Episode 02: Ketamine Vs ECT for Resistant Depression
This podcast episode explores the CAN-BIND study on ketamine vs ECT for treatment-resistant depression. Featuring our study participant, Sophie.
Dr. Sidney Kennedy: I’m Doctor Sid Kennedy I’m the director of the Canadian Biomarker Integrated Network in Depression otherwise known as CAN-BIND. And CAN-BIND is a program sponsored by the Ontario Brain Institute and we’re one of a number of integrated discovery programs, in our case focusing on depression. And very specifically some of the work that we want to do is to help make better choices for the right treatment for an individual at a given time in his or her illness. We really want to understand the innovation, some of the exciting new developments that are taking place.
Welcome to the CAN-BIND podcast.
Dr. Wegdan Rashad: Thank you, Dr. Kennedy, and hello and welcome to the CAN-BIND podcast! I’m your host, Dr. Wegdan Rashad, and in this episode, we are going to talk about one of our newer and exciting studies at CAN-BIND.
We know that about 30% of people with depression do not fully recover from it with conventional antidepressants and so they may be referred to other types of well-established treatments like electroconvulsive therapy or as we commonly refer to as ECT. Recently, there has been a new treatment emerging called ketamine which has been shown to also be effective in treatment-resistant depression.
Our study basically asks; which of the two – ECT or ketamine – is more effective and safe? That’s the idea in a nutshell. We have with us today Sophie who has reached out to share her experience as a patient participant in this study. And we also have Dr. Jennifer Phillips who will answer some of our questions as well.
Are you excited to know more? Let’s find out!
First, let’s hear from Sophie.
Sophie: My name is Sophie, I’m 51 years old. I’m an only child and I’m the primary caregiver to my mom. I live in Ottawa and I’ve suffered from depression for many many years. And I’m so thankful to have been part of this study that I have been in because my depression was so difficult. I’m off work, because of my illness. I’ve got more than one illness. But that’s essentially who I am.
Dr. Rashad: And on top of that, Sophie is an avid gardener, volunteers in her local MPs office and participates in community events. We are grateful to her for taking part in this podcast to share her experience, so thank you for that, Sophie. I asked Sophie how she got to know about this study.
Sophie: Yeah, I’ve been suffering from depression and anxiety for a few decades now. I was in a very deep depression two years ago. It took quite a while to be referred to the Royal, but eventually, I got referred. It’s through an interview with one of the psychiatrists that I have been made aware that I had the option of going into study where it could be ECT or ketamine and that was very interesting for me. Now to go back in my medical history I’ve had post-traumatic stress since I was a child so I have gone through multiple traumas. I have battled depression for a long time. I wasn’t officially diagnosed with depression until about 20 years ago but now going back I know some of the struggles I’ve gone through. I also have a service dog who helps me with my depression, my anxiety, and my post-traumatic stress. But despite having medication, having an awesome medical team, I just wanted to die. I just wanted to drop dead, not to do it myself, but to just, I just wish my life could end. And I knew that I needed help. And I pushed, and I pushed, and then finally I was referred to the Royal Ottawa Hospital. Which was an excellent team. I went through the interview process and met the psychiatrist and at that time I wanted to have ECT. I had heard ketamine through, in American news, that was experimental in the U.S. but I had no idea until I came to the Royal that that was even an option. As soon as I heard of this study I was automatically ecstatic. I knew what it was like to have ECT, and I knew that ECT would definitely work for me, but I was very intrigued with ketamine. So I signed up for this study, and I knew there was a 50/50 chance that I could be in either group, and when I found out that I was in the ketamine group I was totally ecstatic.
Dr. Rashad: We will follow up with Sophie on how her experience was with ketamine, but first let me introduce our next guest, Dr. Jennifer Phillips.
Dr. Jennifer Phillips: I am an Associate Scientist in the Mood Disorders Research Unit at the Royal Institute of Mental Health Research which is affiliated with the University of Ottawa. And we have been conducting clinical trials looking at the use of low dose ketamine to treat resistant depression and suicidal ideation in patients who are not responding to other forms of treatment.
Dr. Rashad: Dr. Phillips, this is such an interesting study and I’m curious, could you tell us more about treatment-resistant depression and options available for it?
Dr. Phillips: Okay, well both electroconvulsive therapy or ECT and ketamine are effective treatment strategies for severe or difficult to treat depression. About 30% of people with depression do not obtain an adequate relief of their symptoms using available treatments, so things like medications or psychotherapy. Patients with treatment-resistant depression have generally been ill for many months, and sometimes years, as they undergo trials of different medications that do not significantly alleviate their depressive symptoms. So this is one of the major unmet needs in the field of depression. The need for treatments that are effective for a larger proportion of patients. Right now evidence suggests both ECT and ketamine can yield higher response rates when they are compared to traditional medication treatments for depression. And both these treatments are effective in the same kind of clinical population, so the same kinds of patients might be referred to ECT from ketamine. Generally, these are individuals who are experiencing a severe or treatment-resistant episode of depression.
