View episode transcript

Featured Guest

Daniel Maixner, M.D.

Objectives

• Define treatment resistant depression.
• Define electroconvulsive therapy, and its risks, benefits, and rationale for treatment modality.
• Define transcranial magnetic stimulation, and its risks, benefits, and rationale for treatment modality.
• Define ketamine therapy for treatment resistant depression, and its risks, benefits, and rationale for a treatment modality.

Resources

• Systematic review: electroconvulsive therapy for treatment-resistant mood disorders in children and adolescents (European Child & Adolescent Psychiatry) 
• Transcranial magnetic stimulation for adolescent depression (Child & Adolescent Psychiatry Clinics) 
• Efficacy of intravenous ketamine in adolescent treatment-resistant depression: a randomized midazolam-controlled trial (American Journal of Psychiatry)
• Annual research review: defining and treating pediatric treatment-resistant depression (Journal of Child Psychology Psychiatry)

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Transcript

Dr. Christina Cwynar:

Hello and welcome to season two of Breaking Down Mental Health with myself, nurse practitioner, Dr. Christina Cwynar, social worker, Syma Khan, and child and adolescent psychiatrist Dr. Heidi Burns. We are joined today by Dr. Dan Maixner to discuss treatment resistant depression. Dr. Maixner is a clinical professor of psychiatry. He has served as the ECT program director for over 25 years. He has experience in treating treatment-resistant depression and research in electroconvulsive therapy, transcranial magnetic stimulation, and ketamine, welcome and thank you for being with us today.

Dr. Dan Maixner:

Great to be here.

Dr. Christina Cwynar:

Let's start today off with a definition. What is treatment resistant depression?

Dr. Dan Maixner:

Treatment resistant depression typically is referring to an illness or depression that has not responded to many treatments. Quite commonly, it means that a person has failed a number of medications and or psychotherapy in combination. So quite often there's resistance that builds up over time and other treatments are sought.

Dr. Heidi Burns:

There are several treatments for treatment resistant depression, with one of the oldest being electroconvulsive therapy or ECT. ECT was developed in Rome in the 1930s and found to be highly effective for severe depression and catatonia. Dr. Maixner, can you talk with us a little bit about what ECT is, how does it work, and what evidence is there to show for pediatric patients specifically?

Dr. Dan Maixner:

Sure. So ECT, as you mentioned, is the oldest interventional psychiatry strategy or brain stimulation strategy for depression. It was developed in around 1938 in Italy and subsequently spread to the United States and other parts of the world. It was found very useful for depression, bipolar mania, catatonia, as you mentioned, which is a syndrome where patients might become completely withdrawn and stuck and may be connected to a lot of other psychiatric illnesses such as schizophrenia as well. ECT can also treat psychosis associated with schizophrenia. This treatment fell into less use in the 1970s, but since about the 1980s, the use has risen to its current numbers, which tends to be about a hundred thousand or so patients in the United States are treated with ECT. This treatment is not overly used based on those kinds of numbers, but again, it's used for very hard to treat illness for child and adolescent patients.

It is also used at the University of Michigan. We are one of a handful of centers in the country that do a fair number of patients that have severe resistant illness with depression and psychosis as well as catatonia. So as far as outcomes with this treatment in child adolescent patients, the outcomes are actually rather similar to adult patients. And what we're looking for with depression is a remission rate of 60% or more. And what remission is to define that briefly, is that we're looking to improve depression symptoms to very low level to no symptoms of depression at all. And so that's remission. And so, when you look at many treatments for depression, whether it's therapy, medications, the term response is typically used, and response, usually means a reduction of your symptoms by about 50%, not necessarily remission. So, all in all, ECT is quite effective in inducing and helping patients get into remission greater than essentially all psychiatric treatments.

Syma Khan:

Thanks so much for summarizing the history of ECT, its uses, and I think all four of us in the room here I think have extensive experience working with patients who've received ECT treatment and other interventions for treatment-resistant depression, and seen really the positive outcomes. Unfortunately, media has misrepresented ECT and created many misconceptions about the procedure. Can you speak about some of the myths or fears that you often hear about ECT?

