We want to welcome you to the first day of the APA. My name is Ira Glick. I'm sitting here with two distinguished professors, Dr. Carl Salzman from Harvard and Professor Dr. Sid Zizek from UC San Diego. This, I think, is going to be a very important session. The reason is we all hope to change how you think about doing clinical practice of psychiatry. And the change that we are looking at is don't think about just getting good psychotherapy and psychopharmacology and whatever else for your patients. But to think of this, to think of your practice now like the rest of medicine, that is we now have treatments for virtually every disorder in psychiatry. And we no longer think of treating people, having them do better, and then stopping medicine when they're doing better. What the purpose of this session is, and I've got a guy in the audience, Professor Stefan Leut from Munich, who's been a champion of this. The purpose of this is to look at lifetime treatment of psychiatric disorders, not stop quickly. We now know that long-term treatment is better than short-term for most, not everybody, but for most people. And the way to think about this is think like diabetes. These are chronic, genetically caused illnesses that show up at different points in life, teenage, early 20s, and they don't go away. I see some nodding heads. And therefore, you have to think about how long to treat, like you would think about how long to treat in diabetes. And right now, what I want you to do is think how you treat patients with psychiatric disorders as you hear for the world's experts in anxiety disorders, Dr. Salzman, Dr. Zisek, depressive mood disorders, and me a little bit with schizophrenia and psychotic disorders. Everybody clear? Any questions? Anybody want to fight? No? OK. All right, so our first presentation is Dr. Carl Salzman, who's going to speak on long-term treatment of anxiety disorders. And remember, don't yell at him. He's very shy. Thank you, Ira, and good morning, everybody. And it's a privilege to be on this panel. I've known Ira longer than I care to remember. And Sid and I go back at least several decades. So I'm going to talk about anxiety. Presumably, everybody in this room is an experienced clinician, so it's not likely that I'm going to say anything that you don't already know. But I think that Ira's introduction is correct, that we do know that for a number of our disorders, including anxiety disorders, they're chronic. They may come and go, but they often persist throughout life and sometimes intermittently. And then when they recur, they're a little bit worse. So let's just set the stage with a little bit of data. It's nice to have some data. Forty to 60% of our patients are unchanged during their illness. And the majority of patients who have a generalized anxiety, panic, social phobia, are the same as they were 12 years earlier. Patients with social phobia are less likely to improve in this period, and the recurrence rates were very high for GAD. This should not be news to any of us who treat these patients. Now, I also want to be clear as we move along, we're talking about real anxiety. We're not talking about worry. I mean, we all have things to worry about. And worry, discriminating between worry and clinical anxiety sometimes is difficult, but we want to be sure we're talking about a diagnosable disorder. Now, we also are aware that anxiety is very common as a comorbid psychiatric disorder. It's very common with other anxiety disorders such as social phobia and panic. And it's also very highly comorbid with affective disorders, particularly major depressive disorder. And in these cases, anxiety disorders are chronic, with low rates of recovery and high rates of recurrence. Now, the long-term treatment of anxiety is sometimes thought of as not as critical as, frankly, depressive disorders, but it may be part of a depressive disorder and contribute to a substantial burden in the quality of life. And again, I think all clinicians are aware of this. Patients who are chronically anxious really suffer, and it cripples their lives, constricts their lives, and makes them vulnerable to lots of other things, including medical illnesses as well as affective disorders. So a substantial percent of our anxious patients have a long-term course, probably through much of their life. It may fluctuate, but it is there, and they will tell us that as they go along. Now, not everybody who worries needs treatment for anxiety. As I said, we're all warriors. The world is a worrisome place right now, and sometimes people may need treatment, but not necessarily pharmacologic treatment. It's when the symptoms get serious enough to persist and interfere with daily living. That's when we may turn to our pharmacology as part of other treatments as well. So we know that non-pharmacologic treatments can be helpful. We know about CBT, DBT, even dynamic psychotherapy, family therapies, et cetera. But relapse is common in the anxiety disorders. 20% to 50% of patients with chronic anxiety will relapse. When they stop their medication, Ira's point, stopping medication for patients with chronic disorders of anxiety invariably leads to relapse, and the patients who are at risk for relapse should be maintained on their medications for as long as possible, or at least comfortable to them. Now, long-term treatment is common with medication. Panic disorder, for example, and phobic avoidance may require a year before it's brought under control, but will recur if a patient stops their medication. Now, we know that antidepressants as well as anti-anxiety drugs are good for panic and phobic avoidance. It doesn't necessarily require benzodiazepines, although we'll come back to the benzodiazepines in a little while and talk about how useful they really are. You might note at the bottom of the whole list of SSRIs, but also MAO inhibitors. Now, I don't know how many of you are still using MAO inhibitors, but I would encourage you to try them out. They are extraordinary drugs, particularly for panic disorder and phobia. You can save a person's life. If I may be permitted to have a vignette. A young man, a very nice young man in his 30s, married with children, was rising in his business. The business required him to travel, so locally around Boston, his wife would be in the car with him, so he was able to do it, but pretty soon he had to go away from Boston, and he was terrified he'd get a panic attack on a plane, driving through the tunnels, et cetera. He tried a whole bunch of medications. Nothing really worked. We put him on some phenylzine and just a tiny bit of a benzo at bedtime, and the panic stopped, literally stopped. This is one area in which we can actually almost cure, as long as the patient doesn't stop the medication. So he then did well in his business, and I would see him two or three times a year just to check in. Several years later, I was flying to this meeting in San Francisco, and I was getting up to go to the bathroom on the plane, and from the back of the plane, somebody comes running up, and it's him, and in front of everybody on the plane, he hugs me and says, thank you very much, look at what you've done. I am now the president of the company, and I'm going out to give the talk, and it's all because of you, and everybody in the plane sort of clapped. Obviously, one case, but it was very vivid, and I would suggest you consider MAO inhibitors, along with other things that we'll get along to in just a few minutes. So now, there are data which can show us just how bad relapse rates are, okay? And I want to go directly to the next slide. So this is the probability of recurrence on the ordinate, and if you look, you could see that the highest is patients who have anxiety with major depression. They have the highest probability of recurrence if they stop their medications, but everybody has a risk of relapse if they stop their medications, and at best, 50% of the people don't relapse, but 50% do, which is an enormous number of people. If we look at recovery during chronic treatment, and this is on the ordinate, the probability of recovery, so the top lines are good rather than bad, as in the previous slide, we can see that at the bottom, social phobias and panic and GAD, are the least likely to recover, but when you combine the antidepressants and anti-anxiety drugs, the probability of recovery goes up to about 80%, and we've known