ECT is the most effective treatment we have for severe resistant depression. It remains the gold standard. It yields high response rates for about 50% to 80% of patients who receive ECT for depression…Dr. Jennifer Phillips
Dr. Rashad: Sophie mentioned that ECT had helped her before, Dr. Phillips, could you share with us more information on how ECT can help in treatment-resistant depression? Just how effective is it?
Dr. Phillips: ECT is the most effective treatment we have for severe resistant depression. It remains the gold standard. It yields high response rates, about 50% to 80% of patients who receive ECT for depression will have a decrease in their symptoms and antidepressant response with ECT is often faster than for traditional medications for depression. Generally, those have to be taken for several weeks before we start to see any clinical benefit. Yet ECT is largely underutilized this is due to many reasons but they include enduring stigma, potential side effects, as well as issues around availability, accessibility, and cost. In some cases, to receive ECT there may be a need for inpatient hospitalization. Ketamine, on the other hand, is sort of the new kid on the block. The discovery of ketamine’s antidepressant effects has been hailed as one of the biggest breakthroughs in the field of depression in the past half-century. Like ECT, ketamine can elicit higher response rates than existing medications, and generally, they are much more rapid.
Dr. Rashad: A 50% to 80% response rate is pretty big, but as Dr. Phillips said, it is underutilized. Sophie shares her experience with us on ECT.
Sophie: There’s a stigma when it comes to ECT, it’s not something I like to talk about in public, except for an audience that needs to know about ECT. It’s something that my family and friends don’t necessarily know, there are very few people that know. But despite the side effects of ECT, I had headaches and memory loss, it all resolved itself eventually, after the treatment. So I would say to anyone if you’re suffering from depression take either one, if ECT is the only option, take it. For me, it was life-saving and when I had ECT I had them in 2008, and I didn’t have a relapse until 2015, which was seven years, which was really amazing when you consider everything.
Dr. Rashad: That is pretty amazing. Ketamine started off as an anesthetic agent in surgery…only recently has it been discovered to play a significant role in treating depression and suicidal thoughts. After the break, we will hear more about it.
With ketamine […] you feel intoxicated. It is at first a little bit scary, but it is done in a clinical environment so you know that you are in a safe environment with people that are looking after you.Sophie, study participant
Dr. Phillips: To treat depression, ketamine is administered as an intravenous infusion using much smaller doses than those that would be used for inducing anesthesia. Clinical trials with ketamine have shown that its antidepressant effects are rapid, often apparent within a few hours to a day of a single infusion. And evidence from our group and others have shown that repeated administration of ketamine giving infusions several times per week can elicit sustained and even cumulative antidepressant effects. Ketamine has not been adequately compared to another treatment that has antidepressant properties. That’s where our study comes in, where we are directly comparing the efficacy of ECT and ketamine for severe or resistant depressive episodes.
So the primary goal of this study really is to show that ketamine is as effective as ECT as a treatment for depression. So, technically this is what is called a non-inferiority trial. We want to test whether ketamine as a treatment is not inferior to ECT, which is the gold standard. We think that they will be equivalent. So while we expect them to have similar efficacy rates, we are also examining some other outcomes. We think that ketamine might produce more rapid antidepressant effects, have less side effects, less costs, and less health care resource use. So it may need fewer outpatient visits and less inpatient hospitalization. Ultimately we want to know whether ketamine can eventually be used as a less burdensome or better tolerated, less expensive, treatment than ECT as an alternative for patients that are severely depressed or treatment-resistant.
Dr. Rashad: Let’s hear from Sophie about her experience with ketamine.
Sophie: With the ketamine, there is an effect when you get medicine that you feel intoxicated. It is at first a little bit scary, but it is done in a clinical environment so you know that you are in a safe environment with people that are looking after you. And the great thing about it is if the side-effects are a little bit too difficult because you feel the intoxication, they can pause the drip and by pausing it, then the effect goes away and then they can just restart it. But it is something that you learn to tolerate. The drip lasts, I think if I remember correctly, it lasts 40 minutes. And it is time that goes by very quickly, you have a nurse there and I had Dr. Blier and some of the associates that were there. So I was constantly under supervision. And the effect goes away, for me it was less than an hour. And then after that, you can just walk away. You can’t drive because you’ve had the medicine, and it’s still up to a certain point in your system, so you can’t drive for 24 hours. But you’ve got no memory loss, you feel great. you go in you feel very sad and when you come out of the treatment you feel that much better. After that, you’ve got another treatment, and it’s the same thing and the effect builds on it. During the treatments, I was chatting away, and that’s why like time went by so quickly.
