New Clinical Guidelines for Mood Disorders: Management of Major Depressive Disorder and Treatment Non-Response

Welcome to another PsychMatter's podcast from the Royal Australian and New Zealand College of Psychiatrists. Psych Matters is a series of discussions on training and practice issues facing trainees and fellows of the college. In this episode of Psych Matters, Professor Jim Mali and his guests discussed the 2020 Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. This discussion is the second in the series and focuses on management of major depressive disorder and treatment on response. So welcome everybody to this second podcast in a series of three in which we're going to be discussing in greater detail mood disorders but specifically depression. The first of these podcasts, if you haven't already heard it, discussed classification and diagnosis and the third one will be addressing specifically bipolar disorders. In this podcast, we're going to focus on the management of depression, though of course we will touch on diagnosis and classification very briefly where necessary and also discuss some paradigms and approaches. As in the first podcast, I'm joined by some illustrious colleagues, all of whom contributed to the guideline development and I will introduce them now. We have Greg Murray from the Swinburne University of Technology, Phil Hazel, Phil Boyce, Erica Bell and myself from the University of Sydney and Malhopwood who's at the University of Melbourne. We might kick off by first of all describing a little bit about the general approach we've taken in developing these guidelines and I'm going to turn to Erica here to talk us through the foundations and how we've built into that our approach of actions, choices and alternatives. When we were putting together the guidelines, one of the main challenges was trying to work out how best to show where each type of treatment sits in a treatment algorithm or management plan for depression and bipolar and the paradigm that we developed is the actions, choices and alternatives paradigm. The thinking behind it is that actions are essentially things that you must do. Choices are choices in that. We've guided the choice to be a select pool of agents or combinations of agents and then alternatives are the final step in that treatment algorithm. The most important concept behind this is that each of those layers are helping an individual with a mood disorder to achieve functional recovery which is our aim in treatment. The actions we've described as the foundation for treatment. They should be in almost all circumstances administered or in all circumstances administered. In most individuals that may be all that's required to achieve functional recovery. However, even if functional recovery isn't completely achieved with just psychological interventions or lifestyle changes, they serve as an important foundation for ongoing treatments such as pharmacotherapy or physical treatments. That was the thinking behind the foundations of treatments paradigm that we came up with. This is quite a significant departure from other guidelines which try to compartmentalize management and we've tried to incorporate everything into this foundation because we firmly believe that there are many strategies that are important in alleviating depression that we often overlook and don't take responsibility for. Even checking them or reassuring patients that we're examining these aspects is important. We've put those front and center. One of those is the incorporation of psychological therapies as a front line, as a must do, as a part of the actions. The other actions are fairly straightforward in as much as they're obvious. They're not easy as we discussed last time but they are imperative and have to be given consideration on each occasion. For example, lifestyle interventions. Stopping and cessating smoking and drinking and other illicit substances. Alongside psychoeducation, psychological therapies. To elaborate on these further, I'm going to ask First Greg Murray to talk about psychological therapies and even within that, to perhaps elaborate as to how we evaluated the evidence. Thanks, Jen. This is a really important part of the guidelines and does in fact represent a bit of a shift from the 2015 guidelines where in the 2015 guidelines we used probably a more traditional or familiar perhaps logic to selecting psychological versus pharmacological interventions. The 2015 guidelines took that more traditional approach of really asking an overarching question about severity with less severe versions of depression being offered psychological treatments but one severity gets up. We probably need to move to antidepressants. It turns out that the literature, the evidence actually doesn't support that distinction. So we've moved away from that but we will talk a little bit in a minute about how severity or particular clinical features in the individual case are not being overlooked but just using severity as an overarching logic has been removed. So in the current 2020 guidelines, we are recommending that everyone is offered one of the evidence-based psychological therapies for acute depression. There are now at least six brands of psychological therapy that have received evidence support in more than 10 randomized control trials but as everyone will know CBT is the one that has had by far the most attention followed by interpersonal psychotherapy, IPT and so they are the two that we are expecting people to draw from. Remembering that the trials that show these things work always involve clinicians trained specifically in that modality. So it's not as if people can just pick up a book on CBT and say, "Well, I know how to do CBT, I'll administer that." The logic of the evidence base is very much tied to the clinician having specific training in that therapy. So we're expecting that most people will be offered probably CBT followed by IPT. Just a couple of other things, if I can, the other things that have changed since 2015, obviously, you first thought as a clinician is, "Well, maybe there are access problems with the psychological therapies." But of course, 2020 was a tipping point in that because of the rapid uptake of digital delivery. And so as part of these guidelines, we did a significant investigation of the evidence around ICBT, Internet CBT, and the evidence is very strong that it is as effective as face to face CBT. Of course, there's some caveats on that. Information you get from a trial is not exactly the same as what we're going to experience in real-world practice. So it remains the case that when it comes to digital interventions, which do overcome the accessibility problem, there is still an issue. With the fact that the individual client needs to be strongly motivated to engage. So we're not ignoring that. And then just finally, I think we're paying more attention to patient preference in these guidelines. And it's well known that something like three quarters of people with depression prefer psychological treatments over antidepressant medication or physical treatments. And so we are taking that into account. And that's why they've ended up in this foundation step of the framework. And I think that prominence is evident throughout the document. And time and again, we emphasize that. But I'm glad you've talked about the other two issues, one of which is the preference from patients perspective. They certainly want to have talking therapies. And the second, the logistical issue of access, which I think is a big limitation and something we need to examine and keep on the radar as it were. So one other component which you've not touched on is the communication between psychologists and psychiatrists and primary care physicians, which is something we haven't