About the Episode

Over 17 million adults in the United States alone suffer from depression. For those who struggle with the most severe depression, treatments like talk therapy, exercise and traditional medication don’t always provide relief. Cristina Cusin, MD, has dedicated her career to working with patients with the most severe forms of depression. This mission led her to working with ketamine, a drug traditionally used as an anesthetic that has shown promise for treatment-resistant depression. Dr. Cusin talks about what first drew her to these challenging cases, how she hopes to provide relief for her patients and why it’s important to support them in rebuilding their lives when they find a depression treatment that works.

About the Guest

Cristina Cusin, MD, staff psychiatrist at the Depression Clinical and Research Program (DCRP) and co-director of the Ketamine Clinic for Depression, is passionate about helping patients with the most severe and treatment-resistant forms of depression. After completing her residency in adult psychiatry at Mass General, she joined the DCRP under the mentorship of Maurizio Fava, MD.

Dr. Cusin is involved in many clinical trials exploring new treatments for major depression and treatment-resistant depression. In 2015, she launched the Intravenous Ketamine Clinic for Depression to provide IV ketamine treatment; the clinic now provides nasal ketamine treatment as well. She has published extensively on the effects of ketamine on treatment-resistant depression. She was previously involved in a pivotal trial that investigated deep brain stimulation for most treatment-refractory forms of depression. She also has an outpatient clinic at the DCRP where she provides consultations.

Dr. Cusin received the Dupont-Warren Fellowship Award at Harvard University and earned her medical degree in 1997 at Universita degli Studi in Milan, Italy, where she also completed a residency in psychiatry. She completed a postdoctoral fellowship at Vita-Salute San Raffaele University in Milan. After moving the US, she completed the Adult Psychiatry Residency at Mass General/McLean Hospital.

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Depression is one of the most common mental health disorders in the United States, affecting over 17 million adults each year. That’s over 7% of the population. Psychiatrist Dr. Cristina Cusin has devoted her career to helping patients with the most severe depression find relief. Many have struggled for months or years with treatment-resistant depression.

This pursuit has led her to work with ketamine, a drug traditionally used as an anesthetic. Ketamine has also shown promise for treating severe depression, and doing so much more rapidly than traditional medications. In 2015, Cristina extended her research expertise into the clinical space with the launch of the Intravenous Ketamine Clinic for Depression at Mass General to provide IV treatments for patients. Today Cristina continues to hone her expertise in ketamine and think about what’s next for these patients.

So, welcome, Cristina.
A: Thank you.
Q:  I wanted to start off talking about your professional work treating depression and why that's been important to you.
A:  It was towards the end of medical school in Italy and I went through a rotation in psychiatry in a unit where primarily patients with mood disorders were admitted. And I was fascinated by a disease that is intermittent, unlike other diseases in psychiatry that are chronic. The peculiar aspect of mood disorders is that they can be present for a period of time and then remit, and then come again. And they have a cycle.
And I thought there was a lot to discover about those disorders. And depression was a huge challenge because of lack of effective treatments for a number of patients.
Q: And early on, I'm wondering, where there particular patients that you encountered that really sparked your interest?

