Antidepressant Discontinuation Syndrome: Diagnosis, Prevention PDF

Antidepressant Discontinuation Syndrome: Diagnosis, Prevention Click here to watch the video https://goo.gl/OMCpSF Discontinuation symptoms can occur with all antidepressant classes, and you will see many articles referring to SSRI dis...

Antidepressant Discontinuation Syndrome: Diagnosis, Prevention Click here to watch the video https://goo.gl/OMCpSF Discontinuation symptoms can occur with all antidepressant classes, and you will see many articles referring to SSRI discontinuation syndrome. The reason is that SSRIs are by far the most commonly prescribed antidepressant class. This syndrome consists of usually mild and reversible symptoms that can be grouped into six categories. As a general guideline, management involves restarting antidepressant medication. Author: Flavio Guzman, MD Editor Psychopharmacology Institute Diapositiva 1 Antidepressant Discontinuation Syndrome Flavio Guzmán, MD In this presentation we discuss the antidepressant discontinuation syndrome. 1 Diapositiva 2 Overview Discontinuation symptoms can occur with all antidepressant classes Usually mild and reversible symptoms Symptoms can be grouped into 6 categories Management involves restarting medication Let’s see an overview of this topic. Discontinuation symptoms can occur with all antidepressant classes, and you will see many articles referring to SSRI discontinuation syndrome. This has to do with the fact that SSRIs are by far the most commonly prescribed antidepressant class. This syndrome consists of usually mild and reversible symptoms that can be grouped into six categories. As a general guideline, management involves restarting antidepressant medication. 2 Diapositiva 3 Clinical Relevance 3 Diapositiva 4 Are antidepressants addictive? Discontinuation vs withdrawal No evidence of antidepressant craving Haddad, P. M., & Anderson, I. M. (2007). Recognising and managing antidepressant discontinuation symptoms. Advances in Psychiatric treatment,13(6), 447-457. The first question we are addressing here is: Are antidepressants addictive? The term withdrawal is often avoided, as it may imply that antidepressants are addictive or cause a dependence syndrome. As pointed out by Haddad and Anderson, the occurrence of withdrawal symptoms doesn’t in itself indicate that a drug causes dependence. There is no evidence that patients crave antidepressants once they have stopped them. So, one of the messages we can send our patients is that antidepressants are not addictive. This is important as fear of addiction can reduce treatment adherence. 4 Diapositiva 5 Why are discontinuation symptoms important? Morbidity Misdiagnosis Treatment adherence Why should we care about antidepressant discontinuation syndrome? In this slide I list three reasons: the first is morbidity. Even though discontinuation symptoms are rarely fatal, they are associated with discomfort and some degree of psychosocial impairment. The second is misdiagnosis. Discontinuation symptoms can be confused with recurrence of psychiatric illness or other medical problems. We’ll discuss this in the next slide. The third is treatment adherence. After experiencing discontinuation symptoms, patients may be unwilling to use psychotropic medications in the future. 5 Diapositiva 6 Misdiagnosis Adverse effect of a new medication Recurrence of the underlying psychiatric illness Haddad, P. M., & Anderson, I. M. (2007). Recognising and managing antidepressant discontinuation symptoms. Advances in Psychiatric treatment,13(6), 447-457. Let’s focus now on the problem of misdiagnosis. Discontinuation symptoms can be confused with adverse effects of a new medication. This may lead us to the incorrect conclusion that the patient can’t tolerate the new medication. This can happen when switching antidepressants with different mechanism of action, for example, from paroxetine to bupropion. Discontinuation symptoms can also be confused with recurrence of the underlying psychiatric illness. An example of this would be the following situation: a patient has achieved remission of depressive symptoms and the physician recommends stopping the antidepressant but doesn’t advice how to do it. So, the patient stops medications abruptly, leading to discontinuation symptoms. If the prescriber is not aware of this abrupt interruption, then he or she might confuse this with depression recurrence. 6 Diapositiva 7 Misdiagnosis Failure to respond to treatment Physical disorder Haddad, P. M., & Anderson, I. M. (2007). Recognising and managing antidepressant discontinuation symptoms. Advances in Psychiatric treatment,13(6), 447-457. Discontinuation symptoms might also be confused with failure to respond to treatment, especially mental symptoms such as irritability or anxiety. Discontinuation symptoms can also be misdiagnosed as medical problems, this may lead to unnecessary referrals and evaluations by other specialists. 7 Diapositiva 8 Clinical features General Sensory Disequilibrium somatic symptoms symptoms Affective Gastrointestinal Sleep symptoms symptoms disturbance The discontinuation syndrome can be divided into six clusters of symptoms. Sensory symptoms, disequilibrium, general somatic symptoms, affective symptoms, gastrointestinal symptoms and sleep disturbance. This syndrome was initially based on case reports, but the evidence expanded to include prospective studies, with randomized double-blind interruption periods. 8 Diapositiva 9 Sensory symptoms Paresthesia Numbness Electric-shock-like sensations Rushing noise “ in head” Palinopsia (visual trails) Haddad, P. M., & Anderson, I. M. (2007). Recognising and managing antidepressant discontinuation symptoms. Advances in Psychiatric treatment,13(6), 447-457. Sensory symptoms include: paresthesia, numbness, electric shock-like sensations, rushing noise “ in head” and palinopsia, or visual trails. 9 Diapositiva 10 Disequilibrium Light-headedness Dizziness Vertigo Haddad, P. M., & Anderson, I. M. (2007). Recognising and managing antidepressant discontinuation symptoms. Advances in Psychiatric treatment,13(6), 447-457. Disequilibrium symptoms include light-headedness, dizziness and vertigo. 10 Diapositiva 11 General somatic symptoms Lethargy Headache Tremor Sweating Anorexia Haddad, P. M., & Anderson, I. M. (2007). Recognising and managing antidepressant discontinuation symptoms. Advances in Psychiatric treatment,13(6), 447-457. General somatic symptoms have been compared to a flu-like syndrome. This includes lethargy, headache, tremor, sweating and anorexia. 11 Diapositiva 12 Affective symptoms Irritability Anxiety/agitation Low mood Tearfulness Haddad, P. M., & Anderson, I. M. (2007). Recognising and managing antidepressant discontinuation symptoms. Advances in Psychiatric treatment,13(6), 447-457. Affective symptoms that can be part of the discontinuation syndrome are irritability, anxiety, low mood and tearfulness. 12 Diapositiva 13 Gastrointestinal symptoms Nausea Vomiting Diarrhea Haddad, P. M., & Anderson, I. M. (2007). Recognising and managing antidepressant discontinuation symptoms. Advances in Psychiatric treatment,13(6), 447-457. Gastrointestinal symptoms include nausea, vomiting and diarrhea. 13 Diapositiva 14 Sleep disturbances Insomnia Nightmares Excessive dreaming Haddad, P. M., & Anderson, I. M. (2007). Recognising and managing antidepressant discontinuation symptoms. Advances in Psychiatric treatment,13(6), 447-457. The last cluster of symptoms is related to sleep disturbances, including: insomnia, nightmares and excessive dreaming. 14 Diapositiva 15 FINISH: A mnemonic for discontinuation symptoms F – Flu-like symptoms I – Insomnia N – Nausea I – Imbalance S – Sensory disturbances H – Hyperarousal Warner, C. H., Bobo, W., Warner, C., Reid, S., & Rachal, J. (2006). Antidepressant discontinuation syndrome. American Family Physician, 74(3), 449-456. There’s also a mnemonic to help us remember the discontinuation symptoms. It’s the word FINISH, F for flu-like symptoms, I for Insomnia, N for nausea, I for imbalance, S for sensory disturbances, and H for hyperarousal. 15 Diapositiva 16 Primary TCA discontinuation syndrome Lack of : Sensory abnormalities Problems with equilibrium MAOI discontinuation syndrome More severe: worsening of depressive episode, acute confusional state, anxiety symptoms, catatonia The symptoms we discussed in the previous slides are commonly associated with the discontinuation of SSRIs and SNRIs. Specific symptoms for tricyclics and MAOIs have been described. In the case of tricyclics, there is a lack of sensory abnormalities and problems with equilibrium. In the case of MAOIs, symptoms can be more severe, including a worsening of depressive episode, acute confusional state, anxiety symptoms and even catatonia. 16 Diapositiva 17 Time of onset and duration Onset: Generally in the first week Studies suggest a mean time of onset of 2 days after stopping Duration: Spontaneous resolution between 1 day and 3 weeks after onset Warner, C. H., Bobo, W., Warner, C., Reid, S., & Rachal, J. (2006). Antidepressant discontinuation syndrome. American Family Physician, 74(3), 449-456. Let’s see now the time of onset and duration. Discontinuation symptoms occur generally during the first week after stopping the antidepressant. Studies suggest a mean time of onset of 2 days after stopping. Regarding duration, spontaneous resolution occurs between 1 day and 3 weeks after onset, most commonly around 10 days. 17 Diapositiva 18 Discontinuation syndrome and half-life Paroxetine: highest risk Fluoxetine: lowest risk Renoir, T. (2013). Selective serotonin reuptake inhibitor antidepressant treatment discontinuation syndrome: a review of the clinical evidence and the possible mechanisms involved. Frontiers in pharmacology, 4. The discontinuation syndrome has been reported in relation to almost every SSRI, although there are increased reports in patients stopping paroxetine treatment. So far, half-life is the pharmacokinetic property that has been linked to risk of discontinuation symptoms. Fluoxetine has a half-life of around 7 days, this makes it the SSRI with the lowest risk of this syndrome. 