that clinically for a long time. It's nice to have some data to support that. Now, to talk about the drugs specifically, just to remind you that there's a great history of pharmacology of anti-anxiety drugs coincident with my own presence in psychiatry, beginning with in the 1960s when I was a resident and right up to the present time. Before benzos, people treated anxiety with opiates, barbiturates, the drug Miltown, if you remember, Miltown, meprobamate, what Ogden Nash called under the spreading atrophy, and these were used for GAD as well as for anxiety. And then the breakthrough came with imipramine for depression and amitriptyline for depression, and the first of the benzodiazepines, Librium, chloridase epoxide. Librium was very quickly replaced by valium diazepam, which became the number two drug prescribed in the world in the early 70s. Anybody know what the first one was? It was tagamine, which is an illness that your stomach ulcer might have some anxiety in it as well. So valium became very commonly used, and then there was a concern about overuse of valium, and there were books and newspaper articles about it. I'm sure you're aware of those, even movies showing people who are overly dependent on these drugs, Mother's Little Helper, The Rolling Stones. So these drugs both were a great gift but also a worry. And then Xanax came along in the 1970s, Alprazolam, clonazepam around the same time, maybe a little bit before, and these drugs began to be used for panic and social anxiety in higher doses than for daily anti-anxiety properties and are still used today. There's abundant evidence that high doses of Alprazolam or clonazepam can be very therapeutic for panic disorder, phobic avoidance disorders. The doses are about 10 times higher than what we use for generalized anxiety. So instead of 0.5, two or three times a day, it may be three to six milligrams a day. And that obviously raises questions of side effects and safety, which we'll talk about in a minute. Then the SSRIs came along in 1987, 88. Prozac was released for use, and for those of you who remember those days, it was like a miracle. Suddenly we had this drug that didn't have the side effects of tricyclics, didn't have the worry of benzodiazepines, and it seemed to be the drug that treated people with these kind of chronic disorders. It was wonderful. Of course, we didn't know about all the side effects of the SSRIs, but it was wonderful. But these drugs continue to be one of the mainstays of long-term treatment of chronic anxiety disorders. Okay. So what I'd like to do is spend a little bit of time talking about benzodiazepines. And those of you who've heard me before know what I'm about to say. And in terms of fighting, it may well be that we're gonna have some arguments about this. Just to state it at the beginning, I am a benzo lover. I think these are terrific drugs. I think these are safe drugs. When appropriately used for appropriate patients, I don't deny the side effects, the dependence, and the possible use by substance abusers. All true. But if you take those and put them in a little package over there, and in our package you have patients with a chronic anxiety disorder, these are terrific drugs. And this is just to show a list of all the data that would support that statement. Now, currently, we use benzos for anxiety, and I'm not now discriminating between GAD and the other subcategories. I'm talking about the clinical experience of an anxious patient who's really coming and saying, doc, you gotta give me something because I can't sleep, I can't function during the day, I'm worried all the time, et cetera, et cetera. So these drugs are now still widely used, maybe too widely used in some cases for GAD. They're widely used as add-on drugs for other anxiety spectrum disorders. They're widely used as adjuncts to antidepressants, and we'll look at some data for that. They're used for sleep, and that's a little bit more controversial, and that raises the question about the Z drugs, which I'm not going to be talking about this morning. And then there are some people that we think probably who are psychiatric patients probably should not get benzos unless absolutely necessary, and these are patients with bad PTSD and personality disorder, patients who may be a little bit irresponsible in how they use medication. Benzos are very good for panic disorder. I made a case about MAO inhibitors, but in fact the same thing is true for alprazolam and clonazepam. And if you're going to use these drugs, and I do, for panic disorder patients, I ask my patients to keep a record of how many they're taking every day. I say, listen, after you've brushed your teeth at night, before you get into bed, close your eyes, just make a note of how many pills you took during the day and keep that running. And my patients seem to like doing that. They often do it on a computer. And then they bring me the list, and you can see they're taking three, three and a half. Occasionally I'll jump up to four milligrams. Why? Because they're giving a lecture at the APA, and then it goes back down to 3.5 or three. But by and large, they stay at a steady dose level. They don't drink, or the instructions are, benzos and alcohol don't mix, but if you want to have a glass of wine on Saturday night with dinner, that's okay, but that's it. And never drive and take a pill and drink, never. Okay, and that seems to work out very well. These drugs are combined with antidepressants and also with other forms of anti-anxiety treatment, namely CBT and even DBT. Now, what is the problem with using these drugs over a long period of time? Long-term users, as I've said in the beginning, have clinically significant symptoms. They may have other psychiatric disorders. They may have medical disorders. They may have both. Do they, in fact, increase the doses over time would be a suggestion of tolerance? And the answer, believe it or not, is no. We actually have known that since the 1960s and 70s when there was what was called the Cross-National Panic Disorder Study out of NIMH, which showed that patients taking high doses of Alprazolam actually gradually decreased the dose over years, period. And I can't give you the citation because it's still under review, but there is a paper now that with a very large population base which suggests that doses of benzodiazepines given chronically actually go down over time, not up. Okay, now, it is true that people wanna stop their benzodiazepines, and therein is a separate story because these drugs do produce a physiologic dependence. We'll get back to that. But you can't make a case, in my opinion, you can't make a case that these drugs cause the opioid epidemic or other substance abuse. They are part of it because benzodiazepines work at the gamma chloride ionophore that interacts with the mu opioid receptor, and so people who are taking opioid substances find that benzodiazepines actually enhance their experience and also ease the crash. So there's no question that these drugs are part of the opioid epidemic, and that's bad, but that's not what we're talking about, and it's not the patients we're talking about. I would advise, or what I would do is if I have any sense that the patient is a potential substance abuser, how do you do that? Well, the patient comes to Boston and says, Doc, I just moved to Boston, and I'm out of my, out of hand, you know, my prescription from Colorado is run out and I can't get anymore. Red light goes on, or the dog ate my prescription, you know, that sort of thing. You watch out for that. You can often get a body language hint as well. Now, it's absolutely critical that we're honest about these drugs and there are side effects and risks. So first of all, as I said at the outset this morning, not everybody needs medication. But a lot of people in this troubled world right now are very unhappy, struggling, and don't have the capacity to solve some of life's problems. And they come to their primary care doc who throws up their hand and refers them to a psychiatrist. And the poor psychiatrist, this is a true story, his waiting room is filled with patients demanding Klonopin, almost to the point of physically fighting if they don't get the Klonopin. This poor doc is, like many people, an emergency room, overwhelmed. Now, that doesn't mean that this is appropriate use to give these people benzodiazepines. What I suggested to this particular doctor is hang up a sign on your wall which says this doctor does not prescribe Klonopin for any reason. 