TCPR: What type of patient is best suited for the ketamines?

Dr. Greenway: Treatment-resistant depression is where we have the best evidence, which means the patient has not recovered after two antidepressant trials (at least six weeks at a therapeutic dose). That is for unipolar depression. In bipolar depression, the evidence for ketamine is emerging. The other indication is in depression with suicidality (Kritzer MD et al, Expert Opin Drug Saf 2022;21(6):725–732). There is some suggestion that ketamine’s benefits in suicidality are partially independent of its mood benefits.

TCPR: When should we avoid the ketamines?

Dr. Greenway: Well, treatment-resistant depression is a heterogenous condition, and comorbidities are common here. The one we worry about most is a current substance use disorder (beyond nicotine) or anyone who is at high risk for a substance use disorder. We don’t want to set off an iatrogenic use problem (Le TT et al, J Psychiatr Res 2022;151:476–496). Another concern is psychosis. I would avoid the ketamines in people with psychotic symptoms until we know more about ketamine’s safety there.

TCPR: What about medical risks?

Dr. Greenway: The major issue is increased blood pressure and pulse. So ketamine is not a good idea if someone has had an aneurysm or a recent heart attack or cerebral hemorrhage. But most people can tolerate their blood pressure going up by 20 or 30 points for 40 minutes. If I think the patient could tolerate a 40-minute brisk walk, then it is probably safe.

TCPR: How should we choose between esketamine and ketamine?

Dr. Greenway: Ketamine is the original racemic drug, which is made up of 50% esketamine and 50% arketamine. Ketamine is given off-label as an IV therapy, while esketamine is given intranasally as the branded Spravato. Often the choice comes down to availability. Esketamine is more expensive, but also more likely to be reimbursed by insurers. However, in terms of efficacy and tolerability, all the preliminary evidence we have that indirectly compares these two points slightly in favor of IV ketamine, which is the form I use in Canada (Bahji A et al, J Affect Disord 2021;278:542–555). 

TCPR: In the US, we’d have to refer to a ketamine clinic. Are there any red flags to look for in terms of quality?

Dr. Greenway: Yes. One of them would be that the clinics are overly biomedical in their orientation or are staffed only by anesthesiologists. They may not have the training to assess and monitor all the comorbidities that go along with treatment-resistant depression. At the other extreme, some clinics may be operating out of a psychedelic paradigm and may be loose with the doses and protocols. For example, they might give IV doses in the clinic and sublingual doses for the patient to take at home, perhaps with a therapist on Zoom in front of them. Clinics need to have protocols in place to avoid diversion. 

TCPR: Are there any psychiatric medications that can’t be combined with the ketamines?

Dr. Greenway: There are no absolute contraindications, but one class to consider stopping is gamma-aminobutyric acid (GABA) agonists like benzos and Z-drugs. Ketamine is thought to both raise and block glutamate transmission, and GABA and glutamate interact in complex ways. In theory, GABA agonists may blunt this mechanism, and there is evidence that benzodiazepines reduce the acute psychological effects of ketamine, particularly in high doses (Andrashko V et al, Front Psychiatry 2020;11:844). Benzos have good evidence in acute depression, but their long-term use is controversial and may even worsen the illness. So that’s another reason to consider stopping a benzo before ketamine. It’s also a good opportunity to come off other kinds of irrational polypharmacy that aren’t clearly helping the patient.

TCPR: And how do you taper the benzo?

Dr. Greenway: The conventional wisdom is to treat the depression first before attempting a taper, but we’ve found that the ketamine process itself is an excellent occasion to try to get people off their benzodiazepines. Most patients are excited to start ketamine. I’ll say “To maximize your chances that this will work, we should taper your benzodiazepine such that the last dose is a couple of nights before your first dose of ketamine.” We published an open-label study of this and did not find significant worsening of depression, anxiety, or even sleep because ketamine is such a powerful treatment by itself. Ketamine also has anticonvulsant effects.

TCPR: How long is an adequate trial of ketamine?

Dr. Greenway: If someone has zero response after four treatments, I would stop. If there is a partial response, I would go to six treatments and reevaluate. Those are some general guides, but we don’t have good data here. I’m referring to ketamine, which is dosed IV 0.5 mg/kg over 40 minutes, approximately twice a week. For esketamine, it is probably similar.

TCPR: If they recover, when do you start to taper off the treatment?

Dr. Greenway: This is where we are in the Wild West. A common protocol is administering ketamine or esketamine twice a week for three to four weeks and then shifting to a maintenance phase with less frequent dosing, such as every two weeks for a few months and then once a month for a few months, and then stopping. The whole taper might take about six months (Kritzer MD et al, Expert Opin Drug Saf 2022;21(6):725–732). But at our clinic, we do it differently.

TCPR: How so?

Dr. Greenway: We use a psychotherapy model where ketamine is not the primary treatment. We use it to reduce acute symptoms and increase engagement in psychotherapy. In this Montreal Model we start by setting the stage for behavioral work, then give six doses of ketamine over a month and stop. After that, we typically keep them on other psychiatric medications that they were taking before ketamine, but we use psychotherapy to maintain the response (Garel N et al, Front Psychiatry 2023;14:1268832).