Candidates who are eligible for, or candidates for ECT who are interested in this study can just ask their physicians to provide a referral for the center closest to them and that will allow us to assess whether they are eligible to undergo formal screening for this study.Dr. Jennifer Phillips
Dr. Rashad: It sounds like Sophie had a positive experience with ketamine as a treatment for her depression. Listening to all of this has me thinking, well…if someone is suffering from depression and they’d like to take part in this study what do they need to do?
Dr. Phillips: Okay, great question. We are actually recruiting 200 patients, and they are being enrolled in multiple sites in Canada including Ottawa, Toronto, Kingston, and Montreal. We are enrolling individuals who have been referred for ECT by their doctors and who have already consented to receive ECT. So that is the first step really to be a good candidate for ECT. So the treatment has to be clinically indicated, the individual needs to be medically stable and have depression of at least moderate severity and it is not only unipolar major depression disorder we are actually including individuals who have bipolar disorder as long as they are in a depressive episode at the time of the study. Candidates who are eligible for, or candidates for ECT who are interested in this study can just ask their physicians to provide a referral for the center closest to them and that will allow us to assess whether they are eligible to undergo formal screening for this study.
Dr. Rashad: So, if you are interested in learning more about the study, visit our website, canbind.ca and there is a tab there for ongoing studies that provides contact information to the site coordinator. Or you can just check the transcript where will have the links there for you.
I asked Dr. Phillips about how this study is being carried out. How do you choose what treatment a participant gets and how often are treatments given?
Dr. Phillips: Yes, so the clinical trial is what is called a randomized cross-over clinical trial. So I will break that down. A randomized trial means that there are two treatments, of course, we are comparing ECT and ketamine, and patients who are enrolled in this study get randomized to one or the other treatment, so they don’t get to choose. There is an equal chance of being randomized to either one. So this helps us determine that there is more validity to this study and that it is just how clinical can be conducted so that we can adequately assess the efficacy of each of these treatments without biasing the sample in one arm or the other. Participants undergo a course of treatment in whichever arm they have been randomized to, using a similar administration schedule. So for patients randomized ECT and patients randomized to ketamine they both receive either 9 to 12 treatments which, ECT or ketamine are administered three times a week. We are really looking to see if patients are responding to the treatments. So we are hoping that they are having an improvement in their symptoms and a decrease in their scores on depression of at least 50%. We consider those people to be antidepressant responders.
The cross-over part of this study, if participants don’t respond to treatment and they don’t have a significant decrease in their symptoms they are able to cross-over and try the alternate treatment. So let’s say an individual was randomized to ECT, but it doesn’t work for them they have the opportunity to then try ketamine, or vice versa. So from a patient perspective, it really gives a benefit, this part of the trial having the cross-over really is beneficial for patients to be able to try both therapies. The other unique aspects of the trial include the collection of biological data, as well as a longer-term, follow up of the responders as they receive maintenance treatments.
Throughout the trial, we have individuals who are conducting interviews and assessments of the participants to ask them questions to see how they are doing in terms of their depression. And we are using validated scales to be able to measure the severity of depressive symptoms and to see whether they change with treatment. And these writers are blind to the treatment that the participant is receiving. So in other words, they have no idea whether the patient in front of them is receiving ECT or ketamine. And we look at how these clinical scales basically change over time to determine how well the patient is doing with the particular treatment they are receiving.
Dr. Rashad: Ah so in summary, all participants are randomized to ECT or ketamine treatment 3 times a week for 3-4 weeks. For those who don’t respond to their designated treatment, they are crossed over to the other treatment modality and then assessed in the same way.
When I was researching this study on clinicaltrials.gov it mentioned that besides the depression questionnaires, other tests including blood tests and brain scans are also being done. I wonder the reason for that.
Dr. Phillips: Yes, so these data are what we call biomarkers, the participants in the trial undergo blood draws, brain scans, and cognitive testing before they start treatment and then again at various intervals throughout the trial. What we are doing with this data is we are examining these measures overtime to try to identify any changes that might indicate that the people receiving a particular treatment are actually responding to the treatment. We may find that a particular marker is present prior to starting treatment that indicates someones more likely to respond to that particular treatment over another. So these may be from blood samples we can measure DNA, or measure different proteins in the blood, looking at inflammatory markers. We are using brain imaging to look at brain structure and brain activity. So really we are trying to see whether or not there are any changes in these biomarkers over time or whether any of the biomarkers predict how a patient might do. So now presently we really have no way of knowing who is going to respond to ECT or ketamine. That is one of the benefits of conducting this kind of biomarker collection alongside the clinical trial.
