Good morning. Warmest welcome to this newly established track, we call that clinical updates, at the 2022 APA annual meetings. So what the purpose for this newly established track called clinical update is that by the end of the sessions, we want to leave clinicians with the practical evidence-based tools you can take home and use right away in your practice. So under the so-called anxiety track, anxiety domain, includes three renowned speakers who present on the top three topics, different topics, that clinicians can deal with every day. So yesterday we heard from Dr. Charlie Nemiroff on the neurobiology of treatment of post-traumatic stress disorder. And today we have Dr. Helen Blair Simpson to speak on how science can transform treatment for OCD. And after this session, the third presentation is scheduled for today at 1030. And our speaker is Dr. Mark Rappaport to speak on anxiety disorder treatment, current state, and future promise. And my name is Edmund Pai. I serve as a moderator for these three sessions. And I'm a professor emeritus of clinical psychiatry and behavior science at the University of Southern California, as well as clinical professor of psychiatry and the biobehavior sciences at University of California, Los Angeles. So it certainly is my privilege to introduce the speaker, today's session speaker, Dr. Helen Blair Simpson, MD, PhD, who is interim chair and professor of psychiatry, Department of Psychiatry, Columbia University, interim director of the New York State Psychiatric Institute, director of the Center for OCD and Related Disorders at the New York State Psychiatric Institute. And this institute is funded by the National Institute of Mental Health since 1999. And she used clinical trials to identify the treatment, the best treatment for OCD, and partners with neuroscientists to explain how the brain produces anxiety, obsession, and compulsions. So she has advised both the World Health Organization and the American Psychiatric Association on classification and treatment of OCD. And she's also the co-director of the research program for the New York State Psychiatric Presbyterian Hospital Youth Anxiety Center. So now, this is a prerecorded session, so I will start her presentation. To transform treatments for patients with OCD and related disorders by conducting research. And the research we do is we use clinical trials to test what are the best treatments for OCD, and we join with neuroscientists to study what causes obsessions, compulsions, to identify novel treatment targets. So today, I plan to review how to diagnose and treat OCD, and we'll focus on a series of clinical trials that we conducted in collaboration with Dr. Edna Foa at the University of Pennsylvania. And I'll also highlight two clinical problems that illustrate different ways, and illustrate different ways we're working to solve those problems through research. And so my goals in the talk are both to teach you about OCD, and to describe different types of patient-oriented translational research, and how each type can advance the clinical care of individuals with OCD. So let me start with my disclosures. The vast majority of my funding comes from the National Institutes of Mental Health, for which we're very grateful, and also some funding from the New York State Office of Mental Health and Philanthropy, with a little funding from industry. So what is, when I say patient-oriented translational research, what do I mean? And for me, it means translating from basic science into human studies. And that can be taking observations from basic science to study those same processes in humans. It also means, once you have targets for intervention, identifying new treatments, and then testing those in clinical trials. And finally, it means going from what are so-called efficacy studies, clinical trials that demonstrate a new treatment might work, whether it's psychotherapy or medication therapy or neuromodulation therapy, and then studying how to implement and disseminate that treatment to the community. And so it's this whole circle that's patient-oriented translational research. And my research program encompasses all of these aspects, and I work with many different collaborators in the process, and so I'm going to tell you about some of my collaborators along the way. So today, I'm going to start by talking about how to diagnose and treat OCD here, and then I'm going to tell you how that work has led to implementation and dissemination studies, and also has led to imaging studies to look at mechanism. So what is OCD, and how do we treat it? So the hallmarks of OCD, in some senses, OCD is very straightforward and very simple. There are two core features, obsessions and compulsions. It's in the name. And obsessions are repetitive thoughts, images, or urges that are intrusive and distressing. And compulsions are repetitive behaviors or mental acts that someone feels driven to perform, often in response to an obsession. And the key thing is that the symptoms are not just, it's not just an isolated intrusive thought, it's not just checking your door once when you go for work. Obsessions and compulsions, to be a disorder, the symptoms must be distressing, time-consuming, and impairing. A rule of thumb is at least an hour a day. And many of my patients are obsessing and compulsing three, five, eight all day long. So it's not subtle. It really is symptoms that really get in people's way. Now that's where the simplicity sort of stops, because then there's a lot of variation. So one of the variations is the content of the obsessions and the compulsions and the target of the fear. And in the field, we've called these symptom dimensions. And what I mean by that is one person with OCD can have obsessions and compulsions about contamination. For example, a fear that they might get HIV disease with lots of washing rituals. A different person with OCD might have obsessions and compulsions focused on harm. Either intrusive thoughts that harm might fall to them or someone they love, with lots of checking compulsions, as an example. Yet another person might have obsessions and compulsions focused on symmetry or exactness, having to do things just so or just right with arranging compulsions. And finally, there's another group of people with OCD who are bothered by taboo thoughts, intrusive images or thoughts about taboo thoughts about sex or religion. So the point being is while all people with OCD have obsessions and compulsions, the content of those obsessions and compulsions can really vary. And it's also true that a single person can have content in more than one of these dimensions. People can have contamination and harm, for example. So that's one way it can become a little bit complex how to diagnose OCD. If you don't understand the full range of content and fears that people can present with. The second one is that people with OCD can have different affects. While many people experience anxiety, and some people have frank panic attacks when