Adjustment Disorder in Patients with Cancer

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepherd, a Medical Oncologist and Co-Director of the Sarcoma Program at Cleveland Clinic. Today, I'm happy to be joined by Dr. Brian Barnett. Dr. Barnett is the Director of the Cleveland Clinic Psychiatric Treatment Resistance Program here at Cleveland Clinic. He's here today to talk about adjustment disorder in patients with cancer. So welcome.

Brian Barnett, MD: Thank you for having me.

Dale Shepard, MD, PhD: So absolutely. Give us a little bit of an idea of what you do here at Cleveland Clinic.

Brian Barnett, MD: Yeah, so I divide my time between clinical work and research. Clinically, I direct the psychiatric treatment resistance program. That's a program focused on the treatment of patients who are not responding as we would expect to regular treatments for psychiatric conditions such as psychotherapy and antidepressants. It ends up being a pretty large proportion of patients. A about one in three patients need other types of treatment for their psychiatric conditions. So we do a lot of what are called interventional psychiatric treatments. We treat patients with intravenous ketamine, for example, transcranial magnetic stimulation where we're using magnets to target parts of the brain where we think depression and other disorders are localized, electroconvulsive therapy, vagus nerve stimulation, which is a surgical procedure for depression, and also deep brain stimulation, which is a surgical procedure for obsessive-compulsive disorder.

Research-wise, I focus on the development of new treatments for psychiatric conditions. A lot of those are treatment-resistant conditions, but we're also looking at agents and other therapies for psychiatric conditions in general that might work more quickly, they might have fewer side effects. And we work with drugs, ketamine, psychedelics like psilocybin and LSD, surgical procedures. And there's a lot happening in the field right now. So it's a great time to be in this field and it's a great time for patients who are struggling with these conditions because we have more options than we've ever had to treat them.

Dale Shepard, MD, PhD: That's fantastic. Well, we're going to focus today on adjustment disorder in patients with cancer. So, a lot of different people might be listening in. They may not be familiar with adjustment disorders. So let's start basic. What is it?

Brian Barnett, MD: Yeah, it's one of the lesser-known psychiatric conditions, but it's also very common. So, this is a condition that develops when someone experiences psychological distress or a behavioral disturbance after they have experienced some type of stressor. And you can really point to that stressor and say, "That's when this started." And that's not true for other psychiatric conditions. For example, some people with depression, they just cannot find any reason why they would be depressed. Life is going well. There's nothing that triggered it. It just came out of the blue. But with adjustment disorder, there is something that triggered the process. And in this case, it could be a cancer diagnosis. It could be a recurrence of cancer. It can even be a remission of the cancer when people are going back to work, for example, that can be a very stressful time going back into their old life, their old identity.

And adjustment disorder takes different forms, but it often looks like a milder form of major depressive disorder or a milder form of anxiety disorders. The aspects that we see the most are depressed mood, difficulties experiencing joy. A lot of isolation patients are just not able to engage socially with family or friends or get out of the house. It can be a lot of episodes of crying, sometimes problems focusing, but it can't reach the level of a full major depressive episode. Then that diagnosis takes over and the treatments are somewhat different, but there is overlap. And adjustment disorder, we expect that it will resolve on its own within six months of the stressor resolving. But with things like cancer, where it can last for the duration of someone's life or there's always the threat of recurrence, it can be a little bit difficult to figure out what that time point should be for it resolving.

If it really starts to impair function, if it gets to the point where people are feeling suicidal, things like that, then we start to think more, maybe this has moved on to a major depressive episode and we need to approach this differently.

Dale Shepard, MD, PhD: Then how does the things... You talked about recurrence and this chronic issue with patients. They may have had treatment and the treatment's over, but how does things like fear of recurrence play into this?

Brian Barnett, MD: Yes. That's a very common component of adjustment disorder in patients with cancer, especially adjustment disorder with anxious features. They really get focused on the potential for recurrence, even when things look good, even when they've been reassured by their providers, the various scans and tests that it doesn't look like a recurrence is at least happening now and unlikely to occur in the future, they just can't seem to break away from that. They get stuck in these thought loops around recurrence.

Dale Shepard, MD, PhD: I've had patients that can take comfort in a positive scan for about five minutes and then they're automatically, "Well, but what's the next scan going to show?"

Brian Barnett, MD: Yeah, and those can be the types of patients that we're talking about with adjustment disorder.

Dale Shepard, MD, PhD: Interesting. How frequently do we think this occurs? You mentioned that oftentimes people don't recognize it. So how often do you think it really occurs?

