. For some patients, they come in once a month and get the infusion. Some patients come in once every two weeks and get an infusion. Some patients have durable responses and only come in once every three to four months. That’s a highly variable regimen. Spravado, or the ketamine nasal spray has a similar maintenance schedule for some patients, it varies depending on their needs and durability. But I think one of the messages is, that although there’s been a lot of interest in the media and in the community of practitioners about ketamine, it’s not a cure for depression. It still requires chronic maintenance treatments and without administration of the treatment, patients will be at great risk for relapse. That’s an important message that we have not by any means found the cure for depression.
What have some of the participants in the study said about their depression after the IV ketamine?
Mathew: Yes. Many patients report that they feel more motivated and what depression has left for them is a feeling of being stuck. They’re in a rut. They don’t see colors particularly vividly and what they often report is colors look brighter, the world appears brighter to them, and they feel that there’s hope, there’s optimism for the first time. They feel like getting together with friends for the first time in a long time, making some phone calls, going for a walk in the park, doing things that seem commonplace and not necessarily even exciting things. They often feel more motivated. Besides feeling less sad, less despondent, and so on. It’s really this positivity and this motivational state.
END OF INTERVIEW
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