Hello and welcome. I'm Dr. Donna Rowland, Program Director for the Psychiatric Mental Health Nurse Practitioners at UT Austin and Clinical Nursing Expert for SMI Advisor. I am pleased that you're joining us for today's SMI Advisor webinar, Insomnia, Hyperarousal, and Suicide and Psychosis. SMI Advisor, also known as the Clinical Support System for Serious Mental Illness, is an APA and SAMHSA initiative devoted to helping clinicians implement evidence-based care for those living with serious mental illness. Working with experts from across the SMI clinician community, our interdisciplinary effort has been designed to help you get the answers that you need to care for your patients. Today's webinar has been designated for one AMA PRA Category 1 credit for physicians, one Continuing Education credit for psychologists, one Nursing Continuing Professional Development Psychopharmacology Contact Hour, and one Continuing Pharmacy Education credit. Credit for participating in today's webinar will be available until November 7th. Slides from the presentation today are available to download in the webinar chat. Select the link to view them. Captioning for today's presentation is available. Click Show Captions at the bottom of your screen to enable this. Click the arrow and select View Full Transcript to open captions in a side window. Please feel free to submit your questions throughout the presentation by typing them into the question area found in the lower portion of your control panel. We'll reserve 10 to 15 minutes at the end of the presentation for Q&A. Now I'd like to introduce you to the faculty for today's webinar, Dr. Brian Miller. Dr. Brian Miller is a professor with tenure in the Department of Psychiatry and Health Behavior at Augusta University. Dr. Miller's current research focuses on inflammation and immune dysfunction, as well as insomnia and suicide and schizophrenia, and it has been funded by the National Institute of Mental Health, the National Institute of Mental Health, and the and it has been funded by the National Institute of Mental Health, the Stanley Medical Research Foundation, and the Brain and Behavior Research Foundation. He has over 100 peer-reviewed publications and has been recognized with several awards. In addition to his research, Dr. Miller provides clinical care for patients with schizophrenia and supervises and teaches residents and medical students in general psychiatry. Dr. Miller, thank you so much for leading today's webinar. Hello, everyone. Greetings from beautiful Augusta, Georgia, home of the Masters, where it's been in the mid-90s all week, and my wife's fall dreams of a cool pumpkin spice latte on a cool day are currently in flames, but we know that hopefully fall is just around the corner. Thank you so much for that kind introduction. Thank you to the folks at SMI Advisor who have been wonderful to work with, and particularly Dr. Rob Cotez for this invitation to share some of our work with you today. These are my disclosures to make things official for the past 12 months. I would like to make you aware in particular that I will be talking about some off-label investigative use of the following commercial products, the neuroptics, 3,000 portable pupillometers. We talk about the use of eye reflexes as a novel biomarker of suicide in our patients with psychosis. We have three objectives today for the next 40, 45 minutes. I want you to be able to assess the evidence for associations between insomnia and psychopathology in patients with psychosis. Similarly, we'll assess the evidence for associations between insomnia and suicide in psychosis. Then lastly, as I alluded to earlier, we'll talk about portable pupillometry as a novel marker of suicide risk in our patients with psychiatric disorders. We'll start with that same order as the objectives. We'll talk about insomnia and psychosis, particularly relationships with psychopathology and suicide. Then we'll finish by talking about our novel work on pupillometry and suicide. Psychiatry and mental health can certainly be exhausting. This is my daughter, Kate, who's now eight, but this is back when she was three. I'm sure we've all been tired at times. I'm not sure we've all been so tired that we've fallen asleep literally in the middle of eating a chip, but she managed to do that. Of course, as a psychiatrist, we look for patterns in behavior. Here she is again, asleep with a pretzel in her mouth. You'll be relieved to know that she does not have narcolepsy. With that, let's talk about sleep disturbance and suicide and psychiatric disorders. A meta-analysis of 19 studies found that patients with any psychiatric diagnosis and comorbid sleep disturbances, including insomnia, were about twofold more likely to report suicidal behaviors. Importantly, this is a transdiagnostic phenomenon. I don't think it's specific to psychosis, though it has been seen in schizophrenia, but it's found in depression, it's found in PTSD, panic disorders, across the entire spectrum of psychiatric diagnosis. In fact, a meta-analysis of 42 longitudinal studies found that insomnia was a significant predictor of current suicidal ideation and that nightmares were a predictor of suicide attempt, again, with an odds ratio of about two for each of these associations. My chair, Dr. Vaughn McCall, has long been interested in relationships between insomnia and suicide. A number of years ago, he suggested we look at this association in more detail in our ongoing studies of patients with schizophrenia. I took his sage advice and will share with you, subsequently, some of the interesting findings that have come out of this association in our patients with psychosis. We know that both insomnia and suicide are extremely common phenomenon in schizophrenia and other psychotic disorders. In general, I'd say one-quarter to one-half of our patients have insomnia at any given time point. We know that about one in four