they're exposed to one of their triggers, one of their OCD triggers, still others have more of this just sense of discomfort that it just doesn't feel right, and still others might have a sense of disgust. So different affects people can present with. Another aspect of the disorder that actually can also lead to some confusion in diagnosis if people don't understand it is that the insight of an individual person can really vary. While many of my patients can say to me, doctors, this doesn't make any sense, I shouldn't have to wash my hands this much, but I just feel like I have to. Others may really not understand that these intrusive thoughts and these repetitive behaviors are irrational and might be to the point of being delusional about it. That's a small subset who are truly delusional, but many people are sort of in that zone of they're not really sure. For example, in my office they might say to me, I really shouldn't have to wash so much, but if I took them out on the street and we were doing an exposure exercise together as part of treatment, which I'll get to in a minute, and asked them to put their hands on the sidewalk as I did, right in front of me they might not be able to do it and say, I can't do it, I might get ill and I might die. So again, varying insight. Finally, OCD often comes along with other problems. We call it comorbidity. The most common other disorders that people with OCD have, if you're an adult, are other anxiety disorders and depression. Tick disorders can also come along. Eating disorders can come along. So again, it's not just OCD by itself, but it's OCD in a larger portrait of all the problems that someone's suffering with and that can make the presentation look different as well. So the clinical tip to remember is everyone has obsessions and compulsions, but the content can really vary and the associated features can really vary. Now, the other thing I really like to emphasize is that OCD is a disabling disorder. Its lifetime prevalence is about 2%. The lifetime prevalence of schizophrenia is 1%, so people are often surprised to learn that OCD is twice as common as schizophrenia. Half of the cases start by the age of 19. This is from epidemiological studies. If you looked at that same number for major depression, it's 32. And 25% of cases in OCD start by age 14. So it has a relatively early age of onset relative to depression, for example. When people get OCD, typically, not always, but typically, there's a chronic waxing and waning course. And finally, when you look at all the cases of OCD in an epidemiological survey, the vast majority are moderate to severe in their symptoms. So unlike other anxiety disorders where there are often a big proportion of mild cases, with OCD, 85% will be moderate or severe cases. So the clinical tip here, if you add that all together, the prevalence, the early onset, the typically chronic waxing and waning course, and the fact that when you get OCD, it can be moderate to severe in its severity, that is what makes OCD disabling. So the good news is we do have first-line treatments for OCD that work. They include a class of medications called serotonin reuptake inhibitors, and that includes clomipramine, which is a tricyclic antidepressant, but which has very strong serotonin reuptake inhibition. And then all the selective serotonin reuptake inhibitors, and I've listed them here. These names I'm sure you're all familiar with. All of them work. We have randomized controlled trials of all of these medications, and they all work for OCD. It's just that some haven't been FDA-approved, but it isn't that they don't work. It's just that the companies didn't go forward to approval because they didn't know that that would be profitable for them. The other treatment that works in OCD is cognitive behavioral therapy of a very particular type. It's called exposure and response or ritual prevention, and it's got a lot of acronyms in the literature, EXRP, exposure therapy, ERP. The older literature used to call it behavioral therapy. It's all really one and the same thing. It's exposure and response or ritual prevention. So it's really important that psychiatrists know what it is, because even if you don't deliver it, you want to be able to ask your patient with OCD whether they've ever had it, or you want to be able to, if you want to refer your patient to it, you want to be able to describe what this treatment is about. So the treatment is, if you will, the key procedures are in the name. The EX part is exposures, and this is where you create a hierarchy with the patient of what they particularly are fearful of. Let's say it's contamination. It's a specific hierarchy of, you know, on a scale from 0 to 100. If 100 would make them really, really anxious, and 0 would not make them anxious at all, to talk to them about what would be a 50, what would be a 60, what would be a 70, 80, 90, 100. So you would then, in this treatment, very deliberately and in a very specific way, expose them to that hierarchy, starting with a 50 and moving up as they habituated to the anxiety. And you would do those exposures both in the real world. So, for example, I told you the example of touching the sidewalk. That might be a 50 for someone with contamination fears, and you would go and touch the sidewalk. But you can also do exposures as imaginals, where you can actually create a very vivid story of something, such as the person who has intrusive thoughts about harm, worrying about a fire starting in their apartment because maybe they haven't turned off their gas stove, and you could actually do an imaginal story with them of they forgot to turn off their gas stove and their house burning down, as an example. So one procedure is exposures, exposing people in a very specific way, in a prolonged, exposed way, to triggers that they fear, both in live exposures and imaginal exposures. But the other procedure, which is really, really critical, too, is ritual prevention. And this is where you map all of their different rituals, and you start coaching them on how to stop them all. And the goal is to stop them all as quickly as possible. So, for example, the person who's washing would stop washing. During the treatment, you might even limit their showers to, let's say, every third day, to really try to expand their sense of what's possible while you're doing the exposures. And data suggests that it's these two procedures together that gets you the best results. And what do we think we're doing? Well, the goal is to disconfirm the fears. For example, if I touch the sidewalk, I'm going to get sick and die. Well, you can touch the sidewalk and not get sick and die. And that's disconfirming that fear. And to challenge those distorted beliefs that everything's dangerous, or I have to wash every hour of the day, or I'll get sick. It's to challenge those distorted beliefs. It's also, obviously, in the ritual prevention, to break the habit of ritualizing and avoiding, but really, fundamentally, it's