addressed directly in the guidelines. But this is another contextual problem that we do have to examine and understand that that is not 100% at present and needs to be improved. Yeah, there's no doubt about that. We actually do so a couple of things right at the front of the guidelines about encouraging people to be very aware of the context in which they are working. So a recommendation to offer psychological treatment for acute depression does put responsibility on the person providing. that treatment to think about, you know, do they have acute emergency backup? Do they have a relationship with a prescriber such that if the psychological intervention is insufficient, we may move to combined treatment, which we do know, is the strongest most effective treatment for depression, is the combination of psychological and anti-depression. So those contextual and relationship features of where the clinician is operating and how they communicate with other professionals involved in treatment. We really are making a strong point about that that that's a professional responsibility and we can't think about these interventions in isolation of the context in which they're being delivered. I've just on the regards to psychological treatments, one you haven't mentioned, Greg, and that a lot of our colleagues would be doing as a matter of routine is dynamic psychotherapy. Is that an appropriate treatment as well? I certainly think it for some patients, dynamic psychotherapy is a very good approach to treating them as a sort of basic action. Yeah, that's a good point, Phil, and as you know, we went through a bit of a loop around that. One of the six evidence, what we call evidence-based psychological treatments, that have been subjected to randomized controlled trial, which of course is not the be all and end all of assessing the quality of an intervention, but it is one point. One of those six is short term psychodynamic psychotherapy and by short, and that's a specific branded therapy with a structure, and by short term we don't mean 10 years, we mean a number of months. That is one of the evidence-based psychotherapies. And then we did a review of the literature on the more longer term psychodynamic therapies and the psychoanalytic therapies. And I'd encourage people to have a look at how we've summarized that debate in the guidelines, because it is a bit of a nuanced story. But really it's one of those very interesting issues in mental health where there is polarization. There's a camp of people who strongly believe that longer term psychodynamic therapy because of its targeting, perhaps potentially, of more personality basis of the depression, is inherently more valid and maybe is more difficult to generate evidence for than the shorter term, more symptom-focused evidence-based treatments. And then there's another camp that says, "Well, we really are concerned about, as it were, letting therapists make it up as they go along, that there's no constraints on their behaviour and there is a camp of people who think that it is the heading psychodynamic that does, perhaps, commit some unconstrained practice or more improvisational practice. They're two different camps. It's a polarized literature and in fact some of the people who are really expert in that literature say it's a real problem that we're it's hard to stand above those almost ideological issues. But yeah, we've written a lot about it in the guidelines. Greg, with all the psychotherapeutic modalities, does patient characteristic and therapist characteristic make any difference? We don't have much data on that. In practice, what tends to happen if you go and see a psychologist, you will receive the therapy there, expert in. And the other thing that that leads to, of course, is the brands, CBT, IPT, short term, psychodynamic suggest that these things are probably more different than they actually are. And we also mentioned in the guidelines some work that some of us have done, which show that we still don't understand the mechanisms of action of the psychotherapies and there are generic factors across the psychotherapies that do account for a lot of variance. So in short, we don't have a sort of rubric about, you know, this person might benefit more from psychodynamic, though there are some hints that personality features in the case. And that's what many people believe that personality features in the case would lead us more to a psychodynamic orientation. CBT is very practical and quite behavioral. So more people who have that sort of aesthetic preference may warm to that more. But in practice, what tends to happen is you get the therapy that the therapist is skilled in providing. And we don't have any strong data to argue against that. Which is a problem in and of itself because what we're trying to sort of get everyone to have an understanding of is that you need to tailor treatment to the patient's needs, not what your capabilities are or what your preferences may be. And so that's a key point that we need to bear in mind. I'd like to move on to lifestyle issues because that's another key innovation in our guidelines where we've put those right at the front as being mandatory, at least for consideration. And I was wondering, Phil, boys, if you could perhaps say a few things about the kinds of recommendations we've made. Yeah, look, I think there's a really important aspect of treating depression. Firstly, I think in the assessment phase of treating someone who's depressed, we really need to be trying to tease out what sort of lifestyle factors may be contributing to the patient becoming depressed. And what lifestyle factors may be maintaining the depression. Because unless we address those, the depression is going to persist. And I think the ones we focus on are obviously sleep. That's a very important factor. And it's surprising how this can affect people. I recall a patient who was a student and he would sort of start working on an assignment at sort of 10 o'clock at night, finish at about four or five o'clock in the morning and then not get up during the day and was feeling miserable. And he didn't carry out his normal activities. He used to be very keen on going to the gym. So and he had been through multiple antidepressants and wasn't responding. So working with him on having a regular sleep wake pattern, getting him to go to bed at a reasonable time, making sure he got up at a regular time every day, sort of basics of sort of social rhythm therapy and encouraging him to go back to the gym. A week later he said, look, I've been going to bed, you know, sort of 10 o'clock at night and getting up at eight in the morning. I've been going to the gym three times a week and I'm feeling terrific. The problem was he didn't keep it up and kept slipping back into the old patterns and kept getting depressed again. So this is really hard work but very, very important. One thing I think is coming through now and there's getting it to be an evidence base is about how diet can affect mood and we really want to be asking about diet and certainly where I work in the west of Sydney, the diets aren't the healthiest and getting people to work towards having the classic Mediterranean diet rather than focusing on fast foods which is going to contribute to their depression. But anyway, encouraging patients to have a healthy diet is really important. Also, I encourage them to stop smoking or cut down smoking, reduce substance misuse, certainly to cut down the amount of alcohol they drink or all key aspects in management and we go through a series of sort of strategies that you can to help patients have a regular exercise, improving their sleep quality and addressing smoking. And I think it makes some very good points there feel about the longevity of these