patients with schizophrenia will attempt suicide during their lifetime and unfortunately, suicide will be the cause of death in about five percent of our patients with schizophrenia. Surprisingly, despite how common they are, neither of these phenomenon are part of the diagnostic criteria for any psychotic disorders, nor are they a specific individual item in any of our main rating scales that we use for psychopathology, such as the PANS or BPS. Over the next few slides, I'll talk about how do you build a system of research in a given area. Step one is to play in the backyard. We started looking at associations between insomnia and suicide in our own patients. Here in Augusta, we recruited over 100 inpatients and outpatients, roughly half with schizophrenia, half with schizophrenia, and about a third with psychosis. Inpatients and outpatients, roughly half with schizophrenia, half with schizoaffective disorder. They were in their early 40s. About two-thirds were male, two-thirds were of African descent, and about a third were Caucasian. We used the insomnia severity index as a measure of the degree of insomnia and the Beck scale for suicide ideation to look at suicidal thinking and behavior. What did we find? We found in regression controlling for a number of important potential confounding factors, including age, sex, and race, and severity of symptoms, that the patient's level of insomnia, as measured by the insomnia severity index, as a continuous measure, was a significant predictor of the severity of their suicidal ideation and behavior, again, as a continuous measure using the Beck scale, with a correlation approaching 0.3. Modest correlation, but significantly correlated. Furthermore, when we looked at the insomnia data categorically, so if you divide insomnia into four categories, according to the ISI scale, there looked to be a dose-dependent effect of insomnia on the risk of or severity of suicidal ideation. Patients with the most severe insomnia had significantly higher levels of suicidal ideation and behavior compared to patients in any of the other categories. Also, we found that patients' levels of insomnia were significantly correlated with the severity of their psychopathology, specifically total psychopathology, but also positive symptoms of psychosis, general psychopathology, but not negative symptoms of psychosis. And as you'll see in the next few slides, that's a pattern that has seemed to ring true regardless of the particular patient cohort that we've examined. So the next step was to invite some friends over to play, and I was reading some articles and found a research group in China that appeared to have some of the data that we were looking for, and I asked them if they'd be interested in looking at this association, and fortunately, they responded affirmatively. So we looked at over 300 inpatients with chronic schizophrenia in China, about 40 of whom had suicidal ideation, again, mean age similar, early 40s, mostly male. This group had also used the insomnia severity index as a measure of insomnia, and then they also used the Calgary depression scale for schizophrenia, which includes an item regarding suicidal thinking over the past two weeks. So what did we find? We found that the patient's insomnia score, whether we looked at it as a continuous measure or as a categorical variable, was a significant predictor of suicidal thinking over the past two weeks, even after controlling for the total severity of psychopathology, current antidepressant use, and a history of suicide attempt. Admittedly, this association was attenuated after controlling for depressive symptoms, but that's not entirely unexpected, given that we know that insomnia is a core symptom of depression, although the findings were still significant, even when we controlled for concurrent antidepressant use. Just as we found in our cohort in Augusta, we found that insomnia scores were also significantly correlated with total positive and general psychopathology scores, but not negative psychopathology. So now that we'd found this association twice, we decided, let's throw a big party. So we're very fortunate to have on faculty one of my esteemed colleagues, Dr. Joseph McAvoy, who was the project medical officer for the large NIMH-sponsored CADI trial in schizophrenia. We were able to access the publicly available data from the CADI trial, which includes information on over 1,400 patients with schizophrenia or schizoaffective, very similar to our own data, patients on average early 40s, mostly male, mostly patients of African descent. In the CADI trial, there's data available on the Calgary depression scale, which includes not only a suicide item, but also a specific item on terminal insomnia or early morning awakening over the past two weeks. And then in a subset of patients in the CADI trial, there was self-report data on the presence of current, either initial or middle insomnia, and whether they'd made a suicide attempt in the past six months. So we found that at baseline, at the start of the CADI trial, that the presence of insomnia, regardless of what phase, whether it be terminal, initial, or middle insomnia, predicted recent suicidal ideation in the past two weeks with an odds ratio in the range between two and three. We also found that the presence of baseline terminal insomnia was a predictor of a suicide attempt in the past six months with an odds ratio of five, but that baseline initial or middle insomnia was not a predictor of recent suicide attempt in the CADI sample. Again, with remarkable consistency, patients who had terminal insomnia had higher total positive and general psychopathology, but not greater negative psychopathology in the large CADI trial. So we were sort of three for three with our associations with the severity of psychopathology. Interestingly, we also looked at other correlates of insomnia, and we found that having insomnia at baseline