to improve functioning and quality of life. This treatment has been delivered in a lot of different ways, but the treatment sort of protocol that's been studied a lot, and I'm going to show you data from those clinical trials, typically consists of two planning sessions and then 15 exposure sessions. And ideally, it's delivered twice a week or more frequently. The key also is that in between each session, there's homework that the person is expected to do, and that that's actually to really push the exposures and to actually train the person to be able to do the exposures on their own, not just when the therapist is around, because the real goal is to actually do lifestyle exposures when the therapist isn't around and to move into your life in that way. So daily homework is really important. And the other thing is the therapist does home visits or visits into their environment to promote generalization. So once again, the goal is to teach the patient a different way of handling the intrusive thoughts, the obsessions, and the repetitive behaviors, and to, in essence, just try to make them into their own therapist so they can move into their life and know what to do. So I'm now going to briefly tell you about a series of randomized controlled trials that we did at Columbia, and these trials are all in collaboration with Dr. Edna Foa, who's here on the left. I guess my left. In collaboration with Dr. Edna Foa at the University of Pennsylvania. Now, what is a randomized controlled trial? And this is an example of a type of patient-oriented translational research methodology. A randomized controlled trial allows you to test what treatments work and whether a treatment is safe. And the typical design is you recruit a group of patients with a particular disorder and you randomly assign them to different treatments and to, ideally, a placebo treatment or to no treatment so you have something to compare against. You train the study staff to deliver the treatment as intended, so you know that you're delivering the treatment correctly. And you use evaluators who are blind to randomization to assess for change in clinical symptoms over time. So one of the first studies that we did together asked this question. I just told you there are medications and therapy that both have been shown in prior clinical trials to work for OCD. What's the best treatment? Is it that medication? Is it that therapy? Or is it the combination? So I'm going to show you the results of that trial on this slide. And on the y-axis here is a scale of OCD severity. And this measure, the Yale-Brown Obsessive-Compulsive Scale, is one of the scales typically used in these clinical trials. It's called the Y-Box for short. And it goes from 0 to 40. And I'm showing you the range, typically, that you see in outpatients. And 16 and above is considered clinically significant symptoms, warranting treatment. And on the x-axis, I'm showing you treatment weeks, so weeks in treatment. And in this study, we recruited a group of adults whose primary diagnosis was OCD. We randomly assigned them to, some people got Tull placebo, which is this yellow line, over 12 weeks. Some people got clomipramine, which is that serotonin reuptake inhibitor I told you about, the tricyclic antidepressant. And you see a slow decline in their OCD symptoms over 12 weeks. Remember, lower is better. But finally, I want to draw your attention to the people who got the cognitive behavioral therapy that I told you about, the EXRP, with or without the clomipramine. And the therapy was delivered five days a week for three weeks, then two home visits in the first four weeks, and then with weekly 45-minute sessions out to week 12. And what you can see with your eye, without my having to show you any statistics at all, is that all the active treatments were better than Tull placebo, but that the groups that got exposure therapy, with or without the medication, did better than the medication alone. So these were very exciting results. They were a bit challenging to the field because I think psychiatrists had an assumption that our medications were more powerful than a psychotherapy, but in fact these data do not suggest that. But with a couple caveats, obviously, these are people with a primary diagnosis of OCD. They didn't have a lot of comorbidity, and the therapy was delivered by highly skilled therapists. That's what gets you results like this. But here's the truth. Back then, this study was completed a long time ago. Back then, it was very hard to find this therapy in clinical practice, this cognitive behavioral therapy with skilled therapists. And frankly, it's still hard to find this treatment today, so that most people, as a first-line treatment, what they get is a serotonin reuptake inhibitor, choleraquimine or one of those selective serotonin reuptake inhibitors. But if you notice, at the end of the trial, on average, the people who got the medication, on average, still were above 16. So although they were a lot better than when they entered, if you will, they could have reentered the trial, on average, at the end of the trial. So these data led to the next question, which is, so if you're an OCD patient and you are on a medication, a serotonin reuptake inhibitor, but you still have symptoms, like many people will, as I just showed you, what would happen if you added the therapy then? Let me go back for a second just to show you. If you take these people, you recruit these people, and you added the therapy then, could you drop them further? That was the question. And what we wanted to do here is we wanted to compare that to a psychotherapy control to be sure, because what's the possibility that just time and support with an empathic therapist might just get you better? We wanted to test whether this CBT therapy, the EXRP, was specifically going to be helpful at that time. So let me show you the results. So it's the same Y-axis, which is the Y-box, same scale, 16 and above is considered clinically significant symptoms warranting treatment. It's a different X-axis. This was now an eight-week trial, and the therapy here was delivered twice weekly. Both therapies were delivered twice weekly, and we did that because twice weekly is a more reasonable therapy schedule in community practice than that intensive version that we used in the prior trial. There are some other differences here to pay attention to. Here we recruited people to come into the study, but all were already on a serotonin reuptake inhibitor, so that's different than the prior trial, but look at how symptomatic they still were, even though they were on a serotonin reuptake inhibitor, and all reported some benefit from their medication as well, but still, on average, very symptomatic. So yellow is the stress management therapy, which was the psychosocial control. You can see very minimal decrease in symptoms, and then look at what happened when the other group who was randomly assigned to exposure and ritual prevention, what you see