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Lucy Chen: [00:00:15] Welcome to PsychEd, the Educational Psychiatry Podcast for Medical Learners. Biomedical Learners. We are a group of first and second year residents at the University of Toronto in Canada who have come together to discuss important topics in psychiatry through our own research and with the help of our world class psychiatrists.
Carrol Zhou: [00:00:35] Today's episode will provide a comprehensive overview on the treatment of depression as a continuation of our last episode on the diagnosis of depression. I'm Carol Zoe, and I'm joined by my co hosts, Lucy Chen and Alex Raben. We will also hear from Dr. Sidney Kennedy, the founder of the CAMMAT Guidelines on Depression, who sat down with Lucy and Alex to share his expertise in this area, as well as highlight some of the changes to the soon to be released 2016 guidelines that are different from the current guidelines from 2009.
Alex Raben: [00:01:09] Our discussion will once again revolve around our case patient. We will start off by explaining what the CANMAT guidelines are. We will talk about the general approach to starting treatment and then we will delve deeper into each type of treatment and how and when they should be used.
Lucy Chen: [00:01:26] So to start, remember, Erin, she's a 24 year old resident who's been experiencing fatigue, poor sleep, and is having a difficult time enjoying and concentrating at work for the past few months following the end of a long term relationship. In our last episode, we diagnosed Erin with a major depressive disorder. Now she wants to know what you might suggest to help her feel better. So where do we start?
Carrol Zhou: [00:01:50] There are many different types of treatments for depression, and so it's easy to get overwhelmed. The CANMAT guidelines were developed to make this enormous task easier for psychiatrists as well as primary care providers. And although it does not replace clinical judgement, it provides an evidence based framework from which we can work from. As with any psychiatric illness, we want to take a biopsychosocial approach to treatment, and we also want to consider the culture and spirituality of the patient. Can that limits its scope to biological, for example, drugs and psychological, for example, psychotherapy treatments, Likely because social treatments are often region specific. For example, a specific crisis centre that you can refer to only in your city. And so we too will limit our discussion to these treatments with the understanding that in real life you may have additional options at your disposal. Let's hear from Dr. Kennedy, who gave us a better understanding of the CANMAT guidelines.
Alex Raben: [00:03:02] Start. Could you just introduce yourself to our audience?
Dr. Sid Kennedy: [00:03:06] I'm Syd Kennedy. I'm a professor of psychiatry at University of Toronto. I'm actually the founding chair of the Canadian Network for Mood and Anxiety Treatments. CANMAT and I've in recent years been the lead for the Depression Working Group.
Alex Raben: [00:03:23] Great.
Lucy Chen: [00:03:24] Excellent. And perhaps you can tell us a little bit about CANMAT and where with the origins of CANMAT.
Dr. Sid Kennedy: [00:03:33] So the origins of CANMAT can actually be traced back to a Chinese restaurant and College Street in Toronto, just across from the former Clark Institute. Now, Camh which where a group of us used to meet on a Wednesday for lunch and talk about some of the issues that we were developing in our research and our teaching and the idea of developing guidelines similar to guidelines that had been produced, for example, for Anti-infectives in Ontario was a model. We decided on different names. We thought about the Canadian Network for Mood and Anxiety Disorders. But that said, Can MAD, and we thought that was probably not very sensitive. So in fact the mood and anxiety treatments are CANMAT became the the term that we selected. This was a group in Toronto, but we had many connections across Canada, so we held our first meeting in 1995. I sit one of the airport hotels in Toronto, so we had people come from Vancouver, Calgary, Winnipeg, Halifax, various other centres across Canada, and we agreed on a guideline project As the first initiative we became incorporated as a not-for-profit corporation. We defined our goals as patient advocacy, education and clinical research, and we've actually developed guidelines in bipolar disorder, which have been frequently updated, and also in depression with the most recent guidelines now being 2016.
Alex Raben: [00:05:27] Right. And you mentioned that you came together sort of around a common common issues. What were those issues and how do the can guidelines solve those issues?
Dr. Sid Kennedy: [00:05:39] I don't know if we actually solved all the issues, but we did feel that there were a number of other countries or regions that had looked at ways to improve patient care. And I've always thought that you can really do two things when you're trying to treat patients, and it would apply beyond depression. But in this area we'll talk about depression. So you can think about doing the best with the treatments and the options that are available. And then you can think about the new options that you can develop through research. So our CANMAT guidelines were really designed to promote optimal use of existing treatments.
Alex Raben: [00:06:24] The CANMAT guidelines has its own system of evaluating current treatments, as Dr. Kennedy explains.
