Major Depressive Disorder Podcast

Novel Treatments in Major Depressive Disorder: Ketamine and Esketamine

Madhukar Trivedi, MD; Manish Jha, MD, MBBS


May 11, 2022

This transcript has been edited for clarity.

Madhukar Trivedi, MD: Hello. This is Madhukar Trivedi. I'm a professor of psychiatry at UT Southwestern and I have the pleasure of inviting our guest today, Dr Manish Jha, who is assistant professor of psychiatry at UT Southwestern. He's been a colleague and trained at UT Southwestern. He did some time at Mount Sinai, and he's now returned here. So welcome, Manish. Very excited to be talking about novel treatments, especially ketamine and esketamine. Maybe before I start, can you give us a sense of how do you see the landscape of treatments and where these new treatments fit into the landscape?

Manish Jha, MD, MBBS: Thank you, Dr Trivedi. It's really an honor to be a part of this conversation with you. We are talking about ketamine or esketamine. And I want to emphasize that esketamine is FDA approved for treatment-resistant depression, as well as major depressive disorder with suicidal ideation or behavior, and ketamine is often an off-label treatment. As work that you have done — and others — have shown that major depressive disorder is a really common illness that affects 1 in 5 adults during their lifetime and often goes undiagnosed. The current medications are effective only for maybe 1 in 3 people. The burden of treatment-resistant depression is quite prevalent. As many as 1 in 3 people with major depressive disorder may not improve with currently available antidepressant medications. That's where medications such as esketamine are such a useful tool because they belong to a new class of medications and also have an effect that starts very rapidly.

Trivedi: Can you give us a little background on the newer class when you mentioned that people are obviously likely to be familiar with all the traditional antidepressants medications like selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), like Prozac, Zoloft, duloxetine, or Cymbalta? How does this fit into the understanding of where we are going with novel neurochemistry?

Jha: The great thing — and as we know that almost all medications that are called antidepressants — is that they most often target monoamine neurotransmission, so transmission that target serotonin or dopamine or norepinephrine, whereas medications like ketamine or esketamine, our understanding is still in the early stages, but we know that their predominant action is on the main excitatory neurotransmitter on our brain called glutamate. But learning the lessons that are still evolving, they are much faster acting. Conventional antidepressants, work led by you has previously shown, can take 6-8 weeks to become effective, whereas most people who respond with ketamine or esketamine do so within a day, and some people may require repeated treatments. But most people do in a matter of days to weeks rather than waiting for weeks to months.

Trivedi: How does a clinician decide when to think about esketamine as a treatment?

Jha: Sticking to what is the FDA-approved label would be people who have not improved after at least two courses of antidepressants at an adequate dose and duration. So it is making sure that the antidepressant medication is at least at a minimum therapeutic dose, and I refer people to looking at the package insert. And then [observed] at that dose for at least 6-8 weeks before saying that that particular antidepressant has not worked. When people have gone through two similar trials and have not improved adequately, that's when esketamine would be indicated as an add-on to the current indications, adding on to the background antidepressant and using that.

Trivedi: Let's take a minute to highlight some of our work and other people's work in terms of this adequate dose and duration. Before we jump into the exact content with esketamine, give us a little bit of your perspective on this idea of adequate dose duration. How do you monitor it? Where does measurement-based care and collaborative care fit into it? You've published on this also.

Jha: Work led by you as part of the Sequenced Treatment Alternatives to Relieve Depression, or what we call STAR*D trial, showed the paradigm in what you refer to as measurement-based care, wherein we are monitoring symptoms of depression; we're monitoring side effects and we're monitoring adherence. These three things together, when they're used with regular follow-up — so visits every 2 or 3 weeks, rather than waiting for weeks to months, when they're used very regularly — then we are able to get much better outcomes compared with just prescribing medications without the use of measurement. Other studies, such as your work from Texas Medication Algorithm Project, wherein measurement-based care was used in a randomized fashion, have shown that these measurements are helpful in improving the outcomes, but they also allow us to get a sense of whether the medication was not effective or it was intolerable because so often in clinical practice, we may see someone who said we took medication and it didn't work, but they only took it for a week because the side effects were burdensome. It could be that someone took something for months, but the dose was not therapeutic. Measurement-based care is not only an important tool to improve the outcomes but it also is a very crucial tool to help us find those who are struggling with treatment-resistant depression.

Trivedi: If I am a physician, I have tried to use rating instruments and measures like PHQ-9 and GAD-7 and have done two adequate trials of two antidepressant medications. I'm about to start thinking about esketamine; what would I tell the patient? How would I explain to them about esketamine and what to anticipate?