there instead when that treatment was delivered twice weekly, a nice linear decline in their symptoms over time, and so people who were randomly assigned to the exposure and ritual prevention did a lot better than the people who got the stress management. Whether you look at these lines, where the data is modeled continuously over time, or whether you look at response rates or remission rates, and by response, people have different definitions for response, in this trial it was a 25% reduction in symptoms, and remission was a score of 12 or less on the Yale-Brown obsessive-compulsive scale. Large differences in how many people, individuals will respond, large differences in how many people will remit. So that study led to the next question, so here's now the third trial I'm telling you about, and the next question really was, okay, well it looks like adding exposure and response prevention looks really good for OCD patients on serotonin reuptake inhibitors who still have symptoms, but how does that compare to adding another medication? And at the time this study started, that was the common thing that psychiatrists would do, if you had an OCD patient on a serotonin reuptake inhibitor who still had symptoms, a psychiatrist typically would add an antipsychotic, and at that time the best data was for the antipsychotic risperidone. So this study wanted to directly compare those two approaches to allow practicing clinicians to give them data as to which path was better. And here are the results of this study. So by now hopefully you're getting used to this Y scale, Y axis, again it's the Yale-Brown obsessive-compulsive scale, or YBOCS, 16 and above, or clinically meaningful symptoms warranting treatment. The X axis is treatment weeks. This is just like the last study, it was eight weeks, we delivered the therapy twice a week over eight weeks, that's standard protocol, just like in the prior study. And once again, everybody entered this study already on a medication, maximum dose at least 12 weeks, many had been on their medication for months. And again what you see is people entered quite symptomatic, despite the fact that they said their medication had benefited them, which is why they were staying on it, but they still had a lot of symptoms needing more treatment. What you see here is the placebo arm, and we put a placebo arm in to keep everybody honest because that independent evaluator who's evaluating those symptoms over time doesn't know what the treatments are, and by putting in a full placebo, which you anticipate will have no effect, it means that they can't have a bias towards rating everyone as better. So it's about, again, keeping integrity of the study. And what you see is, in terms of OCD symptoms over time as rated by those independent evaluators, very little change if people got pill placebo. What you see is what happened if people got that twice weekly EXRP therapy, this again nice response, that was quite amazing to us, it's an almost identical line as what I showed you in the prior study, only this is a study five years later, completely different therapists, completely different independent evaluators, completely different patients. You often don't get to replicate psychotherapy studies, and here is a really nice replication of our prior findings. The surprise of this study, I would say, at least for me as a psychiatrist, were the results for Risperidone, which is what you can see here is this red line. And even though it was a little better, the red's a little better in response and remission rates than the yellow, which is pill placebo, the Risperidone in this study, in this sample, was not significantly different from pill placebo, but the CBT was significantly different from both. Now I want to be super clear. That does not mean that antipsychotics don't work as an augmenting treatment for a patient on serotonin reuptake inhibitors. Other studies have shown that they do work, but I think that there are reasons why in this study they didn't, and here's the big reason. Antipsychotics can work for OCD patients on serotonin reuptake inhibitors who still have symptoms, but the key is they only work in a subset. So when you look across all the other clinical trials that have tested them against pill placebo and you do meta-analyses of all those clinical trials, it's about a third. Only about a third of your patients, on average, will respond to an antipsychotic. And so you can see that depending on a clinical trial and the size of its sample, it may get more of that third or less of that third. And I think this study and this design where people had to come in being willing to get any of the treatments, therapy, medication, or pill placebo, I think we recruited a slightly different sample than the medication trials that only offered add-on medication that probably got people who were more open to medication only than our study, which people had to be open to all three. Anyway, the take-home point is that antipsychotics may work in OCD patients, but they're only going to work in a subset. So if you try it in your patient, you're going to see an effect in two to four weeks. If you don't see it, please take them off of it, because if you don't take them off, someone may never take them off again. But they don't work as well as adding the therapy. So if you look at the response rate and the remission rate, those are really great numbers. So take-home message from what I've shown you today is that serotonin reuptake inhibitors are effective for some, but response is usually partial. Your patients might benefit, but they may still have clinically significant symptoms, and you as a psychiatrist are going to be needing to think, what do I do next? This exposure and response prevention therapy, it's effective for more, even as monotherapy, but patient adherence is key. I don't have time to show you those data, but we've shown that over and over again in those studies, too. You want the patient to adhere to the treatment, and if they don't adhere to the treatment, you're not going to get results like what I showed you. But if you put these two treatments together, the way I just showed you, actually about 40% of your OCD patients with a primary diagnosis of OCD could not just get a little better, but actually achieved minimal symptoms with just 17 sessions. That's quite a remarkable finding for such a chronic and disabling disorder, and that's before doing anything fancier. That's a really good news. But obviously, as you probably are seeing right now, every trial leads to more questions, and so this one did, too. Those findings, the first question is, well, who attains remission and who doesn't? Can we figure out what factors might determine that? Because then you as a practicing clinician will know who might really benefit from being referred for EXRP and who may have less benefit. The other question that actually our patients ask us once they attain remission, minimal symptoms after getting this combination, can