TCPR: How do you set the stage for psychotherapy?

Dr. Greenway: The first thing that we do is set goals. We say “Imagine that your depression improves with ketamine. What activities do you see yourself doing to stay well?” Sometimes patients are so focused on symptoms that they forget the basics, like daily routines, sleep hygiene, exercise, and healthy diet. We aim for at least three “SMART” goals, which stands for Specific, Measurable, Actionable, Realistic, and set in Time. A goal might be “I’m going to get out of bed every day at 9 am and take a shower.” Sounds simple, but many of our patients practically live in their beds.

TCPR: What comes next in the Montreal Model?

Dr. Greenway: We always ask people to start psychotherapy. There are many psychological issues involved with treatment-resistant depression, and they are going to need some kind of evidence-based therapy in place to prevent relapse after ketamine. Also, many of our patients are isolated, and the ketamine process is almost guaranteed to generate psychological material that will benefit from a therapeutic process. It ranges from “Wow, I feel better, and I don’t know how to make sense of the last 10 years of my life” to being really disappointed that ketamine did not work the way they had hoped. 

TCPR: Does the ketamine experience generate new ways of thinking?

Dr. Greenway: It may, and in our clinic we prepare the patient for this over two to three sessions before starting ketamine. In the first session, we establish the diagnosis and get a snapshot of what a day in their life is like. I ask how they spend their time hour by hour. If they say “I do nothing,” I don’t stop there. My “doing nothing” and somebody else’s “doing nothing” might be totally different. In the second session, we set behavioral goals and start any medication adjustments we need to. In the third visit, we help them prepare psychologically for their first ketamine session.

TCPR: How do you do that?

Dr. Greenway: We often teach a meditation exercise, such as mindfulness or a body scan. We want them to cultivate a sense of curiosity, to be open to their own experience. Sometimes this preparation may take longer. I won’t schedule the first ketamine session until I feel there is a strong collaboration. I want them to have the best chance of success with the treatment.

TCPR: How do you judge collaboration?

Dr. Greenway: I look to see that we’ve set some goals and seen some progress on them. This may not involve another session. After they set goals, I may follow up with a phone call to check on their progress. If they say “I just can’t find the motivation,” I’ll say “Maybe we shouldn’t rush into this.” 

TCPR: Tell us about the setting where you deliver ketamine.

Dr. Greenway: It’s actually quite medical, with an IV pump and a machine to monitor heart rate and blood pressure. That’s intentional because this is a medical procedure. But the setting is also very pleasant—we have carpets and plants. While receiving ketamine, patients typically wear a blindfold and listen to music through headphones. We have playlists that create an arc over 40–50 minutes, beginning with calm songs and building in intensity and then returning to calm as people come back to reality. You can find it on Spotify (search for Montreal Ketamine Clinic). We have several playlists—jazz, classical, electronic—and let the patient choose. In later sessions, we might invite them to make their own playlists. The main thing is it should be instrumental, or at least not have intelligible lyrics. We want their imagination to flow.

TCPR: Is the patient alone during the treatment?

Dr. Greenway: No. There is a therapist in the room, and the patient may turn to them for support or guidance, though typically they are not interacting much during the infusion. Afterward, as they come out of it, they talk about what happened.

TCPR: What sort of experiences do patients have?

Dr. Greenway: Powerful stuff often comes up—emotional, dream-like, even spiritual. It might also simply be fear—in all the trials there is usually a rate of 1%–5% of people dropping out due to anxiety or panic. We discuss this possibility in advance, but we avoid pathologizing it with words like “dissociation.” The message is to “let go and be open.” In other words, be curious without being too literal about the experience. Don’t jump too quick to conclusions about the content. 

TCPR: What happens in the therapy sessions that follow the ketamine treatment?

Dr. Greenway: The therapy we use follows the acceptance and commitment therapy model. Briefly, it involves teaching patients to feel their emotions, to diffuse their thoughts, and to change their behavior. By “diffuse,” I mean to gain some detachment from their thoughts, similar to what happens in mindfulness. They learn to view their own thoughts as phenomena in their mind, or as words on a screen, rather than “the truth.” 

TCPR: Is it important that they set goals that align with their values?

Dr. Greenway: I think values are important in behavioral therapy, but it’s hard for people with severe depression to get in touch with them. So my patients often choose very basic goals, things that are generally good for anyone, like walking in nature, socializing, or brushing their teeth every day. Of course, there is a value in those goals, which is taking care of themselves. Starting those routines can build self-esteem, helping to chip away at the guilt and worthlessness that are part of depression.

TCPR: Back to the collaboration, it’s almost like you’re asking them to care about themselves before they start ketamine.

Dr. Greenway: That is the implicit message. We need to communicate “Ketamine can help, but it won’t fix you. Eventually you’re going to have to fix you.” That is a hard message to deliver, and it takes a lot of trust and kindness. It may be better conveyed implicitly, saying things like “Can we find three small changes in your life that we can work on together?” You’re engaging the patient to make changes in their life without shaming them for spending all day in bed, for instance.

TCPR: Thank you for your time, Dr. Greenway.