18 Diapositiva 19 Differential diagnosis Discontinuation Depression Relapse Dysphoria, appetite changes, sleep problems, fatigue. Dizziness, “electric shock” sensations, “ rushing” sensations in the head, headache, nausea Rapid reversal of symptoms after restarting the antidepressant Warner, C. H., Bobo, W., Warner, C., Reid, S., & Rachal, J. (2006). Antidepressant discontinuation syndrome. American Family Physician, 74(3), 449-456. How do we differentiate discontinuation symptoms from a depressive relapse? They have in common symptoms such as dysphoria, appetite changes, sleep problems and fatigue. It’s practical to look for symptoms that are not seen in depression relapse, some examples are dizziness, “electric shock” sensations, rushing sensations in the head, headache and nausea. Also, we can see a rapid reversal of symptoms after restarting the antidepressant. 19 Diapositiva 20 Prevention and Management 20 Diapositiva 21 Who is at risk? Patients who begin to feel better Women who discover they are pregnant So who is at risk of discontinuing medication without letting you know? Generally, patients who begin to feel better and are not comfortable with the idea of taking medication for a long time. Also, women who discover they are pregnant are more likely to abruptly stop medications, because of safety concerns. 21 Diapositiva 22 How to discontinue antidepressants Warn patients about the possibility of antidepressant discontinuation syndrome May be possible to stop fluoxetine therapy without tapering Here are some considerations on how to discontinue antidepressants. First, patient education is very important. We need to warn patients about the possibility of antidepressant discontinuation syndrome. Also, it may be possible to stop fluoxetine therapy without tapering, this hasn’t been explored in studies specifically designed to address this observation. 22 Diapositiva 23 What to do ? 1. Provide reassurance to the patient Reversible, not life threatening, will run its course within 1 to 2 weeks Warner, C. H., Bobo, W., Warner, C., Reid, S., & Rachal, J. (2006). Antidepressant discontinuation syndrome. American Family Physician, 74(3), 449-456. So, what do we do with a patient suffering from discontinuation symptoms? First of all, we provide reassurance. We do this by explaining that this syndrome is reversible, not life threatening, and that it will run its course within 1 to 2 weeks. 23 Diapositiva 24 What to do ? 2. Consider restarting the medication with a slow dose taper If symptoms occur during tapering: Consider restarting at the original dose and then taper at a slower rate. If slow tapering is poorly tolerated: Consider substituting with fluoxetine Warner, C. H., Bobo, W., Warner, C., Reid, S., & Rachal, J. (2006). Antidepressant discontinuation syndrome. American Family Physician, 74(3), 449-456. Second, we restart the medication with a slow dose taper. What if symptoms occur during tapering? In this case we should consider restarting at the original dose and then taper at a slower rate. If slow tapering is poorly tolerated, we can consider substituting with fluoxetine. 24 Diapositiva 25 Key points Discontinuation symptoms include flu-like symptoms, insomnia, nausea, imbalance, sensory disturbances and hyperarousal (FINISH) More commonly seen with paroxetine Restarting the antidepressant is generally enough The key points are the following: Discontinuation symptoms include flu-like symptoms, insomnia, nausea, imbalance, sensory disturbances and hyperarousal. We can use the mnemonic FINISH to keep these symptoms in mind. This syndrome is more commonly seen with paroxetine. From a therapeutic standpoint, restarting the antidepressant is generally enough as management strategy. 25 Treatment-Resistant Depression: The Clinical Conundrum Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425015-dt-... Treatment-Resistant Depression: The Clinical Conundrum Dr. Wegdan Rashad: Hello everyone, and welcome to The Psychopharmacology Institute Podcast. I'm your host, Dr. Wegdan Rashad. In this series, we'll be discussing topics that matter to you in your clinical practice, sharing expert opinions and latest research. When I started psychiatry practice, I had the notion that depression was one of those conditions that always had a good outcome when treated adequately. I realized however that in some patients, multiple trials of medications don't seem to help them at all. The concept of treatment-resistant depression, or TRD for short, can be a real conundrum for psychiatrists, and obviously a frustration for patients su!ering from it. Today, you will "rst join me on a journey in exploring the options available for TRD, and then we'll wrap up with a treatment algorithm you can apply in your practice. I will do this with the help of snippets from Professor Philip Cowen's lecture on treatment- resistant depression, available for our premium members on psychopharmacologyinstitute.com. Dr. Cowen is a Professor of Psychopharmacology at Oxford University in the UK. So before we jump in, how do we de"ne treatment-resistant depression? In simple terms, a patient who has failed to respond to two separate adequate trials of antidepressant medication could be thought of as treatment-resistant. Now, that's out of the way. How to treat it? Not so fast. Before we rush to label a patient treatment-resistant, we need to fully assess him or her properly. Here's Dr. Cowen on assessment of TRD. Dr. Philip Cowen: In practice, every patient needs to be assessed as an individual. So you want to know exactly what treatment they've had, how many kinds of medication, what psychological treatment they've had, and also want to get an understanding of how long the condition's been going on for. And what's the level of symptomatology? Are they completely disabled? Can they work still? What's their social life like? Another 1 of 10 6/26/24, 8:35 PM Treatment-Resistant Depression: The Clinical Conundrum Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425015-dt-... key factor in the assessment is to check the diagnosis. Is it major depression? Are there other comorbidities that we know tend to make response to treatment less satisfactory? For example, comorbid anxiety, substance misuse. The other issue to think about is, might they have a depression in the bipolar spectrum? Because we know now for patients with bipolar disorder, standard antidepressant treatments don't seem as e!ective as they do in major depression, and other kinds of approaches might be necessary. Dr. Wegdan Rashad: So, in short, we take a su#cient history of past therapy, how disabling their illness is, and of course, to revise the diagnosis. I could add that some patients may need further workup to exclude a possible secondary medical cause to their depression. Now, how about depression with psychotic features? Dr. Philip Cowen: It's often quite hard to know when the negative thinking of a depressed patient crosses the line into a psychotic symptom. But one just wants to look out for patients who feel, rather persistently, they've made a failure of everything, that they're never going to recover. And really hang onto this with a great intensity. And here it's important to remember that treatment with an antidepressant monotherapy is rarely successful. And patients will normally need an antipsychotic drug, fully dosed as if one was treating a psychosis, and an antidepressant. And undiagnosed depressive psychosis counts for "ve or six cases I see each year. And you normally "nd when you add an antipsychotic drug at a good dosage, patients will make a good response. Dr. Wegdan Rashad: It can be easy to omit asking about psychosis in a patient with depression. So this is an excellent point. Now, you might be thinking, after how long do I wait on an antidepressant trial to judge its response, or lack thereof? On average, if the patient is not responding within four weeks, then it's unlikely that waiting will make much of a di!erence. Just like combating any tough dilemma, we employ multiple strategies to tackle it from all sides. We will touch upon four modalities: namely, pharmacologic strategies, psychosocial interventions, brain stimulation, and amusing experimental strategies not yet approved, but showing promise. So for pharmacologic strategies, we can switch, augment, and combine. Over to Dr. 2 of 10 6/26/24, 8:35 PM Treatment-Resistant Depression: The Clinical Conundrum Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425015-dt-... Cowen. Dr. Philip Cowen: So most guidelines suggests that where a patient doesn't respond to a "rst line medication, which generally nowadays is going to be an SSRI, you should switch to a di!erent treatment. Intuitively, you'd think if a patient hasn't responded to a drug such as an SSRI that potentiates serotonin function, there wouldn't be much point switching to another drug that has the same mechanism. So in this case, a second SSRI. In fact, randomized trials suggest it doesn't really matter too much if you switch