they stop their medication? Patients ask that for a variety of reasons. Even though serotonin reuptake inhibitors are very tolerable in general, it's sort of a drag to take a pill every day if you don't have to. Serotonin reuptake inhibitors can have sexual side effects that, over time, can be really annoying and problematic for people in their relationships, and also, for example, there are women who might like to go off their medication because they'd like to get pregnant. So there are a variety of reasons to address these questions, and that's the last trial I'm going to tell you about. So this trial was designed to ask those two questions. So this is a trial where, in this trial, we recruited people on serotonin reuptake inhibitors. We then offered everybody up to 25 sessions of EXRP. So we gave them the standard course, 17, but if they weren't quite remitted yet, if they had not quite received, got to that minimal symptoms, which we defined as a Y box of 12 or less, we could offer them up to eight more sessions, up to 25. And then those who became well, we then randomly assigned them to either stay on their serotonin reuptake inhibitor or to be tapered off and be put on pill placebo and follow them for six months. So let me show you what we found. So here's the preparatory phase, where people were offered up to 25 sessions of EXRP. So again, they all came in on a serotonin reuptake inhibitor. They all got offered the 17 sessions, and what you can see is that some people got to under 12 with the standard course, about 49 of the 95 who were remitted. And another dollop, another big group, got to under 12 with only up to eight more sessions. So when you put both the 17, if you look at the whole course of up to 25, it's 69% of people got to remission after they entered, and that's pretty remarkable, 69%. You know, two-thirds of your subjects can get there. And the other thing that we did in this preparatory phase is we asked, well, who got to remission either with a standard course or with the extended course of up to eight more sessions for a total of 25? And once again, the thing that came through loud and clear, patient adherence, replicating our prior work. So the clinical tip here is, first of all, adding exposure and response prevention can be very powerful if you've got an OCD patient, we're talking about adults now, who still have symptoms despite being on a good dose of a serotonin reuptake inhibitor. And the second clinical tip is it's not, when you think about, should I refer this person for exposure and response prevention? It's not their severity that matters. We can get very severe people really well with EXRP. It's whether the patient's going to do the homework, whether the patient's going to practice, whether the patient is going to adhere and really engage in the treatment. That's what you should think about. Okay, ready for the second phase. This is now then. The 95 who were admitted, we put them in, we randomly assigned them to that double-blind discontinuation phase, and then we followed them over six months. So this is where they came into that discontinuation phase, and we followed them for 24 weeks over six months. And we looked at change in obsessive-compulsive symptoms, change in depressive symptoms, change in quality of life, enjoyment, and satisfaction. So obviously here, up is bad, and here, down is bad. And what you can see with your eye, without my having to show you all the fancy statistics, is that actually there's very little difference between the two lines, meaning the people who were tapered off of their serotonin reuptake inhibitor and the people who were continued on their serotonin reuptake inhibitor, over those 24 weeks or six months, did not have a difference in increase in their obsessive-compulsive symptoms. And you can see the increase in both, there was a little increase in both, but even there, not very much, on the average of less than three points. Had very minimal increase in their depressive symptoms, seven and below is considered remitted for depression, they don't even come close. And finally, some small decline in their quality of life, enjoyment, and satisfaction, but once again, the key thing is, looking at these individual scales, rated by independent evaluators who didn't know what they were randomized to, once again, no differences. But there's a really important caveat that I want to emphasize. We also asked the therapist and the clinicians, the people monitoring the medication, to rate each time they saw the patient on clinical worsening. And that was really a safety measure. And we looked at that, when we looked at that, the rates of clinical worsening differed. Now this was for any reason, this wasn't tied to any particular type of symptoms, this was just overall clinical impression by the clinician. And there, those who were randomized to taper, 45% of that group worsened to the point that they came out of the study, whereas those who continued on the SRI, it was only 24% to whom that happened. And that difference, indeed, was significant. So how do I understand that? The way I understand that is if you look at the specific symptoms by those specific scales, you don't see a difference between those who stayed on their SRI and those who discontinued. But these data suggest the SRI is doing something, maybe less specific, so that when you take it away, more people worsened. It's also interesting, though, to notice that even those who stayed on their medication, they also worsened. It's not like they were like a rose over the six months. And so now one of the things that we're doing is really studying what predicts who worsens. And so here the clinical tip is, I think you should educate your patient. If you've got a patient who's got serotonin reuptake inhibitor treatment, then got exposure and response prevention, and now have minimal symptoms, and they ask you, can I come off my medication? I think now you have some data to say, well, there was a study that asked this question. And the data aren't for an individual. The data are for the group. And overall, while there was not a difference in specific symptoms of OCD or depression, overall, more people who came off clinically worsened. So 55% didn't, 45% did. So it's about half and half. And so the key is, if you want to try to your patient, if you'd like to try slowly tapering off your medication, we just want to be monitoring you carefully over that time frame. And there is a risk that you might actually worsen. That's what I think is the take-home message here. So let me just summarize what I've just shown you. For the patients of today, we test treatments with clinical trials like what I just showed you. That's the gold standard. They're really important. It's one type of methodology that clinical researchers like myself use. And they're very important. They tell you what treatments work. So what we've learned is that serotonin reuptake inhibitors, many respond, but the response is usually partial. So