50% of the people disappeared and he then had a useful practice because he could help the remaining people. And that happens in emergency rooms too. People will come in and demand. So these are the patients that we want to watch out for. Abusers, personality disorders, PTSD, and patients who are really struggling as many people are and it's getting worse. Okay, now, some people use benzos, as you gather from my comments, to cope with life's stresses. And you can't. Five minutes, go. I'm getting anxious. I think I'm anxious. I've known Iris for so long, when he says five minutes, he really means another half hour. Okay, so people want benzos to cope with. But we have to really carefully decide whether to prescribe or not. And if we do, we probably ought to prescribe small amounts, non-renewable, and follow the patients closely. And there are some patients who take benzos and then don't want to stop because they feel so incapacitated by their struggles that they can't give it up. So they say they're hooked and they're both angry about being on these drugs, but at the same time don't want to give them up. Now, there are side effects. I'm not gonna spend any time. You know the side effects. These are sedative-hypnotic drugs. They share the same side effect profile as all sedative-hypnotic drugs. These drugs, like sedative-hypnotic drugs, produce a physiologic dependence. It depends on dose. It depends on how long you've been taking. So it's the dose times duration. And the risk is highest in people who have been, they're in self-help groups because they have been dependent on other substances like alcohol. And the severity of the withdrawal symptoms will depend on how long they've been taking the drug and the doses and the rate that they discontinue the drug. And I want to make the case that it is possible for people to get off their benzodiazepines, but in most cases, if they've been taking it more than just for a couple of weeks or a couple of months, you need to do it very slowly. Okay. So then there's the half-life issue, short half-life drugs will produce a withdrawal syndrome, a discontinuation syndrome quicker than a long half-life drug. So sometimes people will shift over to the long half-life drugs, but you're gonna get a withdrawal syndrome from clonazepam and diazepam as well. Okay. So, there's, just to summarize about benzodiazepine, therapeutic doses are prescribed to appropriate patients who are appropriately screened. These are safe and effective drugs and should be used. But I think there's a hysteria going on in medicine and psychiatry so that people just don't want to prescribe benzodes because they're afraid of all of these things. And so patients are being under-medicated both acutely and for long-term. Now, the other side of it is that antidepressants have now taken over from benzos for the chronic treatment of anxiety. And there's a lot of data showing that SSRIs do have a long-term effect on decreasing anxiety, but they're not as good as the benzos and it takes a while. So I wanna just show you some data here and then I'll be able to stop. The dark lines are the treatment of panic and generalized anxiety over a 10-year period. And the little shaded is the rise of SSRIs. So one can conclude that indeed SSRIs are being more frequently used for treatment of chronic anxiety disorder, but the benzos have not stopped. That in fact, the modal patient who's taking an SSRI for their anxiety is also taking a benzo, probably for sleep or maybe occasionally for daytime anxiety. And that's probably okay. So we now would say that the first choice treatment for panic and other anxiety disorders would be the antidepressants with benzos as a backup or maybe a small augmentation. And we have lots of evidence for antidepressant efficacy for this kinds of anxiety. And here you can see imipramine and alprazolam for panic. And this is the old study done a long time ago, but it still holds up. Both drugs work more or less equally. Now, as Ira indicated in the beginning, the point of this whole talk is if people have chronic anxiety, they should stay on their medication. And if they insist on stopping, whether it's antidepressants, benzos, MAO inhibitors, whatever, they should do so gradually under medical supervision. Do it, ask them to do it with you. And in most cases, you can get people off these drugs, but that may not be what is needed because as we've heard, both from Ira and these data, anxiety disorders are recurrent and chronic. And it may well be that patients do very well on low doses of these drugs over the course of a lifetime. And I would imagine that many people in this audience, like myself, have patients who religiously take their benzo or other drug at the doses, never more, don't mix it with alcohol, don't give it to anybody else in the family, and find it very useful. So I think, Ira, I'll stop there, trying to make the point that you beautifully introduced us to. Thank you. Thank you, Carl. I mean, for me, I'll say I know you a lot of decades, but it's worth the whole meeting to hear the expert word on treating these very difficult disorders over a lifetime. I know APA wanted us to do this as interactively as possible. I've broken Dr. Salzman's arm, and we'll stick around at 12 o'clock for questions. So we'll be here. Okay, next presentation, as I said, is Dr. Sidney Zizek from UC San Diego, who's been a leader in doing controlled studies of long-term treatment of mood disorders with medication and psychotherapy. So let me now bring Sid on for this overview. Thank you. Just a couple quick comments on Carl's talk, if I can open this. One is that if you were to say you're a benzodiazepine lover out loud again, to anyone who's trained in psychiatry in the last two decades, they would either say, at best, that you're misinformed and naive, at worst, that you're evil. So we have our work cut out for us, because I agree with you. And also, my best friend, who's been on antidepressants for chronic depression for more than the last three decades, daily use, who's a psychiatrist and knows the literature well, whenever he talks about getting his refill, he mentions he needs his refill for his anxiety medications. So that goes to show that the boundaries between anxiety and depression are a little more porous than we often think. So everything Carl said in the last half hour applies equally well to what I'm gonna talk about in terms of depression. And I must say that long-term treatment of depression is the bread and butter of what I do in my practice, and that's probably true for many of us. Yet I wasn't sure how much of my practice is really consistent with the best evidence. So when Ira asked me to give this talk, and I've never given this talk before, I thought, well, I'll go into the literature and see what the literature says. And I ended up with almost as many questions, if not more so, after reading the literature as I did before. But I thought what I'll do with you is to a large extent share that literature as well as sharing some of my lingering questions about what the evidence tells us. And, okay, good, that works. Um. All right. We'll skip that. Why worry about it? You know, we've already heard. Depression is, tends to be a very chronic and or recurrent disorder. For many people with depression, it's a lifelong disorder, which is associated with substantial suffering morbidity, comorbidity, mortality associated with it. And treatment clearly makes a difference, yet we don't have as much data about what to do after the first six to eight weeks of treatment than we do for the rest of that person's life. And again, it's the rest of that person's life that is what we do in our offices every day. So it makes a difference. Just a quick reminder, this is a slide many of you have probably seen many times over, about the phases of treatment. And phasing from when you're doing well into the acute treatment period, which is measured in weeks. The idea of the acute treatment period is to get someone to respond to the treatment, get better, and ultimately remit, become asymptomatic. But that acute treatment isn't enough. All guidelines say the depression is still there, even if they're doing better. Treat through the natural episode of that depression, meaning treat for another four to six