to a drug with the same mechanism of action or a di!erent one. Dr. Wegdan Rashad: So switching to an SSRI or an SNRI, something like bupropion, for instance, doesn't actually matter too much. They're just as e!ective, according to the famous STAR*D study. My Psychopharmacology Institute colleague, Dr. Dana Wang, hosted Dr. Cowen in one of our expert consultation interviews. And she posed a very interesting question. Dr. Dana Wang: In your lecture on switching after a failed trial of SSRI, you brie$y mentioned the "Prozac poop-out". Would it still be advised for the patient to switch to another SSRI or SNRI? Would waiting one week before switching SSRI enough time to reverse this phenomenon? In your clinical experience, what are some of the strategies you would use to deal with this problem? Dr. Philip Cowen: So, I don't think this is a problem that's being studied systematically, so what I say will be based on my own experience. My sense is that when someone has stopped responding to an SSRI, switching to a further one isn't very helpful. And the same applies to lowering or stopping the SSRI for a week or two, and then trying again. So my usual practice is to try something rather di!erent, either as a treatment by itself or added to the SSRI. And I'm thinking of something here pharmacologically rather di!erent. So adding another antidepressant, such as the noradrenaline and dopamine reuptake blocker, bupropion, or perhaps bupropion by itself. The other approach would be to use an augmentation approach with, for example, a drug such as aripiprazole. I think it's an interesting idea. So the notion would be, I suppose, that if you took away the 5-HT reuptake blocker, then perhaps the desensitized receptors would be able to restore themselves to normal again. I'm just not sure whether one or two weeks would be long enough for that to occur. Often one is looking at neuroadaptive changes in the brain that might have occurred over several months, and might take several weeks to go back to normal again. During that time, 3 of 10 6/26/24, 8:35 PM Treatment-Resistant Depression: The Clinical Conundrum Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425015-dt-... the patient might be quite depressed and despairing, so it would be hard just to stop the drug without doing anything else. Dr. Wegdan Rashad: And this leads us, ever so swiftly, to our next line of defense, combination and augmentation. What's the di!erence between combination and augmentation, I hear you ask. As for those who didn't ask, here's the answer anyway. Dr. Philip Cowen: Conventionally, the phrase "combination treatment" refers to adding a second drug that's also an antidepressant in its own right. So a drug such as mirtazapine. Augmentation consists of adding a drug that's not normally thought to be an antidepressant by itself, but can produce an antidepressant e!ect when added to an ine!ective antidepressant treatment. An example of this would be lithium. In fact, though people tend to swap between the two kinds of expressions. Combination or augmentation are used fairly interchangeably. Generally, augmentation treatment seems a bit more e!ective than switching, particularly if patients have made a partial response to the "rst treatment. Dr. Wegdan Rashad: Interesting that you should mention mirtazapine, Dr. Cowen, because I recently came across a multicenter, randomized placebo-controlled trial, published in October 2018, revealing that they found no evidence of bene"t with mirtazapine added to SSRIs or SNRIs compared to placebo. In fact, the side e!ects were responsible for relatively more participant dropout. But in general, when combining, we start low and go slow. And I'd like to add, keep your eyes open for adverse e!ects like serotonin syndrome, for example. The third and most e!ective pharmacologic strategy is augmentation. On the augmentation menu, we have many delicious options to choose from, including second generation antipsychotics, lithium, stimulants, and thyroid hormones. Dr. Philip Cowen: So the augmentation strategy with the best evidence base is the addition of atypical antipsychotic drugs. So it's been found in a series of placebo- controlled randomized trials in over 3,000 patients that adding drugs such as olanzapine, quetiapine, aripiprazole, brexpiprazole, can be useful in securing an antidepressant response in patients who failed to respond to an SSRI. The same kind of e!ect seems to occur in patients taking SNRIs, though this has not been studied so systematically. The doses of atypicals used for this purpose is distinctly lower than that used to treat psychosis. So one's thinking of a dose of about 2.5 to 10 milligrams of aripiprazole, 50 4 of 10 6/26/24, 8:35 PM Treatment-Resistant Depression: The Clinical Conundrum Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425015-dt-... to 300 milligrams of quetiapine. Pharmacologically, 5-HT2 receptor blockade has been implicated. Dr. Wegdan Rashad: The cool thing about augmentation is that you can choose your add-on tailored to your patient's symptoms. Dr. Cowen explains more. Dr. Philip Cowen: So for patients who are sleeping poorly, with anxiety, adding quetiapine at night might be helpful. Patients who seem to have more problems with motivation and anhedonia can be helped by the addition of aripiprazole. Dr. Wegdan Rashad: But for how long do we keep second generation antipsychotics for, given their unsavory side e!ects like movement disorders and metabolic syndrome? The answer, dear listener, is not going to satisfy you. Because simply, we don't have conclusive data on that yet. But Dr. Cowen does mention in his lecture that we may use it for months, and if you want to withdraw it, do it slowly and with a close eye on signs of relapse as you go. Now for augmentation with mood stabilizers. Let's start with our historical friend, lithium. Dr. Philip Cowen: I think also, lithium is a less popular treatment. It's harder to use because of the need for blood tests and continual monitoring with blood tests. Nevertheless, the meta-analysis suggests that it is in e!ective treatment, and the number needed to treat is about four or "ve, which, if that's generally the case, would be rather better than augmentation with atypicals. People sometimes ask, what's the right dose of lithium in patients with resistant depression when you are adding it to antidepressant treatment? And generally, you might be able to use rather more modest doses that in bipolar disorder. I would tend to go from between 0.4 to 0.6 millimoles per liter. Dr. Wegdan Rashad: So lithium is an e!ective option, and I'm sure you remember that lithium is the drug to use in suicidal patients with a mood disorder. So keep this in mind. Have you ever used psychostimulants like methylphenidate to augment antidepressants in TRD? It is not very common practice, but here's the evidence in a nutshell. Dr. Philip Cowen: Even though psychostimulants don't seem to be very helpful in 5 of 10 6/26/24, 8:35 PM Treatment-Resistant Depression: The Clinical Conundrum Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425015-dt-... treatment-resistant depression, there is some bene"t from moda"nil augmentation in SSRI-resistant patients, particularly those who are sleepy or feeling fatigued. And there is evidence from a case series that high-dose pramipexole might be useful in patients with treatment resistance, but it would need to be used with some care. Dr. Wegdan Rashad: So the verdict says, maybe not the best. The strategy of adding a thyroid hormone triiodothyronine is an old strategy, when it was typically added to tricyclic antidepressants. Who would make a good candidate for T3 augmentation though? Dr. Philip Cowen: So T3 was tried in STAR*D, and actually appeared numerically better to the addition of lithium in antidepressant-resistant patients, and it was slightly better tolerated. On the other hand, remission rates of both treatments in STAR*D were fairly low. And the dose given in STAR*D was between 25 to 50 micrograms daily. I would generally start at a low dose, something like 20 micrograms daily, and see how people feel with that. The things to watch out for would be typical signs of excess thyroid function, such as increased pulse rates, sweating, and feeling hot. It's also wise to precede treatments with an assessment of thyroid function and an ECG. Clearly, if there's any evidence of cardiovascular disease, it's prudent to avoid T3 treatment. There are no clearly established predictors for T3 augmentation in terms of which patients are going to do best. But intuitively, patients with tiredness, low energy, apathy would seem to be the right kind of candidates. Anecdotally, women patients are said to respond rather better than men to T3 augmentation. Dr. Wegdan Rashad: So in simple terms, patients with TRD who happen to be female, tired all the time, and do not have cardiac problems, could be great candidates for thyroid augmentation. Of course, there are more augmenting agents available discussed by Dr. Cowen. And I would recommend you watching the full lecture to "nd out more. Now, as psychiatrists we know very well that medications are not everything. Ideally, psychotropic medications should be prescribed hand-in-hand with psychotherapy. Imagine going through months and maybe even years of failed treatment and disabling depression. The least you could feel is hopeless. Dr. Cowen shed some light on this matter. Dr. Philip Cowen: Taking time to see the patient with family or partners can be very helpful for both, just to hear how things are going at home