what we are doing, as well as others in the field, what are we doing? We're testing other treatments and new treatments to see whether we can find better treatments for the people, for people with OCD. And we need treatments that more people will respond, more medication treatments where people will respond. And there's a lot of interest in testing new medications. With EXRP, even more people will respond, but adherence, patient adherence and therapist adherence to the protocol is key. And something I didn't have a chance to talk about, but the other one is access. How do you find this very powerful treatment for your patient? It's a really important problem, which I'm going to address next. What are we doing here? Well, we're using technology to improve access, internet CBT or mobile apps. Other research that's ongoing is can we enhance learning from the exposures so that actually people not only get better, but stay better? We reduce relapse rates. And around the world, people are also using intensive formats, even more intensive than the first study I showed you, where it's five sessions a week. For example, there's something called the Bergen method, where people go inpatient and it's all day, every day for five days, I think is the format. And finally, when you put these two treatments together, many can attain minimum symptoms. What I just showed you is about two-thirds of adults, if you optimize the medication treatment and the therapy treatment. And what do I mean by optimized? You want the SRI at the highest tolerated dose that they can have. And you want to offer extra P, up to 25 sessions with a skilled therapist and with a patient who will adhere. So from clinical trials that I don't have time to show you, this is how you come up with treatment algorithms, like the American Psychiatric Association publicizes. And what I've been talking to you about is the clinical trials that show you these boxes in white, and that's the first-line treatments and where everybody should start and what everybody should be doing. And again, two-thirds of adults, you can get people well, just if you stay in those white boxes. But obviously, there's still a third that isn't getting well. And that's when that leads to other types of trials and more different types of algorithms. What's your next step if the SRI doesn't work or a partial response? What happens if you try all of this and you still don't have a good response? There's a lot of research going on here looking at TMS and ketamine and alternative therapies. There's also residential and intensive treatment. And finally, when all else fails, OCD is one of the disorders where actually neurosurgical interventions are used, but only in the people who failed the white boxes, the green boxes, the yellow boxes. So that's how you build a treatment algorithm. And that's, again, if you go to the American Psychiatric Association, there are published guidelines from 2007 and there's an update from 2013. And if you go to the literature, there are more recent updates that sort of mirror what I'm showing you on this slide. But I now want to turn in the last minutes of my talk to two challenges that we face as practicing clinicians and two challenges that my research program is working to try to address. So challenge number one, which is I just showed you that with our first-line treatments, serotonin reuptake inhibitors and exposure and ritual prevention psychotherapy, you can get two-thirds of people well, not just responding. But the first challenge is most people with OCD don't receive evidence-based treatment. And there are multiple reasons for this. You know, in some cases, it's patients don't know they have OCD and don't come for treatment, and obviously that's really important. You know, responding to that is really important in terms of public education and family education about what OCD is. A second possible reason why people don't receive evidence-based treatment is because clinicians don't detect OCD when people show up, don't diagnose it correctly, or don't actually offer evidence-based treatments. And in particular, may not be offering the exposure and ritual prevention, which arguably is our most effective treatment. And then there are just system issues, right? Which is clinicians, the patient is coming for help, the clinician knows what they'd like to do, but our system, our mental health system, doesn't actually provide access to the evidence-based care. So my Center for OCD had the wonderful opportunity to partner with the Center for Practice Innovation at the New York State Psychiatric Institute and the New York State Office of Mental Health to try to address this problem. And this is an initiative called Impact OCD, which is to improve assessment, care, and treatment of OCD in New York State. And the initiative, our goals are to develop online trainings for frontline clinicians in an OCD toolkit that they can use and their patients and families can use, to disseminate our trainings using the New York State online training platform for clinicians, and to provide expert feedback on cases to clinicians in the New York State OMH settings, Office of Mental Health. And here's some of the key people who started this project with me at my center, the key people at the Center for Practice of Innovation who we work with, with my colleagues, Supana Patel in particular I want to shout out, give a shout out to, and also leadership of the New York State Office of Mental Health, who without this project couldn't be happening. And we're so grateful for their partnership because when you partner with the state, big things can happen. So our process, this is a completely different type of science, by the way. Our work, it follows the principles of a patient translational research methodology called implementation science. And this is where you engage your stakeholders, you find out what they need, not what you think they need, and then you deliver what they've asked for and what they say they need, and you study the outcome. And in this case, it's studying their engagement with the trainings and change in their behavior. So again, another type of patient-oriented research, which is very different than a randomized controlled trial, and which my colleague, Dr. Supana Patel, has been educating me all about. So what was our process here? We first had to find out what our stakeholders wanted and needed, and so that was conducting a webinar and a needs assessment. We then developed a training curriculum with lots and lots of input from our stakeholders with many different advisory boards, frontline clinicians, individuals with OCD, supervisors and directors of these OMH clinics. And that ended up with very specific topics that they were particularly interested in, and we developed that curriculum in partnership with them. We then, and developed all those webinars, we then, to put out on that online training platform, we then developed methods to evaluate, you know, what did they