of the CADI trial predicted higher levels of triglycerides, not only at baseline, but over the first six months of the trial. And when we looked at that categorically in terms of having clinically high triglycerides, again, the presence of terminal insomnia at baseline predicted high triglycerides, not only at baseline, but also predicted high triglycerides at three months in the patients in CADI who were treated with olanzapine. I don't have a slide on the data, but we also found some associations between insomnia and other inflammatory markers, including C-reactive protein and interleukin-6 in the CADI sample. So after looking at the largest existing cohort that we could find of patients with chronic schizophrenia, we also wanted to know, do these associations exist in patients with early psychosis? And so, again, with publicly available data from the RAISE first episode schizophrenia trial, this is 400 patients with first episode schizophrenia, and we also found that the first episode schizophrenia mean age in their 20s, again, mostly male, predominantly patients of African descent. The RAISE trial also had the same Calgary depression scale with data on terminal insomnia and recent suicidal ideation, plus a self-report on a more general sleep problem. So a lot of information here on this slide, but let me try to distill it down for you. What we found is that at the baseline of the RAISE study, that patients with any kind of sleep problems were over two times more likely to endorse current suicidal ideation. Again, that association was no longer statistically significant. It was attenuated, as you can see here in model two, after we controlled for the severity of depressive symptoms. However, if we looked at patients over the 24 months of the RAISE trial, those who had sleep problems at any point during that two-year trial were over three-fold more likely to have concurrent suicidal ideation at the time that they were having sleep problems. And perhaps most importantly, subjects who endorsed sleep problems at every visit through the two years of the RAISE trial were almost 14 times more likely to endorse suicidal ideation at some point during the trial. And even after controlling for depressive symptoms, these same patients were almost eight times more likely. So the persistence of insomnia was a very significant predictor of suicidal ideation over this two-year trial in early psychosis. I apologize. There is a train that goes through here right behind our building at the most inopportune time of day. So if you're hearing a train in the background, I apologize. It should pass in just a moment. And again, a lot of information here, but in the RAISE trial, we found the same associations as we did in every other trial when we looked at relationships between sleep problems and psychopathology. In general, at every visit over two years, we found significant or very nearly significant associations between insomnia as a predictor of worse total psychopathology, positive psychopathology, and general psychopathology symptoms, but not negative symptoms. So as a next step, we've been looking at a lot of cross-sectional data. We also wanted to look for additional opportunities for some longitudinal analyses. And so I was fortunate as part of a NIMH grant, a K award for the proactive NIMH-funded proactive trial, we did a secondary analysis. This was a trial of patients who were 300 patients who were randomized to treatment over 30 months with either risperidone long-acting injectable or other oral second-generation antipsychotics. The demographics look very similar to our other studies, except the proactive trial was predominantly more Caucasians than patients of African descent. In this particular study, there wasn't a formal assessment, a formal rating of insomnia, but instead it was assessed as an adverse event, and items related to depression and suicide were assessed on a biweekly monitoring assessment. And this is data that's currently under consideration. We're revising the manuscript for this submission in schizophrenia research. And so what we found is that the presence of moderate to severe insomnia at baseline being reported as an adverse effect, those subjects were about two and a half times more likely to endorse concurrent suicidal ideation than those with no insomnia. At individual time points throughout this 30-month trial, we did not find other significant associations at these other time points, although most of the odds ratios were in the direction of an association between insomnia and suicide. Although, as you can imagine with a long-term trial in patients with schizophrenia, there was some significant loss of patients to follow up over the course of the trial. So with study attrition, the sample sizes were much smaller as the trial progressed. But in general, we found also that if the patients had moderate to severe insomnia baseline, those patients were about two times more likely to endorse suicidal ideation at some point throughout the two-and-a-half-year trial. And again, we found using a non-standardized measure of psychopathology, but the PROACTIV trial did have its own specific biweekly monitoring of severity of psychopathology at several time points throughout the study, including at baseline. The presence of insomnia was significantly associated with the total level of psychopathology. So with all of these studies, and given my background in epidemiology, we decided to do a meta-analysis of these associations. The reason for the Star Wars image is that when I was a resident, I was fortunate to have mentorship from Dr. Brian Kirkpatrick and Dr. Eric Macias. And Dr. Macias taught me some of the nuts and bolts of how to do a meta-analysis. And then years later as a faculty, Dr. Kirkpatrick was kind enough to invite me to give a talk to teach his faculty how to go about doing a meta-analysis. So this image is kind of a Star Wars reference