and to give advice about the 6 of 10 6/26/24, 8:35 PM Treatment-Resistant Depression: The Clinical Conundrum Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425015-dt-... best way to try and help people and to avoid criticism where this is possible. Patients with depression often don't have a structured day, particularly if they aren't working. So working out some kind of activity scheduling, which hopefully will include some rewarding activities, is always worth doing. There is a rather simpler treatment called behavioral activation, which focuses again on people's activity and trying to incorporate rewarding experiences. This might be easier for the more depressed patients to deal with. And in fact, a recent controlled trial showed that behavioral activation was possibly more e!ective than CBT in severely depressed patients. Dr. Wegdan Rashad: It has been found that not only are psychosocial interventions e!ective, but they prevent relapses of depression as well. So de"nitely, it's something worth trying with your patients. Now, we have two tactics left. One, brain stimulation modalities like electric convulsive therapy, transcranial magnetic stimulation, and deep brain stimulation. And two, experimental strategies like using hallucinogens, ketamine, and even anti-in$ammatory drugs. So, stay tuned. Medications and psychotherapy may not be doing it for your patient. This may call for more invasive procedures. I will brie$y touch upon each one. Electroconvulsive therapy, or ECT, is e!ective for more serious symptoms like psychotic depression, suicidality, and catatonic features. Transcranial magnetic stimulation, or TMS, is less e!ective, but does not have known cognitive side e!ects. As for deep brain stimulation, or DBS, well, the evidence base is still inconclusive for our patients with TRD. And now for some fun and games. Well, it's not exactly fun and games, but certainly there are exciting experimental strategies on the horizon that you should know about. It is likely that you've heard of the rapid-acting antidepressant ketamine, that within hours can rid a patient of depressed mood and suicidal thinking. It is used o!-label in some places, but its safety pro"le for long-term use is still inconclusive. Now, do you imagine in the near future, prescribing an anti-in$ammatory agent like celecoxib along with your everyday sertraline or escitalopram? Over to Dr. Wang and Dr. Cowen. Dr. Dana Wang: You talked about some fascinating evidence and clinical applications of using in$ammatory markers. Have you had experiences of using this data in your clinical practice? What would you like to see more researched in this area? Dr. Philip Cowen: So there are a number of studies going on in patients with raised 7 of 10 6/26/24, 8:35 PM Treatment-Resistant Depression: The Clinical Conundrum Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425015-dt-... in$ammatory markers. And that normally means raised levels of C-reactive protein, CRP, in the blood, and various biological agents. So things like drugs that block TNF alpha, drugs that block IL-6. So these are quite powerful biological agents and there are a number of registered clinical trials going on at the moment. And I think at the end of those in a year or two, we'll have quite a good idea about whether these drugs work in patients with raised in$ammatory markers and what the range of side e!ects might be. Before then, what can we do as clinicians? I have started measuring CRP in my patients because I think it's an interesting marker. And above a level of three milligrams per mil, then people do think that patients have signs of raised in$ammation. There are one or two approaches one might try there, particularly if patients aren't doing well with conventional treatment. So one I may have mentioned was a study that found that patients with CRPs greater than two or three, did better with nortriptyline, the noradrenaline-related tricyclic antidepressant, than with the SSRI escitalopram. So when patients haven't responded well and they've also a raised CRP, then I sometimes think of a trial of nortriptyline. Equally, there are lifestyle things patients can do if they have raised in$ammatory markers. And these would include things like exercise regularly and perhaps the use of omega-3 "sh oils. It's still a bit early to say that these patients should be given speci"c anti-in$ammatory drugs. I think we'll know the answer to that in a couple of years. But prior to that, as I said, there are some things one could do on an everyday level, ranging from things like the use of nortriptyline to various other activities which could be designed to lower in$ammation. And that would certainly include things like diet and exercise. Dr. Wegdan Rashad: Very interesting. I am sure we will hear more about the use of anti-in$ammatory agents in treatment-resistant depression, so watch this space. Another intriguing development is the increasing interest and studies on the use of hallucinogens like shrooms or ecstasy, also known as psilocybin and MDMA, respectively. Actually, I hosted an interview with Dr. Robin Carhart Harris at the 2019 ASCP annual meeting, and he spoke more in detail about this controversial modality. Check out the podcast entitled "Psilocybin for Treatment-Resistant Depression" in the podcast section. Phew. Now let's wrap up with an algorithm you can take home with you. Or rather, take to your clinic. But you must keep in mind, there is no one-size-"ts-all algorithm. Each patient has their own unique history and circumstances which need to be taken into 8 of 10 6/26/24, 8:35 PM Treatment-Resistant Depression: The Clinical Conundrum Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425015-dt-... account. Dr. Philip Cowen: In general, what we have to start with are the two newer antidepressants that are thought to be among the most e!ective from the various network meta-analysis. So here we're starting with either the SSRI escitalopram or the SNRI venlafaxine, both given at reasonable doses. So if patients are taking either of those drugs and they haven't responded, we could think about adding an atypical antipsychotic. Mirtazapine is an alternative. Another possibility might be to think of lithium. Moving down, I think there's a place for ECT in patients who don't respond well to these treatments, who are more treatment-refractory, but ECT can be considered earlier in patients with very severe symptoms. On the "nal line, just to point out that psychological treatment is a key part of the management of resistant depression, with CBT and behavioral activation always worthwhile trying. Dr. Wegdan Rashad: And that's all folks. A short and sweet algorithm right there. Now, for those who have dozed o!, listen up, because here come the long-awaited key points. The "rst step in the management of treatment-resistant depression is adequate history taking and assessment for comorbidities and bipolar depression. Augmentation is more e!ective than switching. The evidence base supports augmenting with second generation antipsychotics at lower doses than for psychosis. Adding lithium is also e!ective, particularly if the patient is suicidal. Moda"nil and T3 have been shown to be good add-ons in patients with fatigue. Psychosocial interventions, such as mindfulness CBT and behavioral activation have been shown to improve outcomes and prevent relapse of depression. Electroconvulsive therapy has shown e#cacy for severe and psychotic depression. However, TMS is better in terms of cognitive adverse e!ects. Depression may have an underlying in$ammatory component, and it has been found in some studies that patients with raised CRP above three milligrams per deciliter did better with nortriptyline than with SSRIs. Liked our podcast? Visit us at psychopharmacologyinstitute.com, where you can "nd more podcasts and some lectures absolutely free. You can choose to become a premium member to access all lectures and interviews. Also, we would be thrilled to hear from you. Drop us an email at [email protected]. 9 of 10 6/26/24, 8:35 PM Treatment-Resistant Depression: The Clinical Conundrum Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425015-dt-... The following people participated in this episode: Dr. Flavio Guzman, as a general editor. Rosario Anon Suarez, as the audio engineer. Pamela Gonzalez, as a project manager. And myself, Dr. Wegdan Rashad, as the host. Thank you for joining us in today's podcast. Until the next episode, goodbye. Print this page 10 of 10 6/26/24, 8:35 PM Safe Use of Benzodiazepines: Clinical, Regulatory, and Public Health P... https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425015-dt-... Safe Use of Benzodiazepines: Clinical, Regulatory, and Public Health Perspectives Day 2 Mark McClellan: All right. Well, I'd like to say good afternoon or good morning, depending on where you happen to be, and welcome back to day two of our public meeting on Safe Use of Benzodiazepines: Clinical, Regulatory, and Public Health Perspectives. This webinar is being convened through a cooperative agreement between FDA and the Duke-Margolis Center for Health Policy. I'm Mark McClellan. I'm the director of the Duke-Margolis Center, and on behalf of Adam Kroetsch and Mira Gill and the rest of our team, would like to, again, welcome you all back to joining us for this very important and timely meeting. We are hearing from a diverse range of perspectives, including clinicians, patients, researchers, regulators, and others on the how to e!ectively balance the bene"ts and risks of benzodiazepines and ensure that they're