know before, what did they know after, how were they treating before, how are they treating after, and we're now in the process of disseminating these statewide and evaluating the outcome. We also, if you'd like more information, you can search Impact OCD and you can learn all about this project. You'll also see there the Impact OCD Toolkit, which is for both individuals and families, but also for clinicians, lots of materials up there on the website. In parallel, we've been thinking about the problem of access, because what we are predicting is we will find more cases of OCD, and getting the treatment with medication, the serotonin reuptake inhibitor is really quite straightforward to actually get that to people once they've diagnosed OCD. But once again, the issue of how do we increase EXRP access, and one of the things we've been doing on the research side is studying different types of technologies to see if they work, and to see if those could be tools to increase access, and that includes internet CBT and mobile apps and telehealth. And the big goal here of all of this work, Impact OCD's work, is if we could get to early detection, so people with OCD don't wait 5, 10, 15 years for a diagnosis, which has been true in the past, and don't have their life unravel because of those years of untreated OCD, so one thing key is early detection. Remember I told you half of the cases start at age 19. We'd like to get to people in the first year that OCDs start. But the other one is to make sure that it's not just detected, but you give them access to evidence-based treatment, again with our goal to deliver both the therapy and the medication as soon as we can to get to that two-thirds of people becoming well. I didn't have the time to show you the data, but the data I showed you for adults about those two treatments is very similar for kids, with obviously the psychotherapy being the first-line treatment in kids, and that psychotherapy can be wildly effective in kids too. So again, early detection, access to evidence-based care, with the goal of early intervention for OCD. That's the goal. So I want to turn now to the second challenge in the field. So the first challenge was we have these treatments that work for many, but many people aren't getting them. That's the implementation science project and the project called Impact OCD. But even if we were perfect at being able to detect and give everybody those front-line treatments, there's still people, about a third, who those treatments are not enough. And even if you go down all that algorithm, the green box and the yellow box, there still are people who are getting to neurosurgery. So the question is, why is that? Why do our treatments not work for everybody? So that leads to the question, well, what causes OCD? So let's talk about that for a second. So what causes OCD? And when you say cause, there's sort of two different ways to think about cause. One is, well, how does the brain produce obsessions and compulsions? And what I mean by that is when I talk, my brain allows me to talk. When I move my hands, my brain allows me to move my hands. Likewise, if I have obsessions and compulsions, it must be my brain is producing those obsessions and compulsions. And the working model is that there's specific brain circuits that aren't functioning properly. And those circuits underlie key neurocognitive and neurobehavioral processes. And so the hypothesis is that there's certain alterations in those processes in people with OCD and their data, not just hypotheses, that there are some alterations when you look at people with OCD and compare them to people who don't have OCD, that there are alterations in how they process threat or extinguish fear. There are alterations in the balance between goal-directed and habitual behavior. There are alterations in processes called cognitive control and response inhibition, where you're able to inhibit an action or a thought. And there are alterations in reward processing. So that's the working model of pathophysiology of OCD. But there's a separate question about what causes OCD, which is, well, if there are these alterations in the brain and in these circuits, how did those alterations in the brain happen? That's a completely different question. That's etiology. And there, there is a different set of hypotheses, which are about specific genes. Some people may be at risk for OCD because of genetic risk. People might also be resilient and not get OCD because of genetic risk or because of genetic contributions. There's some evidence that certain metabolic issues can lead to OCD. There's evidence that infectious agents and autoimmune mechanisms can lead to OCD. There are case reports of people getting neurological insults, like a stroke in a circuit, in a specific circuit that can lead to new-onset OCD. And then environmental causes. There's data on people after severe trauma. While some people might get depressed, some people might get PTSD symptoms, there are also case reports of people developing new-onset OCD. So this is a big area. It's a big series of questions, what causes OCD? And my work mostly, to date, has focused on pathophysiology. So when you look at the brain of people with OCD and you compare it to the brain of people who don't, in fact, from a whole range of imaging studies published over the last decades, in fact, you can find alterations in different brain circuits, in different brain circuits that are now here highlighted in color that underlie different functions, such as response inhibition and habitual behavior, executive function, including cognitive control, emotional regulation. So sort of alterations in the circuits that map onto those processes that are thought to underlie or to lead to the generation of obsessions and compulsions. But there's a big problem with these imaging studies, and the fundamental one is, or the fundamental one, as I think about it, is three problems as a clinical researcher, which is first of all, what's cause and effect, right? So I image people with OCD, and I image people without OCD, and I see these differences. Well, are the symptoms causing the differences? Or are the brain alterations causing the symptoms? It's not a question we can ask using an imaging technique, which is really just cross-sectional at one point in time. The second issue is, well, these imaging studies, depending on what they look at and what circuits they look at, actually you can get sort of various findings from different studies. And then that leads to the question as well, do we think all OCD patients have the exact same brain alterations? And I guess I would say, I don't think so. Remember I told you that everyone has obsessions and compulsions, but then there are many variations in the associated features, and I guess my sense of it is, is probably that variation in the associated features must map onto the brain. So we should be expecting maybe some similarities, and then some differences depending on the person