Treatment resistant depression

In this episode of PodMD, experienced Psychiatrist Dr Jason Pace will be discussing the topic of treatment resistant depression, including what is treatment resistant depression, the different treatment approaches, optimising medication trials, the difference between ECT and TMS, when a GP should refer and more.


  • Transcript
    Please note this is a machine generated transcription and may contain some errors.
    *As always, all in this PODMD podcast is intended for health professionals and the comments are of a general nature. Information given is not intended as specific medical advice pertaining to any given patient. If you have a clinical issue with one of your patients please seek appropriate advice from a colleague with expertise in the area.

    Today I’d like to welcome to the PodMD studio Dr Jason Pace

    Dr Jason Pace is an experienced Psychiatrist who established and practices at Sydney TMS, an innovative clinic providing treatment for Treatment resistant depression where other treatments don’t seen to be working. TMS is short of Transcranial Magnetic Stimulation.

    After graduated from the University of UNSW in 1996, Dr Pace founded the Hills Clinic private hospital in Kellyville in 2010 which included one of the first private youth mental health inpatient programs in NSW. In 2014 Dr Pace launched Sydney TMS, after traveling to America and visiting several TMS clinics in the US. At that time Transcranial Magnetic Stimulation, TMS for short, was virtually not heard of in Australia. Jason now operates four TMS clinic locations across Sydney and practices at all four, offering extensive experience in TMS treatment.

    Today, we’ll be discussing the topic of Treatment Resistant Depression.

    *We do hope you enjoy this podcast but please remember that the advice here is of a general nature and is not intended as specific advice about a given patient. The views and opinions expressed in this podcast are those of the doctor, not PodMD.
    If you do have a patient on whom you require specific advice, then please seek advice from a colleague with appropriate expertise in that area.

    Jason, thanks for talking with us on PodMD today.

    Jason: Thanks for having me.

    Question 1
    The topic of today’s discussion is Treatment Resistant Depression. Jason, can you give us first give us a brief overview about Treatment resistant depression?

    Jason: Sure. Well, I think there are a few different criteria that you’ll come across, but I think mostly people agree that. Treatment resistant depression would be when someone’s had adequate trials of at least two treatments for the depression, and they’re still not feeling any better or they’re only getting a partial response. They’re still not reaching a remission. They’re not remitting and significantly in their symptoms. So it’s important to have that in mind because studies would suggest that if you’ve had two depressant treatments. Or you’ve had two sort of robust treatments of treatment depression and you’re not getting the response, the chances of a third or a forth antidepressant treatment working is very unlikely. So you need to really stop and think at at that point, you know, what other factors here that might be stopping someone getting better or what else do I need to consider?

    I guess the sort of things you should be looking at are, you know, contributing factors. You know, what are the stresses that are contributing to this depression? Do we need to address those? Do I have the correct diagnosis? Is there anything else going on? Additionally that maybe I’m I need to be considering? Does someone have a physical illness for example like do they have an under active thyroid or something that that might be also contributing to their depression not improving? Do they have a sleep apnoea for example? Other treatments you know that need to be considered. So if you think that you know, you’re pretty much on the money with depression and there’s nothing else really going on that if you can’t exclude, you know, you need to consider changing your treatment approach.

    We need to look at second line treatments. We look at look at either augmenting the medications with some mood stabilisers or look at something like TMS. As I guess the next stage of treatment is to be considered, you can’t just keep doing the same thing over and over again. And for some of those things, you’re going to engage with the sort of specialist service to do that as well. So some of these things are going to sort of take you out of sort of what your sort of comfort level is and maybe be asking for help from someone else to help you with that.

    Question 2
    What do GPs need to consider when dealing with Treatment resistant Depression (TRD) ?

    Jason: Sure. Well, as I said, the diagnosis is probably the key thing for them to consider. So I guess reviewing the symptoms you’ve looked at. Maybe going back and seeing if there’s any gap in your information that you have about this patient that might sort of fill up the picture a little bit more, have a think about whether you know you’re sitting with someone who’s got unipolar depression or bipolar depression. Because if you, I guess most people thinking that they’re treating some with unipolar depression, but if there’s someone with a bipolar affective disorder. That might have this sort of more pendulum sort of moods disorder, where they go from mania to depression. Those patients don’t respond, so don’t respond so well to the conventional treatments. In fact, they may find that the antidepressants actually make them feel worse.