used as safely as possible. Yesterday, we heard a series of presentations reviewing the available epidemiologic data on benzodiazepine use, abuse liability data, as well as clinical use. We heard reactions from a range of perspectives, including clinical and pharmacologic and public health experts, as well as some presentations of additional information on understanding risks associated with use, misuse, and abuse of benzodiazepines. We heard that benzodiazepines have potential for abuse, alongside their bene"ts in certain clinical context, and that non-medical use of benzodiazepines contributes signi"cantly to morbidity and mortality as well. We took a close look at di!erences across the benzodiazepine class, and heard from a variety of perspectives on whether certain benzodiazepines, particularly alprazolam, may carry greater risk than others in the class. We also examined the use of benzodiazepines in clinical practice. These drugs have clinical value in treating certain conditions, as I mentioned. Those include acute anxiety, 1 of 54 6/26/24, 8:34 PM Safe Use of Benzodiazepines: Clinical, Regulatory, and Public Health P... https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425015-dt-... alcohol withdrawal, epilepsy. But concerns remain about appropriate use of benzodiazepines, including their long-term use and the co-prescribing of benzodiazepines and opioid analgesics, as well as e!ective approaches to tapering and discontinuing benzodiazepines, a topic that also had extensive discussion yesterday. Across all of these conversations, we identi"ed some key gaps in our understanding and identi"ed a number of critical challenges to e!ectively balancing bene"ts and risks and maximizing the net bene"ts of these products. We want to build on these discussions today, as we have a chance to expand on many of the topics that came up yesterday in the panels and the discussion with all of you that's going to follow. So we look on the slides of the meeting agenda for today, we've got two major sessions. Session three, which will feature three presentations related to clinician identi"ed best practices and gaps in education, including a discussion of FDA's work in this space. And then session four, we'll focus on synthesizing some of the key takeaways from the meeting and the next steps in balancing the bene"ts and risks of benzodiazepine use. Just a few reminders before we get going again, you can visit the Duke-Margolis event website for materials from today's meeting. That will include the recording after we're done, as well as the materials that are presented. If you have any questions for the panelists, you can submit those through the Zoom Q&A function at the bottom of your screen. And I just want to thank all of you who did submit questions as well as comments and perspectives on yesterday's discussion. That was very helpful for increasing the robustness and the range of the topics we talked about. And I hope people feel free to contribute again today, and we'll try to get to as many of those as possible. Because we are recording, we want to remind our speakers to please check that your camera and microphone are active before you're speaking. If you have any di#culty activating your microphone before speaking, our production partner can remotely activate and deactivate your microphone on your behalf. Also as a reminder, when you're not speaking, if you could stay on mute to minimize the background noise and activity. Also as a reminder to the presenters, Thomas Roades will be advancing the slides today. Remember to provide a verbal cue. Just let him know when you're ready to move to the next slide. Additionally, Mira Gill will be providing timing reminders to our speakers and panelists through the Zoom chat function, too. 2 of 54 6/26/24, 8:34 PM Safe Use of Benzodiazepines: Clinical, Regulatory, and Public Health P... https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425015-dt-... We encourage all of you to join us, not only through the Q&A, but also on Twitter, @DukeMargolis. Or you can use the hashtag, #SafeUseBenzodiazepines. Safe use benzodiazepines. So with that, I think we're ready to move on to the "rst session for today, session three for this two day meeting, on key themes emerging from replication e!orts. So this is focusing on health professional, patient advocate perspectives, I should say, on best practices, experiences, and concerns. To kick o! this discussion on best practice, experiences, and concerns from health professionals and patient advocates, we've got three presentations. First, we'll hear from Steven Wright, who's the medical consultant for the Alliance for Benzodiazepine Best Practices. Steven, thanks for your chat and Q&A contributions to the discussion yesterday as well. Barbara Farrell is our second speaker. She's a pharmacist with the Bruyere Continuing Care Geriatric Day Hospital, and senior investigator with the Bruyere Research Institute in Ottawa, Ontario, Canada. And next, Sangeeta Tandon, who's a pharmacist member of the Professional A!airs and Stakeholder Engagement Sta! in the O#ce of the Center Director at FDA. After those three presentations, we're going to hear from four panelists before diving into a moderated discussion. Our panelists for this session are Chinyere Ogbonna, who is the medical director of Addiction Medicine and Recovery Services at Kaiser Permanente, San Jose, and adjunct faculty member at Stanford University, Sumit Agarwal, who is a physician and health policy researcher at Harvard Medical School and Brigham and Women's Hospital, Christy Hu!, who's cardiologist and director of the Benzodiazepine Information Coalition, and Scott Winiecki, who is director of the Safe Use Initiative at the FDA. So a great range of perspectives and a lot of people to hear from. Let's get started. I'd like to turn this over to Steven Wright. Steven? Steven Wright: Good morning. Mark McClellan: Good morning or afternoon, yes. Steven Wright: Or afternoon. That's exactly right. Let's see if this works. Okay. Hi, my name is Steven. I'm a recovering benzodiazepine overprescriber. It's true. I grew up in family medicine. Started doing addiction medicine about 33, 34 years ago, 3 of 54 6/26/24, 8:34 PM Safe Use of Benzodiazepines: Clinical, Regulatory, and Public Health P... https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425015-dt-... medical pain management about 17 years ago, and along the way came benzodiazepines. And I did what my mentors, my attending physicians taught me to do, use them probably not in excess like we've seen in other circumstances, but nonetheless, as I was taught over a long period of time. And I found that indeed about four or "ve years ago, that a lot of these assumed received knowledge information was really untrue. So I acknowledge for those of you that are benzodiazepine survivors that hung in there with us when I wasn't listening in this particular space. And just like with opioids, we have distress among individuals that have pain, that have benzodiazepine use, and we get confused often as to which is causing the problem. Is it the underlying condition, or is it the substances that we're using in and of themselves? I want to start out by highlighting an important thing that for most individuals with BZRA-related problems. That's benzodiazepine receptor agonist, because it includes benzodiazepines as well as Z-drugs, as well as the barbiturates so that it is related to physiologic dependence and not so much addiction. We took a look at the addiction- related issues, non-medical use issues. That probably is not the most important feature. Although, we don't have data relative to the numbers in relation to that, but there are many out there. So disclosures. Primarily I'm involved with the Alliance for Benzodiazepine Best Practices. I'm involved doing benzodiazepine activities in other domains as well. The Action Work Group in Colorado, NEMA Research, and some research initiatives through The Schreiber Research Group and Stader Opioid Consulting. The only commercial disclosure that I have, Cordant Health Solutions drug testing and pharmacy services, which isn't relevant for our discussion today. So today, I want to have some remarks about the best practices, highlight limiting duration to two to four weeks, and then outline some basic deprescribing practices as they go along. So the best practices overall, we want to encourage limiting initiation. For this, the supplemental sides outlined that, and I put that into the Q&A and chat yesterday. Limit duration of use to two to four weeks, and there's a rationale for that. And then for those individuals that are on benzodiazepines or related substances, slow, safe, supported, and shared, though patient-led, tapering to discontinue use. And we'll go through some of that as well. Prescribing itself begins with the informed consent, and that's a standard process that 4 of 54 6/26/24, 8:34 PM Safe Use of Benzodiazepines: Clinical, Regulatory, and Public Health P... https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425015-dt-... we use for all medications and all procedures that we provide to patients. That encompasses the risk, the bene"ts, the alternatives. And I'm encouraging the use of a written informed consent, which is available through the Benzodiazepine Information Coalition site, as well as our site at the Alliance, and is authored by Christy Hu!, who will be speaking on the panel here as well. The other piece to this is how to prescribe benzodiazepine is really a relevant part of informed consent. How these