as a thank you for that. And so together with Dr. McCall, we published a meta-analysis of insomnia and suicidal thinking and behavior. Again, largely derived from our own data, but overall we found that the presence of insomnia was associated with about a twofold increased risk of concurrent suicidal ideation. That's pooling data together from eight studies. We did not find a significant association between insomnia and prior suicide attempt. Although there are two prospective studies which found that the presence of insomnia was a predictor of incident, suicide attempt or suicide death. And again, when we looked at psychopathology and pulled all the data, as I've mentioned repeatedly here with each of the individual studies, we did find that insomnia was significantly correlated with levels of total psychopathology, positive psychopathology and general psychopathology, but not negative symptoms scores. So with that, we said, well, there's kind of one last group of subjects that we should consider tapping into as we've looked at the spectrum of illness, of psychosis. And so let's go back to the beginning or even before the onset. And so we asked the question, are these associations found even in patients with prodromal psychosis? So together with my colleague, Dr. David Goldsmith at Emory, we've had the opportunity to look at these associations in the Naples, the North American Prodromal Longitudinal Study. And again, these are brand new data that are currently under review. So with the Naples three cohort, we looked at almost 600 patients with prodromal psychosis and they have a number of different rating scales of sleep and symptoms, including the Calgary Depression Scale, the Pittsburgh Sleep Quality Index, and then the scale of prodromal symptoms or SOPS as an index of psychopathology. And so again, we found many significant associations between the presence of insomnia or sleep disturbances, regardless of the instrument, whether it's in the Calgary Depression Scale, whether it's in the SOPS or the Pittsburgh Sleep Quality Index, we found that these sleep disturbances are significant predictors of psychopathology in patients with prodromal psychosis. And we also found a number of significant associations between insomnia and sleep disturbances and suicidal ideation in this population as well, again, after controlling for a number of important potential confounding factors. So hopefully I've convinced you that insomnia is clearly associated with suicidal thinking and behavior, as well as the severity of psychopathology and psychosis. So what's going on here mechanistically and how can we begin to understand this? Well, we started thinking about what two psychotropic medications do we know have clearly established anti-suicidal properties? And those are, of course, clozapine and lithium. And so what's interesting is the very large intercept trial. This was clozapine versus olanzapine for patients with schizophrenia at high risk of suicidality. And when you look at the adverse event data, we found that they found that patients treated with clozapine had significantly less insomnia than patients treated with olanzapine. And this rings true with my clinical experience. I think olanzapine's a pretty sedating antipsychotic, but I know that clozapine is extremely sedating and can even be a potentially limiting side effect of clozapine. And so we wanted to investigate that further. And similarly, we know that lithium has anti-suicidal properties, and there are even some ecological studies that have shown that concentrations of lithium in the public drinking water seem to correlate with suicide risk, which is quite interesting. So again, looking at publicly available data, we searched the U.S., it's called FAERS, it's the FDA's Adverse Event Reporting System, where any second-generation antipsychotic or mood stabilizer was reported either by a patient or a clinician as the suspected agent of some kind of psychiatric adverse drug reaction. And so we were able to look at data on 10 different second-generation antipsychotics and five different mood stabilizers. We calculated the reported odds ratio setting the risk of, the odds of insomnia or suicide for clozapine and lithium to one. So a lot of data here, but if you set the odds of insomnia with clozapine to one, what we found is that every other antipsychotic that we looked at had a significantly higher odds of insomnia as being reported as an adverse effect of these antipsychotic medications. And similarly, compared to clozapine, every other antipsychotic had an increased odds of some kind of suicidal thinking or behavior being reported as an adverse effect of antipsychotic treatment. So again, these data from pharmacovigilance data support the idea that clozapine has anti-suicidal properties. We found a very similar pattern with lithium, interestingly, that compared to lithium, there was an increased odds of insomnia being reported for other mood stabilizers, although that only reached statistical significance for lamotrigine, but however, compared to lithium, all of the other mood stabilizers had a significant increased odds of suicidal thinking and behavior being reported as an adverse reaction to these other mood-stabilizing agents. And what's very interesting is when we plotted these data against each other, so when we plotted the odds of insomnia on the X-axis versus the odds of suicide being reported as an adverse effect of these antipsychotics, we found a significant positive correlation. This is after excluding quetiapine, which for unclear reasons was kind of an outlier in that regard, but the overall correlation was almost 0.7, so very highly correlated between the odds of insomnia and the odds of suicide as an adverse effect using these pharmacovigilance data. We started asking further, well, could this have something to do with effects of these antipsychotics on sleep? And so what was interesting