in front of us and what their exact symptoms are. But a really fundamental problem in the field of neuroimaging is, are neuroimaging findings robust and reproducible? And what I mean by that is when a person with OCD walks into my clinic in New York City and I image their brain and I find an alteration in their brain, if it's really a robust and reproducible signature of OCD, the same should be true if that person walked into someone else's research lab, whether they are in Atlanta or San Francisco or anywhere else around the globe. So it's that last question that we decided to actually address. So this is a project that we're just in the last phases of recruiting, and it's a project that's a collaboration between my group in New York City, Dr. Odile van der Heuvel's group in Amsterdam in the Netherlands, Dr. Jonathan Reddy's group in Bangalore, India, Dr. Dan Steins' group in Cape Town, South Africa, and Dr. Yuri Miguel and Rosalie Chavit in Sao Paolo, Brazil. And it's exactly to address that question, which is, you know, can we identify robust and reproducible signatures of OCD? So that's the imaging part. Are they there? And can we link these to the different clinical profiles? To answer that question you need a big sample, but it's also true we chose a global sample because it's a really hard test of the question, right? Which is, again, if we all recruit the same way, if we all evaluate the clinical symptoms the same way, if we all do the same neurocognitive testing, and we all do exactly the same imaging, then if there are robust biosignatures, I should see them in New York, and they should see them at all their sites as well. So it's a really, it's a hard test of the hypothesis. And then the real goal of this, though, is can we, if we find those robust biosignatures, can we use them as a diagnostic tool or a novel treatment target for people with OCD? And that's really what this work is leading towards. It's this idea of towards precision psychiatry, where in an ideal world maybe there are different circuits that underlie and contribute to obsessions and compulsions. Again, that same, those same different circuits where alterations have been found in different studies, but maybe they underlie different types of clinical profiles and different types of neurocognitive alterations, and maybe to address those circuit abnormalities, maybe one uses different types of treatments. So that's the simple idea, is if you can link different brain signatures to different clinical profiles of OCD, can you then develop more precise treatments that target these brain signatures directly and lead to better outcomes for individual patients? Completely unknown. The study was addressed to answer that question. And hopefully we're going to have results in the next year. So that leads me back to the picture I showed you at the beginning. So just to review, I showed you a number of clinical trials where we're testing and improving current treatments for OCD. That led to the IMPACT-OCD initiative, which is really focused on implementing and disseminating treatments. That's implementation science. And lastly, I talked a little bit about some of the imaging studies we're doing, which is to identify new targets for intervention. So my goal here was to not only teach you about OCD, but illustrate how all these different types of patient-oriented translational research can be used in different ways to advance clinical care. And I would just pause for a minute and get us all to reflect. We just saw one of the most extraordinary translation from basic science to mechanisms and targets for intervention to testing and improving treatments to implementation and dissemination that I have ever seen in my lifetime. And that was the development of the COVID-19 vaccines, which really started with all this work on messenger RNA from the basic science side that then got translated up when we had this dire need into a novel vaccine. And then that vaccine was tested for safety and then in large trials for efficacy and now disseminated to all of us listening who chose to get vaccinated. So that's a really incredible cycle of the power of science, different types of science, to actually come up with, in this case, a treatment that, you know, and I could have picked the antiviral treatment cycle as well. This was really a credible demonstration of the importance of research and of basic and clinical research to really advance treatments for patients. And what I would like to leave us with is imagine if we could figure out and do this cycle for mental illnesses like OCD. And, you know, I appreciate that that's an idealistic goal, but that's what my program is dedicated to and that's what I think researchers across the country are dedicated to, is to really make sure that the scientific discoveries of today get translated into better treatments for people with mental illness tomorrow. And what I do know is going to take all of this type of research to make this happen and to make this transformation. With that, I just want to thank my team. You never do anything by yourself. Here we are during the COVID-19 pandemic in Central Park. This was summer 2020 when we really wanted to see each other. So you see us physically distancing without masks on because we're outside. And here we are a little bit, you know, still outside, but all vaccinated and all feeling a little more comfortable being a little closer together. And with that, I want to stop and thank you so much for your attention. How about a round of applause for her? Even Dr. Simpson is not with us in person, but for this pre-recorded session presentation, there's no live Q&A. But there's good news that there will be APA online meeting scheduled from June 7th to June 10th, 2022 via WebEx event platform. So anyone who would like to ask Dr. Simpson questions, please join us. And her session will be scheduled for Friday, June 10th from 12 p.m. CDT, that's Central Daylight Saving Time, which is 1 p.m. Eastern Time, and then 10 a.m. Pacific Daylight Saving Time. So this concludes Dr. Simpson's presentation. And under the anxiety track, as I explained to you in the beginning, the clinical update, this is a new track we established, and this is the first year, and it's well attended. And the third, we have three presentations under the anxiety track that yesterday we heard Dr. Nemiroff's presentation on the PTSD, post-traumatic stress disorder, and then today we heard Dr. Simpson on the OCD. And the third presentation is scheduled for 10.30 today in this room. The presenter will be Dr. Mark Rappaport, and he will present on the anxiety disorder, anxiety disorders, treatment, current state, and future promise. So if you please come and join us at 10.30 a.m. today. All right, enjoy your break, okay?

Clinical Updates

APA Annual Meetings

clinicians

evidence-based tools

anxiety domain

neurobiology

post-traumatic stress disorder

obsessive-compulsive disorder

treatment

translating scientific discoveries