Depression is pretty complex, we can have two individuals that are experiencing a depressive episode that may be exhibiting very different symptoms. So one may sleep too little, another may sleep too much. Somebody could have extreme anxiety, while another person is very calm but has really no interest in what is going on around them. The fact that we see these different symptoms in patients suggests that they likely have different biological underpinnings and that would make it unlikely that the same treatment would be effective in these different patients. But we really haven’t figured all of this out yet. So, the comprehensive collection of the biomarker data, the molecular, the neuroimaging, the cognitive data through the CAN-BIND program, allows us to maybe discover more about depression and the underlying biology which might lead to novel ways to treat it. We are also hoping to be able to better understand who will respond to treatments and have the ability to direct patients to the appropriate therapies as well.
Dr. Rashad: So, we collect biomarkers to see if they will help us predict response to treatment…and perhaps down the road, it’ll be a tool that mental health professionals will use to guide more tailored treatment for depression. Actually, the B in CAN-BIND stands for that, Biomarkers.
Also, if you’re interested to learn more about biomarkers we have created an animated video entitled “Why are biomarkers important in treating depression?” on our YouTube channel and the link is in the transcript of this podcast.
So far we spoke about how both ECT and ketamine could help manage treatment-resistant depression, we spoke about the study goals and how one can participate. We also got to hear about biomarker collection in this study.
I have a question about maintenance treatment…so basically continuing to get ECT or ketamine over longer periods to prevent relapse of depression. Does this study also address this?
Dr. Phillips: Absolutely. The objective of the longterm follow-up part of the study is really to determine an administration schedule that would allow patients who have responded well to ketamine to maintain their response. For both ECT and ketamine, generally, you can’t just administer a couple of treatments, you really need a good course of repeated treatments in the acute phase, and then for both, there is generally some maintenance that is offered.
For ECT, we have a lot of evidence that administering continued treatments is a safe and effective way of preventing relapse. For ketamine, actually our group did some of the first research into potential maintenance strategies, beyond a sort of short course of treatment. We showed that in a one month period, we could space out ketamine infusions, administer them less frequently. We tried once a week, rather than three times a week, and we were still able to maintain patients’ antidepressant response. So in the current ECT-ketamine trial, anyone who obtains an antidepressant response to ECT or to ketamine is able to enter a six-month maintenance phase. For ECT, the treatment is following standard of care, it is whatever the prescribing physician would like to offer them in terms of maintenance, so it is not a set schedule. But for ketamine, we are hoping to determine whether we can use a predetermined schedule of infusions where we are decreasing them in frequency as the maintenance stage goes along. In the maintenance phase for ketamine, patients go from receiving once a week to biweekly infusions to finally receiving infusions only once a month, in the final few months. And this is really important because it is not practical to continue administering to individuals three times a week. We need to find a way to administer ketamine long term, as we really translate its use into routine clinical settings.
Dr. Rashad: So in summary, it is quite established that ECT can be used for maintenance treatment. As for ketamine, the investigators of the study are currently exploring a schedule that is effective and safe for maintenance.
We are nearing the end of our episode today…but before we go let’s hear some closing words from Sophie.
Sophie: Suffering from depression is very difficult it’s very painful, and sometimes it’s hard to reach out, but you have to reach out, you have to reach out to your close ones, you have to reach out to your physicians, and sometimes even family doctors, they are not always aware how severe your depression is, but you have to speak for yourself. And also, if you have a close one, like a family member that you can trust, talk to them, and also be your advocate but don’t suffer in silence. And sometimes you may need to push to have a psychiatrist, but do it. It’s worth it so that you can feel better. You do not need to suffer from depression, and there is relief. And I would say when you are suffering from depression you’ve got nothing to lose, but to just get better.
Dr. Rashad: Excellent! And that’s about it for today’s podcast. We hope you learned something new and enjoyed this rich discussion. To keep up to date on our research and content, please visit our website, canbind.ca. Please visit the “Ongoing Studies” tab for more information on our current research studies.
Also, don’t forget to follow us on social media, we have a new series of short videos that give tips on how to cope and take care of your mental health during COVID-19 times. Find us on Twitter and Facebook by searching: “The CAN-BIND Program”. See you there!
We would like to thank our guests, Sophie and Dr. Jennifer Phillips. And our reviewers, Dr. Sagar Parikh and Dr. Franca Placenza. Special thanks to Dr. Sidney Kennedy and the rest of the CAN-BIND family and of course, Damien Murphy as our audio editor.
Thank you for listening and until the next episode, goodbye!
Why are biomarkers important in treating depression? https://www.youtube.com/watch?v=RnA608WKAJE