is that we looked at the binding affinities of these different antipsychotics for histamine and plotted those against the reported odds of insomnia and found, again, a very high correlation. Those agents with the highest affinity for histamine, which can cause sedation, also had the lowest reported odds of insomnia. Taking that a step further, we also wanted to validate our clinical experience with clozapine causing significant sedation to look at clinical trials of clozapine versus other antipsychotics, and so we recently published a meta-analysis of the odds of insomnia with clozapine treatment compared to other antipsychotics, and we found that other antipsychotics had about an over two-fold increased odds of insomnia being reported compared to clozapine, again, confirming that clozapine definitely helps people with sleep, and it raises the possibility that improvements in insomnia with clozapine might mitigate some of its antisuicidal properties, and so what was fascinating is if we compared the data from this meta-analysis of clozapine randomized trials with a pharmacovigilance data, they almost line up perfectly, so again, whether we're looking at clinical trials of clozapine, whether we're looking at pharmacovigilance data, highly correlated that clozapine seems to be associated with significantly less insomnia compared to other antipsychotics, and so some current work that we're writing up, phase two, phase three of the CAITI trial included a treatment with clozapine for a small number of patients, so there are data on 76 patients from CAITI who got treated with clozapine, and we have data on the Calgary Depression Scale both before they started clozapine and at the end of their clozapine treatment, and so what did we find? Well, consistent with every other cohort, we found a significant association at baseline prior to clozapine between current insomnia and current suicidal thinking, so patients with insomnia were almost five times more likely to have suicidal ideation than those without insomnia before starting clozapine, so then what happened? They got clozapine treatment, what happened to these 76 patients? Well, the rate of insomnia dropped about threefold, dropped from 30% to 11%, and the risk of current suicidal ideation dropped about two and a half fold, so with clozapine treatment, we see both reductions in insomnia and reductions in suicidal ideation, so what about these 23 patients who had insomnia at the beginning of before starting clozapine? So these 23 patients who all had insomnia before starting on clozapine, eight of the 23 had suicidal ideation, what happened to those patients in particular after they got clozapine? Well, what we found is that insomnia was slashed, only four of the 23 patients still had insomnia after treatment with clozapine, and only one of those patients still had suicidal ideation after treatment with clozapine, so essentially, if you can put that in an odds ratio, the resolution of insomnia with clozapine treatment was associated with an eightfold increased odds of resolving suicidal ideation, so again, some additional evidence that seems to support this hypothesis that improvements of sleep may mitigate some of the anti-suicidal properties of clozapine. So let's talk about some clinically relevant things. I see lots of patients with schizophrenia and other psychotic disorders. Based on all of these data, I ask about sleep at every outpatient visit, given the associations with suicide, given the associations with the severity of psychopathology, I ask my patients and any informants that might be available about their sleep, and particularly have interest if their sleep is worsening. Can you assess this objectively? The insomnia severity index is only a seven-item scale. It's a five-point Likert scale. This could be done quickly during the outpatient visit or even during the waiting room as an objective measure of insomnia, and then how do we treat insomnia in our patients with psychotic disorders? Unfortunately, I would argue that if you look at the evidence, any kind of evidence-based guidelines, and especially what sequence of treatments to try are really lacking, so neither the APA practice guidelines nor the Schizophrenia Port psychopharmacologic treatment recommendations really specifically mention treatment of insomnia. The consensus view of the British Association for Psychopharmacology states that benzodiazepines or antihistamines may be appropriate adjuncts for insomnia, but again, this is just derived from a consensus view rather than specific evidence-based data. So what do we do? Well, with our patients with psychosis and particularly those with insomnia, I think everyone needs psychoeducation on good sleep hygiene. Here in the South, where sweet tea is more common with water and our patients drink tons of caffeinated beverages, they need a lot of psychoeducation about the effects of caffeine on their sleep. I also strongly recommend shared decision-making with your patients in terms of selecting treatment. In terms of what works, there is some evidence for efficacy of both pharmacologic and non-pharmacologic treatments. That includes sedating antipsychotics, melatonin, some of the Z drugs, and then of course cognitive behavioral therapy for insomnia, if that's available, is certainly a viable treatment option. But hopefully I've convinced you with the evidence that if we can get patients sleeping better, that we can reduce risk of suicide and that we can even improve their overall level of symptoms. So taking a turn now to kind of the suicide prevention side of things, which is an overarching goal of our work in this field, hopefully I've convinced you that all of these things are connected. There are strong links between insomnia, suicide, and psychosis. And when it comes to, in general, in psychiatry and psychology, preventing suicide risk, we're really limited by a lack of factors other than