treatments in terms of us having to persist with them. And certainly in my practice, I've become much more forgiving of people not being able to sustain a particular diet or exercise regime or even maintain sleep rhythm. Their job may not allow that for example if they're working shifts. So I think as doctors as psychiatrists, we need to work with our patients and try to tailor whatever advice we can and keep repeating it. I think that's the key. I don't think we should ever give up. And that's really why we have put them front and center of the guidelines as being important reminders and not in a punitive way, not in a embarrassing way, but to really an encouragement that we need to provide at every consultation. And just as a checklist to see how things are going and are they being able to address those and part of that's also checking things such as motivation, which is a core feature of depression. Feel you want to add to that? Yeah, just kind of, sort of things like exercise is also built into CBT where you have a great response. So giving them setting goals each day for a matter of exercise and whether they've achieved a certain goals, that's also a very, very important aspect of it. And it really is important in improving self-esteem. I just want to add in the context that I listen. So we're going to focus on one thing, it's sleep. Because it's a big challenge anyway. Adolescents naturally have sleep phase delay. They want to stay up later and sleep in longer the next day. And those who are at risk of depression or are already in a depressed state will tend to stay up even later. That combined with adolescents high usage of devices at night is quite a risk factor. So when we're providing cycle education to adolescents who are depressed or at risk of depression, we always talk about our surrendering devices. And our also for bedtime definitely not allowing them to be using social media after sleep time. Feel just if you can elaborate just to tag more. Because I think this is also pertinent to adolescence is the use of alcohol and other substances which often is this is the time and adolescence will experiment and perhaps first trial in any of these things. What role do you think they should play in terms of the advice we give when managing depression in younger people? Yeah so we tend to talk in terms of you have a sense of brain therefore your brain is going to have more adverse responses to substances such as alcohol marijuana and therefore it's a good idea to either not use it at all or use it in moderation. The good news is that the current generation of young people are actually much more amenable I think to those messages the previous generations we have a lot of young people these days who are basically asked to. Greg you wanted to come in. I was just going to say you know Philip Boyce was talking a lot about sleep and the importance of that in mood disorders and filled hazel was then saying that obviously in adolescence that's a particular issue. There's a significant chunk of the guidelines on chronobiological approaches to depression and mood disorders generally and so there's quite a lot of detail there about how we can help people maintain lifestyle regularity which in turn supports sleep in a sort of virtuous cycle way. So yeah that whole issue of that 24 hour with misity and sleep it's kind of been elevated in these guidelines and we provide quite a bit of detail about it. And quite rightly because we normally associate that with bipolar disorder but I'm glad we're discussing in the context of depression because it's equally if not more so important as all of you've pointed out. Philip Boyce. Yeah I'm just going to add one more thing about that and particularly the comments about using devices at night and to remind the patients that the blue light that will come from your phone or your tablet suppresses melatonin and so you can't get asleep and you actually can change your phone to have what's called night shift, certain on iPhones which takes away the blue lights. So you're not getting a melatonin suppression. Okay thank you very much for that and I'm sure we'll have to mention some other types of devices now that you've mentioned a specific time. I'd like to move on to settings because that's really important as well although most people listening to this will be psychiatrists and psychologists and specialists of one sort or another. We are obviously talking about interventions that primary care physicians will be providing and already are providing and I was wondering now if you could make a few comments really about the guidelines in terms of management of depression, what we've considered in terms of settings and why that's important. Yeah thanks Dean and congratulations on you. It is very important to consider there is a natural risk with guidelines written predominantly by a group of specialists that will focus on how to manage depression in the sort of settings we work in and yet we need to acknowledge that the vast majority of depression in Australia and New Zealand isn't treated by us. It's either not treated at all or treated in primary care or as great touched on earlier increasingly online and we need to make some comments as we've done in the guidelines about how we might map the population of people with major depression against those services and how we think about the escalation points between the different levels of care and I think we acknowledge that there's challenges in that in both of our countries in terms of things like access to psychiatrists particularly or access to inpatient resources when needed and we advocate strongly that mood disorders including depression need to be adequately considered when we're planning the serious end resources they need access to inpatient services at times too. I kind of support the call for us as professions too to think how do we support our primary care colleagues who bear on this burden I guess from other work I'm very pleased to see that there's an increasing use of us in a more consultant capacity but perhaps traditionally we've been a little bit coerbier I think that's a very good thing and I know our primary care colleagues value that a lot but I think any of our recommendations about the management of depression we really need to see them in that life that we talk about the big goal of people with major depression presenting either in primary care or to specialists and that's why we've got the focus we've got this time on broad recommendations. Thank you, Mal and you're quite right that we need to have that sort of flow back and forth between primary care and specialist and an understanding that we're all actually working in unison and I think the guidelines do reflect that and just to summarize the actions section that we've just discussed now we're asking people to institute things such as sleep hygiene examine exercise and diet we're asking people to be aware of and needing to address things such as substance misuse and in particular alcohol and smoking but at the same time ensure that they implement psychological interventions from the outset and then add to these with pharmacotherapy and this is where the guidelines become slightly different from other guidelines in the sense that we have nominated choices we've assisted in saying these are the treatments that are perhaps most useful to you. So when we talk about pharmacotherapy there are many agents available and that's a good thing we have a huge number of molecules particularly in Australia perhaps less so in New Zealand but the important thing to consider is what are their actions and the two types of actions we have to examine are their efficacy and the effects that lead side effects in other words their tolerability and that's the key distinction to