A:  There are patients with bipolar disorders where they could go from extreme lows of depression and suicidality to extreme high of buying a Ferrari while on disability checks. And then having to figure out the aftermath of impulsive purchase.
In patients who are depressed with psychotic features, that could go back to being completely normal functioning and having a job and trying to figure out why the brain can go through those extreme states and then go back to normal, how is that possible? How does it work?
Q: Do you have any insights? Over so many years, I'm curious if you have a sense of things.
A:  We're still far away from understanding the biology of mood disorders. We have a little bit of understanding that some– neurocircuitries are circuitries implicated, some areas are implicated. But causes still escape.
Q:  Yeah
A:  For most of the psychiatric disorders we don't have good explanation or animal models that we could use. We use chronic stress models, but it's not the same thing as an episode of depression that comes out of nowhere.
Cancer or diabetes or traumatic brain injury in animals is very different from psychiatric disorders.
A:  There's still diseases of the brain for which we don't know enough. Psychiatry's much younger than other disciplines. And the brain is so much more complicated than other organs. And we know very little. We barely scrape the surface of functioning. And we have the sense of network, but how the network integrate and how they change and adapt, we really don't know.
And how this process can go, can be disrupted after onset of a chronic condition versus an intermittent condition. We are really working hard trying to figure out what are the pieces of the puzzle.
Q:  Is that changing? It seems like we're at a moment where technology is maybe at the tipping point of giving us more insight into the inner workings of the body.
A:  Definitely we have technology that allow to study neurons in glial cells and supporting cells in a 3D and really try to understand what are the connection between millions of cells packed in a teeny, tiny space instead of just studying the neuron or in a flat surface of a slide.
But this, again, it's so interconnected. The chemical part of neurotransmitters with the electric part of the conduction and how the two are integrated, we are barely, barely scraping the surface of understanding it.
Q:  There's a lot of people out there treating depression, what's different about your approach?
A:  We don't know what depression really is, and probably will label depression a number of different conditions that look alike, but they're probably not alike from the biology point of view. There are patients who start at eight, nine year old with severe depression and have family members with severe depression as well. So there's probably more of a biological component. And other patients who have depression after taking certain drugs or after medical illness or multiple sclerosis or Parkinson's, so probably the biology's different.
So we're trying to figure out what are the boundaries between different disorders. But the impression is we're probably calling depression something akin to fever. We see some phenomena, we see some aspect that are shared of a syndrome. But the underlying causes may be very, very different. It can be a bacteria for fever, it can be a virus, it can be cancer, it can be a reaction to drug, it can be something completely different from one person to the next.
And the problem, we're studying treatments by lumping them all together. So if you study a treatment for fever and you put together 20 patients with fever of different origins, you're not going to be very successful. But we don't know any better.
So we're trying to refine diagnosis. We're trying to refine our, understanding of the time course, understanding of the response to medications, and see if we can refine our phenotypes a little bit better.
Q:  Are there trends that are emerging within that field of types of depression?
A:  No. We have some flows on different models, looking again at symptoms, looking at the response to drugs, looking at genes. But nothing that really was replicated and proven. So far, we're still calling it depression, the label is fairly generic.
And then the problem is the spectrum of severity. You may feel a little bit down or blue for a week in occurrence of some life stressor. But this is different from months or years of unrelenting, profound depression, lack of interest, lack of pleasure in anything that happens, and thoughts about killing yourself as a way to end the pain.
Q:  And how do you determine the line between, I'm blue or I'm down, and, I'm depressed?
A:  The common agreement from diagnostic system is you have to have at least five out of nine symptoms lasting for at least two weeks and impairing your functioning on some domain. So if you have a certain number of symptoms and you have functional impairment in your work, in your family relationship, in your social life, you have insomnia or you start losing weight, or you're terrible concentrating, and this cause a problem, then it's warranted some attention and possibly treatment.
And what type of treatment is complicated answer as well because it depends on patients' preference, on what has been tried before, on time and availability of certain treatments in different areas.

Q:  And do you find that people have common misconceptions about what depression is or how it's treated?
A:  Yeah. It's really sad, but one of the most common misconceptions is that depression is caused by a lack of will, where if you just try hard enough, you get yourself out of there. Nobody will say anything like that about a cardiac arrhythmia – if you try hard enough, your heart rhythm will go back to normal, right?
So there is this misconception that you are in complete control of the functioning of your brain, if you just try. Most of my patients try to keep up a job. They're highly educated, they're struggling, they're really trying to push themselves to keep up with everything. They have no secondary gain whatsoever. They're just miserable day in, day out.
And it's not lack of will. They have an illness. There are parts of their brain that are not functioning well.