are used and whether there should be, as I argue, limitations on their use as well. So what about the utility of benzodiazepine? Short-term e#cacy has been well demonstrated, and we see that in many studies in many populations. However, we also know that cognitive behavioral therapy in relation to anxiety works just as well. And get this. It is durable 12 months after completion of the cognitive behavioral sessions. That's pretty great, because we want durability of response with regards to the various interventions that we provide to patients. However, we also "nd that bene"t often declines after that initial bene"t is realized, and that's a challenge. We have not seen, in good methodologic studies, long-term e#cacy. This is a research concern for those of us in the "eld. We see when we look at the online communities that indeed, those communities have expressed how benzodiazepines have lost e#cacy over time. And in fact, we see a circumstance where benzodiazepine cessation actually can improve anxiety and seizures, and there are a number of articles that re$ect that. And indeed, I think of this as an entity that could be called benzodiazepine-induced hyper- anxiogenesis, because we see on re$ection retrospectively, a cohort of individuals that get better with regards to their anxiety. So this is the covert issue that my attendings never taught me, that indeed, the medication, just like with opioids and opioid-induced hyperalgesia, there's a cohort of individuals for whom the substances actually create the problem intended to help. Even so, 80% of those that are on benzodiazepine and Z-drugs have been taking them for more than six months. We heard of a study yesterday where one-third on long-term use. This is one that used NHANES data published in 2018. In any case, the majority of individuals are on for a very long period of time, and I would argue without a validation in the re$ected literature. So what do we look at in terms of best practice? These are just some of the highlights 5 of 54 6/26/24, 8:34 PM Safe Use of Benzodiazepines: Clinical, Regulatory, and Public Health P... https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425015-dt-... that I think I've learned over time. I think it's important to prescribe for indications only when individuals are functionally impaired. Just like with opioids, it's not just the symptom in and of itself, it's whether or not these symptoms result in functional impairment. So that's the primary indication. At the same time the benzodiazepines are prescribed. If they are, prescribe an alternative treatment. These very often take longer to work. And while you use the benzodiazepines short term to bridge the gap, bridging to the e!ectiveness of an alternative Rx is often the way to go. Follow-up then weekly with weekly prescriptions, and discontinue by week four, while the other alternative treatments are moving into e#cacy. And then for the cohort of individuals that are on long-term benzodiazepines, discontinue benzodiazepine for all that are on greater than one month. Now, this is an o!er that ought to be provided to individuals. It should not be forced, with the exception of one thing, and that's in the circumstance when individuals have identi"ed respiratory depression of a signi"cant sort. This often occurs in relation to co- prescribing with opioids. And there, it's really imperative for us to move towards discontinuations for the safety of patients. But the o!er ought to be there to all individuals on benzodiazepines for more than a month, that discontinuation can take place and for them to consider doing that. Initiate the tapering, which we've discussed to a certain degree already, by reducing just less than 5% of the original dose. The reason is that there is a cohort of individuals that larger reductions, and these have been described in studies, this cohort does not do well with a 25% reduction or a 10% reduction. What can happen is that subsequently if the 5% reduction is very easy and not a problem, you can enlarge on that in the prescribing space. But adjust this tapering amount and the frequency of reduction according to individual response. This is important. This is patient led. This upends the model that we usually have, where the prescriber is taking the lead on all this. But it is the expertise of the patient, their individual response, that really counts in terms of the amount of tapering and the frequency of tapering reductions. Listen, validate, and support. And it may take 12 to 18 months to complete, or even longer than that for some individuals. Benzodiazepine withdrawal is a di!erent animal. It can take far longer than that for other substances. Even years of this, we've heard. I've heard up to 11 years and more in individuals. And it brings to mind the possibility that we're dealing with an injury 6 of 54 6/26/24, 8:34 PM Safe Use of Benzodiazepines: Clinical, Regulatory, and Public Health P... https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425015-dt-... syndrome, where there may be durable adverse e!ects for individuals over a long period of time, and this needs to be supported as well. Symptoms can be wide-ranging, severe, very unusual, they may seem to be quite bizarre. There's a tendency for us to think of alternative diagnoses or psychosomatic processes going on. We need to evaluate, as clinicians, the possibility of alternative diagnoses, but not to sit there forever, thinking that the patient simply is in denial about an addiction which isn't there or another diagnosis that indeed is not there, but to validate their concerns. Symptom patterns often $uctuate dramatically, and this is unlike any other substance withdrawal. In 1984, David Smith actually introduced the concept of this $uctuating pattern. Heather Ashton spoke to this in the 1980s about waves of worsening, windows of relative relief. This puzzles us. These are not necessarily environmentally stimulated, something bad going on in the environment, hopping up the symptoms that patients have, but they occur in these waves and windows unpredictable and uncertain in terms of duration. It is usually not a benzodiazepine use disorder per se, and so addiction treatment is not helpful. We hear anecdotally of individuals entering treatment centers, and they're mysti"ed by 12 step and those sorts of things, because craving is really not part of their experience, they're just having di#culties with the discontinuation process. This is unlike other addiction-prone substances, where we often see addiction as the background for the di#culties in withdrawal processes. So for those of you that are benzodiazepine survivors, this is not news. For those of us that are researchers, there are major questions that remain unanswered. That includes really redoing all of the studies way back in the day, because the methodology was o!. And I understand we didn't know about how to do methodologically these various studies for e#cacy or adverse e!ects. And then the background etiology and mechanism for physiologic dependence and injury as well. As well as then to manage benzodiazepine discontinuation. There are a lot of ideas out there. The data is quite limited in terms of the options out there as well. And then for us, as prescribers. Much of the received knowledge about benzodiazepines, I found to be untrue, and we need to recognize this. We need to acknowledge the experience, the lived experience that are expressed by our patients. We need to check out the alternative diagnoses, but not forever, and validate for these patients the reality of that. Update our knowledge in relation to that. Engage and allow 7 of 54 6/26/24, 8:34 PM Safe Use of Benzodiazepines: Clinical, Regulatory, and Public Health P... https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425015-dt-... our patients to lead. They have the expertise in their own experience that drives the process for how fast to move through a withdrawal process. And then to become benzo-wise. That's what it means to be benzo-wise in this particular space, and important to do that. One last thing. There's a quote out there, "Pain is real when you get other people to believe in it. If no one believes in it, it's madness or hysteria," Naomi Wolfe. She could have just as well said benzodiazepine withdrawal experiences is the same thing. Because indeed, individuals that are in this space and challenged by their experiences, and those of us in this prescribing space, not recognizing and not validating their experiences, this is quite di#cult. Feel free to reach out to me through my email, as well as through the Alliance for Benzodiazepine Best Practices. And I'm going to step away at this point. Thank you very much to Duke-Margolis and the FDA for putting on this program. Adam Kroetsch: Great. Thank you, Steven. Next, we're going to hear from Barbara Farrell. Barb? And we'll get your slides ready in a second. Barbara Farrell: Awesome. Thanks very much. I'm really pleased to be able to speak today. I really enjoyed listening yesterday afternoon. And I'll just get started right away. If you want to move ahead to my next slide, please. Since 1999, I've been working in a geriatric day hospital. I want to start my discussion by saying that yesterday, we talked a lot about benzodiazepines in terms of abuse, dependence, especially with respect to concurrent use with opioids and other drugs of abuse. My clinical experience is di!erent in that I'm dealing primarily with frail, older people who are struggling at home with cognitive impairment, falls. General frailty and weakness that's