    So you may get a sign of this if you’ve had a. If you get a history of, say, mania or hypomania or elevated mood. But that may not be obvious, particularly in younger patients. They may not get a manic episode or hypomanic to their 30s, and so if you’re seeing someone in their 20s, for example or early 30s, you may not get that that history, so you need to look at other things that may be characteristic of a bipolar illness. The two things I would recommend you look at is ask about energy levels because you know the other thing that’s very common in bipolar patients is they have a very significant shift in their energy levels that go along with the depression. So they often feel extremely lethargic, much more than maybe. Regular patient with depression. The other thing which you may find is what we call sort of atypical symptoms. So typically if someone with depression, for example, will tend to sort of be off their food and reduce their appetite, that tend to have reduced sleep as well. But with people with bipolar disorder, their depression can be sometimes not always, but can be sort of the reverse of that, so they can tend to overeat or oversleep when they’re when they’re depressed, so they can just be slightly different to the symptoms, which we’re not quite, which is not typical of what we typically would see.

    And then maybe some signs that someone might be suffering with bipolar illness. And that you may not be going to be doing so well with the SSRIs, for example. And may me introduce mood stabilisers a bit earlier on the piece. The other diagnosis to keep an eye on is, you know what psychological aspects to their personality might be hindering their improvement. Do they have some sort of personality disorder. That’s really make it difficult for them to to relate to other people. Do they have a neurotypical disorder. Do they have sort of autism or they have ADHD or other things that might be also contributing to their? So you know, a secondary sort of maybe diagnosis which could be actually the primary diagnosis could be the main reason why they’re getting depressed is because they’ve got this other condition neurologically, that’s really making them struggle and functioning with life and keeps wearing them down.

    So comorbid mental illness is really important and then comorbid mental medical illnesses. So things like sleep apnoea is very common in older patients. It’s important. And I get a lot of sleep studies done on my patients. Endocrine conditions, haematological conditions, things that other other that may be sort of being masked by the depression. But you know, it’s worthwhile to do a full sort of work up organic work up to make sure there’s nothing else going on. Things like oncological conditions, cardiac conditions sometimes can present with with depression, you know, things like thyroid conditions ended chronic conditions, diabetes, a lot of these things can sometimes present the firstly, with depressive symptoms. And then you’d look a bit deeper and you. Find other things going on.

    And then finally, you know what are the, what are the factors that continue to to irritate this depression and and stop it from getting better? Is there a a chronic work condition? Is there a person getting bullied at work or is there a person getting sort of bullied or harassed at school or is there a really bad relationship at home is you know, is the person’s daughter really sick or is it something else going on in the dynamics of the family that might be contributing? I guess until that thing gets addressed, it may be really hard to get a good outcome for your depression. So these are sort of other things that you might want to consider, I guess if you got someone who’s really not responding the way they should be responding or you expect them to respond.

    Question 3
    What different treatment approaches do you need to have when dealing with TRD?

    Jason: So initially things start off much the same way you would start on a antidepressant like you typically would be comfortable using. And I guess when you get to the point where you’ve used a lot of these, you’ll start getting a sense that some people just don’t respond so well to these. So we expect around 70% of patients to have a good response, so by response. The definition of that really is that you get a 50% reduction in the severity of symptoms, but the response doesn’t equate to a remission, so the remission rates or a full recovery is much less. So we expect about sort of 30 to 40% of patients to get into remission. So you want to, I guess start to think about that and how to capture that.

    So again using things like. Screening tools can be really helpful for you to decide whether someone’s. Just getting better or they need a bit more work done to them. I think it’s really key because if you do find that you’re only gonna get partial response and then you’re not optimising, maybe the treatments you’re maybe increasing the medication dose a bit further along or not offering other support. You may not quite get there and you may develop a treatment resistant depression where it could have been avoided. So I guess the approach I would have is to just really monitor very carefully what the symptoms are and how they’re tracking and whether they’re improving completely or whether they’re only partially improving.