Jha: This is often the conversation I have with people when I'm doing a treatment-resistant depression evaluation and discussing the treatment options. We have oral medication options, like the combination of fluoxetine and olanzapine, which is one approach that is there. Intranasal esketamine is another FDA-approved approach that is there. There is transcranial magnetic stimulation (TMS). Electroconvulsive therapy (ECT) is another approach, and there are several off-label options, including the intravenous ketamine or esketamine. And really, what I talk about is from a shared decision-making perspective; there are definitely factors that are involved. For example, the use of olanzapine has a lot of metabolic side effects, so that is a part of side effects burden that we keep in mind. TMS requires coming 5 days a week to a center that should be conveniently located because that requires coming to the center 5 days a week for 6-8 weeks. So that's quite frequent visits, whereas esketamine or ketamine are dosed treatments so people come twice a week for intranasal esketamine, but they have to be there for 2-3 hours. Often when they're going back home, they need to arrange for transport because driving is not recommended. As you and I who live in Texas know, something that requires using public transport could be very burdensome. These are some of the benefits, as well as disadvantages that go into the matrix of shared decision-making. Those are the options I typically discuss with my patients.

Trivedi: What should a prescriber think about in terms of what happens? What does the first session look like?

Jha: The first thing that we do is we want to make sure after the diagnosis of treatment-resistant depression that the use of esketamine is safe. Often, that requires maybe doing a physical examination yourself; because we are all trained physicians, we can do the physical examination and workup ourselves, or maybe partnering with the patient's primary care doctor to make sure that the blood pressure, if they have a history of hypertension, is controlled because we know that esketamine does tend to increase heart rate and blood pressure. Making sure that the individual has those concerns that they are well-controlled. There are also certain contraindications for esketamine. They are included in the package insert. For example, anyone with a history of intracerebral bleeding or bleeding inside our brain, that's a contraindication. Anyone with a history of aneurysms is a contraindication. Doing some medical history to make sure that these contraindications are not met. That's when we make the decision to pursue with esketamine treatment and then preparing people a little bit about what the experience of intranasal esketamine is also a key aspect for preparing for the treatment

Trivedi: Talk a little about what doses and how you determine the dosing regimen for esketamine.

Jha: The dosing for ketamine is relatively straightforward. There are only two doses that are available: the 56-mg dose and 84-mg dose, so everyone is started on the 56-mg dose. That's according to the FDA label. And then if it's tolerated, and there hasn't been much improvement, then we can go up to 84 mg. That's my typical practice. I use 56 mg on the first visit. If that was not effective at all, there was no improvement in depressive symptoms, but if it was well tolerated but the dissociative symptoms or blood pressure was not burdensome, then we go up to 84 mg. However, if the 56-mg dose was barely tolerable, then we stay at 56 rather than increasing the dose to 84 mg. We often see the 56 mg may be effective in improving symptoms. If I see the improvement occurring with 56 mg and I would stay at 56 mg. There is a little bit of clinical judgment required to make that decision of whether staying with 56-mg dose or increasing to 84-mg dose.

Trivedi: What are the major side effects that a physician should be worried about during the observation period and after that?

Jha: We know that esketamine has a very short half-life, so what that means is that when a person takes esketamine, most of it is excreted from the body in a matter of hours. So the direct recommendation right now is for a person to be monitored for at least 2 hours after they have started their esketamine treatment. And as they're taking their esketamine treatment… So the 56-mg dose requires two nasal sprays (in) each (nostril) that are 5 minutes apart. Two sprays followed by a 5-minute gap, then two more sprays, then an 84-mg dose is two more sprays another 5 minutes afterward. During these 10-15 minutes, it's recommended to be under close observation by a provider, such as I would do that with my patients. After that, the side effects of dissociative symptoms or out of body experiences, people getting a sense that the sense of time may become elapsed, that there could be like visual perception that can get distorted. Sounds may become either too loud or too distant. Light can feel very bright. What we label as dissociative symptoms, they tend to peak about 20-40 minutes into the treatment. I often orient my patients who are going to have this experience to keep that in their minds. Then, at 40 minutes after we started, we should be checking blood pressure and heart rate because that's typically when the peak effect of the drug is. Then it's also recommended to check the heart rate and blood pressure 2 hours after the dosing started to make sure that the increase in heart rate and blood pressure has come down to the baseline. Most people will benefit with actually in less than 2 hours of monitoring, but 2 hours is minimum. Once in a while, in rare occasions, some people may have those dissociative symptoms lasting more than 2 hours or blood pressure requiring further monitoring to make sure that it has become its normal level. In terms of monitoring, just briefly: These are anesthetic medications, so the balance tends to get impaired. One of the things I've learned to tell my patients when coming for esketamine treatment is to use the restroom before they come in for treatment. Because if they know they need to go use the restroom under the influence of the drug, the balance may be impaired and that can lead to falls. That's something to warn about and monitor in our clinical practice.