Dr. Dan Maixner:

Sure. Media and television has historically not done a great service for our treatment. ECT is a very brief procedure that's done completely under anesthesia. We are inducing a very brief seizure that we can monitor on EEG; however, we're not actually seeing a vigorous seizure or epileptic fit during this session. In decades past when there was no anesthesia, that was a different story, but that was many, many years ago when ECT was first developed as a treatment. So, from a safety standpoint, it's a very safe and straightforward procedure under anesthesia and doesn't look like the way it's usually portrayed on TV.

And so, we do face this constant issue of Hollywood and other arenas where it may be overdramatized as a treatment that's painful, torturous, and when in fact, it's a very straightforward procedure where you have anesthesia team members that are in the room and a full complement of medical monitoring during the session. And the session itself is really only about 10 minutes, and the patient is in and out of a treatment room usually in about 15 minutes.

Dr. Christina Cwynar:

Thank you for explaining that common misconception that we see with ECT, and unfortunately, we see that with many things in psychiatry. So, I appreciate your insight to what actually happens in those sessions. So ECT is just one type of treatment that is being used for treatment resistant depression. Another treatment is transcranial magnetic stimulation, also known as TMS, which was introduced in 1985 by Anthony Barker and his colleagues, but the technique dates way back to the late 1800s. Dr. Maixner, could you speak a little bit about what TMS is, how it works, and the risks and benefits to this type of treatment?

Dr. Dan Maixner:

So back in the 1800s, scientists would've understood that if you generate an electrical magnetic field that you can induce neuronal changes, brain changes. And that is what was happening back in those far off years when if you entered an electromagnetic field with your body or your head, you could actually induce things such as seeing some visual changes based on activation of your occipital cortex and your visual cortex. And so again, this electromagnetic field can induce brain changes. And then later on it was used as a brain mapping technique and you can stimulate the brain with this electromagnetic field and you can monitor and map the brain in different ways. But it really wasn't until the 1990s when TMS was developed for depression in particular and as a specific treatment indication. And at that time in the mid 1990s is when there was a number of smaller studies emerging.

And then eventually this led to the development of a device in the early 2000s and the first FDA approval of a TMS device for depression around 2004. It's been now for many years, but because of some of the response rates with TMS, it was not necessarily readily accepted as a treatment by insurance companies. There were some other analyses that happened with the first device that was approved for depression. And it wasn't until around 2008 when full FDA approval was given to this treatment. And then it's slowly bit by bit has become a mainstay of our interventional psychiatry strategies.

Dr. Heidi Burns:

When speaking to patients about treatment resistant depression treatments, we often think about ECT having a lot of stigma associated with it. And I've seen myself talking with patients that that's often the treatment that causes more concern initially or needs a lot of education surrounding that. But do you feel like TMS comes with the same stigma?

Dr. Dan Maixner:

Typically, not. With regards to ECT stigma, it usually is a major issue and point of discussion when I'm consulting with patients. And so, I usually reserve extra time during my consultations with patients and families, so I can explain side effects. The biggest concern is that it's dangerous. It's going to hurt me, it's going to damage my brain. You're inducing this brief seizure and you're going to actually do some damage when in fact there's no evidence to support that. I do tend to focus on, with ECT, the major primary concern of memory side effects, which again, is a particular cost benefit ratio that patients have to think through. But with the memory side effects with ECT, it tends to be two types of memory issues. And one of them is anterior grade memory difficulties, where during a course of treatment, you may have some difficulty holding onto new information and remembering new information coming in.

And so, it's usually not advised that you're working or going to school during those weeks that you're getting treatment. But if the depression is better, the medications are stabilizing things after the ECT course, the short-term memory does tend to get back on track. For another type of memory impairment, which is retrograde memory issue, you could have some memory loss for recent past events, but it tends to be closer to around the time of the ECT course. Usually around the few months of ECT before ECT, and maybe going back maybe six to nine months is somewhat typical to have some spotty memory loss, but it tends not to wipe the brain clean or wipe the slate clean, which patients often worry about that somehow, you're going to hurt my brain that I'm never going to be remember who my family is or remember who I am, that kind of thing.