Q:  And it seems to me that, fighting these misconceptions is really important. I've read statistics that depression costs the United States over $200 billion every year in lost productivity. I'm wondering how you think we can best combat those misconceptions and really, emphasize that this is an illness and it's not something that can be controlled.
A:  The answer is really complicated. For example, college students, they're extremely reluctant to seek help for fear that this is going to come back and have them put on medical leave, forcibly, even without their agreement. And this has repercussion on their ability to graduate and to complete a course of study. So they binge drink, or they use marijuana, they use other drugs. They try to cope in some other way because they're afraid if the same entity that provides you help and treatment is also the same entity that can kick you out of your college, it's just that privacy becomes an issue.
And similarly, for a lot of employees, if going to their health services or health employee services might be reported, might end in medical leave or some consequences on their promotion or their– some consequences on the workplace makes, especially professionals, very reluctant to involve insurance, to involve anything regarding medical records. It's highly sensitive.
So that there is a stigma where the presence of any sort of mental illness, even if it's panic attacks or even if it's a mild form of depression, might be, or has been used in the past as a weapon against the person suffering. And that leads to a culture of secrecy and ending up in suicide when all the friends and the family say, "No. We didn't see that coming, we had no idea that the person was suffering this much." There may be some subtle sign, but the person was very careful about hiding for fear of repercussion.
So keeping in mind that this is an illness like any other illness. If you have diabetes, then you need to get care to prevent this from getting worse. If you have a heart condition, you need to get care to prevent this from getting worse. And no one should be discriminated or treated in a different way because they have depression. That is just absurd, that if a quarter of the population suffer from depression, we're just discriminating against the quarter of the population for no good reason.
Q: It's almost surprising that there's such a stigma with something that happens so frequently.
Q:  I'm curious, You were trained and grew up in Italy. Do you see differences between the way it's either conceived or treated between the two countries?
A:  In many parts of Italy, like in many parts of the United States, the stigma is really high. You cannot seek mental illness unless it's absolutely a psychotic break and it's undeniable, the need for psychiatric help. Otherwise, if you go to the psychiatrist, you're crazy. And I was a great disappointment to my parents for deciding to go into psychiatry [laughter] because "Can't you just be a real doctor?"
At least back then in Italy, there was this idea that psychiatrist is not a real doctor. Despite going through the same training. [laughter] And treating patients that are not real patients.
Q:  Yeah.
A:  And they just want to talk, or have some secondary gain, or they're faking it. And it's ridiculous.
Q:  And I know you've spent a lot of your career working with these patients who have really most severe forms, who– the treatment-resistant depression. How did you end up in that niche?
A:  I'm not so sure. [laughter] I felt that almost all psychiatrists could treat the patients who are mildly affected. They'll get better by themselves in most cases within a short time-frame. I had an attending back in Italy who was becoming an expert in treating patients with electroconvulsive therapy, and he was more aggressive with more complex regimen with pharmacotherapy. And somehow I was drawn to work with him more closely and learned more about different class of drugs.
And then when I came here, I continued to work along the same lines. And it became sort of a career because I had some success stories.
When you find something that works, after the patient was really desperate and on the brink of suicide, and you say, "Okay, let's try one more thing. Just listen to me, let's try one more thing," and you see the patient doing well for a protracted period of time, this is very rewarding.
Q:  Yeah.
A:  It's what gets you going in the morning.
Q:  It seems to me it would be difficult to work with patients every day who are really, really struggling.
A:  It's what an oncologist does. If you think about it, it's the equivalent of stage three, stage four cancer for a psychiatric illness. You know that they're at risk of dying. You know it's a lethal condition. But you can't say, "Okay, we're just going to treat the milder form of cancer; we're not going to invest any energy in trying to treat aggressively the patients who are having the most severe forms." That doesn't make any sense in oncology. Why would we be doing the same in psychiatry?
We have to take care of the most advanced form to progress, to find something different, something that works better.
Q:  And do you find that you– are there certain things you need to do for yourself, sort of care for yourself so you can care for these difficult patients?
A:  Trying to keep balance. [laughter] Trying to sleep. But again, it's the balancing out of any working mom and family and figuring out, trying to preserve your weekends, trying to preserve your nights. But sometimes current deadlines impinge into your family. It's a constant struggle. There is no way to have– the famous work/life balance doesn't exist. It's a constant readjusting every month or every couple of months. You rethink the plan and you try to figure out what works for you, what works for your family, what works for your job.
Q:  Yeah. And do most patients, once they find a medication regimen that works, do you usually stay on it sort of over the long term?
A:  Yes. If it's not broken, don't fix it. Again, if you think about a different branch of medicine, if you find a combination of anti-hypertensives that works for a patient with brittle hypertension, you find that three drugs in a certain way keeps the blood pressure within a normal range, would you touch it?
And sometimes people adapt to medication. In treatment-resistant depression, often there is the case that the patients adapt to medication after a certain number of months, so you have to find something else.
Q: Yeah, that's what I was going to ask. I know with bipolar, people can sort of phase out of lithium, right? It stops being as effective?
A:  That may happen over decades, but in antidepressants, there are about 7-8% of patients who can adapt to an antidepressant and to the first antidepressant and may take years. And the second time it may take months. And then it becomes shorter and shorter until you can find something that works. This is why it's great to have something different to try.
Q:  Speaking of something different, I know you've spent a lot of time and effort focused on ketamine, which is definitely a hot topic in psychiatry right now. Can you talk a little bit about what the drug is and what sets it apart from traditional antidepressants?
A:  Ketamine's an old anesthetic, has been used since the '60s/'70s as a part of the cocktail you may receive if you undergo surgery. It's used in emergency room for procedures if you have a dislocated shoulder. It's used in children. It doesn't suppress breathing, so even if you use a large dose to provide analgesia because you need it for a procedure, the patient continues to breath spontaneously.
And the dose used for anesthesia and analgesia are much, much higher than the dose found helpful for depression. There is some tipping point; we're still not sure exactly when it stops being an antidepressant and it becomes more of a sedative. So we're still figuring that out.
And it was found, randomly, first a series of observations in people emerging from anesthesia were saying, "Yes, my gallbladder has been removed, and my depression is gone. And I can't understand how is that possible." And this will last for a sustained period of time.

