Charles Ryan: Thank you. And hello everybody. Good morning. And thank you, Aurelius and Silke for the invitation this year. I come to you this year with a slightly different hat on. I continue to be a professor at the University of Minnesota and care for men with prostate cancer. I now have the additional role slightly additional as president and CEO of the prostate cancer foundation. So it's a real thrill to represent the PCF here as a speaker.

So I was given the title of how to care of brain and mood. And I want to first distinguish between the two as if we needed to, but I think it's important to say that the brain of course is an organ that is replete with androgen receptors and the androgen receptors in the brain drive androgen driven behaviors and cognitive processes. And one can think of it as the brain is a target that receives on target effects of our therapy. And it's important to think about that because we will get to that later when I talk a little bit about cognition. I'm going to begin though, by talking about what mood is. And I really want to focus on the mental health aspects of the impacts of being a prostate cancer patient in particular, an advanced prostate cancer patient. And I think that this is an underappreciated area that we clinicians need to understand and pay attention to over time.

So before I go any further, I would like you to raise your hand if you are a clinician who cares for men with advanced prostate cancer. Okay. And then I would like you to keep your hand up, keep your hand up, just it's exercise, right? Yeah. Keep your hand up if you have lost a patient to suicide. Keep your hand up if you have lost more than one patient to suicide. Okay. We've got a few. I've lost a few. And I would argue that maybe some of us have lost patients to suicide, but maybe we don't know it. And that's something I want to be top of mind as we proceed with learning this. So suicide is much more common in men than in women. Major depression is much more common in men than in women. So men as a backdrop are a population who are at risk for mental health difficulties in the form of major depression.

Having cancer compounds the risk of major depression. Only Parkinson's disease, which is a primary CNS disease is more likely to be associated with a diagnosis of major depression in the context of chronic disease. And as we will see, androgen deprivation therapy, which you may know intuitively compounds the risk of a diagnosis of major depression. So when we face our patient, when we confront and talk to our patients, we are talking to men who particularly have a triple threat here for a mental health background problem of major depression. Of course, depression and cancer patients is multifactorial. I think that goes without saying. You can understand how men who may come in with a slight backdrop of depression face issues related to identity because of the androgen deprivation. They face issues related to intimacy due to erectile dysfunction or urinary or bowel symptoms. They face potentially some societal problems or cultural problems dealing with that loss of identity, all of which can can compound this.

We'll talk about cognitive issues as well. And we'll talk about perhaps other factors that may drive depression. But I think any of you can look at the slide and say, yeah, this applies to our patients because they're facing multiple risks all at once, all in the backdrop of an at risk population.

So how do we diagnose depression? There are multiple ways to do that. I'm highlighting here that the NCCN in the United States does publish guidelines on identifying anxiety, depression, trauma, and distress in our patients. Many of us in our clinics have iPads perhaps in the waiting room where patients do a review systems before they come in. And in most of those cases, I know in my clinic, those review of systems templates do have identifiers for distress and major depression. And I would encourage you to know what your patients are being asked perhaps before they walk into your office for the 15 to 20 minute visit and know what the data are showing in those patients.

I think if you could leave this talk with one piece of new knowledge today after hearing me other than to say, well, maybe Chuck Ryan is the bodybuilder. I would like you to know perhaps how to diagnose major depression in your patients. And this is from the American psychiatric Association's DSM5, which is the sort of the Bible for diagnosis of mental health disorders in the United States, requires at least the two green identifiers, a depressed mood, decreased interest or pleasure in activities. And then three or more of the below criteria, such as psychomotor retardation or agitation, significant sleep pattern changes, feelings of guilt or worthlessness and of course, suicide ideation.

How would having a major depressive disorder impact outcomes? Well, the first and foremost way that it could do this is it's going to affect how patients decide on how worthwhile an intervention is. So in this table published in, this was in the JCO about eight years ago, it was explored what do patients choose in terms of definitive local therapy? Are they likely to choose definitive local therapy, radiation, radical prostatectomy, or are they choosing to do things like primary ADT or expectant management now which would be called active surveillance? And at the blue line, you see that patients who have, this is C Medicare data, so patients who have a coexisting depression diagnosis for low risk disease are 30% less likely to choose a definitive local therapy and about 23% less likely to choose a definitive local therapy for high risk disease.

All of these are statistically significant. So depressed men are more likely to not want to get definitive care for their cancer. That's a big thing. That's a big problem because that's going to compound their risk of death from this disease, perhaps. So as you would expect, that was what was seen by the same investigators as they went in and looked at overall survival data based on risk of the prostate cancer and the coexistent diagnosis of major depressive disorder. And you can see it's modest and in particularly shows up in lower risk population, which is interesting. And to some degree in the intermediate risk population where overall survival is shortened a little bit by the coexistent diagnosis of a major depressive disorder.

Another way that you can diagnose major depression in your patients in your clinic is the PHQ9. This is a scoring system that gives a little bit more weight. It's a little bit less of a checklist than the one I showed before. And as you can see, there are nine criteria as per the name, each of which the number goes up with the frequency of the problem. Little interest or pleasure in doing things. If you have that every day, that's a score of three, for example. And feeling down, depressed or hopeless, if you have that every day, three points right there, you're almost at the diagnosis of major depressive disorder. And it is recommended by various associations that following the PHQ9 that a patient receive professional treatment for their major depression if a score of eight or greater is achieved. So I think I would encourage you to know these data and to at least identify the fact that a good proportion of our patients do have depression. We probably see them more than any other healthcare professional or our teams do and we are really the gatekeepers to effective mental health treatment in those patients.