months. We call that the continuation phase. And for many people, that's not enough. They need longer term, if not lifelong treatment, the maintenance phase, which is measured in years. The five hours response, that's getting better. Remission, becoming relatively asymptomatic. Recovery, being relatively asymptomatic for at least a couple months. And functioning, back to one's norms. The bad hours are relapse, which is an episode occurring during the continuation phase. Before that episode is really done with in terms of its natural history. Recurrence is a new episode occurring during the maintenance period. So that's our vocabulary moving forward. I'm gonna start with some cases. Case one, for which of the following patients is a trial of discontinuation of antidepressant medications appropriate? What's the best answer? A, 30-year-old male in his first lifetime episode of major depression who's now asymptomatic after taking his medications for three months. B, 50-year-old female with depression and an anxiety disorder in her fourth episode of major depression who's taken six months of medication and is now asymptomatic. C, a 40-year-old male in his third episode of major depression who has taken medication for 12 months and is now asymptomatic. And D, a 40-year-old female in her first lifetime episode of major depression who's now asymptomatic after taking medications for 12 months. So I won't embarrass you or force you into voting and we don't have those clickers. So think to yourself which is the right answer here and we will come back to that in just a minute. But part of the answer, or if not the whole answer, is embedded in the APA guidelines for the treatment of depression. Note these guidelines have been around for a while. They haven't been updated in over 20 years but they're still pretty accurate. And in the guidelines, one, in order to reduce the risk of recurrent depressive episodes, patients who have had three or more prior episodes in their lifetime or who have chronic major depressive disorder should proceed to maintenance phase treatment after completing the continuation phase. They don't say how long the maintenance should last. We don't know. There is no literature on how long that should last but we will come back to that. Maintenance therapy should also be considered for patients with additional risk factors for recurrence such as continuing with residual symptoms after the acute or continuation treatment period. Ongoing psychosocial stressors. So if a medical student develops a depressive episode in the context of having failed their board examination, a year later they face the repeat board exam, that's not the time to stop the medication. So psychosocial stressors are part of what we think about in terms of when we stop. Early age of onset, somebody whose first depressive episode occurred during childhood or adolescence is more likely to have more recurrences and they should be treated for a longer period of time. And family history of mood disorders. Additional considerations according to the APA guidelines that may play a role in the decision to use maintenance treatment include patient preference which is critically important in this. They, you know, having patients help us manage their own diseases and their choices in terms of how long they will stay in meds or when they may want to discontinue is an important part of those considerations. The type of treatment received, the presence of side effects. So the more side effects you have during maintenance, the more likely you are to try to taper somebody and see how they do without it. Frequency and severity of previous episodes. Suicidality associated with previous episodes. Co-occurring disorders, et cetera. The guideline concludes with the ideal length of maintenance treatment is unknown. For many patients, particularly for those with chronic and recurrent major depressive disorders or co-occurring medical and or psychiatric disorders, some form of maintenance treatment may be required indefinitely. So if we come back to patient one, based on the APA guidelines, the correct answer is D, okay? The 40-year-old male and the 50-year-old female with recurrent episodes of major depression will benefit from longer or indefinite treatment. The 30-year-old male with the first episode who is now asymptomatic after three months has not completed the recommended length of continuation phase treatment. The 40-year-old female with her first lifetime episode of major depression who is now asymptomatic after taking 12 months of medication is the only possible candidate for a trial of discontinuation at this point but still needs monitoring and education regarding relapse. VA guidelines, much more recent, they came out last year, are very similar to the APA guidelines. But one of the things the VA guidelines have done is they've upped the ante in terms of the value of psychotherapy in long-term maintenance. And I'll just read the second paragraph here. For patients with major depression at high risk for relapse or recurrence, for example, two or more prior episodes, remember the APA said three or more, VA now based on newer data says two or more is enough to think about maintenance treatment. Unstable remission status, residual symptoms, et cetera. We suggest offering a course of cognitive behavioral therapy, interpersonal therapy, or mindfulness-based cognitive therapy during the continuation phase of treatment, that is after remission is achieved, to reduce the risk of subsequent relapse and recurrence. So they don't recommend starting with combination treatments. They recommend start with an antidepressant if the person still has residual symptoms or in their one of the high-risk categories, then consider sequentially adding a psychotherapy to help prevent relapse. The evidence does not support recommending one of these three evidence-based psychotherapies over another. That's the VA guidelines. All right, case two. Your next patient is a 50-year-old married accountant who has a first episode non-psychotic major depression. You treat him with citalopram, titrating him from 20 milligrams up to 60 milligrams over a 12-week period of time. At the end of that time, he feels better, but he still has some residual anxiety, low energy, okay? They haven't totally gone away. He does not wish to increase or change medications. Let's leave good enough alone. Feeling better than he has for a long time? Doesn't wanna change that. You agree. You continue him on the same medication, meet him monthly over the next year. What's the likelihood of relapse for this man during that year? A, 10 to 30%, B, 33 to 60%, C, 61 to 80%, or D, he's doomed, 80 to 100%, okay? So think to yourselves what you would give as the answer here. And, oh, I'm gonna go back a second. This is a little too, all right. The answer is C. And 61 to 80, and in this case is the STAR-D algorithm, and many of you may remember what STAR-D was. Everyone at level one who had a major depression, non-psychotic, appropriate for outpatient care, got treated with citalopram, and the dose was pushed as needed up to 60 milligrams over a 12 to 14 week period. And then if they did well with that, they went into long-term follow-up for a year where they were seen monthly during that year follow-up and encouraged to continue on that same medication. So this is the STAR-D algorithm for level one. This patient had some residual symptoms, wasn't in full remission, but good enough for him. Went into follow-up. This is the data from likelihood of relapse during follow-up. So after level one, just the citalopram treatment, the SSRI, the likelihood of relapse within a year, even though they were continued followed, continued encouraged to take medication, was 40%. The likelihood of relapse went up considerably at each different level of STAR-D, where if the person didn't do well and they were either augmented or switched to something else, they did okay. During their year of follow-up, their rates of relapse was higher, and so on through the four levels of treatment. And what this slide shows is there was a difference, though, between those who went into follow-up in remission versus those who went into follow-up better, but not in full remission. And the group that went into follow-up better, but not in full remission, had substantially higher rates of relapse within that year follow-up period. At level one, 