Brian Barnett, MD: Studies have shown different prevalence rates. On the higher side, up to 40% of patients with cancer. But when you look at studies that have been more rigorous where they've had a screening instrument and the patients speak with a psychologist or trained professional afterwards to do a structured interview, the actual prevalence looks closer to something like 15%.

Dale Shepard, MD, PhD: Okay. I mean, I guess clinically, when you see a patient, what are the kinds of things you look for to rule out things like major depressive disorders versus adjustment disorder? How do you clinically make that distinction?

Brian Barnett, MD: Yeah. Sometimes it can be hard to make the diagnosis, particularly in patients with cancer because some of the features of adjustment disorder with depressed features are actually side effects of the treatments. So patients are not having an appetite. They're fatigued all the time. They're having trouble concentrating. So is that from the cancer itself? Is it from the treatment? Is it from adjustment disorder? So when we're making the diagnosis of adjustment disorder in this patient population, we tend to rely more heavily on the emotional components of their experience. And we're looking for things like hopelessness, for example, feeling worthless, feeling like you've let other people down. Sometimes it can get to the point where people are very demoralized, they're isolating, they're not interacting with people. Those are the kinds of things that we're looking for.

In terms of differential diagnosis, I think you hit the nail on the head. The big thing that we're trying to figure out is this already a major depressive disorder? Could this be generalized anxiety disorder that they already had? And we do know that patients with a history of psychiatric conditions are at a higher risk of having an adjustment disorder when they are diagnosed with cancer. But with generalized anxiety disorder, it tends to be that the patients are worrying about everything. They're worried about finances, family, their children, work, and they just can't seem to turn that off. But if it's in the form of adjustment disorder, it tends to be pretty circumscribed around the cancer and fear of recurrence and things like that.

Dale Shepard, MD, PhD: We know that recurrence happens in a lot of these cancers. If a patient has had an adjustment disorder after say an initial diagnosis, are they more likely to have adjustment disorder again after a recurrence?

Brian Barnett, MD: Yeah. So if you've had adjustment disorder for any reason in the past or any type of psychiatric condition, you're at increased risk for having this in the future. We also know that people with a history of trauma, particularly during childhood, are at increased risk as well. Women who have cancer tend to have adjustment disorder more than men, and patients who have less support at home, who are dealing more with financial struggles, they also tend to have adjustment disorder more frequently.

Dale Shepard, MD, PhD: And we'll talk about treatment here in a minute, but I think as oncologists, we don't necessarily do a great job sometimes of picking these things up. Are there some practical tips in terms of things we should be looking for? We try to get psychosocial support for everyone as best we can, but are there red flags that we should be looking for or asking about that we might not be doing?

Brian Barnett, MD: Yeah, that's a great question. I mean, obviously you all don't have time to do a 60-minute psychiatric evaluation, so you've got short visits, a lot of ground to cover. I would say if you're noticing a change in a patient who before in the initial visits had been more expressive, emotionally, more engaged, if they look more withdrawn now, if they are less interactive, particularly if it's gotten to the point where they're not really even talking that much during the visits when a family member is really speaking for them, then that would raise a red flag for me, and I think it's worth probing.

There's also this instrument called the distress thermometer that you can give patients. It's a visual analog scale and you give it to the patient and basically they rate from zero to 10, how distressed they've been in the last week. And generally, a score of three or four or higher suggests to the clinician that they should refer the patient for some type of psychosocial service. It also comes with a problem list that can be helpful in knowing what to do next. And so the problem list contains questions about finances, activities of daily living where they might be struggling, and then also psychological aspects as well. So that can be very useful for determining what the next step is.

Dale Shepard, MD, PhD: What has the traditional treatment been for this?

Brian Barnett, MD: So because adjustment disorder is typically time-limited and it's reactive, it's occurring in response to something that's happened to the patient, it tends to respond well to psychotherapy. And so that's our first line treatment, first line recommendation for a lot of patients. But the challenge is access. There just aren't enough therapists. And depending on where you live, access to therapy and the quality of therapy really varies a lot. Some of that's changing now. There are online virtual therapy companies that are really trying to focus on this access problem. But for some patients, even if they have access, they can't make it work because of time commitments, maybe for oncological treatments and doing all the other things they need to do in their life, raising their kids, going to work.