Dr. Sid Kennedy: [00:06:31] So there are many different formats of assessing evidence, and we have become somewhat more we've raised the bar in recent years. We've been influenced by the grade system, which has been particularly developed at McMaster and elsewhere. Level of evidence is based currently on at least two robust randomised controlled trials or a large meta analysis and where effect sizes have been reasonable and reasonable might be 0.6 or higher. So that would that would produce level one evidence, one RCT without replication. Several smaller trials could be considered level two evidence. Level three evidence is large case series and level four evidence is really clinical individual case reports. So how do we get from levels of evidence to recommended first, second or third line treatments? And the answer is that we add to the evidence base, clinical expertise or clinical common sense. So if I could give the example, for example, of a drug like Olanzapine or Zyprexa, which is an atypical antipsychotic, but is frequently used as an adjunctive treatment for depression, and it's actually from the efficacy point of view, it's a very good treatment. On the other hand, it's metabolic side effects. The weight gain associated with its use makes it actually a matter of concern, particularly for long term use. So while it might have level one evidence, it would have a level two or a second line recommendation. And another example quickly would be something like the monoamine oxidase inhibitor antidepressants that were developed in the 1950s. For many patients, they're actually very effective treatments. But the issues of dietary concerns, the risk of hypertensive crisis would make it certainly not a first line choice for treatment and in reality probably a third line treatment. But you could argue that it could have second line recommendation.
Lucy Chen: [00:09:07] In CANMAT first line treatments, which are what we mostly will focus on in this episode, must not only have good evidence in the literature, but they must also be practical and useful clinically. An interesting feature of the CANMAT guidelines is in its question and answer format.
Dr. Sid Kennedy: [00:09:25] What we did and what we have done through each of our edits and and additions is we've actually at conferences and at other settings, we've asked community psychiatrists, primary care physicians to tell us what questions they feel they would like answered when they treat patients with depression. And we've got a whole bunch of questions that have come in. We sometimes use a few slides and show the questions that have been asked and we ask, are there any other questions that are not here? So we have I think, one of the differences between the CANMAT guidelines and other, for example, APA or the Nice guidelines in the UK are that we actually take a question and answer format to try and keep it very practical and clinically relevant. And I would hope from a medical student or a resident perspective, that's actually a good thing.
Carrol Zhou: [00:10:26] This question and answer format allows clinicians to jump in and quickly answer their treatment questions. CANMAT breaks the treatments down into four categories psychotherapy, pharmacotherapy, neurostimulation and complementary and alternative medicine treatments, which in CANMAT includes diet and exercise. However, in our situation with Erin, where we're faced with starting treatment for someone with a new diagnosis of depression, it can be difficult to know where to start. We've asked for Dr. Kennedy's advice on this, and here's what he had to say.
Dr. Sid Kennedy: [00:11:00] The first step is making sure you've made a good diagnosis, making sure that there aren't other co morbid disorders ruling out that this is actually a major depressive episode and somebody with bipolar disorder looking at things like psychotic features because those are all issues that would alter your treatment selection. And then we've tried to go into the issues, particularly of so-called specifiers, like you might have a seasonal pattern to your depressive episodes. And so that would influence the use of a light box as part of the treatment, not necessarily the whole treatment. Or you might have atypical symptoms, which means you would eat more and sleep more rather than typically sleeping less and eating less. And does that change your treatment? Some people would say there have been trials to suggest some treatments. Others would say it doesn't really change your treatment. So those would be the first things I think you can think about the treatment selection, what are the patient variables? What are the aspects of the patient I should also mention. If a patient is if there are life threatening issues, acute suicidal beliefs, recent actions, severe emaciation or you know, these are the issues that are going to make you decide whether the person needs to come into hospital or not. So we've primarily tried to take people through the the thinking that would probably help you pass your membership exam if you were being asked these questions before you then start into the treatments.
Alex Raben: [00:12:41] As Dr. Kennedy mentioned, it's important to first get the diagnosis right. We talked all about how to diagnose depression in the last episode. So if you want to learn more about that, go back and have a listen. If there are safety issues such as the patient being actively suicidal, then the treatment approach would be completely different than what we're going to talk about today. But we don't have these concerns for Aaron at the moment. One thing we didn't discuss in the last episode is diagnostic specifiers. These are labels that relate to each DSM diagnosis that have their own criteria. One important specifiers for Aaron would be the severity, which can either be mild, moderate or severe. These categories are subjective, but mostly depend on the severity and number of symptoms, as well as the degree to which the disease impacts the patient's life. Although Aaron finds her low energy and poor concentration distressing so far, she's been able to cope with them and has continued to function well at work. Therefore, her depression would be considered mild. This will help inform our treatment going forward. So after these general considerations, you and the patient are left with the decision of which therapy or therapies to initiate. Let's go through each of the domains. We will start with Lucy, who took a deeper look into psychotherapies for depression. First of all, Lucy, what exactly is psychotherapy?