Trivedi: Give us an idea of the duration part, which is always a little tricky. How long to continue for somebody who does well for the first several weeks? How long do you continue and how do you make decisions about it?

Jha: We know — and you're part of those studies — that the phase 3 trials were people who had improved on esketamine and were randomly switched to placebo. Even in follow-up to a year and a half, over 60% of people stayed improved with esketamine ongoing treatment. So there really is no deadline of how long to continue the treatment. The guidance really is to use it as infrequently as possible to maintain the improvements. If someone needs to come only once every 2 weeks or once every month, then that's the recommended dosing. We know that depression, as your work and others have shown, is a chronic or recurring illness for a lot of people. In the chronic disease management, the treatment may need to be for a few years. I know that with people who we started as part of the study, even in clinical practice, some of them have been receiving this treatment for years now. For a subgroup of people, this may be an acute phase treatment. After a few months, they may be able to discontinue it. And for a subgroup of people with recurrent depression or chronic depression, this may end up being a much longer-term treatment over several years.

Trivedi: Fantastic. Now tell us a little more about the effects on suicidal ideation and behavior.

Jha: Studies using intravenous ketamine, as well as intranasal esketamine, have been shown to rapidly improve depressive symptoms in individuals with major depressive disorder who have suicidal ideation and behavior. Often, those studies were done on the inpatient setting, where we see the improvement in suicidal ideation themselves. The effect on the symptoms of suicidal ideation have been more inconsistent, but I have to say that and you are leading a study right now, which is aiming to show ketamine's effect on suicidal behavior that is a repeat suicide attempt or worsening of ideation warranting hospitalization. Those studies haven't been done yet. We haven't shown that ketamine actually reduces or that esketamine reduces future suicidal behavior or recurrence of events so that is really an aspect of illness. But what is definitely shown is that the benefits with ketamine or esketamine in a subgroup of people can be very rapid. This could be a treatment that is very effective in reducing suicidal ideation in a subgroup of people with major depressive disorder very rapidly.

Trivedi: Thank you for bringing up our study because I think one of the things that we are interested in is studying the very group of people for whom the risk is very high. That study studies teenagers who have attempted suicide, so therefore the reattempt risk is very high. We are trying to see if intravenous ketamine can reduce the reattempt rate.

In the remaining minutes, maybe give us a preview of what's to come because there's some very exciting findings. The Yale Group has done obviously a lot of work in this. John Krystal and Gerry Sanacora are in that group. Give us some idea of what are we finding in this biomarker related to ketamine, esketamine in terms of imaging circuits, as well as some of the molecular effects?

Jha: A lot of the work in terms of what is the mechanism of ketamine or esketamine has been done in the preclinical model and really what has been shown is that it increases synaptic plasticity. There is a school of thought that it may open up this window of opportunity where a brain becomes more plastic and can modify or be more malleable in certain ways. And that has led to the paradigm of combining psychotherapy with the period right after ketamine. As some of what you mentioned, Yale Group has been doing. In terms of other mechanisms that it has been our notions that ketamine may alter levels of glutamate in our brain. That has not been very consistent based on spectroscopy data. Part of the issue is that the science is limited; the way that we can image brain and monitor changes in the brain that may not align with the timescale of changes that we see happening with ketamine or esketamine. For one thing, that with our work addresses, is trying to see longer-term changes with ketamine and then using imaging in a longer-term paradigm rather than giving ketamine today and then scanning someone within a matter of hours to a day. To be able to see that the circuit-level changes — if they are longer lasting compared with a very acute short effect of the brain on drug, right? Like if you give someone ketamine, what are the changes in the brain rather than just seeing that? What circuit level changes are produced in the long-term?

Trivedi: Give us a preview of what your fantastic study is really trying to accomplish.