And so, there's a lot of effort that goes into trying to discuss these kinds of side effects with patients. Otherwise, ECT is extremely safe as a medical procedure. For TMS, TMS is easier in the sense that there's no cognitive side effects associated with it. It's an outpatient procedure. You can report to a clinic, an outpatient clinic, and sit in a dental chair type of setup and have this device rest on your head and it tickles or taps on your scalp for a few minutes to a half an hour, and then you go home and you can come and go as you please without difficulty. So, for that reason, it's simpler. It's a simpler treatment it, and because of that and because it doesn't have that long-term history of being perceived as a dangerous treatment, it has less stigma with it.

Syma Khan:

Thank you so much for discussing the different types of myths and concerns people have about ECT and TMS. And it sounds like with a lot of education and support, we're able to engage families to access this treatment that can be really helpful in treating treatment resistant depression. A much newer treatment for depression is one that is undergoing many ongoing clinical trials is ketamine. We believe we have a clinical trial here at University of Michigan as well. And the first randomized trial that demonstrated the effectiveness as an antidepressant was conducted by Yale in 2000. Dr. Maixner, can you talk a little bit about how ketamine works for depression? What are the risks and benefits and how is it administered?

Dr. Dan Maixner:

So, with ketamine, it's a treatment where you can administer it a couple different ways. Right now, there's an FDA approval since 2019 in the use of S-ketamine, which is a formulation of the ketamine anesthetic agent that you can give to a patient intranasally. And so like TMS, like ECT, it's a course of treatment that you might report to a clinic a few times a week, and you have a session where it lasts about two or three hours and you have a dose of this agent intranasally. And that's one way to administer the ketamine. The other way to administer ketamine is by using intravenous ketamine in a similar fashion, two or three times a week. And the courses tend to be anywhere from three to six treatments to really see if it's going to show some strong benefit for patients. So that's the typical course with ketamine.

For how it works, ketamine is different than typical antidepressant agents that we use for depression. Historically, we think of depression treatments with medications as trying to adjust or alter the monoamine neurotransmitters such as serotonin, norepinephrine, and dopamine. This is actually affecting a different neurotransmitter system altogether, the NMDA receptor system or the glutamate excitatory brain system, and it's an antagonist to those receptors and affects the excitatory brain system differently.

And so, there's a number of things that it's doing, but that's a major difference for how it may work. So regarding the risk and benefits of ketamine treatments, ketamine also is very safe treatment. It's not very invasive except for when you do have intravenous ketamine, you do have to report to a clinic and have an IV placed. The sessions for both IV and intranasal ketamine tend to be a few hours. So with the IV ketamine, it's a session where the infusion lasts for about 40 to 60 minutes, and then the medication has to wear off and wash out.

For both the intranasal and the intravenous ketamine, the side effects tend to be things like a mild sedation feeling, a feeling also that you might be disconnected from reality to a certain degree or an out-of-body experience for some patients if it affects them strongly. But typically, it's a very mild sensation and it's not usually unpleasant. In rare circumstances, we do let patients know that they may experience some visual disturbances, and this could include double vision. In rarer situations, somebody might have a hallucination like experience. But again, that tends to be very mild if it does happen. Sometimes people have an experience where they see colors or shapes, and that's part of that visual disturbance, but again, not usually an unpleasant experience for them.

And so, in general, it's very safe. The biggest issue with that is that you have to be at the clinic for a few hours at a time. The benefits with ketamine have shown some very good effects in treating severe depression as well as suicidality in patients with depression. And the numbers that we're discussing with, or the outcomes with ketamine tend to be in the range of 50% remission in a number of studies. So that's also a very good number when we're talking about remission that I mentioned earlier that we're looking to try to treat depression to get the depression all the way better.

Dr. Christina Cwynar:

When thinking about these three different modalities, what does a typical course look like for a patient for each of them?