a!ecting their independence. So not typically people who are struggling with abuse or other dependence issues, although sometimes. My role in the geriatric day hospital, which is an interprofessional team of healthcare providers, is to work with patients and the rest of the team to try to minimize di!erent types of drug-related problems. That's often through deprescribing, reducing doses, or stopping of medication. So I'm going to speak primarily to that experience as a clinician and also through my knowledge of the literature. One thing I wanted to say was I was so thrilled to hear Lucinda Busto's name mentioned yesterday, because as an undergraduate and then a graduate student, she was one of my supervisors back in the '80s and early '90s. So I think a lot of my interest 8 of 54 6/26/24, 8:34 PM Safe Use of Benzodiazepines: Clinical, Regulatory, and Public Health P... https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425015-dt-... in this area stems from my work with her. For the last 20 years, I've been working in this geriatric day hospital environment, and I have found that most of my patients have started using benzodiazepines for insomnia, often for grief and then it was continued on for long periods, or during hospitalization. Di!erent studies showed that somewhere between 10 and 40% of people started and continued on a chronic benzodiazepine from their hospitalization period. So these medications, as you know, are often intended for short term, but they're continued long term. So it's not unusual for someone to say to me, "That was started 15 years ago when my husband died, and then it's just continued." The impact that we "nd in our patients is that often alone or in combination with other CNS depressants or anticholinergic medications, they have cognitive impairment, daytime fatigue, and sedation. I keep a little list of the kinds of things people say to me, "It's so hard to get going in the morning. I have no energy. My friends are all still doing things together, but I can't concentrate. I must be getting old." And they often will describe a sort of a hangover e!ect that they have in the morning, and they seldom feel well rested when they wake up in the morning. In addition to that, we've got the falls and fractures risk, risk of motor vehicle accidents, and all of these potential issues. You would think it would be easy to stop a medication that might be contributing to these problems, but it's not. So I think a lot about why is it challenging to stop, and there's a number of reasons. First of all, most of my patients have tried to stop at one point, but the common refrain is, "That's the drug I never miss. I tried stopping once, and I couldn't sleep, so I "gured I needed to keep taking it." They also will say things like, "Well, it must be safe, because my doctor keeps prescribing it. I keep getting re"lls." So there's this sense that it's a safe medication. And people often feel very defensive or targeted about this medication. We could go through a list of 16 medications, and they'll chat about each one. And then we get to the Ativan, and they'll say, "My doctor's always after me to stop that one. I don't even want to talk about it." So instead of talking about the medication, I usually start by talking about the reason they're taking it. And for the most part, this is sleep. So I try to understand more about their sleep history. It helps me understand what other factors might be contributing to problems with sleep, what other medications might be contributing, what's modi"able in terms of insomnia management, and their 9 of 54 6/26/24, 8:34 PM Safe Use of Benzodiazepines: Clinical, Regulatory, and Public Health P... https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425015-dt-... perception of the risk bene"t of the benzodiazepine medication. That really helps inform the next conversation, which is around shared decision-making, as Steven mentioned. So if we could go to the next slide, please. Following this discussion about why they're taking the medication, I typically ask when it was started, why it was started, what has been their experience with taking it, how well they think it's working, what happens if they miss a dose, the potential impact on the issues for which they're coming to the day hospital, such as weakness, daytime fatigue, falls, et cetera. Then we would talk a little bit more about how to make the decision about whether to continue with the medication or not. This involves discussing both the risk and the bene"t of continuing and the risk and bene"t of stopping. So in terms of continuing with a benzodiazepine, we have all of the side e!ects we've talked about already, falls, fractures, daytime sedation, memory problems, respiratory exacerbations, cognitive impairment, motor vehicle accidents, et cetera. And I talk about the fact that even though they've been on it for 15 or 20 years, with seemingly no problem, that they are in fact more vulnerable to side e!ects as they age for a variety of reasons. In terms of potential bene"t, again, I'll go over that we have the short-term studies that show you get to sleep "ve or 10 minutes faster. You may sleep 25 minutes longer. But these studies show that after a few weeks of use, that those e!ects go away, but that sleep architecture, so restful sleep, is not preserved when you're using a benzodiazepine, and that the other adverse e!ects remain. We also go over the risk and bene"t of stopping the benzodiazepine. I like to start with the bene"t. You might have fewer falls. We know from studies that if we stop a benzodiazepine, your thinking ability will improve. There's a great study by Curran in 2003, that showed improved performance on a number of cognitive and psychomotor tests six months to a year after stopping benzodiazepines. So talking about what's the long-term bene"cial impact. Your ability to remember information will likely improve. Your ability to mentally manipulate numbers will likely improve. So card playing might get easier. This sounds weird, but it's a common challenge in older people, that they have more trouble playing cards. And that's something they enjoy doing, and so they want to be able to do it again. They will be able to process information and react more quickly, which could have an impact on their ability to maintain their driver's license. So all of those 10 of 54 6/26/24, 8:34 PM Safe Use of Benzodiazepines: Clinical, Regulatory, and Public Health P... https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425015-dt-... discussions help inform this shared decision-making discussion with the patient. The next step in shared decision-making is to discuss the di!erent options, which could include a variety of tapering plans. My "rst bullet there is, "Can you abruptly stop a benzodiazepine?" Years ago, I would've said no, because I was quite convinced that everyone would have withdrawal reactions. But what I found working in the day hospital is that quite a few people actually do abruptly stop their low dose of Ativan or oxazepam that they've been taking. This wasn't really purposeful, but I would talk about the bene"ts, the risks, what potentially we could do, tell people, "Why don't you take a week or two to think about it? We'll talk about it again." And then when I follow up with them, they say, "Yeah, I stopped that," with seemingly no withdrawal at all. So I know that that's possible in some patients. The challenge is we don't know necessarily which patients that's going to be possible in. So typically, we work together to develop a personalized tapering plan. That's consistent with what doses are available with that medication. There is data to show that the longer you've been taking a benzodiazepine and the higher dose, the longer you will likely need for a tapering plan. One of the things that we do not do in our practice is switch to a long-acting benzodiazepine. That's because we're concerned about potentially worse side e!ects in our older patients. And I have not been able to "nd studies that show that switching to a long half-life benzodiazepine in an older person alleviates withdrawal symptoms more than a slow taper of the medication that they're already on. There's also the concern when you switch to a long-acting agent, and I've seen this happen many times, is the patient, it continues on both the short-acting and the long- acting, because the decision gets made to change, but there is no prescription written to stop the short-acting agent. So sometimes the patient continues on both inadvertently. In terms of monitoring, we monitor "rst for the positive bene"ts of stopping a benzodiazepine. And our patients, the fatigue, typically the daytime fatigue will typically improve within a week or two of making a dosage reduction in benzodiazepines. And people are really... They're reinforced by that improvement. And cognitive tasks can take a little bit longer over, say, six months or so. The rebound insomnia, which is the most common withdrawal e!ect that we see in our practice, tends to occur within the "rst few days of the last part of the reduction or 11 of 54 6/26/24, 8:34 PM Safe Use of Benzodiazepines: Clinical, Regulatory, and Public Health P... https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425015-dt-... stopping of the benzodiazepine. I "nd in general that people, when they understand that that is going to happen and they know the timeframe within which it's going to happen and they know that it will get better within a week to a few weeks, they are willing to commit to that. Most of the time, people