    The second approach you need to have is to think about how much time you give medication, what doses you so you don’t sort of just start on a starting dose of medication and not adjust it. It may. You may require to do some fine tuning of the treatment, the intensity of the treatment as well like if they’re seeing a psychologist say once a month. You may decide to increase that to fortnightly or encourage them to see, so this more regularly the approach to the that psychologist might have might be not the right approach. Maybe you after talking to the patient, you realise they should not really getting what what’s going on in the in the sessions with the psychologist. So, you know, things like changing things around like not expecting the first line of treatments that you you, you put in place are gonna be the right ones, and particularly with the psychologist, you know, it’s a lot to do with the chemistry between the patients, psychologist. So you may think that they’re getting on really well, but you might find out from asking more questions that maybe there’s just not ageing. They’re not gelling together and you might to find someone else for that person to see.

    And then so augmenting with you know and optimising I guess is the things you wanna try and do you wanna optimise the medications, the dose give it enough time to work optimise the psychological support, make sure the right type of psychological support being delivered by the right person. So if and if not working. If you’ve tried all those things and you’ve tried them once or twice they’re having a totally different switch and rethink about what your approach needs to be, and maybe trying something quite different to what you’ve been doing already.

    Question 4
    How do you optimise medication trials?

    Jason: So you, I guess initially start with a starting dose. The key thing in medication is to start a bit slow and to make sure someone tolerates and you’ve got buy in from the patient, make sure they’re not developing any significant side effects and the best way to do that is to go really slowly and often either 1/2 dose or a full dose of the starting dose. This can be if you know someone’s quite sensitive to medication. You might want to start really slowly. And after a few weeks, get them in. Just see, hey, they tolerate the medication and just set some realistic expectation from the patient. Tell them it’s gonna take a good four or six weeks for the medications to work. So they’re not expecting that within a week, they’re going to feel any different. So if you don’t say that often, people like they’ll try the medication for two weeks and they say it didn’t work, stop taking it and won’t come back and see you. So you need to sort of, you know, set a framework that they they can follow and understand what they expect.

    But the first key is to get them on something they can tolerate that doesn’t cause them too much side effects and then increase the dose gradually to a therapeutic dose that you’re sort of comfortable with. And that might be, you know, 1 tablet of the initial tablet. It may be going up to two. Sometimes even three times the dose of the initial. Starting dose and giving each step a good four or six weeks to sort of optimise to see what the full effect of that of that treatment has before you go up any further. I’d strongly recommend just doing one thing at a time as well. I think it gets really confusing if you start to add a second medication quickly or do multiple changes then it becomes really hard to track what’s actually worked and what’s not worked. So having a systemic approach to this going gradually and just telling the patients the whole time what to expect and what you’re looking for and tracking this all the time by doing some questionnaires to monitor the symptoms is really important.

    After that, you know if you’re still not getting, if you’re getting a partial response, you get a sense that something’s happening. You’re not quite getting the results you want. Then you wanna maybe add a mood stabiliser or augmenting agent at that point and that will tip, maybe, hopefully tip them over to get the last bit of improvement they’re looking for. OK. And always thinking about the psychological aspects as well. So are we, are we adding in, you know a psychologist? Are we adding a counsellor? What else are we doing to try and optimise them? They, you know, so other things, other medications can also optimise medication effect even though it’s not medications themselves that are doing that.

    So other things, for example that can augment medication effect is using medication at the right time of the day. So make sure you’re you know when you’re using the medications when they should be used, whether it should be morning medication or nighttime medication and what sort of things can minimise their side effects. So having them with food, not having them with food you know does exercise sort of help in the morning that sort of thing. So just sort of understand and give some instructions as to how to use the medications. To get the best out of them as well. And if you’re not sure you know, ask someone who maybe used these medications a lot more about how pproach these medications.

    Question 5
    If you have tried 2 antidepressants and still don’t get a response, what next?

    Jason: For this I was just start by mentioning there’s a study which if anyone is interested they should look up it’s called the Star D study and the Star D study was one of the largest studies on the depression that was done back in 2006 and it’s still referred to because it’s still quite a pivotal study in, in psychiatry, it enrolled about 4000 patients and it was a multi-centre trial all around the world. And it was a naturalistic study. It was basically looking at clinicians on the ground doing what they would normally do with GPS and specialists, just using medications. It wasn’t a pharmaceutical sponsor study, and it wasn’t controlled by taking people out, if they sort of had other things going on, so unfortunately what this study should did show the big take home message was that the medications aren’t as good as what the you know, the companies told us they.