There were more experiments trying to look for a model of thought disorder for akin to schizophrenia to study anti-psychotics, and low dose of ketamine can give you a sort of, thought distortion. But some of those patients had depression and they realized once the acute effect of ketamine were gone, their depression was also gone.
So it started to be studied more systematically in 2006, and it was in controlled fashion. Those patients who have failed at their antidepressants were responding to ketamine and in some way that was dramatic.
Q:  Has this happened before? It's so interesting.
A:  In psychiatry, almost all the major drugs were found by chance, looking for something else. That has been very common in psychiatry because we don't know the mechanisms, so we can't design drugs to target the mechanism. Lithium, tricyclics, anti-inhibitors, were found when they were looking for something else.

Q:  And in terms of its use with patients, how is ketamine different from other sorts of antidepressants?

A:  It's quick. Sometimes after an infusion, a patient feels much better within hours, 24 hours. While for any other antidepressant, we usually prescribe and say, It may or may not work; we have to wait a month at least, four to six weeks, to see if it works. So knowing if it works within a day, it's great. It's a dramatic change for us. We've never seen anything like this.

And it can be long-lasting; it can last for weeks after one treatment, which is something we've never seen. And when you see it happening in front of your eyes, you start to believe it. The patients you've known for a long, long time and chronically suicidal, are really despondent, failed everything under the sun, failed ECT, receive an infusion of ketamine and say, "Okay, nothing has changed in my life. And I don't feel depressed anymore. And I don't understand it." It's really puzzling for patients to find themselves within hours free from depression when it happens.
And it's a little bit disconcerting because depression has become part of their identity. So they have to relearn how to live a life without the depression. And that is not easy if the depression has been with you for a decade.
And we're trying to figure out how to help patients with that.
Q:  What do you do in that case?
A:  We have found some very common series of problems in patients who are ketamine responders. And we have designed studies to have a manualized intervention of cognitive behavioral therapy to help those patients rebuild a life. They will need vocational training. They will need social skills. They've forgotten how to make friends. They've forgotten how to live a life because they were just not interested or have been disabled for many years and they have nothing in their CV for a decade. Who would hire them? How do they go to find a job if they want to? It's just really hard to rebuild a life. There is no clear path to re-entry in a job– in a workplace if you've been depressed for years and now you're better.

Q:  Yeah. So helping people relearn the skills that they [simultaneous conversation]
A:  Problem solve. Relearn. And try to figure out how to set them up for success in terms of staying out of depression.
Q:  Yeah
A:  So the importance of taking their medications and restarting with exercise, with self-care, medical care. They often don't even bother going to the primary care physician or taking the medications for medical issues because they're too depressed.