One of the problems is we don't have great data cancer, specific data on how to treat major depressive disorder. And I started my talk by saying the brain is this unique organ that's filled with androgen receptors and we are the world's experts on manipulating the androgen receptor. We do it all the time, every day in hundreds and thousands of patients around the world. And yet we don't know if that produces a unique brand of depression that would require a unique therapy. So I was a little bit disappointed as I reviewed the literature to find that there aren't a lot of great specific pharmacologic approaches to ADT induced depression. And I would encourage those in the research community to think of this as an approach that could be taken. With that said, there are a few data to show that in general, the trend is in favor of treating using SSRIs or other antidepressants.

There are some experimental processes underway. This is one that caught my eye because of Michael Carducci being one of the co-authors on this paper out of Johns Hopkins, which was the use of essentially mescaline or mushrooms to produce changes in depressive symptoms in very late stage cancer patients. And I found very interesting the endpoints of this trial, which was not only overall depression, but it was spiritual significance and reduction in anxiety and sense of personal worth and meaningfulness. And I think that it's interesting, I don't prescribe this method of treatment, but I found it very interesting that psychedelics are getting a lot of coverage as treatment for mental health disorders around the world. And this is being studied in advanced cancer patients. So we'll have to watch this space so to speak.

I'm going to pivot and talk a little bit for the final minute or two about the effects of low testosterone on the brain. This is something that I lectured about the last time I was at the APCCC. And it's something that we continue to learn and study with active and ongoing trials. Testosterone drives a lot of activities in life as I think needs no further explanation. And so it would follow that a reduction of testosterone on the brain is going to lead to potentially other problems. And it's really important as we think about this to think about the difference between a cognitive impairment and then dementia, and both are described in the literature as being associated with androgen deprivation. And I want to make sure that we clarify that. So there's three things I want you to leave my talk with. One is being attentive to diagnosing major depression. Two is to know the difference in androgen deprivation therapy as it relates to cognition versus dementia.

Androgens are neuroprotective throughout life. I've shown this slide before, which is that interest cerebral testosterone and DHT go down substantially from the age of 50 to the age of 80. And that is the time when that is associated, I should say, with an increased risk of cognition impairment. And there have been associations between for example, the accumulation of beta amyloid plaques in low testosterone brains versus high testosterone brains. But before I get to that, I want to just, again, talk a little bit about this cognitive issue. Again, this is a study now that's getting a little bit dated. It's seven years old, which there's a study of men going on androgen deprivation therapy undergoing a rigorous cognitive test. And there's a couple of points to learn here. One is at baseline, if you put your patients, your average prostate cancer patient through a rigorous battery of cognitive testing, you're going to find that at baseline, maybe 35 to 45% will have some degree of impairment.

Now, most people don't go through rigorous cognitive testing. And so they're just able to live life, but it's really when you begin to scratch the surface, you will uncover these things. What happens over time is that the androgen deprivation treated patients get worse in these rigorous cognitive tests. As you can see by 12 months, we're looking at about 55% will have cognitive impairment. And the androgen deprivation therapy patients, I have those captions reversed, but essentially what happens is, I apologize for that, essentially what happens is patients who are not on androgen deprivation therapy, learn to take the cognitive tests. So their test scores improve. People who are on androgen deprivation therapy do not learn and may have a baseline cognitive impairment. So their cognitive testing gets worse over time. Okay. So that's something that has been prospectively demonstrated, and is probably happening in many of your patients over time.

So what about dementia? These papers made big splash back when they were first published in JAMA a couple of times. These again, were claims data looking at the use of androgen deprivation therapy and the diagnosis of dementia over time. And again, dementia is a totally different diagnosis, that's why I have it starred an asterisk here, a chronic or persistent disorder of mental processes caused by organic brain disease or injury and marked by memory disorders, personality changes, and impaired reasoning and is not reversible. And so these data were clearly interesting and highly provocative, although they didn't really lead us to much in terms of mechanistic conclusions. I would encourage you also to look at the Y axis on these graphs. What you are looking at is a group of men with prostate cancer nine years after initiation of androgen deprivation therapy, you maybe have 15% who have received a diagnosis of a dementia.

Keep in mind that the androgen deprivation therapy treated patients are seeing clinicians probably a little bit more often. There may be a bias towards earlier and more robust documentation or abuse of a diagnostic code of dementia. So this is not by any chance, this is not by any stretch definitive data, but it is suggestive that we are causing some long term degradation of cognitive function in our patients. I would hypothesize and many do that we have brains at risk who come into our clinic, we put them on androgen deprivation, and yes, we may potentiate dementia. That's clearly different from saying all of our patients face the same risk from, from this treatment. And as with any side effect of treatment, it's really imperative on us as a field to identify who are the patients who are at risk.

There are such risks that can be done. The polygenic hazard score that I'm showing here is not for a prostate cancer outcome, it's for a dementia diagnosis. And you can see that there are patients on this red curve who have a constellation of gene aberrations that put them clearly at risk, but you can also see that there are a group of patients here who are highly protected. So we need prospective data to look at the interaction of this framework and how these various mechanisms AR targeting androgen deprivation will come together for a diagnosis of who is protected and who is poorly served by androgen deprivation therapy or AR targeted therapy.

I will highlight once again, I highlighted this two years ago, and I will now say that this is a trial that is robustly accruing across the country, which is prospectively looking at [inaudible 00:15:14] and enzalutamide treated patients with a rigorous battery of cognitive testing and allowing crossover. This trial was designed by myself and Dr. Morgans is now led by Dr. Morgans given my change in employment. So we look forward to seeing the results of this study and applaud the Alliance for clinical trials and oncology and taking this on. And I want to thank you for your time and allowing me to come and speak on this important topic.