    And so there was and there was increased side effects reported in this study, but also one of the one of the other things it told us was that there’s not one medication is better than another. There was no distinguishable difference between any use of antidepressants. It was very much an individual response that you couldn’t say that, you know, an SNRI with an SSRI or a tri-cyclic was better, there was really no discernible difference between the difference. There wasn’t a ranking of power for these medications. The other thing I told us was that once you have had adequate trials of at least two antidepressants, the chances of response to 3rd or 4th of a very unlikely, and even though this is general practise and psychiatric practise for many years and still is and for many people it just simply doesn’t get borne out in the studies that this is a an effective way of treating depression.

    And so I guess the big take home message is if you you’ve tried too antidepressants and you feel like you’ve optimised, then you get enough time to work. If you’ve got the right dose and you’ve used them in conjunction with some psychological treatment, you’re still not getting results. You just don’t keep doing the same thing. You need to either go to, move to a second line treatment and second line treatments. The guidelines I guess in Australia and for most big colleges around the world, would be to either use augmenting agents like a mood stabiliser, or to look at something like TMS as the next th e next line treatment. So you need to do something different. You can’t keep doing the same thing, and I guess a second or a third line might be even ECT. Or electric convulsive therapy.

    Question 6
    What is the difference between TMS and ECT?

    Jason: So, ECT is a procedure that you have to be hospitalised for. That’s the first thing to say. It requires you having treatment. At least you typically three times a week. You do, they do it on with a day gap in between. So Monday, Wednesday, Friday. Typically it’s delivered and it’s done in most teaching hospitals and most large hospitals around the world including Australia. So it’s a very commonly used condition treatment and it uses electricity, basically uses electrical current that’s delivered to the brain and the aim of the treatment is to cause a global effect. So the whole brain is gonna get sort of lit up with ECT and gonna it’s going to cause you having a seizure or an epileptic sort of activity in the brain. So minimise the danger associated with that, you’re gonna give someone an anaesthetic and you’re gonna put them to sleep, and you’re gonna give them a muscle relaxant. So they’re not convulsing in the bed and they’re not sort of breaking bones and chipping teeth and so on.

    So you’re gonna put someone to sleep for a few minutes. Typically it’s about sort of somewhere between 2:00 and 5:00 minutes. It’s a very short period of time. And then once they’ve had the seizure, you’re monitoring the seizure. You’re making sure it’s a good quality seizure for therapy. And then after that, you’re gonna have. Sort of probably four or five hours of neurological observation. And then you either. And you go back to the ward and rest up, it’s gonna cause quite a lot of confusion when you’re having ECT and cognitive impairment. You’re gonna sort of not have a lot of memory around that sort of month or so when you having the treatment and typically having somewhere between 9 and 12 treatments. So it’s gonna take about four or six weeks of hospitalisation to have ECT. And the response rates very good. So it’s I guess the gold standard at the end it’s you know for people who have treatment resistant depression, we would expect about somewhere between 70 and 80% of patients will have a great response with that with ECT.

    TMS is a newer procedure. It’s been around for about 20 or 30 years. ECT has been around since the 50s, so it’s it’s a very old procedure. So TMS is relatively new. It’s only been around for about 20 or 30 years. And it’s using magnets to simulate the brain, so we’re not using a current straight from the wall. We’re using a magnet that that sort of put much like an MRI machine that’s put close to the brain and it pulses. So it turns on and off on and off on and off very fast and so the modern machines will pulse 50 times a second on and off. And that putting the brain near a magnet that turns on and off is going to cause electrical activity in the brain. So the intrinsic activity of the brain will sort of cause electrical activity. But it’s not doing it through putting it current through, it’s putting it through in the presence of being a in a magnetic field.