So sometimes, because therapy's not an option for everyone, we will use medications. It tends to be SSRI antidepressants. Many people have probably heard of things like escitalopram, fluoxetine, sertraline, but there is no FDA-approved treatment for adjustment disorder. So we're using drugs that are approved typically for depression and anxiety off-label to treat this.

Dale Shepard, MD, PhD: How effective do those tend to be in most patients?

Brian Barnett, MD: They tend to be helpful for a large number of patients, but there's also a significant proportion where they don't respond. And we know just in general that about one in three patients don't respond to antidepressant treatment. So that leaves a lot of patients who really need our help, but we have to think about other treatments for them and develop other treatments to target that particular subgroup. We are doing a clinical trial that hopefully will answer that question. It's with a company that's hoping to get an FDA approval for adjustment disorder in patients with cancer and other serious medical conditions, including neurological conditions like Parkinson's and ALS. So I think that's been a very exciting development that we might in the next few years have an FDA-approved treatment for this condition.

Dale Shepard, MD, PhD: And that clinical trials with the drug RE104?

Brian Barnett, MD: RE104, it's probably a very different kind of treatment than most patients have heard of. It's actually a short-acting psychedelic. For about 25 years now, psychiatry has really been focused on researching psychedelics and potentially developing these as treatments. It's a very different paradigm where patients are given the treatment in a medically-monitored setting and they have a psychedelic experience in the trials if they get the active drug. It's a state of consciousness that's very different than our everyday way of living. And patients can have a lot of things happen during the experience. They can have old memories come up that are very meaningful and that provide them insights on things. They can feel as if they're one with God or the universe. We call that a mystical experience. People's perspectives change on who they are and where they are in the universe. Their perspectives might change on their relationships with people, their relationships to their body, to the cancer. It's been pretty fascinating to work with these compounds because they really work at the intersection of therapy or psychology more generally and psychopharmacology.

RE104 is a short-acting psychedelic. So the effects last three or four hours, whereas the other ones that we've been working with like psilocybin, LSD, those last six to eight hours. And we're anticipating some FDA approvals in the next couple years for things like treatment-resistant depression and generalized anxiety disorder. But one of the challenges is scaling that. You would have one patient in a room with one or two monitors for six or eight hours a day. So obviously that's going to limit access. And the pharmaceutical industry has really been focused on finding shorter acting psychedelic compounds or creating them as they did in this case with RE104.

But that's what we're looking at. We're looking at this compound to see if this psychedelic-assisted treatment might be helpful for adjustment disorder. And that comes from a lot of research that was done in the 50s through the 70s with LSD for patients with cancer who experienced psychological distress. So there were studies back then. Of course, they were poorly-controlled, not designed as well as we do now, but there were some signals there indicating that patients after a single dose, they improved in terms of the psychological distress that they had been experiencing and they were back to their selves or they had made peace with their cancer and their prognosis. And those effects could last three, six, even 12 months after a single exposure.

And there have been more recent studies with psilocybin published around 2016. The first ones were that showed similar effects. That's really what's prompted the interest in looking at this particular patient population of patients with cancer and adjustment disorder.

Dale Shepard, MD, PhD: So, this RE104, short-acting, so less, I guess, personnel-intensive. How many doses... You mentioned some things like the LSD could have long-lasting effects and you didn't need multiple doses. Is this a single exposure or multiple exposures? How's this being given?

Brian Barnett, MD: Yeah. This is the first phase two trial in this population. So it's a single dose administration, high dose versus a very low dose. That tends to be common in psychedelic trials because if you use inert placebo, it's really not blinded in any way. So it inflates the efficacy. And the way that a lot of companies have addressed that and working with the FDA is the FDA will say you can do some trials with inert placebo to look at more of a physical safety standpoint, toxicity, those sorts of things. And then where we're really looking at outcomes for psychological conditions, we want you to have an active placebo to obscure what dose the patient might've gotten.

Dale Shepard, MD, PhD: That came to mind as you were talking. In my trials, people get a rash and you're like, "Oh, I think they got the active drug." It seems like it would be hard to hide who's on control and who's on active drug in these trials.

Brian Barnett, MD: Yeah. It's a real challenge. And maybe surprisingly to some folks, it's a challenge across psychiatry in general. There are some drugs where you would expect blinding is going to be very difficult, things like benzodiazepines, stimulants, but also, meta-analyses have shown that antidepressants tend to have high rates of unblinding because of the side effects. Same thing with antipsychotics. And so there's been a lot of focus on this with psychedelics, but it's really just highlighted a broader issue that the field has been dealing with. I think there have been some clever ways to address this. The most important being dose-finding studies where patients, in some of the trials, they have the opportunity to get three, four different doses, and then we can look and see if there's dose-dependence in the outcomes. And that has sort of consistently been shown. So that helps us separate whether this is a real effect or whether this is just unblinding in the knowledge that they got the active drug and that induces a placebo effect.