60% versus 33.5%. So the idea is push hard for remission, optimal treatment early on, which not only helps the person feel better and enhances their quality of life, but also carries a much better prognosis long-term in terms of preventing relapse or recurrence. So even after remission, though, relapse rates are still high. And we've known that forever. Kreplin, more than 100 years ago, said that one of the characteristics of major depressive disorder, he didn't call it that, but of depression, is the tendency to multiple repetitions. Abraham Lincoln, who we all know suffered from a mood disorder, maybe bipolar, maybe depression. Sometimes I can feel the downward spiral. The worst part is when I know I am getting bad again, but could do nothing to stop it. I just want anything, everything to stop hurting. I want to stop hurting. Lincoln lived before the SSRIs, even before omipramine and Elevil, but was well aware of this being a highly recurrent disorder. And Jules Onk said single episodes are extremely rare if the period of observation is significantly extended. And we've learned with good data how true that is. Case three, your next patient is a 34-year-old woman who had a moderately severe major depression lasting about three years before she finally consulted you to get some help. You recommend antidepressant medications. When weighing her decision about whether she wants to agree with your wise recommendations, she asks you, what is her prognosis over the next few years? Which answer is most correct? No matter what treatment you recommend, there's about an 80% likelihood that it's going to persist or recur over the next three years. B, although medications will help in the short run, they're really not going to affect the long-term prognosis over the next three years. C, women are more likely to get depressed than men and more likely to have recurrences than men. D, risk of recurrence is greatest in those with relatively mild depressions. Or E, risk of recurrence is greatest in those without psychiatric or physical morbidities. Again, think to yourself, which of these is the correct answer? Most of us won't say D or F. But A, B, C probably has maybe some relative equal distribution here. The correct answer is C. Women are doubly hexed here in terms of not only being more likely to get depressed, but more likely to have recurrences of depression once treated. And the data for that, a lot of it comes from what I call one of the oldies but goodies, one of my favorite studies in this field, is the National Epidemiologic Survey on Alcohol and Related Conditions, which gives us a good look at the natural history of depression over time. There were two waves in this study, if you remember how it was done. One wave where patients were interviewed between 2001 and 2002. And the second wave three years later, 2004 to 2005, looking at how many people had depressive disorders, whether it got better, whether they recovered, whether it persisted, whether it got better, and then had a recurrence. Persistence was defined as meeting full criteria at wave one and throughout the entire three year intervening period. Recurrence was defined as meeting full criteria at wave one. And again, during the last 12 months of wave two. The 12 months, some of the epidemiologic data that came from that, 12 month prevalence data of depression was 5.3. Higher in women, higher in Native Americans, higher in those who were widowed, separated, or divorced. Lifetime prevalence of over 13%. Nearly half of those with depression wanted to die. Over a third thought of suicide. And almost 9% reported a suicide attempt. Keep this in mind as we talk about long term management of major depression. That will be my last slide, actually. And for those who had a depression, the mean of 4.7 episodes was reported with a median duration of about 24 weeks. So that's the epidemiology. Prospect, of course, based on that study, a third of those individuals with a major depression at wave one had either a persistent or a recurrent major depression at wave three. So in this kind of naturalistic, long term study, at least a third had persistent, 16%, or recurrent, 21% major depression. The persistence was predicted by several things, including childhood sexual abuse and early onset. And the graphic is just a graphic of people in the full sample who had childhood sexual abuse, a little less than 10%. Those with major depression, twice that many. Those with chronic major depression, even a higher history of sexual abuse. And those who had persistent depression during that entire three year period had very high rates of sexual childhood abuse. Much higher than we would think about. This is horrifying data. But it really begs the question of if you're taking a patient on for either short or long term care, get a good history. Find out about early childhood experiences. Because they're going to color the prognosis. And they're also going to color the kind of treatment that will maximally benefit that person. In older adults, persistent mood disorders were predicted by physical and mental comorbidity. Financial, and economic, and interpersonal stressors were related to relapse. A wave one panic attack predicted the incident of suicidality. But not necessarily whether or not they ended up receiving treatment. Let me go to the last bullet here. The last one, about 5% with major depression transitioned to bipolar disorder by wave two. So that's another consideration in long term management. And that was predicted also by a history of early childhood abuse. Those with childhood abuse were more likely to switch into bipolar. Anxiety disorders increased the likelihood of switching. And recent disruption of social supports and financial problems was also associated with switching. This is another way of looking at all the data from that study. Looking at a large number of potential risk factors. And whether they predicted persistence or recurrence. Because Ira is going to kick me off of here in another 10 minutes, so I won't go through all of this. Five minutes. The strongest predictor of persistence and recurrence in individuals were the severity of depression, the initial severity, the severity of comorbidity, and most important, failure to seek treatment at wave one. So again, this was a naturalistic follow up study. I'm going to skip that. A lot of patients failed to receive treatment. Only about 20% with major depression entered treatment. And those who didn't were way more likely to have both persistent and recurrent depressions. Case four. A woman previously seen decides to take antidepressants and has a full remission lasting two months. Because she would like to discontinue her medications, she again queries you about long term prognosis. Which of the following is most accurate? A, almost 80% of those who have recovered will most likely have at least one subsequent episode during 10 years of follow up. B, almost 100% of those who have recovered will most likely have at least one subsequent episode during 10 years of follow up. C, the duration of each subsequent episode will likely be longer than the preceding one. Or D, married women have a greater number of recurrences than unmarried women. How many of you say yes to D? Correct answer. A, about 79% of people who have recovered will likely have at least one subsequent episode. And if you've had one, it's more likely you've had three or four during that period of time, actually. And this comes from another oldie but goodie study. The National Institute of Health Collaborative Program in the Psychobiology of Depression, where patients were initially treated for 16 weeks randomized to either cognitive behavioral therapy, interpersonal therapy, imipramine, or placebo. And then a natural follow up period of 18 months. And I might say, for the initial treatment, actually imipramine did very well. The antidepressant actually beat cognitive behavioral therapy for that initial period of treatment. But our interest here is what happens after the initial treatment over the next 18 months. And over the next 18 months, the rate of recovery, as defined by eight weeks of minimal or no symptoms following the end of treatment and remaining well during follow up, 30% for CBT, 26% for interpersonal therapy, 19% for imipramine, 20% for placebo. So none of the treatments, including placebo, given acutely beat the other, including beating placebo, at 18 month follow up. All of them had relatively low rates of recovery. Among patients who recovered, the rates of relapse were 36% for CBT, 33% for IPT, 50% for imipramine, 33% for placebo. No, these were not significantly different numbers. So there was no winner in this. But what we have here is low rates of recovery and high rates of relapse during this 18 month period. And as you might guess, the conclusion is that 16 weeks of treatment simply isn't enough, that you need longer term treatment. And the biggest predictor of non-recovery and relapse during this 18 month period were really people who didn't take treatment, didn't accept treatment. A 10 year follow up, that same data, found that only 12%, even after five years, had not had an initial recovery. 