make at the outset and then after that are their particular agents that can be tailored to a specific clinical profile so within the pharmacotherapeutic armamentarium we've chosen seven agents and all of these are distinct in terms of their pharmacological profile and then we've shown them very simply in terms of efficacy and tolerability and so we have esitalopram, bortiopsytine, agamelotine, bendifaxine, metasopine, bupropion and amitriptoline. In terms of efficacy amitriptoline is clearly the most efficacious but it also comes with the greatest burden in terms of side effects and this is how we've arranged them on this spectrum but beyond that it's the mechanistic insights that are really important and so I wonder Mal whether you can expand a little bit on each of those agents or some of them in terms of where you see them fitting in in primary care and which agents and how we should be utilizing them in more specialist settings. Yes thanks Jim and it is worth acknowledging this is quite a departure from the sort of thing we wrote in the previous version of the guidelines in 2015 where we had a table of first, second, third line that we often see in guidelines. It is worth pausing for a minute and thinking about what was the evidence like that supported that and how did we as a group consider that evidence both then and now and we haven't previously touched on the methodology we used as a group around consensus and evidence-based recommendations. So if I may just a moment on that to say that this area typifies one of the challenges we have where our evidence is incomplete we would desire always to be able to produce evidence-based guidelines where we can say there is high-level evidence using perhaps multiple meta-analysis for example that tell us exactly what to do. Within our guidelines where that's available we do that we call it an evidence-based recommendation and give it a level of evidence supporting that. Unfortunately it's so many of our management decisions in the treatment of depression including pharmacotherapy but not limited to pharmacotherapy. The evidence doesn't always tell us what to do and we need to develop a consensus-based recommendation where we as a group have considered the available evidence to a degree reflected on our collective experience and our knowledge from others and reach some form of consensus always acknowledging that we never forget the patient in front of us and I think reflecting on that methodology is really important in each of these areas. Coming back to pharmacotherapy then our approach this time rather than ranking first-second guidelines to acknowledge actually they have different mechanisms of action that does influence their overall tolerability and efficacy and that is a group we thought it more appropriate to select if you like a group that we thought reflected the most useful spectrum. I think that's the best way of describing it. They have the best balance of efficacy and tolerability and they do varying within that group as you highlighted with Amy Trip to Lane but these are the agents that we thought on most occasions should be most appropriate. It doesn't, as you outlined, necessarily indicate that any one of those should be first-line. Indeed, when you think of the only trip to that example, I'm sure we would all generally say not first-line and probably increasingly less likely to be a primary care medication, but still has properties that mean it should be in that list. I think thinking back on mechanisms also is very relevant to how we think about something we might talk about in a minute. Those cases that are struggling and things are not getting better, and how do we think about difficult to treat or to use an older term, resistive cases. But I'm sure we'll come to that in a minute. Thanks, Marlon. One of the things I think is important to emphasise is that we're not being prescriptive. We don't have to limit yourself to these seven agents. What we're saying is that these provide a nice choice, and each of them is somewhat different. So if you want to move from one agent to another, there is a good rationale for doing so. At the same time, though, we have provided in separate charts and also text, clear indications of side effects, which is a very important consideration. So agents that perhaps cause less sedation or less sexual dysfunction or are less likely to cause weight gain or running to problems with cardiac side effects. These are important considerations as well, and clearly have to be contextualised and applied to the individual. And then there are other aspects of each of these molecules that we need to consider in terms of potential clinical profiles. So we have a table in the guideline if everyone remembers that where we've talked about the key or prominent symptoms that can be targeted by various molecules. And we've tried to map on broadly these seven agents to those particular symptoms. So these are other considerations that clinicians need to also formulate. Phil? Yeah, I think another consideration we paid a lot of attention to was we recognised that the run about 50% of patients may not respond to the first agent they're put on. So you need to be able to switch them to another agent. So the first agent you put them on needs to be one. It's going to be relatively easy for the patient to come off while you're switching over to a new agent. That's right. And in terms of the approach after you've started a particular antidepressant, we tried to develop a schema and we called it Midas, the M-standing for medication, and then the ID stands for increasing dose and A for augmentation and finally S for switching. And this is a short hand just to remember that once an agent has been instituted, you can work through those processes. And I wonder going back to Mal, if you wanted to make any comments about increasing dose as a first step and how often that's done and what the virtues are of that approach. I think it's a very important question, Jim. One of the things we're aiming to do here is to develop a sense of what's good quality practice and good quality practice involves the use of medications in an informed way. And they vary in the effective dose range and they vary in the likelihood of further response as we escalate through dose. We've also got good information about how long do we wait if we increase dose or switch? And as a group, I'm sure we all share the concern that out there in the real world, people aren't always escalated in what we think is a timely manner or indeed switched or augmented as you describe within the Midas paradigm. So we're really encouraging use of doses initially within the product information range and escalation in a timely fashion measured in a few weeks, not a few months. Just to add another layer to that, reflecting in a sense what Greg was talking about before with therapy, we also need to acknowledge that this is a shared process. We need to increasingly recognize that patients are coming to us with their own thoughts about pharmacotherapy. That might be about agent based on family member exposure or something like that. It may also be about side effects that are most meaningful to them. So we really need to add that layer of individual nuance at each step of Midas as well. And in relation to that, I think that's a really important point now because often patients will initiate the change or the shift or express dissatisfaction with the response they're achieving. And sometimes they're looking to the clinician to make that decision. So obviously in each instance, you have to either take the driving seat and say enough is enough, we need to move to another agent or allow the patient to do that. But I agree with you totally, you've got to be vigilant and maintain some sort of reasonable