clinical or demographic factors, such as being male, older age, the presence of mental illness, comorbid substance use, or a history of suicide attempt, as are established predictors of suicide risk. And importantly, there are no practical point-of-care biomarkers of suicide risk that can supplement our clinical management. So our group has thought for a while now that hyperarousal may be a candidate marker that mediates some of these associations between insomnia and suicide. And so a test that's called the PLR, the pupillary light reflex test, is a potential measure of physiologic arousal. And what's even better is it can be measured by a self-contained handheld device that is portable, that potentially could be scalable to the outpatient clinic setting. So this is what the pupillometer looks like that we're using. It's a handheld device that looks sort of like a big ophthalmoscope. We allow the patients to adapt to the darkness for five to 10 minutes. When you hold the pupillometer up to the eye, this is the image that you see here in the screen, you press a button, and the pupillometer shines a very brief pulse of light. And then it goes on to measure a number of different parameters of the eye reflex to that flash of light. Excuse me, these parameters are calculated automatically and can be downloaded directly to an Excel database. So we know that the pupillary light reflex itself is under both parasympathetic and sympathetic nervous system control. So this gray bar denotes the brief light stimulus. The pupil begins to constrict. And we have two important parameters here. The MCV is the maximum constriction velocity. That's the fastest rate at which the pupil is constricting. Then we have the ACV, which is the average constriction velocity. So the average speed at which the pupil constricts. And so the pupil goes from its initial resting diameter to its smallest, the minimal pupillary diameter after the light reflex ends. And then the pupil slowly begins to recover. And the ADV is the average dilation velocity. And the T75 is the time it takes for the pupil to get to 75% of its resting diameter. So all of these parameters are measured automatically and calculated by the pupillometer. And so we recently published some preliminary data on this test as a point of care test for suicide risk, including in patients with depression, but also patients with schizophrenia. And what we found so far is that the average constriction velocity in patients with either schizophrenia or depression is significantly faster in patients who are endorsing current suicidal ideation. This is a small sample of about 70 patients, but after controlling for potential confounds, the average constriction velocity is a significant predictor, about threefold increased risk of current suicidal ideation. In our patients with schizophrenia, these constriction velocities here, the maximum constriction velocity seems to be significantly associated with the severity of insomnia. So more negative scores mean faster constricting pupils. So patients with perhaps higher levels of arousal have faster constricting pupils and those are patients with higher levels of insomnia. So our next steps, we've certainly been vigorously searching for additional funding for this work through both NIMH as well as the American Foundation for Suicide Prevention. And so hopefully with continued work, we'll begin to develop this portable pupilometry as a full-fledged biomarker for suicide risk. At least that's what we hope. With that, I'd like to acknowledge my family for their unwavering support. My lovely wife, Kelly, we've been married for over 20 years now. We have four kiddos. As you can see, they're all awake. Ethan is 18 and just went away to college. Jacob is 15, Drew is 13, and Kate is now eight, going on about 28, I think. So with that, I think we've got about 15 minutes. I see we have probably a number of questions that are being generated, but happy to stop here and try to answer your questions as best as I can. Thank you so much for your time and attention today. I hope this has been interesting and helpful to you in your clinical practice. Thank you so much for such an interesting presentation, Dr. Miller. Before we shift into Q&A in just a moment, I wanna take a moment and let you know that SMI Advisor is accessible from your mobile device. Use the SMI Advisor app to access resources, education, and upcoming events, complete mental health rating scales, and even submit questions directly to our team of SMI experts. Download the app at smiadvisor.org slash app. And now, yes, we have quite a few questions and I've tried to group some of them together. If we don't get to everyone's question, I'll show you at the end how you can submit questions on our discussion board site, and then we can hopefully get back to you on those. All right, so the first one, when you identify depression as a correlate with suicide, this was from very early in your presentation. I'm wondering if that includes bipolar spectrum disorder depression. To the best of my knowledge, I have not seen specific publications on the associations with insomnia and suicide in patients with bipolar disorder, but I have every reason to think that just as it holds true for depression, schizophrenia, PTSD, and other anxiety disorders, I would expect to see similar associations in our patients with bipolar disorder. Thank you. There were three about the RAISE trial that were asking about concurrent meds. So I'll group those all together. This may be a little long-winded. Were these patients under antipsychotic treatments? And then the other said, what medications treatments were they on? For example, were they on antidepressants or any treatment for insomnia? And then were the patients who develop psychosis taking any meds for sleep disorders? So, yeah, so great questions. The publicly available data for RAISE really delimited our ability to