have never been told that the rebound insomnia will eventually go away. And I'm not saying, and I know Steven is talking about perhaps a di!erent group of patients. I'm not saying that that happens for all patients, but in my frail, elderly geriatric day hospital patients, that's what I tend to see. Anxiety as well can be there for a few days, and typically also improves. So I check in with those patients every few days after a dosage reduction or a cessation. The other thing that I do is have people pick a start date or a stop date. Really, a start date for tapering and a stop date for stopping, similar to how they would choose a stop date for smoking cessation. Doing that actually has also allowed me to "nd out more about how people want to stop. So a lot of people would choose to stop on a weekend or just before a few days when they don't have anything planned. I had one fellow tell me he was going to stop while he was away visiting someone, because he'd be staying at a hotel and he always got a fantastic sleep at this hotel. So that led us to a discussion of the fact that he hadn't bought a new bed mattress for 20 years. And ultimately, his intervention was buying a new mattress, and then he was able to stop his benzodiazepine. In terms of support, I would help them to identify and avoid substances that can worsen sleep, so di!erent medications, ca!eine, alcohol, salbutamol right before bedtime. Albuterol in U.S., pseudoephedrine. Anything stimulant is obviously going to cause insomnia or worsen anxiety. There are a lot of di!erent guidelines, educational pamphlets, sleep hygiene approaches, CBTI approaches that I'm going to cover in the next few slides very quickly. But I "nd in general, the most important thing is to provide reassurance that withdrawal is temporary and manageable and accompanied by improved cognition, and to provide a timeframe around when we expect to see those symptoms arise. So if we can go to the next slide, I just wanted to point out a number of resources. I was involved in a team that developed an evidence-based deprescribing guideline for benzodiazepines receptor agonist, speci"cally when they were being used for insomnia. So this doesn't apply to other conditions where benzodiazepines are potentially appropriately used. And those are listed in the inclusion criteria on the algorithm. So the algorithm is here on the left hand of the slide, the front and the back pages. 12 of 54 6/26/24, 8:34 PM Safe Use of Benzodiazepines: Clinical, Regulatory, and Public Health P... https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425015-dt-... There are sleep hygiene strategies, both for community dwelling folks, and also for people living in residential care highlighted there. This guideline is available open access in Canadian Family Physician. It is also part of an app that you can get through the IAM medical guidelines. The app is great because it links di!erent parts of the algorithm, which you see on the left to the content and the actual guideline and the references. On the bottom here, you see a patient pamphlet that we developed that essentially repeats the information in the guideline, but in a format that's a little bit more accessible to the public. And all of these are available on our website deprescribing.org. And I also wanted to point out this testimonial on our website. It's a short little 2, 3 minute video with a patient who went through the process of benzodiazepine. Deprescribing this particular lady had been taking it for some severe anxiety. And I think it took her about six months to stop the medication, but she talks about her experience, which can be very helpful to patients, to people who are new to the process and trying to understand what to expect. Next slide. We also have an infographic based on our algorithm that can be used as a poster in a pharmacy or clinic o#ce to alert people to discuss this medication with their drugs, or sorry with their prescriber. I also wanted to point out the Canadian Deprescribing Network, which hosts a number of patient handouts developed by Dr. Cara Tannenbaum and her team in Montreal. You may have heard of the Empower guide and this particular pamphlet has information about benzodiazepine myths around side e!ects of the medications, and then tapering strategies, including a pictorial representation of how medications might be tapered. And they've actually shown that by mailing this to patients, they can reduce benzodiazepine use in the community. I would also encourage you to check out the Sleep Well website, which was developed by Dr. David Gardner and Andrea Murphy in Halifax. And they have put together a lot of resources around cognitive behavioral therapy for insomnia as an approach to reducing benzodiazepine use. So I also share that website with patients, as well at the Mayo clinic has similar information available on CBTI. Next slide. And then also in Ontario and Canada, we have the Center for E!ective Practice, which has a number of di!erent algorithms and educational pamphlets available around benzodiazepine use, a little bit more focused on alternatives. So for example, if someone has anxiety, what could that alternatively be treated with? So it's helpful from that perspective. And then recently the Canadian Coalition for Seniors Mental Health developed a guideline around benzodiazepines use disorder in older adults. And of course there's the Ashton manual, which has useful information, particularly for people who are really struggling 13 of 54 6/26/24, 8:34 PM Safe Use of Benzodiazepines: Clinical, Regulatory, and Public Health P... https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425015-dt-... with benzodiazepine dependence. And I know I've talked a lot about a very speci"c population, which maybe doesn't have the severe dependence issues with the severe withdrawal that other people may have, but I "nd on occasion that this resource is helpful for people, as well. And I think we'll go to my "nal slide now, which are my thoughts around avoiding chronic benzodiazepine use. And I think for me, it's important for prescribers to begin with the end in mind, always thinking that particularly for insomnia, mild anxiety, that benzodiazepine has been used as a temporary strategy, maybe as short as seven days, maybe a few weeks. Always use low doses, as Steven said. Decide and talk about the exit plan upfront, as soon as you prescribe. Prescribe small amounts, and this is important even at hospital discharge. There's probably not a need at hospital discharge to give someone 30 tablets of a sedative, if they've only been using it to help them sleep in the hospital. So a few days to help them get sorted out at home. And that's it. And then look at nonpharmacological strategies, particularly in the hospital around safe sleep protocols, education for sta! and prescribers, both of which have been showing to reduce benzodiazepine chronic use. Removing benzodiazepines from the admission order set, and again, limiting discharge quantities and providing a deprescribing plan. And then just in thinking over the last day or so, and even listening to Steven, I'm thinking about gaps in education and research. And I think I do think we need more rigorous qualitative information about the experiences of people going through benzodiazepine tapering and their preferences would be helpful, particularly in di!erent groups, such as the frail elderly. I do think it would be valuable to study tapering protocols because we don't really know which ones work best. And we don't know what the risk factors for withdrawal are. And now I'm even wondering listening to some of the presentations yesterday, and to Steven, as well, is there something di!erent about the frail elderly group that they do not necessarily experience the severe withdrawal that other people do? Because that has not been what I have seen in 20 years of practice. So I'd be really interested to hear comments about that from the panelists later on. And I'll stop there and I'll look forward to the discussion. Thank you. Adam Kroetsch: Great. Thank you, Barb. Next up is Sangeeta Tandon. Sangeeta. It looks like you may be muted, Sangeeta. You may have your microphone muted Sangeeta. You're not muted on Zoom, but you may still be muted. Can others hear Sangeeta? 14 of 54 6/26/24, 8:34 PM Safe Use of Benzodiazepines: Clinical, Regulatory, and Public Health P... https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425015-dt-... Not able to hear you yet? It may be a problem on my end, so let me... Oh, okay. So we just got con"rmation that, yeah, it sounds like your microphone may not be working, Sangeeta. We're going to try one more time, and then we may need to move on to our panelists, and we'll try to come back to you. I'm afraid the audio is still not working. We're going to move on, I think, to the panel, and in the meantime, we can try to do some troubleshooting o%ine. So with that, I know that folks are going to be eager to hear your thoughts and the thoughts from the FDA team, and I hope we get to circle back to that. But we'll start with some panelist remarks and then when we get you up and running against Sangeeta, we'll jump right back over to you. But maybe for some initial reactions, Chinyere would love to hear some of your initial thoughts. Chinyere Ogbonna: Can you guys hear me? Okay. Okay. Adam Kroetsch: Loud and clear. Chinyere Ogbonna: Great. Yeah. I thought the slides that were presented were really great. And I could think of a lot of patient experiences that I've had or interactions that I've had that