time frame. Greg? It's just going to say, yeah, completely agree with all we're saying. And that's why we've sort of underlined the importance of some form of monitoring of progress. So instead of having a sort of strict rubric of you do this, then you do this, and then you do this, the science is just not strong enough to tell us that. And even our consensus-based practice, we don't know the individual client that a clinician is thinking about. The sort of magic solution to that is to monitor the progress of the individual client against a goal that they find meaningful. And as Phil Boyce said before, that could be back to functioning, but it could be a much more specific thing. You know, I'm sleeping better. Or some marker that's important for the individual about progress. Just as an aside, we do know that simply instituting that monitoring, asking the patient how they think things are going, is a very powerful mechanism of action of psychotherapies. He's just asking them, how do they think they're going? And obviously that could relate to the therapist changing their plans. But perhaps it's also about empowering the patient to realise that they're at the centre of the treatment and they need to keep sharing information with the therapist. So as you say, Mel, it's a shared activity, isn't it? So the more actions we can take that communicate that, the better. Thank you Greg. I think that's a really important point. And we'll come back to monitoring in a little while because I think it's really key. But just to finish off the discussion around the pharmacotherapy. So Mel, you were talking about increasing dose. And the next step is usually that of augmentation. And in the guidelines, we've put that again centre stage as part of our Midas approach. And the most common agent in this regard is lithium. And the beauty of lithium in this context is that it can be added to any other entity. It's a very important element of the patient. And the dose to be prescribed should be equivalent to what is used in terms of its mood stabilising action. That's to say aiming for a maintenance dose of 0.6 to 0.8 millimoles per litre. But even lower doses can still act as an augmenting agent. The only caution is not to persist with this if you don't see an improvement. And so once an agent has been increased in terms of its dose and you've added an augmentation strategy such as lithium, then there has to be a time point at which you decide there hasn't been sufficient response and you move on and you switch. And it was here that I really wanted to mention the diagram and turn to Erika to just give an overview of the Midas figure that we have and how that should be utilised. It's a very colourful diagram for those of you that haven't seen it. But if you can just talk us through the logic of that Erika, that would be really quite helpful. Yeah, well I think tying it back to what we were saying earlier about where treatments fit in managing mood disorders. It's a useful diagram because it shows almost like a flow chart, the general pathway that we want patients to follow. So starting from diagnosis of course it goes to the actions that we've discussed previously. That is lifestyle, cessation of smoking, alcohol, substance misuse, implementing psychoeducation and psychological interventions. Following that in terms of pharmacotherapy choices, we do start if necessary with a medication. And then as Mal was discussing, we can then increase the dose, augment, and failing to achieve any sort of response or desired outcome as expressed by the patient, as Greg was saying, you can then switch to another agent and the cycle begins again. So with that secondary agent you may then again increase dose or augment if appropriate, failing that you may switch again before proceeding onto something like physical treatments. And that's useful in the guidelines as well because it's mirrored on the opposite page by our response paradigm, which is tied into this as well because it essentially again puts the patients response to the agents at the center of management rather than simply ticking check boxes and following a rigorous set list of agents or strategies. It's all about achieving the desired response and recognizing that depression is very heterogeneous and individuals very considerably. And so what agents and strategies might work for one person may not work for another. And so it's worthwhile persisting in this regard with all stages of management, not just simply trying one, giving up and then moving on. It's about persistence to achieve that desired response? Absolutely. Phil, do you have a comment to make as well? I was just going to make a brief comment about Lithium and also another comment about augmentation. Lithium augmentation I think is fantastic and one useful thing about it is if you're not getting a response in a week it's probably not going to work. I don't know if you agree with that Jim but certainly that's been my practice. I would qualify that just a tad, Phil, by saying that once it's got to a therapeutic dose, if you have a week after that because sometimes you might have to tie a trade lithium gradually and that that can take several days up to a week and itself sometimes. So that week is when you've got to the optimal dose, you've checked the levels and let's say you're running at 0.7 or 0.8 millivolts per litre, if after a week there's absolutely no flicker of a response, then it's unlikely. Though again I would still say that you might just want to persist a few days more. So I would say perhaps 10 days or even two weeks but then there has to be an absolute cut off. I agree with you. But the other side of the coin is where you get a good response with an augmentation agent and you're getting horrible side effects because of it and I saw a patient yesterday that augmented with a second-generation anti-psychotic and she'd put on, well she'd ground three sizes in her clothes in two months and you know really had put on an awful lot of weight and how long do you persist with that augmentation agent even though you've got a good response to the repression? That is a really difficult issue. And I think we can all guess which agent you're talking about. But coming back to the important point you're making there in terms of what it is that we're trying to achieve. So when we're using those particular molecules, a second-generation anti-psychotics, they can be used to augment or facilitate. And what I mean by the latter is when we had that discussion earlier when we were developing the guidelines if you recall, it was about appeasing and countering the initial side effects of the agent that you're prescribing. So having those agents initially assists with sleep, they can also help with anxiety and they can facilitate the initiation of an antidepressant. And that's what we're seeing a lot with certain agents being prescribed alongside an antidepressant at the outset. But that's not augmentation per se. That's just countering the initial side effect. It still facilitates treatment. But what we're talking about here is actually having an effect which has an antidepressant response but also facilitates the prime response of the antidepressant or allows it to occur much later on. The difficulty which you've outlined is when do you stop that treatment? And a lot of these agents, obviously, if they're persisted, if they're persist in terms of weeks or months, are likely to cause weight gain and metabolic syndrome and so on. Mal, you had your indication they wanted to talk? Yeah, do you know, I think those issues go back to the one of the characteristics of the MIDAS framework, if you like, don't they? That all mentation strategies are a particular area where our evidence base has many holes, particularly comparing