79% recovered at some point during that 10 years, but subsequently had at least one additional major depressive episode. Some people developed mania during that period. And most of the patients did not have very good prognosis during that period of time. And again, the treatment and optimization of treatment was a major, major contributor to non-recovery and relapse. 15 year follow up of that same data. By this time, 85% had experienced a relapse. So Angst was right. The longer you follow, the more you're going to see people having recurrences of their disorder. The predictors of recurrence, women. Longer prior episodes, never having been married. And of those who experienced a recurrence, 77% were taking no antidepressants in the month before the recurrence. So long term treatment. Case five. Your next patient's a 50-year-old man with recurrent episodes of moderately severe major depression and a history of recurrent episodes. His symptoms remit after several weeks of combined treatment with interpersonal therapy and antidepressant medications. He remains well over the next four months. Which of the following treatments is most likely to result in lasting remission over the next three years? Continuing antidepressants at about 50% of the dose that he used to get well. Continuing antidepressants at the same dose he needed to get well. Monthly IPT, interpersonal therapy, placebo meds. Or just monthly therapy without placebo meds. Or placebo meds. So those are the five choices. Which is most likely to result in a lasting good prognosis? And the answer is B, continuing antidepressants at the same dose. A subsequent study, after the one quoted here, looked at 50% dose versus same dose and found he really needed the same dose. This is a graphic of that study. And what we see here, I'll wind it up in a minute, is that the top two bars are the people who continued on imipramine, on antidepressant medication. The top bar, the red line, is also getting psychotherapy. And what we see is initially the combination did far better. People got better with the combination than imipramine alone. But over the three year period, just staying on the imipramine, whether or not you started with the psychotherapy, was very effective in terms of reducing the likelihood of relapse or recurrence. The middle two lines represent those who stayed on, who had the interpersonal psychotherapy. And what we see is they did better than placebo. So they delayed the onset of relapse or recurrence. But they didn't do as well as staying on the antidepressant medication. I'll say, because Ira's going to kick me off of here in a minute, there's been some meta-analyses that do suggest that starting with psychotherapy has a protective effect, and in the long run, is as effective, and in some studies, more effective than starting with an antidepressant in terms of relapse. But it's an open question still in terms of how long lasting the effect of psychotherapy is compared to staying on antidepressants during that entire period. So I'm going to skip the rest of the data on this, because what I want to get to now is two things to consider in long-term management. One is discontinuation symptoms, which occur not with the same degree and robustness as Carl was talking about with stopping anti-anxiety meds. But if somebody's been on antidepressants for months or years, they often experience difficulty tapering the medications. Flu-like experience, such as nausea, headaches, lightheadedness, chills, body aches, not uncommon. Neurologic symptoms, such as paresthesias, insomnia. Electric shock phenomena, which I thought was a bunch of hokum when I first read about it. But subsequently, I've had two studies where we've had to taper people off antidepressants that I've been involved in. And at least 5% to 10% of people do have these electric shock-like experience. It's a real phenomena that's very uncomfortable and may last for days to weeks after stopping a med, particularly shorter-acting meds, like Efexor or Paxil. So taper slowly over weeks for most people, and for some people, maybe even over months to help keep them comfortable. Is psychedelic therapy the answer? And just in brief, there's some good data that psychedelics can affect lifelong changes in the way people look at the world, in kind of feeling oneness and connected to the world around them. Is that true of psychedelics for the use of treatment of depression? We don't know. There's a suggestion. This is the data from the largest controlled trial yet of psilocybin therapy for treatment of depression. And we see 25 milligrams was a very effective dose within a day of the treatment. And even 12 weeks later, still had substantial benefits. Single dose, no, it's not daily taking psilocybin. Single dose had persistent effects for about a quarter of the people, lasting at least 12 weeks. Gives a hint. If it was not single dose, but two or three doses, would there be more sustained? Or what is the role of some of these newer therapies in terms of lifelong maintenance treatment? And I think these are really interesting and totally unanswered questions that we need more data on. And so I'll skip the rest of this. Oh, the last thing to comment on is if you're treating depression long term, and all of us are, don't forget about suicide risk. Suicide risk is a major risk factor with major depressive disorder. Of all of the risks for suicide, the most actionable risk that we can do something about is depression. And so often, depression is there and not treated. And so really good treatment of depression is one demonstrated method of reducing suicide risk. But when we treat somebody for depression who is at risk for suicide, I think having a safety management, incorporating a very flexible way of treating the person, seeing them as often as needed during transitions, like when you're trying to lower the dose of a med, or stop psychotherapy, or from inpatient to outpatient, those are high risk periods. They beg more careful monitoring, et cetera. So always being aware of the risk of suicide during the course is incredibly important. And we're going to skip the rest, because I think we've basically covered it. And hopefully, we'll have some Q&A later to go over other questions. Thank you. Okay, so thanks, that's a terrific talk and I have one serious disagreement. Just back from, I was just back from London, my wife and I did our 40th wedding anniversary and she said to me, how do you expect me not to get depressed married to a guy like you? So maybe we can, you can put that in your next slide, but my presentation is a little bit different. I usually do this part as part of my Grand Rounds, when I do Grand Rounds on treatment of schizophrenia. So I'm just going to focus on how this all got started. After being at Stanford about 20 years, I decided to look back and ask the question I always ask, am I helping anybody? So I've done what almost no one has done. I've done 24, 20 to 50 year follow-ups of patients treated with antipsychotics and schizophrenia to see what happened. So that's what I'm going to do here. Okay, so I'm going to run through this disclosure, and I'm going to give you a talk on a long-term follow-up of patients on antipsychotics anywhere between 20 and 50 years. And I've done this in four different settings. And it's been published, there's four published. I'll give anybody who wants the references, I'll give you the references. But let me run through this quickly and then take questions. The way I'll do this, give you a brief introduction, what I'm doing now, talk about the methodology from the study, talk about the results, and