Dr. Dan Maixner:

So, with ECT, it's a course of treatment where you do have to report to the hospital or a ECT program and receive treatment two or three times a week. And the course usually is somewhere between six and 12 to treat a severe depression. Oftentimes people feel that 12 is the end of the typical range, however, 12 is not a magic number. And patients who are severely ill, who may be experiencing severe resistant depression, mania or catatonia, it may take more than just 12 treatments. And the other issue with ECT is that when we're treating these very resistant illnesses, they tend to want to come back. They tend to induce relapse within six to 12 months for a number of patients, and upwards of maybe a third of patients may have a significant relapse later on, even if they do really well with the ECT, and they may need some form of maintenance treatment, which might include a taper of treatments to once a week, once every two weeks. And we do have some patients that really benefit from our help, even coming once a month.

With TMS, the course generally is five days a week, up to 30 treatments for about six weeks. So, it does take a little bit longer to complete a course of TMS, but again, it tends to be a little bit easier to do as an outpatient, and you don't need anybody bringing you to and from the treatment. And it usually is about six weeks for TMS. For ketamine, it is a course that lasts about three to four weeks, ranging from about three to eight treatments, three to 10 treatments, something like that. All in all, though, you can see that TMS tends, if it's going to work, is going to start to show improvement in about four to six weeks. ECT can start to show benefit even as early as a couple of weeks, as well as ketamine in the same ballpark. So, when ECT and ketamine work, they seem to be a little bit faster.

Dr. Heidi Burns: 

As a provider who comes and does consultations for treatment resistant depression, how do you choose which pathway a person should go on, if they should be getting ECT, TMS or ketamine?

Dr. Dan Maixner:

The way I think of it is TMS usually is used for maybe a milder or moderate resistant level of depression. So perhaps failing a handful of medications and the symptoms oftentimes may not be as severe as some of our patients that are receiving ketamine or ECT. And so more of a moderate depression with a less resistance. For ketamine and ECT, both are extremely helpful for severe depression. There are ongoing studies evaluating the use of ketamine and ECT. In looking at trials of which one is better, the data would support that overall ECT still has a higher chance of inducing remission despite a recent study that was published in the New England Journal of Medicine highlighting that ECT and ketamine might be similar in outcomes. But there was a number of issues that I have with that particular study and some confounds that I think are concerning.

So, if you look at the overall outcomes and remission level, ECT still tends to be showing the highest percentage of remission. However, patients, they may be nervous about starting ECT, they may want to do something that's less invasive. And so, I think right now, ketamine does have some strong antidepressant benefit and patients may actually prefer that ahead of ECT. So right now, we do have some patients that might try ketamine ahead of ECT just because there's less of invasiveness. Even if you do the IV ketamine, you still have to come into the hospital or a unit or a program where you can have an IV placed and do the treatment. You still have to have somebody bring you to and from treatment cause; you've just had a sedative. And so, it's more difficult to do a course of ketamine or ECT for that matter, but there's no risk of any cognitive side effects.

So, some of it is patient preference, and there are cases that we have right now in our ECT program and our IV ketamine program where if that particular treatment doesn't work, it doesn't exclude ECT as a reasonable option to get to. And patients still have a very good chance of responding to ECT even if ketamine doesn't work.

Syma Khan: 

Thank you for summarizing the treatment course and how these interventions are provided to individuals with treatment-resistant depression. Recognizing that this podcast is geared towards our adolescent population, are there other thoughts that you have about these modalities within pediatric populations?

Dr. Dan Maixner:

Sure. Right now, ECT is the oldest that's been studied in this population for the last 25 to 30 years. There's even a book that is focused solely on ECT in child adolescent patients, and that is the main treatment right now that we have for the most severely ill child adolescent psychiatric patient. For these other strategies with ketamine and TMS, there is a number of studies that are out there in this population. These studies tend to be harder to do because it involves studying special population with younger patients, but there definitely shows promise with TMS in treating child adolescent depression. There's less known about ketamine at this time.

Dr. Christina Cwynar:

Thank you for joining us today and sharing your expertise. We appreciate your time.

Thank you to everybody who tuned in this week. Nurses, social workers and physicians can claim CMEs and CEUs at uofmhealth.org/breakingdownmentalhealth. You're able to do this at any time within the first three years of the initial air date. We hope you will join us next time.