Jha: The study that we are working on together is the study about neuro circuit mechanisms of irritability, which we have shown is often an underdiagnosed aspect of depression that is strongly linked to suicidal ideation. The study that we are doing is imaging people with depression at baseline and then randomizing them for 2 weeks of treatment with either ketamine or midazolam and having them come back again for a scan after the 2 weeks. Our data and others have shown that ketamine does rapidly improve irritability. Work done by James Murrough at Mount Sinai shows that ketamine reduces irritability very rapidly — the spectrum of changes in depression. So we are really using that experimental medicine paradigm for ketamine as a pharmacologic probe, which is the other exciting aspect that ketamine and esketamine have opened the gate for us to do these interventions in contrast to your studies before, when we had to treat someone for 8 weeks to see whether depression actually improved or not. We are really excited about the opportunity to make this experimental medicine studies using ketamine.

Trivedi: The field is very excited that these N-methyl-D-aspartate (NMDA) receptor antagonists are doing the novel approach and differences from monoaminergic agents, and the rapid rapidity of the effect is really transforming the way we see psychiatry and depression in particular. Though esketamine and ketamine are exciting, there remain some people who don't really do well.

Jha: You're absolutely right. We can see that maybe one in two people do not improve much with even esketamine, even though it is a much-needed improvement over conventional antidepressants and really ketamine and esketamine, they are not our classic psychedelic drugs. In fact, most of the studies we have done to date, we have not combined that, or leveraged, the psychedelic aspects of ketamine. That's where a lot of the new studies and studies of 3,4-Methylenedioxymethamphetamine (MDMA) for posttraumatic stress disorder (PTSD), or studies of psilocybin for depression, and even other psychedelics like N-dimethyltryptamine (DMT) are showing a lot of promise. The key aspect of those treatments is that the psychedelic experience itself is integrated, so psychotherapy becomes a key part of that psychedelic treatment. Whereas in the studies of ketamine or esketamine, psychotherapy was even not provided often. Allowing that whatever we see, or at least the early data… What's promising is that if the change occurs, if the improvement occurs, that tends to be much more durable. An improvement lasting on the scale of months, to several months, that is much more durable compared with the benefit with esketamine that we see is on the order of magnitude of days to weeks to months. So that really is exciting. I do want to say, and I've heard you say that often, the excitement about psychedelics far exceeds the number of people who have actually received treatment in a research setting, so there is a lot more needed to be done to really validate these psychedelics as treatments for not just depression, but PTSD and other psychiatric disorders.

Trivedi: Wonderful. Do you have any final thoughts on the topic?

Jha: I have a few thoughts. First is use measurement because that helps us identify people with treatment-resistant depression. Use treatments that are more treatment-resistant depression–specific, like esketamine, TMS, ECT, rather than using conventional antidepressants that are often ineffective and then really engaging the audience, not just the providers, not just the researchers, but everyone getting together because we need to do a lot more research to identify who would more precisely benefit with esketamine as maybe the first-line treatment rather than having to go through two levels of failures or multiple levels of failure before they get to a medication that works for them.

Trivedi: It just means we need to do more research. Thank you very much. That was very enlightening Manish. I'm so glad you joined us and look forward to more conversations about this and thank you all for listening in.


Symptom Clusters as Predictors of Late Response to Antidepressant Treatment

Intranasal Esketamine

Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study

Clinical Results for Patients With Major Depressive Disorder in the Texas Medication Algorithm Project

Efficacy and Safety of Olanzapine/Fluoxetine Combination vs Fluoxetine Monotherapy Following Successful Combination Therapy of Treatment-Resistant Major Depressive Disorder

Esketamine Nasal Spray for Rapid Reduction of Depressive Symptoms in Patients With Major Depressive Disorder Who Have Active Suicide Ideation With Intent: Results of a Phase 3, Double-Blind, Randomized Study (ASPIRE II)

Esketamine Nasal Spray for the Rapid Reduction of Depressive Symptoms in Major Depressive Disorder With Acute Suicidal Ideation or Behavior

Ketamine Versus Midazolam for Recurrence of Suicidality in Adolescents

Youth Depression and Suicide Research Network (YDSRN)

The Neurobiology of Depression, Ketamine and Rapid-Acting Antidepressants: Is it Glutamate Inhibition or Activation?

Effect of Ketamine on Limbic GABA and Glutamate: A Human In Vivo Multivoxel Magnetic Resonance Spectroscopy Study

Identifying Novel Mechanisms and Treatment Targets for Irritability and Aggression in Psychiatric Disorders

Ketamine Versus Midazolam for Recurrence of Suicidality in Adolescents

Ketamine for Depression: An Update

MDMA-Assisted Therapy for Severe PTSD: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study

Trial of Psilocybin versus Escitalopram for Depression

The Clinical Pharmacology and Potential Therapeutic Applications of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT)

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