Lucy Chen: [00:14:19] Well, essentially psychotherapy is a non medical treatment that aims to help patients change the thoughts and behaviours that contribute to depression. There are many forms it can take, but the main aim is to change the pathological thought patterns that make people feel low or down about themselves.
Alex Raben: [00:14:38] So when is it appropriate to use psychotherapy?
Lucy Chen: [00:14:42] When thinking about when to employ psychotherapy. Clinicians need to think broadly and consider firstly the availability of the therapy, but also the provider and the patient's presentation. Let's see what Dr. Kennedy had to say.
Dr. Sid Kennedy: [00:14:56] Well, I think there's a very good section in the 2016 guidelines written by my colleague Professor Perich, where the question of who gets psychotherapy is really. Raised. And so the first question is about availability of the treatment, because it's all very well to recommend cognitive behavioural therapy, but if nobody is trained to deliver it, that's a bit of an issue. Secondly, what is the patient preference? And many people have said I would like cognitive therapy, but I actually think the medication treatment might work more quickly, for example. So you have to look at issues of how much time have you got in reviewing that area. One of the issues that was the best predictor of response to a psychotherapy was the connection between the patient and the therapist, irrespective of what the modality of psychotherapy was. So these are the kind of non-specific issues.
Lucy Chen: [00:16:02] We'll explain CBT a little later in the episode. But here Dr. Kennedy emphasise the importance of knowing who the therapist is and what kind of therapy is offered before contemplating the option of psychotherapy. In addition to access, we also need to think about the quality of the therapy. There are many people who can get training and deliver psychotherapy like psychiatrists, psychologists, nurse practitioners, but it should be delivered with sufficient time and quality. Dr. Kennedy mentioned a very interesting point that the best predictor of response to psychotherapy is the connection and rapport between the patient and the therapist. This is also known as a therapeutic alliance, highlighting again the importance of quality of delivery of therapy. The therapist should have the capacity and skills to engage the patient. Elaborating on the point of patient preference, we need to think about how interested the patient is in talk therapy. If they're disengaged and not interested, then psychotherapy is not likely to be fruitful. In addition, there's a certain level of understanding and capacity that the patient should have to process the exchange that happens in psychotherapy. If they're confused, delirious, or cognitively impaired, it could be hard to participate. Also, it's imperative to think about the severity of the depression. If a patient is presenting as severely depressed with poor concentration, lethargy and evolution, it could be difficult to engage them psychotherapeutic. As Dr. Kennedy mentioned, timing is also an important consideration. The efficiency and speed of medication may serve as a more appropriate choice for therapy until the patient has a more severe episode. It would also be unwise to recommend monotherapy with psychotherapy in a severely suicidal patient or patient with psychotic depression. In this case, stabilisation with medication , ECT would be much more appropriate as a first choice.
Alex Raben: [00:18:02] That makes a lot of sense, Lucy. Now, I'm wondering how this relates to pharmacological treatment of depression. Is it more effective to have both medication and psychotherapy? Do we start them together or one after the other?
Lucy Chen: [00:18:15] That's a great question and one that I asked Dr. Kennedy myself.
Dr. Sid Kennedy: [00:18:19] So you've asked about when would you start two therapies at the beginning or even later on versus one. And the truth is that most of the studies look at treatments in a sequential way, although there's a small literature, particularly in medications, that has looked at the idea of starting two treatments right from the beginning. And I think from the psychotherapy point of view, people who've had recurrent episodes or perhaps have a chronic depression, then the combination of, say, cognitive therapy with an antidepressant might be particularly helpful. And an interesting evidence to support. That was a study done at least a decade ago where a drug that we don't use anymore called Nefasedone or Searson was actually used with a modified version of cognitive therapy. It was actually called cognitive Behavioural analysis System Psychotherapy or C bass. So you can remember by the fish. Now, what happened there was interesting that the combination of treatment was better than either alone for people who had chronic depression. On the other hand, if you looked specifically at the question of early childhood trauma, those people who had early childhood trauma did better when they got the psychotherapy either alone or with the drug, and they did less well with the drug alone. So, again, it's telling you how certain variables with an individual patient might influence the treatment choice.