augmentation strategies. And we often get a little confused, and I think sadly, sometimes we end up seeing lots of examples of not so great use of pharmacotherapy in augmentation strategies. And one of the things might as really reinforces, I think, is that just like the primary antidepressant, augmentation strategies need to be reviewed in a timely fashion, the balance of good and bad weight up carefully, and each of them has both good and bad. And augmentation strategies need to be changed as well if the overall balance is not worth it. In some ways I often see clinically augmentation strategies are more likely to be subject to a kind of set and forget prescribing where someone was started on one, and they kind of just got left on it. And he might view that's clearly not good practice and not consistent with the MIDAS framework. But it is a strategy that we're employing throughout. I think it makes very valid points, but I wanted to broaden it a little because with this particular algorithm that we've developed, we're also saying combining psychological treatments with pharmacotherapy from the outset. So that can also be viewed as a combination stroke augmentation strategy. And the research shows that psychological therapies being on board actually enhances engagement with pharmacotherapy and is likely to produce a better response. So we have a consistent message throughout in terms of using different strategies together and combining them where possible. And augmentation is just one facet of that, but you're quite right. This particular point about setting and forgetting is not appropriate. You need to be constantly re-evaluating. Now, I imagine that's probably even more important in adolescents and children. And so I might use this juncture to turn to Phil, Hazel, to talk a little bit about what we've discussed in terms of our approach to management of depression thus far, how that varies in the context of younger people. Thanks, Jen. So in the context of children adolescents, the recommendations are somewhat different than they are for adults because the evidence our landscape is different. So first of all, in terms of medication choice, at the present time, there is only one agent that reliably separates out from placebo and efficacy trials, and that's for the oxygen. So the recommended first line pharmacotherapy for depression and children and adolescents in any treatment setting is for oxygen. Now, a few comments about prescribing for oxygen to young people. One of the limitations, I think, is that people underdose. They think because children and adolescents are smaller, they need less. That is manifestly not true. They metabolise drugs faster, and oftentimes actually need higher doses than adults. So it's not uncommon for young people to require 40 or even 60 milligrams of floxateen to achieve a response or to get to remission. If an adequate trial of floxateen is unsuccessful, the next step is not what am I going to prescribe next. It is what's going on here. Are there other things going on in this young person's life and the model's life that I need to address? And those can include issues such as bullying, family stress, undetected learning difficulties that are causing the young person's life as school to be miserable, all of those things. Now, they shouldn't have been thought of right at the outset even before prescription, but in the context of non-responsive, it's really a good time to come back and look at those issues again. Now, the other area where we depart quite a bit from the recommendations for adults is that in children and adolescents, there is no compelling evidence. They're combining psychological treatments with pharmacotherapy is any better than either treatment, modality on its own. And so in the guideline, we haven't recommended combined treatment first up. We've said it's either a choice of a psychological treatment or pharmacotherapy, and that pharmacotherapy is going to be flocks of tea. If there's a non-response then, then adding the other modality is the advice we give in the guideline. When would you use psychological therapy? When would you use pharmacotherapy first? Well, patient preference and circumstances is an important consideration. But the subtle difference between the two pharmacotherapy faster time to response. Psychological therapy lists risk of suicide-related behaviours in the context of treatment. So if concerned about suicide-related behaviours as large, if there's been previous behaviours of the clinician thinks that's a big risk, then probably psychological therapy is first. If the young person is quite impaired by the depression and then dropping out of school, you're needing a response as fast as you can, then probably pharmacotherapy. In the situation where you do need to move to another pharmacological agent, there is no evidence really here to guide us. The consensus advice is either switch to an addict person from a different class, such as then with vaccine or metasopin. Some people might go to another recess or eye in our clinical practice we don't. We go to a different, an agent from a different class and then consider augmentation. But in terms of augmentation, strategies and children and adolescents, there isn't a lot of evidence yet to support it. It's just consensus-based. Thank you for that Phil. And that's really important to have as part of the main guidelines because as you know, 40% of patients with major depression will experience their first episode by the age of 20. But unfortunately, a lot of those people will have further episodes. And so I want to return to a couple of the issues we touched on. One is monitoring and the other is longer term management and something that Eric mentioned, which was our shift towards a responsibility paradigm or approach rather than dealing with treatment-resistant depression. The other point I wanted to make at this juncture was that we have not specifically focused on suicide, neither in the context of the pandemic. context of depression, nor in bipolar disorder, largely because we felt this is a very big issue, it requires specialized management and consideration, and we didn't feel we'd do it justice within the guideline. That's not to say we don't acknowledge the fact that suicide is extremely prevalent within the context of mood disorders, and indeed suicide ideation is a key feature of depression, and therefore needs to be assessed properly. But returning to the shift we've had in terms of our approach, we came across the same hurdles that any group that has looked at treatment-resistant depression or non-response, that is to say where do you draw a line, where do you set a threshold, how do you define what is treatment-resistance, and does it actually mean that the disorder or group of patients that are not responding are somehow fundamentally different? And we struggled with that, we didn't really feel confident that that was the case. And so we've adopted this responsibility paradigm, which is much more optimistic, which talks to looking at what works, and understanding from some of the trials that we have had, such as STARDE, that response is possible, with perseverance and trialing different strategies, and hence why we have a diverse range of strategies, and we ask you to consider employing all of these, either similarly or in unison, to achieve that response. And so I might ask Erica once again to describe a little bit of how we've tried to present this before going to others to talk a little bit about the monitoring of patients and how that fits into our response paradigm. Yeah, well I think, Jin, you've put it well there, where initially we did try and look at how we can incorporate models of treatment-resistance, or non-response into the guidelines, but eventually, yeah, we