then quickly the discussions and try to summarize what I said. So the question was, you know, with these patients who I knew very well, and I always work with the families, I wanted to ask the question, did what I did treating your schizophrenia with antipsychotics, how did it work out? How did it work out globally, you know, on a 10-point scale and on the GAF scale, 100-point scale, and life-satisfaction, given you had this terrible illness, this serious illness, how did it work out for you? So in terms of the methodology, what I did was, this was a naturalistic, retrospective follow-up. I consulted with Helena Kramer at Stanford, who's the world's expert on psychiatric epidemiology. She said it was fine to do. It's single-blind. that is, not only did I ask the patients how they did, but we had a rater blind to whether or not the patient took antipsychotics. The sample, it's sampled, as I said, to four different settings. The Sanford sample was 35 patients, they're mostly white, single, unmarried males. The usual should be very similar for your practices. I did the rating scales and had the blind rater to adherence. The scales we used was an adherence scale, one to 10, how did you do? One being, if I remember correctly, terrible, 10, I did terrific, or maybe vice versa. Normal outcomes, zero to 100, and most of the patients when they come in, just to put you in the same place I was at, they come into Stanford at about 20 when they come in with acute schizophrenia, they go out about 30, and they function between 30 and 50 on this 100-point scale. We did a validated life satisfaction scale, one to seven, how satisfied were you with your life given you had this illness on a one to seven scale? What were the results? The first slide shows you who these people were. As I said, mostly male, white, single patients, mostly not on substances, and they were in treatment anywhere from eight to 50 years of treatment of antipsychotics, mean being 20.7. I asked them, because as you know, I have a big interest in family therapy, have a textbook on it, how supportive was your family? These people had families who were supportive to their treatment. What we see, for this sample, not the results, most of these people that I treated had good medication adherence, they had a global outcome of about 6.1 on that 10-point scale, which is good, and the blind clinician rated them 5.3. The global outcome, they did pretty well, 48 out of the 100-point scale, I said, usually these people function between 30 and 50, and how satisfied with your life? This group that I treated over these years was pretty satisfied, 5.2, but the important point is the correlation, and remember, correlation is not causation, could be coincidental. What you can see with all of these scales, here's how the data came out, and what you can see is the line going up is, for everything we looked at, the better you adhered to your medication, the better your outcome on global and on life satisfaction. Everybody clear on that? This is the key slide. The better you adhered to your medication, as you've heard from Carl in anxiety and Sid for depression, and now me for schizophrenia, the better that you did. Well, Dr. Glick, you may say, you know, this isn't the sample that I treat, maybe it's because you gave him decent treatment, maybe it's not the medicine. So we did another study beside this one, this was published in Journal Clinical Cycle Forum, and we did ratings in another sample, looking at the same period. I had this worked out, two sets of slides in this. We did this at a VA, where it was all males. We did this at a clinical research organization that I run, looking at new medicines, where the sample was mostly black, a lot of substance abuse, and we've done it in a clinic, a community clinic, and the results are all the same. The correlations all go up like this. The better you adhere, the better the outcome. So in discussion, there are a lot of reasons not to believe this naturalistic study. It's not a randomized, controlled style. We didn't study patients over 50 years who one group didn't get the medicine, the other didn't. It's not that study. This is a naturalistic study. Some of the reviewers who read the paper said, look, maybe you got people with, you know, this is genetic disease, maybe you only treated people in all of these four different settings that had good genes, not bad genes. Maybe the patients lied to you. Maybe they didn't tell you the truth. Maybe the samples were too small. Maybe the sample is unique, not generalizable. That's why we, that's why you got the results. I don't think so. I don't think, I think it was anything. And this is, I pulled a nice quote from one of the, we did, we have a long questionnaire. Patients filled out part of it. This is one of the things that one of the guys, this is one of the black VA patients said to me. It's best to take your medicine for a lifetime. If you don't, you get a change in mood. It drops. You get suicidal. You get into recreational drugs or bad things. That these disease, schizophrenia can bury you. The drugs you're giving us keep your level even when stressed, like having no money, which this guy had often. You can be more patient and calm. My family is a lot happier if I'm taking my meds. So in summary, the data suggests, not proves, the better the adherence to antipsychotic medication, the better the lifetime outcome and satisfaction. The worse the adherence outcomes were, as you well aware, as you think about your own patients with schizophrenia, the results were disastrous. High suicide rates, high rehospitalization rates. And I'm acutely aware of this, having run psychiatric hospitals for 50 years. So that's the quick and dirty summary of how I got into this, and I'm open for the five minute of questions that the APA wants. They're going to throw out Salzman and Zissick, but I'm open to questions and comments. Far away. There's a microphone right in the middle. As I said, we did just ... Go up to the microphone. Quick and dirty. Hi. I'm Tanja. You're a resident from New York. You don't touch on this topic, but I wanted to know your clinical opinion. Now that they've been using antipsychotics, augmenting agents for depression, what is your input in the long-term maintenance of antipsychotics for depression? Actually Sid may be better to answer this, but I rarely use ... I occasionally use antipsychotics for depression. I do what Zissick recommends when I treat depression. Sid, do you want to comment? Yeah. Thanks for the great question, because so many patients are on antipsychotics. When we started putting together the algorithm for STAR-D, which meds are going to be in a minute, there was a decision to not use atypical antipsychotics at that time. In part, we didn't have as much data that they were helpful, but in part, the fear of long-term side effects and weight gain. We did a study at the VA for treatment-resistant depression. Thirty-five VAs were involved, and aripiprazole augmentation did very well in that study. It did better than switching to bupropion for treatment-resistant, and it did in some ways a little bit better than augmenting with bupropion. However, it also was associated with more weight gain, more sexual side effects, more daytime sedation, so there's the trade-off of the long-term benefits for treatment of depression versus the long-term liability. In my practice, I don't augment with antipsychotics very frequently. When I do, I'm carefully monitoring it and trying my best to taper them off of it as quickly as possible. Next question. Thank you. Thank you so much for this talk. For the female population, is it still true that as they reach menopause, the SSRIs can further either exacerbate, accelerate osteoporosis? Yes, and that's, again, a risk factor. Mark, you want to say something about that, too? Because you know that literature well. No, but I did want to address a couple of things. First, Carl, thank you for taking on the myth of benzo and benzodependence. I think it's really important for young people to understand that these are useful medications if used appropriately. Second, I think a point made by all three of you that's really important, and, Sid, of course, we talked about this earlier, is the paucity of long-term data to inform us what we do with treating any group of patients that we have, whether we look at medications or psychotherapy. It's