investigate some of the concurrent medications. So in terms of, were they on sleep medications? Were they on antidepressants? Can't say for sure. In terms of antipsychotics, if I remember correctly, I think about 90% of the RAISE sample was treated with antipsychotics. So the answer to that is a definite yes, most of the patients were antipsychotic treated. I would presume that there was some degree of use of medicines for insomnia, some antidepressants. And so I would expect that that may have, those medications probably attenuated some of the associations we found in the RAISE sample. Okay. And there was one question from the PROACTIVE study. Yeah. How about controlling for anxiety? Specifically related to associations with insomnia and suicide in the PROACTIVE trial, we did not specifically control for anxiety. We did control for total psychopathology. And in some of the previous studies that we completed, if I remember correctly, if we looked at specific items in the different psychopathology rating scales, the PANS has an anxiety item. And we did find that insomnia was a significant predictor of anxiety as an individual item on the PANS in a number of our studies. So these are certainly, anxiety, depression are certainly important correlates of insomnia. That's to be expected, I think. But it's interesting that in some cases, the link, the association with suicide persists even after we control for kind of those levels of psychopathology. So they certainly, I think they certainly play a role, but there's maybe even more to the story than just that. Okay. Thank you. Does insomnia develop in the start of schizophrenia or does it occur over time slowly? So that's a great question. I think that we see insomnia throughout the entire course of illness. So if we go back to the Naples cohort, insomnia is highly present even in patients showing prodromal symptoms, patients present with their first episode of psychosis and insomnia is a common symptom. And we see it in patients with chronic schizophrenia. So I'm not sure that it so much evolves slowly as I think it can be present throughout. And I think it can be very, very episodic as well, in particular during periods of symptom exacerbation, illness worsening. I think we see a lot of insomnia as driving some of that. And any of us who've taken call overnight in the hospital or been up all night, every night with a newborn child, know that when you're not sleeping well, the world is just not the same place the next day. And we're more on edge and we may feel a little down and a little more anxious. And so I think we can, in that way, kind of maybe relate to or think about some of the experiences that our patients are enduring. Right, right. Okay, there were a couple of questions from the meta-analysis section of your presentation. Yes. I'll say both of them. Sure. Were there any specific suicide pattern in different sleep disorders? And chronic insomnia is significantly associated with increased suicidality by itself. How is this different? So to answer the second question first, it's not specifically different. We were just interested in trying to quantify the magnitude of the association in schizophrenia specifically. So again, we think that this is a very trans-diagnostic phenomenon. And the purpose of the meta-analysis in that way was to just kind of quantify and summarize our available data in schizophrenia. And I'm sorry, can you repeat the first question, please? Sure. Was there any specific suicide pattern in different sleep disorders? Hmm. With the meta-analysis, we focused just on insomnia and we did not look at associations between specific sleep disorders and suicide and the studies overall in general, the associations between sleep and suicidal ideation are pretty numerous. Those studies that have looked at associations with suicide attempt, whether past or prospective suicide attempts are much, much fewer. So I don't know that we really have enough data to kind of adequately inform on some of those associations with specific sleep disorders. And a question related to that, could you define insomnia? How many hours of no sleep is required to meet the criterion of insomnia? Sure. So we have a specific definition for terminal insomnia and the way it's described in the Calgary scale, terminal insomnia would involve waking up an hour or more than is usual for you on a regular basis. Initial insomnia being trouble falling asleep, middle insomnia being awakening throughout the night, off and on. There's not a specific threshold cutoff for the amount of sleep. And so some of this has a subjective component. There's kind of a self-report even with the insomnia severity index, those questions ask patients to rate their trouble sleeping on a five point Likert scale ranging from no trouble at all, all the way to extreme trouble, trouble falling asleep almost every night. But there's not really a specific quantitative cutoff time or number or amount of sleep that's used for those definitions. Great. Okay, there are a few questions about increase in CRH. So I'll read them and see if you can tackle them. Do you think the increase in CRH in chronic schizophrenia patients causes suicide? As in most of the people with high CRH, suicidal tendency is increased. So is there any relationship of CRH and insomnia? And then can we say most of the antipsychotics can develop suicide tendency in patients? And lastly, what if we treat patients with medications that can reduce CRH, this way we can prevent suicide due to insomnia? So interesting questions. I'm admittedly not particularly familiar with the literature on CRH. So I don't know, it'd be interesting to look and see if there are data on CRH levels and insomnia. That sounds like an interesting area for investigation. And so I apologize that my comments there are limited. What I want to say about antipsychotics is that I think in general, does antipsychotic treatment