decided that focusing on lack of response doesn't really make sense. When you're implementing a treatment, the aim is that you achieve a response, so you should be looking for that in all patients, and trying to assess whether someone's failed ex amount of treatments doesn't really help, it doesn't inform future management, rather what we've done is we've presented them as channels, so we've labeled it as a channeling response paradigm. And the idea is that the person is traversing this channel from depression to recovery, and the clinician may implement any variety of the treatments that we've mentioned. So in one individual, you may just require only lifestyle changes, some social support, some CBT. However, in another individual, because of the nature of their illness, they might need ECTs straight away, the point is that you shouldn't just simply try a handful and then move on. The point is to constantly re-evaluate what has achieved some kind of response if any, and then to work on the basis of that to inform future strategies. And I guess the point is that we're not implying that there is some sort of upper threshold because there shouldn't be, we shouldn't sort of have a limit to what we can do. We've got arsonal of strategies that we can employ, and we should be trying our best to employ them in any number of appropriate combinations. Absolutely, and we're going back to that earlier point that was made about having patients as part of the conversation and being realistic with them, that we're all trying to achieve the same outcome, but that it may not happen after the very first strategy. And we might require a number of trials of different types of treatments before we achieve a response. But the key message here is that a response is almost always achievable. So it's a positive message, it's a message of hope, and possibility, rather than immediately saying, well, this agent didn't work and that strategy hasn't worked, which sets up a very negative conversation for the clinician to have to deal with, but also for the patient is very demoralising. Greg? Yeah, completely agree. In the context of psychological therapies, we often say a very similar thing, that the psychological therapy will give you new insights into how you cope, things that don't work for you, you'll learn more skills. So it's very much that process of developing knowledge about the person and their vulnerability. And I think you've just said the same thing in the context of pharmac therapy, that we're on this together, we're optimistic that it's going to work. We've got lots of options, and we'll be learning as we go. The learning process might be quick, the first thing might work, or it might be slower, but you're going through a process that will be useful to you, because we're getting a deeper understanding of how come you ended up depressed at the moment, whether that might, you know, what the etiology of that will be, and what things are going to work for you if it ever happened again. Absolutely. And so the core question within this is about response. Mal, you wanted to jump in. Yeah, look, I think it's also worth acknowledging, Jim, that moving away from simple concepts like treatment, resistant depression, most commonly defined as failing a couple of pharmacological treatments, is both a more optimistic and realistic message, including acknowledging the limits on our capacity to predict which treatment you will respond to. So we know that the percentage of people who respond to the grossed antidepressant fully is around 40%, and we don't currently have a capacity to do something that means I can predict with certainty your 70% likelihood to respond to this treatment. So the first two IP, either psychological or pharmacological treatments, are to a degree arbitrary, if they're for seems inappropriate to, you know, sense almost blame you. And that's how some patients experience it. If they don't respond to the first few treatments, it's my job to continue to work with you to look at what the next option is that might often a different mechanism to unlock things for you. And if I can just add to that, Mal, one of the things we haven't discussed in detail today, but certainly within the guidelines and from our clinical experience, is that there isn't a clear cut divide between the sections we've talked about. So for example, assessment and formulation arriving at a diagnosis and initiating treatment, when we've initiated treatment, we're still diagnosing, we're still assessing, we're still formulating, because all of that information is going into our understanding of what the patient is experiencing and how they are suffering. And we're revising the diagnosis and our management strategy. So it's dynamic. I think someone mentioned that before that the whole process has to be fluid and we have to be maintaining vigilance around new symptoms, emerging side effect, etc. So I think giving that clear picture to the patient at the outset that there is hope at the end of this particular journey, we don't know how long it's going to be and which particular strategies will be necessary, but we will get there provided we work together, is important because that changes the conversation from the outset. Phil. I was always going to stress me, need to pay attention to what features of the patient's depression, what symptoms feel like, are responding and not responding. So you may say, "Gesh dogs, the patient do feel better," and they say, "No." And then you need to go through and evaluate different components of the person's depression and you may find some things were a lot better, but other things aren't and you need to modify your strategy to deal with the components or the features that aren't responding at that particular time, where other features have responded. I had a patient yesterday who had a very severe depression and were going through a switching process with a rantied depression and she said she was no better and that's all, what are you doing today? So I've just started a new job and I hadn't realized that she'd been able to go and get a new job after being unemployed for some time and was actually achieving and have functionally had improved considerably. Yet she was still saying she was depressed. So I need to build on that and help her get other features of her depression to keep up with her new functioning role. And what about more specific measures, Phil? You mentioned earlier that perhaps we could use more rating scales and other types of assessments, where do you think those fit into our evaluation of patients? Well, I use terribly simple rating scale with my patients generally, I ask them how well they feel they are compared to their usual self or they 50, 60, 70 percent better or are they functioning at 60 or 70 percent, whatever it is. I think that's a very good gauge and you can then say, well, last week you're only 40 percent, now you're 60 percent. So we're really making some improvement. But then going through a more granular process to see where the areas of improvement and where they don't feel their well. So I'll often say, well, what would make you 100 percent? And they say, well, I need to feel better about myself or I need to be able to sleep better or have more energy. And then you can focus your treatment more specifically at those features. But if you use a more complex rating scale, something like the mattress, you will actually identify where there's been improvement and where there hasn't been improvement. So you can actually target and modify your treatment to deal with the areas that aren't improving significantly. And what about digital monitoring, self monitoring? And we're moving into an age now where patients can do that themselves. Greg, do you have any suggestions as to what