    And so this is a much safer procedure. It’s and it’s focused on the particular part of the brain you’re trying to stimulate and ECT can do one thing. It can basically just activate the brain. TMS can do one or two things. You can either activate the brain, which is what we use in depression or it can turn down the brain as well. So there are some conditions where we’re actually turning down activity in the brain. And it all depends on how you pulse the brain. So if you slow pulse the brain or you rapidly pulse the brain, you will get a different on and on and off effect of the brain. But I guess from practically speaking from the depression point of view, we’re actively activating the brain, your patients fully awake. They’re sitting in an office space in a in a in an outpatient set of setting. The treatment itself takes just a few minutes, so most people have 1/2 hour appointment.

    They might have some treatment and then go back to work or go back to school or go back to doing there every day. They can drive to the session, drive home. They won’t feel significantly different at all. So rather than being a sort of procedure was gonna take quite a few hours, it’s going to be quite sedating and kind of cause you sort of impairment. TMS is going to be quite sort of you’re gonna feel pretty much the same when you walk out of the office. It’s typically done in, you know, between 3 and 10 sessions a week. You can do quite a lot of TMS because it can. It’s quite well tolerated and you’re going to do a course of about 30 to 35 sessions. So it’s going to take you anywhere between 3 to 10 weeks, depending on how your space those sessions out.

    Question 7
    Can a GP refer a patient for TMS?

    Jason: Yeah, yeah. So the Medicare rebates that came out for TMS in Australia in 2021 allows GP’s to refer directly for TMS what’s required at at the other end is that the the TMS clinic has a psychiatrist who will do the assessment for the GP to see if they’re suitable for TMS and go through any exclusion criteria that they may have. So essentially, you know, referring to TMS is like referring for a psychiatric assessment and then from there, if the psychiatrist thinks it’s there’s they’re suitable. They go ahead to progress with TMS. So as a GP, you don’t need to be an expert in TMS to refer, I guess you need. You need to identify that someone’s got treatment resistant depression that you’ve tried a few different medications. And then I guess you leave up to the psychiatrist to work out whether they’re appropriate.

    So the sort of things that may not make them appropriate, for example, if they have a cochlear implant. If they have metal in their brain, if they’re at the moment, if they’re under 18, you know, if they’ve had a history of seizures, they might not be a head injury recently. So the few things that the psychiatrist to sort out. And typically at our clinic about 60% of patients who get referred to us from GPs and psychiatrists will proceed to have TMS and 40% don’t. And for those 40% who don’t, it may be that you know when I assess someone, I might think they could have their treatment optimised a bit better before we proceed to TMS. So maybe the GP. If started, someone with some medication increase the dose and I might think it might be worth just trying to tweak that a little bit more first, so I might get back to the GPs. I’ll try this first and then if they’re still not right, maybe come back to us in a months time or we can have another look at the TMS. So we can help optimise the treatment to make sure that they’ve had two optimal treatments of treatment before we progressed to TMS.

    Question 8
    When should a GP refer to mental health specialists?

    Jason: So I guess there’s two types of mental specialists we can consider as far as referring to a psychologist, I think you should be thinking about referring to psychology very early on in the piece. I think certainly within a session or two, seeing someone with depression, if you think they’re in the. Mild to moderate range. I think a psychologist can really help you support that patient. Identifying any stress, any external factors that can be sort of psychologically dealt with. So I think at the same time we’re thinking of sort of starting some medication. You probably should be also thinking about referring to a psychologist. I think Medicaid gives us quite a lot of sessions with psychologists to sort of support that process. And I think doing. That early would be really useful.

    As far as managing medications, I think GP’s would be very adequately managing medications for quite a few months to give two optimal trials of medications. I think if you’ve been through a couple of different medication trials. So these are two or three months into the piece. If you’re still not getting where you want to be, I think I’d be thinking about referring to a psychiatrist. Keep in mind it’s gonna take a while to see a psychiatrist to get an appointment to see a psychiatrist. So I think if you start the process early and look, there’s nothing wrong with, say booking to see a psychiatrist in too much time. And then two months time, the patient gets better and just cancels the appointment. That’s absolutely fine. And at least you put some things in place to have them sort of tracking in the right way.

    Certainly as a GP, you need to be thinking that, you know, if this person has time to see me today. That I need to try and get them out of this out of this depression. And then the next six months, it’s really key that that we don’t prolong this episode. So I think about two or three months into the process, I’d be thinking if we’re still not where we wanna be, we’ll be worthwhile looking at a psychiatrist referral or a TMS referral at that point I think.