Dale Shepard, MD, PhD: You mentioned something interesting about how people have changes in perception. Do we think this is really changing something fundamental physiologically, or do we think that this is just how people have a different perspective or acceptance of kind of the world around them?

Brian Barnett, MD: Yeah, I would say all of the above.

Dale Shepard, MD, PhD: Yeah?

Brian Barnett, MD: With the current treatments that we have with antidepressants, they're effective for a lot of patients, but they tend to suppress the challenges that they're dealing with psychologically. Psychedelics really have the opposite approach where they can bring these concerns that might be in the back of your mind. You might not even be aware of them. They can bring it really to the forefront of your mind. And when you look back through the old studies of LSD in patients with cancer, the more qualitative studies where they were asking them about their experiences, that's really what it showed was they often felt like they were facing the fear that had been there the whole time head on and learning to accept it better.

And we're learning a lot about how the drugs work now. There's a lot of neuroimaging studies going on that are essentially showing that psychedelics, they affect something called the default mode network, which is a network in the brain that is active when you're thinking about yourself or your problems. And it tends to get overactivated in psychiatric conditions, especially depression, anxiety, substance use disorders. The psychedelics appear to disrupt that. So it takes it offline temporarily, and that's often at the same time the patient is having one of these mystical experiences or what we call ego disillusion, and they feel like they don't exist anymore temporarily. They're just one with everything. And then when it comes back online as the drug is wearing off, it seems to be in a less rigid composition at that point. And so it can get back to the original composition that it was in before the person became ill and got stuck there.

From a neurochemical level, we see psychedelics rapidly increasing something called neuroplasticity, which is the brain's ability to form new connections, new synapses, almost as if adults become children again. It's a temporary effect. It lasts maybe four to six weeks after the exposure, but it's gotten people really excited because there might be applications even beyond psychiatric conditions to the central nervous system. So potentially, you might be able to give these drugs to somebody after they've had a stroke, after they've had a traumatic brain injury. And there are companies now that are looking at neurological applications as well.

So it's been a really exciting time for psychiatry and neuroscience in general, but we think that neuroplasticity is really vital to the benefits that happen here. And many of the trials combine psychedelics with psychotherapy. We think that the neuroplasticity can really enhance the effects of psychotherapy, really let the patients engage in it more, take more away from it, and hopefully turn the insights that they have from the therapy into actual behavioral changes afterwards. And so what I've seen in patients who've taken these drugs before is they might go on to develop a meditation practice or a yoga practice, change their diet, get into exercise. It's almost like it gives you this window where you can learn new habits that will hopefully stay with you for much longer than the actual effect of the drug.

Dale Shepard, MD, PhD: Do we have any indication on impact on their cancer care? So sometimes people, if they end up with depression and perhaps adjustment disorder as well, they are less likely to come back for appointments and follow along with their treatment plans and things. Do you have any early idea of whether their cancer care itself is improved by treating the adjustment disorder?

Brian Barnett, MD: I'm not aware of anything yet since the study's ongoing, and I don't think I've seen those papers reported out from the psilocybin studies a decade or so ago, but I could see the potential there because with adjustment disorder, that's exactly what we see is patients are less engaged in care. They miss visits. If it's severe, they might miss infusions and things like that and just say, "What's the point? I'm not going to get better anyways." That's why it's really important to address these psychological conditions that come up in patients with cancer because it can really get in the way of optimal outcomes for the cancer itself.

I would imagine that if the drug is shown to be successful in the clinical trial, that there would be benefits there because the patients, their mood would be improved, they would have more motivation, less anxiety. But yeah, it remains to be seen, and I hope those are the types of outcomes they'll be collecting in the trial.

Dale Shepard, MD, PhD: Fascinating field and appreciate your insights today. We'll look forward to seeing the outcome of these trials.

Brian Barnett, MD: Yeah. Thank you for the opportunity to discuss the work that we're doing. We think it's a great opportunity for psychiatry and oncology to collaborate and we're very excited to see what happens.

Dale Shepard, MD, PhD: Very good. Thank you.

Brian Barnett, MD: Thanks.

Dale Shepard, MD, PhD: To make a direct online referral to our Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You will receive confirmation once the appointment is scheduled.

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