really a travesty that our institutes are not doing the type of long-term assessment so that we actually understand what to do with our patients. The question to you, Ira, though, is can you discuss the impact of vigorously treating first-episode individuals and continuation of treatment of first-episode individuals in terms of their longer-term prognosis and how they do in terms of functioning? Great question, Mark. I'm all for starting treatment early. You know, Don Kline and I and others talked about the early signs of schizophrenia pre-puberty. And you know, when you get these kids who are bizarre, bullied, can't figure out what to do socially and have trouble in school, I'm all for early treatment. And definitely it improves long-term outcome. And the issue is to involve the family so they know to get their kid treated. I'm going to be talking on Monday on my study of mass shooters, the only scientific study of who these people are. And they're young males who have brain illness. Part of that sample is early schizophrenia. So come Monday if you want to hear more about it. Thanks. Mark, you reminded me of one other thing I want to mention. We talked about some of the mythology related to benzodiazepines and the reluctance of a lot of psychiatrists to use them. Another medication that's almost as bad in terms of mythology and underuse is lithium, which I think does have a role in long-term treatment of mood disorders. I'm not sure it's a great augmentation strategy to enhance an antidepressant overall. But I am sure that it has potent anti-suicidal side effects for some people. And that's a risk throughout the course of major depression. And so I probably have more people on lithium long-term for unipolar depressive disorder than a lot of people do. But I recommend keeping that in your toolkit as well. You know my middle name is lithium MAO clozapine. Yes, sir. Is there any indication that benzodiazepines, long-term use of them, increase the possibility of early dementia? That's a good question. We have an answer to it. The short answer is no. The long answer is that the study that suggested that was a study of drug use from records, not from patients. No patient was evaluated, diagnosed in that first study, nor did they take into account possible past use of alcohol. So the study showed that people who were taking anti-dementia drugs like Aricept were taking benzos more than people who weren't taking Aricept. That was the study. Now, that's a very weak study. It may be suggestive, but it doesn't show anything. So people have gone on to actually look at those data, and the studies that are out now suggest that there's no increased risk of dementia or Alzheimer's disease taking benzos. Now, having said that, it's important to recognize that depending on dose, benzodiazepines can limit recent memory. The most modal way of experiencing that is if somebody is watching a television program at night, and then they take a benzo to go to sleep, and they wake up in the morning, they may not really have a clear memory of what they watched. But they certainly haven't lost their memory of their early childhood, their wedding date, or their grandchildren's names. That's just a fiction. It is true that older people, and by older we're really talking about 80 and up, maybe 75, 70 to 80 and up, they are more sensitive to benzos. Doses should be lower. They should be short half-life drugs only, and limited in use if possible. In a study we did, it was a very small study, we asked people about taking benzos and their memory and what would they prefer, and they said, well, we'd much prefer taking a benzo and feel calmer and sleep better than what we watched on television the night before. I think that's reasonably true. Now, higher doses of benzos, and this is where the substance abusers come in, they're taking 5, 6, 10, 20, 100 milligrams, yes, that probably affects memory. I just want to emphasize, if you believe in science, we know more science about how these drugs work than any other psychiatric medication, and they are the safest of any psychiatric medication. You can't really kill yourself with a benzo unless you combine it with alcohol or other sedative hypnotics. Maybe if you took a bucket full, you might, but in fact, these are remarkably safe drugs, and at the doses we are recommending, which are pretty modest doses, they're very safe. Okay. Other questions? I have a question for you, Dr. Kleckner. Have you ever treated a schizophrenic patient and used stimulant drugs or CBD? Yes. Yes. I often use stimulants. Don Klein, who is actually the one that takes credit for this, clozapine gives such sedation that often I'm using Ritalin, a low-dose Ritalin, to get people going in the morning. I've had no problem with it, Carl. The answer is yes. No problem. I would agree with that completely. Low-dose Ritalin can be an amazing drug to offset sedative effects, inertia, and get people back on their feet and interacting. Absolutely. Yes, ma'am. I just want to check that benzos in elderly patients has a fall risk, especially in nursing homes and geriatric patient population. Using benzos in a geriatric patient population is causing high risk of falls. Okay. That's an important question. Benzos are probably overused in the geriatric population. I may love them, but I certainly understand that they may be overused, not maliciously, but because people are suffering and they're not sleeping, so start a little bit of Ativan. It depends on the patient. It depends on the dose and the circumstances. For example, given my age, I'm now seeing a lot of patients my age, and a lot of them don't sleep, and they've tried everything, none of which really work over any period of time, but a quarter of an Ativan, maybe a half of an Ativan, they go to sleep and they have a good night's sleep, and for older people, a good night's sleep is a lot more critical than almost anything else, and they don't wake up in the morning with hangovers. They don't abuse them. You're scrupulous because they don't want to have them taken away, and I'm very firm about that. If you abuse these drugs, you're going to have to find some other dope to give them to you because I'm not going to keep doing it. Words of wisdom, Carl. Let me just get the last question. Can you hold one second? I want to get Stefan Leucht on before we stop. We'll be here for answering questions. I want to introduce Stefan Leucht, who's probably the world's leading researcher on long-term treatment, and he's come over. Actually, I was thinking of asking you to come on and bike. You got up just at the perfect time. Stefan, go ahead. Thanks a lot, Ira. You exaggerate, of course, but I know your data. Thanks a lot. I didn't know your data, but I found Carl's, in a way, most interesting because, I mean, you showed me a lot of data. You showed me a lot of data. which are on the other side of the coin. Now, if you read a textbook, nobody says, many patients do very well on benzos, not everybody gets addicted. This was something that I learned today. Thank you very much. Still have the question, of course, and you also said that there are patients who become addicted. And more than, you can also speak about addiction when we talk about antidepressants, you have withdrawal effects, you said that. I think people don't have grading. That's a big difference between, say, heroin or antidepressants. Can you people here in the back? No, speak into the microphone. Okay, so now comes the question, which is actually the essential thing. But if, let's say, the textbooks all said the thing that you are saying, wouldn't this mean that we then could have an epidemic of people, many more people taking benzodiazepines? What you say is correct. The right patients, careful, put down how much you take every day. But in practice, would this work if, say, the textbooks, the guidelines, opened benzos up again? What do you think? Thank you. Okay, listen, thank you very much for coming this morning. I hope this session's been useful and we look forward to talking to you again. We're here for answering further questions. Thank you.

psychiatric clinical practices

chronic illness management

anxiety disorders

benzodiazepines

long-term depression management

cognitive-behavioral therapy

relapse prevention

schizophrenia

antipsychotic use

sustained treatment

suicidality

patient quality of life

lifelong management