Q:  When you're working with those patients, do you often involve their families or their support networks?
A:  Absolutely. In order to be in the clinic they must sign a release of information so we can talk to family, we can talk to their psychiatrist, we can talk to their therapist and come up with a plan all together.
We've seen sometimes the patient stops the ketamine because they're doing okay. And they crash. And they become too depressed to call you back and to say, "I'm depressed again, I need to resume treatment." So we need a network of people who know what the plan is in case of relapse. Because relapse happen. So we need a network to keep them safe.
Q:  I'm wondering, too, more broadly, across psychiatry, getting ketamine accepted as a treatment for depression, how does that happen? How do you go from this was– most people either know it as an anesthetic or a party drug, and now we want to use it as this treatment protocol.
A:  A lot of psychiatrists have no idea. They will not touch it with a ten-foot pole. They have no idea. They just don't want to know about ketamine. They just refuse to send their patients to us. So we can't treat the patients if the psychiatrist is not on board. We need a team.
But we try to educate, we try to limit the misconceptions. Certainly the results from J&J studies and the FDA approval has made a difference because now it's really mainstream. There's the FDA stamp that it's really efficacious for patients and it's safe.
Q:  Yeah
A:  They have long-term registry studies that show that it's pretty safe.
Q:  And why is there more caution around ketamine and it's not just another antidepressant to try?
A:  We know it has abuse potential. In Far East and different countries, it's a serious problem, ketamine abuse. Not as much in the United States. It's usually mixed with other drugs. But a lot of car accidents in young people, especially in Korea, are related to people being intoxicated on ketamine. So we know it has potential for abuse.
We don't know how big a problem it is because patients with substance use disorders have been excluded from trials. So once you lower the bar and you offer ketamine to a lot of other patients with recent substance use disorder, we don't know what will happen. We don't know if it could trigger more addiction. This is a concern we have.
And then, we don't know the long-term safety because we don't have the 20-year safety studies. We have a very limited timeframe. So we know it's safe in a relatively short time. So the ethical dilemma becomes, is it right to offer a drug for which you don't have long-term safety data to a young patient who has not tried different drugs for which we do have long-term safety data.
Q:  And within the ketamine field, what do you see as the biggest challenges right now?
A:  There is a lot of hype, a lot of implementation and the expectations are huge. It's not a miracle drug--it's a drug, like any other drug. A number of patients will not respond and it's heartbreaking if you think that this is your last hope and it's not working. This is why we do a lot of preparatory work. We need to have a plan in place, whether ketamine works or doesn't work, because for a number of patients it will not work. And if they're suicidal and become more hopeless, it's a serious problem.

We need to have a plan to either hospitalize or make sure they have a therapy appointment and make sure we have something else to offer.
Q:  So make sure you have a support net in place before you embark.
A:  Yes, way before we approach ketamine.
Q:  In March, the FDA approved this new nasal form of ketamine. I'm wondering, does that mean that ketamine is finding greater acceptance?

A:  I'm not sure what's going to happen because we haven't heard from the payers. Once we know how is it going to be covered, for which patient is it going to be covered, we can figure out a little bit more about access. Whether every insurance is going to cover, or only some insurance, for every patient or for some patients, we still don't know.
Q:  And looking forward for your clinic, kind of what's your vision?
A:  I think the intravenous ketamine administrations are going to stay. They're much more potent, they're really quick, and they can last for a long time. So as a test to see if using ketamine is a good option for you. But they're not covered by insurance. And just a limited number of patients can afford it. So we're going to try to figure out if insurance is going to be willing to cover those infusions as a test and then consider switching the patients to intranasal or to different forms.
Q:  Well, it sounds like there's hope moving forward.
A:  Absolutely.
Q:  Great. Well, it's been such a pleasure talking with your, Cristina.
A:  Pleasure being here.
Q:  Before you go, I have my final five questions. What's the best advice you've ever gotten?
A:  I think it was my mentor who said, Why don't you come for six months to United States and see how it is. That was 15 years ago. [laughter]
Q:  Good advice. What rituals help you have a successful day?
A:  My coffee. [laughter] A shower in the morning and my double espresso. [laughter]
Q: How do you recharge?
A:  In one way, my weekends are exhausting between birthday parties and gymnastics and swim classes. But there's a completely different mindset. So I'm focused on kids and kids' activities. And yes, it's a lot of running around and figuring out what to do if the day is rainy, but I think this is the way to recharge.
Q:  If you weren't a doctor, what would you be?
A:  When I was little, I wanted to be a mad scientist from cartoons. [laughter] So probably some sort of researcher, PhD, biologist, some other version.
Q:  What advice would you give your younger self?
A:  It was sort of difficult; I was being told not to be so tough, not to be so determined, so certain about things. It was not feminine enough. And then the tide has changed, where you don't have to be as tough, independent, assertive to make a career. So probably I would tell myself, it's okay to be who you are. Just keep going and it's going to end up okay.
Q:  Thank you so much, Cristina. It's been such a pleasure talking with you and learning more about ketamine and depression.
A:  Thank you for having me.

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