patients could do and what we should be perhaps thinking about? Yeah, yeah. Obviously, any behavior change is difficult. And if we're asking people to monitor, that is a behavior change, especially if we're monitoring more frequently than say once a month. So they, we might ask them to complete a madras, for example, once a month, but we're not going to ask them to complete a madras each week or, yeah, more frequently than that. But as we've been saying, this monitoring of individual response to treatment is really critical because, you know, in a way, that's the way we bridge the gap between the evidence we've got from trials and the individual patient in front of us is to check are they improving with what the evidence suggested might be useful for them. And so when it comes to monitoring, yes, it's, you know, we're basically saying monitoring is really important as part of this active dynamic approach that we are encouraging clinicians to, you know, maintain throughout treatment. And we do need to be aware, however, that monitoring takes work. And in the guidelines, we make a couple of tips about that. Of course, if I'm asking someone to do something for us like fill in a questionnaire, I really must check in to show them that I have actually looked at the results of that questionnaire and thought about it. Because otherwise they won't do it again. But you're right, Jen, there's a lot of excitement about the possibility that, you know, digital monitoring might solve some of this. And so that's a whole new frontier. There are dozens of different apps for monitoring different features of progress around depression, ranging from the sort of syndrome that Phil was talking about before, what elements of the syndrome are improving versus elements that are not right through to more functioning measures, right through to more idiographic or, you know, personalized measures. I had a client recently where the, what we were measuring was her ability to get through the working day without having to run to the toilet and have a cry. That was the thing that was most distressing for her as a measure of how she was coping in the real world with her depression. So, you know, we were literally counting the number of days in a week where that happened. And a digital, there are digital platforms that will enable people to personalize those things. And in fact, in the guidelines, we direct clinicians to a web page that helps them think through the strengths and the weaknesses of those different sorts of apps. It is one way that we think the digital revolution in mental health will make a difference. But as with all the other aspects of the digital revolution, it takes some expertise building on the part of the clinician. Just adding, some comments about simple digital strategies. So a lot of people have devices these days which monitor sleep and an activity anyway. And I encourage parents who have listened to a risk of depression or a depress to get their kids to one of those devices so that they got some objective measures of their function. Those are very good points. And one of the other challenges we face is that even when patients get well, what do we do at that point in terms of ongoing management, not only monitoring, but do we offer further treatment, do we continue providing support and how long for if that's the case. And I might turn to Mal here to make some general comments before turning to fill more specifically around strategies that we can employ to look at recurrent depression and long-term maintenance of wellbeing. Well, I think just as we talked about sitting to make expectations about response to the first and second treatments, I think it's very important to be emphasising the guidelines about setting expectations about future course of illness. That we need to acknowledge that for some people depression is a recurrent problem and pretty much for everyone it's at risk of being a recurrent problem. So treatment planning about how to reduce that risk and where necessary to introduce things such as ongoing therapy or pharmacotherapy, early warning signs and what to do with a relapse occurs and where does our therapeutic relationship fit into that. So where do I go if I've got a problem and introducing an element of urgency about that as well. That's a discussion that has to happen with every patient. What that will mean with these patients in terms of active seeing and active treatment will vary depending upon circumstance. We've got some specific recommendations about duration of pharmacotherapy in the guidelines, but they need to come with the sort of acknowledgement caveat that the evidence is imperfect, particularly around the patient with multiple episodes of depression. The common sense with suggest longer term interventions may be appropriate, but our evidence is pretty limited once we get beyond one in particularly two years of maintenance pharmacotherapy. So acknowledging for the outset the key principle that for many people depression is a recurrent illness and we should be talking about that now is I think one of the key principles. Yeah, I think it's a very important point and obviously we were if we're using pharmacotherapy we would need to continue on the pharmacotherapy certainly for the first episode for up to a year, but I think this important work to be done there and that is working on relapse prevention and that's working with the patient to identify their early warning signs if they're having a recurrent so their depression. And most importantly a strategy what to do if they're starting to become aware they're slipping back into a depressive episode again where they can they get immediate access to help and I think we should have a sort of fast track for patients to return to us if they're recognising they're having a recurrence of their depression. We also need to look at more subtle aspects of recurrence. Is this a recurrence? It's going to be predictable and there are some patients for example who see some effect of disorder they become depressed you know of the onset of winter and so you can plan for treatment for that and their patients who are totally unpredictable pattern. There are patients who will become depressed when particular life events occur or particular events occur and so we need to talk with them about that and plan interventions around all of that. But then we have to tease out as well whether there's a recurrence, there's a biological form of recurrence and which will need medication or whether it's due to psychosocial factors. With them they need a booster of CBT and that's often provided so they can get back on to their sort of changing their ways of thinking and being able to look after themselves better. And I think that's an important point to finish on because we're talking about depression being a recurrent illness and coming back in the future to spide up their efforts. And emulating that to some extent we'll be coming back again with the next podcast in which we'll be looking at bipolar disorder and all that remains for me to do is thank my co-presenters who've given you a whole range of insights into the guidelines. Obviously we've not been able to cover many aspects and an obvious emission for example is electroconvulsive therapy which is important in certain instances but there are many other therapies as well but we haven't been able to touch upon. So I do recommend you refer to the main guidelines to get advice but I also look forward to seeing or hearing from you again regarding bipolar disorder which will be our next podcast. We hope you enjoyed this episode of Psych Matters. Feel free to share it with others and keep an eye out for future episodes. Psych Matters is produced by the Royal Australian and New Zealand College of Psychiatrists.