    Question 9
    What role does the GP play in the treatment of TRD?

    Jason: Yeah, so the the GP’s pretty key in this role because I think apart from doing the initial management of treatment resistant and making sure they’ve had adequate trials of a few different medications and refer them to a psychologist, I think even if you do refer someone to a psychiatrist or TMS down the track, the role of the GP is not over at that point. You know the GP is still the main person, that’s the the patient’s going to be seeing for observations, for tracking of symptoms, for support on a pre regular basis. If you say if you’re referring someone to a psychiatrist, the chances are the psychiatrist could maybe see them every, you know, six weeks every two months, maybe every three. And they’re going to really rely on the GP to manage things in between.

    So I think the best relationship is where you’ve got a psychiatrist who sort of, you know, implements some, some things, some recommendations, and then refers back to the GPS and the GPS can actively monitor how things are going. Now, you know, if the psychiatrist says, look, I’ll see you in three months, but the GP feels like, you know, the plan is not working. It’s support for the GP to maybe, you know, be recontacted that psychiatrist say look, you know, we’ve start to initiate that plan. It’s not working. Can we please get you to see so and so a bit earlier than what we had planned. So without that, I mean, you know, no plan, doesn’t matter if it comes from a psychiatrist or GP, no plan is always gonna work. So if you’ve started the process, for example, the psychiatrist started a mood stabiliser, started lithium or epilim and within a week it’s pretty obvious that that lithium or the epilim is just not tolerated. You know you don’t wanna wait three months to see the psychiatrist again. You know you want the GP to be able to be on top of that and to facilitate an earlier review for example.

    Yeah, the whole time I think also you know just touching in and making sure the patients are aware what the instructions for the psychiatrists are, you know, and make sure that they’re sort of keeping an eye on things like non medication, things like we’re doing some exercise, we’re sleeping, OK, we’re eating, OK, we’re not drinking too much. All the other sort of stuff that goes along with treating depression and it’s important to sort of touch base quite regularly with the with the patient. Because they’re gonna sort of fall off the perch on some of those things and forget about those things. If you’re not constantly reminding them of that. And and also you know, every couple of weeks just getting out a questionnaire, A screening tool, just see where the symptoms are, just tracking the monitoring and the progress is really important for the GP to be doing as well.

    Concluding Question
    Thank you for your time here today in the PodMD studio. To sum up for us, could you please identify the three key take home messages from today’s podcast on treatment resistant depression

    Jason: Yeah. So I guess the first thing is to identify that. Whether you are an excellent GP at managing depression or whether you are average, or whether you’re not that good doesn’t matter. I mean, you’re gonna find that about 50% of patients that you you look after with depression are gonna probably end up being treatment resistant in some degree. So this is not a failure on your part. This is just the nature of how the illness is and expecting that and be monitoring for that. And be understanding what that means and what that means to your treatment is really important.

    The second thing is thinking about referring onto specialist services, you know, so psychologists pretty early on and psychiatrist within two or three months, if you’re not getting where you want to be. To not slow down the process of recovery is really, really important. If not every TV is going to be comfortable using mood stabilisers and second line treatments and so making sure you have access to that for your patient, you know early on and thinking about the delay in getting to see that person is really important.

    And thirdly, just use monitoring tools. I think it’s really important to find a tool that you’re comfortable with and understand. I talk a lot about PHP HQ or the patient health questioning. It’s a really simple one that we use in our practise and it’s a simple language that patients can understand. Having something like that to track your progress is I think adds a lot more effectiveness to your treatment than just simply asking a few questions. These questions are very effective to be taken home. Brought back the next day or, you know, a week later they don’t have to take up a whole bunch of your time in front of the patient. But they can really help you track how patients are going in a more accurate way.

    Thanks for your time and the insights you’ve provided.

    Jason: Thank you

*As always, all in this PODMD podcast is intended for health professionals and the comments are of a general nature. Information given is not intended as specific medical advice pertaining to any given patient. If you have a clinical issue with one of your patients please seek appropriate advice from a colleague with expertise in the area.