have anti-suicidal properties regardless of which specific agent we're talking about? Overall, I think yes, very much. I think there are data that support the idea that patients who are treated with antipsychotics have decreased risk of suicide mortality compared to unmedicated patients. However, within the spectrum of different antipsychotic medications, I do think that clozapine has the strongest evidence for anti-suicidal properties. And the question that we're trying to get at with our work is some proportion of that variance, if you will, of clozapine's anti-suicidal properties attributable to its beneficial effects on sleep. But we know that within the spectrum of second generation antipsychotics, some are much more sedating than others. And there does seem to be somewhat of a gradient there where agents that are more sedating seem to have less insomnia and seem to have less risk of suicide. But at the end of the day, of course, the best medication for a patient is the one that they will take. And so I really try to employ shared decision-making when working with patients. And if we're selecting a medication, their preferences play a huge role in that selection. Because even if I think, for example, that clozapine might be the best medication for a patient, if they're telling me they're not going to take it, then the game is up. And so I just want to kind of emphasize that, that I do think that antipsychotics in general help prevent suicide, but there may be, by improving sleep, ways to sort of optimize lowering that risk for our patients. Okay, and a related clozapine question. Do you think melatonin along with clozapine would make a significant impact? I think it certainly could. I think it certainly could. And that's one option for insomnia that does have some evidence-based to it. I know that many of our patients somewhat develop a little bit of a habituation to the sedative effects of clozapine over time. And so we may need to add other things. And melatonin is certainly a viable option that has a pretty favorable risk-benefit ratio. It may have some anti-inflammatory properties as well. So I think that's certainly a very viable option. I think one thing to consider with melatonin may be that the over-the-counter melatonin might be one milligram, three milligrams. It may be entirely possible with our patients with schizophrenia and other psychotic disorders that we need to kind of run that melatonin dose up quite a bit higher than kind of the standard over-the-counter dosing. Great, thank you. Okay, how can I get a pupillometer and get training using it? So you can, if you have $9,000 laying around, you can pick one up. So the device is very expensive, but I imagine over time they're designed not for commercial or diagnostic use, but really primarily designed for research purposes. So we've been fortunate to be able to secure that. So in the absence of having an expensive pupillometer, my clinical advice here is do lots of psychoeducation about sleep hygiene, ask patients about their current sleep, hone in on insomnia. And if you're finding that patients are telling you that their sleep is getting worse, then that in and of itself can be a very valuable clinical indicator of this is somebody that maybe, especially if they have a history of prior suicide attempt, that I need to be a little bit more worried about their risk right now, and I need to be aggressive about trying to get them sleeping better. So hopefully one day these instruments are more widespread and we can use them prime time, but for now there's still value in taking a very good and careful history. Great, okay, I believe that is all the time we have time for questions that we have. I have a few more slides about resources and then we will wrap up. Sure. Okay, so if there are any topics covered in this webinar that you'd like to discuss with colleagues in the mental health field or questions that we did not get to today, please post a question or comment on SMI advisors discussion board. This option is located within this activity when you're logged in and will be available after you have completed this activity. This is an easy way to network and share ideas with other clinicians who participated in this webinar. If you have questions about this webinar or any other topic related to evidence-based care for SMI, you can get an answer within one business day from one of SMI advisors, national experts on SMI. This service is available to all mental health clinicians, peer support specialists, administrators, and anyone else in the mental health field who works with individuals who have SMI. It is a completely free and confidential service. SMI advisor offers more evidence-based guidance on suicide prevention, such as the resource, Suicide and Serious Mental Illness, an overview of considerations, assessment and safety planning. This resource will provide an overview of the considerations and suicide prevention measures at the intersection of suicide and SMI. Access the tool by clicking on the link in the chat or by downloading the slides. To claim credit for participating in today's webinar, you need to meet the requisite attendance threshold for your profession. After the webinar ends, please click continue to complete the program evaluation. The system then verifies your attendance for credit claim. This may take up to one hour and can vary based on local, regional, and national web traffic and the usage of the Zoom platform. Please join us next week on September 14th as myself, Donna Rowland, Megan Aratt, and Kate Hanley present Expanding Your Lung-Acting Injectable Antipsychotic Medication Toolbox. Again, this free webinar will be on Thursday, September 14th from 3 to 4 p.m. Eastern time. Thank you all for joining us and until next time, take good care.

insomnia

hyperarousal

suicide

psychosis

schizophrenia

psychotic disorders

pupillometry

biomarker

sleep disturbances