Lucy Chen: [00:20:08] Combination treatment for a major depressive disorder can be employed either sequentially, as in medication followed by psychotherapy or vice versa or concurrently. So basically starting both treatments at the same time. With regards to sequential treatment, you can think about adding psychotherapy. If somebody has a partial response to an antidepressant, it may be useful to add psychotherapy. In this case as an adjunctive treatment. It's been hard to evaluate the outcomes of combination therapy because of the varying modes of delivery. But Dr. Kennedy has suggested that some studies have revealed that combination therapy with an anti depressant and psychotherapy at the same time has been of benefit in chronic depression. There was also a meta analysis conducted in 2009, combining 18 studies with over 1800 subjects that concluded that concurrent medication and psychotherapy was superior to psychotherapy alone, with a small to moderate effect. Size of 0.35. Interestingly, when concurrent therapy is evaluated in more focal populations like the elderly, its superiority increases. This further highlights Dr. Kennedy's point that certain variables within a patient might influence the treatment choice and its effectiveness.
Alex Raben: [00:21:28] I think a lot of us have heard about CBT or cognitive behavioural therapy, but could you explain this further? Lucy and when you might use it?
Lucy Chen: [00:21:36] Sure. So CBT cognitive behavioural therapy is a standardised form of therapy that aims to correct cognitive distortions. So basically cognitive distortions are ways that we convince ourselves is something that really isn't true. These inaccurate thoughts usually reinforce negative thinking. For instance, Aaron might get upset over the fact that a colleague at work made a joke about her when she accidentally pressed a few extra buttons on the photocopy machine and made 100 copies of a patient document instead of just one. Suddenly she feels incredibly stupid and embarrassed and is flooded with negative feelings about herself. But look, looking at the big picture, the joke by her colleague could have also been an attempt to make light of the situation. Or perhaps this is a colleague who always makes jokes to try and get attention. By reinterpreting the intention of the joke and the situation, the patient may feel less poorly about themselves. So CBT uses logical analysis to break down these automatic negative thoughts and reinterpret them to elicit more realistic, healthy emotions and behaviour. So CBT can be done in groups or on a 1 to 1 basis. Either way, the sessions typically occur once a week for about 15 weeks. The skills required to perform to perform CBT can be required through a CME workshop or by collaborating with a psychiatrist.
Alex Raben: [00:23:01] Great. Thanks Lucy. That was an excellent introduction to CBT. Can you tell us a little bit about the other psychotherapies that we might consider in Erin's case?
Lucy Chen: [00:23:11] Sure. Let's turn to our expert for that answer.
Dr. Sid Kennedy: [00:23:14] The evidence base for cognitive behavioural therapy is level one, first line treatment, level one, evidence, interpersonal therapy or interpersonal psychotherapy. IPT would have the same level of evidence. The difference in the 2016 is that mindfulness based cognitive therapy would now be seen as having level one evidence as a maintenance treatment beyond the acute stage, but level two evidence as an acute treatment. So we have three psychotherapies that would certainly be competitive with any of the drug treatments. And there have been a large number of meta analyses looking at cognitive therapy in particular compared to pharmacotherapy and with the exception of people who have psychotic symptoms who are in acute suicidal risk in general, if you have optimal psychotherapy, cognitive therapy, the outcomes can be as good as pharmacotherapy, but the availability also is a problem.
Lucy Chen: [00:24:32] So in terms of first line treatments, it seems that CBT, IPT and NBCT are considered to be the most recommended so and NBCT is another form of cognitive behavioural therapy and it stands for mindfulness based cognitive therapy. Dr. Kennedy mentioned BCT as having level one evidence for maintenance therapy, but level two evidence for acute therapy, which makes sense because NBCT is designed to really help people suffer through repeated bouts of depression and chronic unhappiness. NBCT uses traditional CBT methods and as this extra dimension of mindfulness and mindfulness meditation. And this is really a focus on awareness of all incoming thoughts and feelings and accepting them, but not attaching or reacting to them. This process is known as de centring and AIDS in disengaging from self criticism, rumination and dysphoric mood that can arise when reacting to negative thinking patterns. Like CBT and NCBT, it functions on the theory that individuals who have depression have negative cognitive distortions that trigger a depressive episode. However, instead of reinterpreting them, the goal of NCBT is to interrupt these automatic processes and teach the patient to focus less on reacting to incoming stimuli and instead accepting and observing them without judgement. NC is more so for treating the maintenance phase of depression as highlighted by Dr. Kennedy. And currently, Erin is suffering in an acute phase. So this really isn't the best option to start her off with. Ipt Interpersonal therapy is a problem focussed treatment for depression and this approach, the focus of therapy, is on current relationships and interpersonal events that contribute to the onset and or maintenance of depression. Ipt focuses on a key issue and one of the three problem areas. So one is recent life changes or transitions like a divorce, marriage, moving job loss, two conflicts with others. Three Grief related to loss of a significant other. Ipt helps to reduce distress through understanding and improving relationships at work, home and social life. Adjusting to life changes and building relationship skills.
Alex Raben: [00:27:00] Great. Thanks, Lucy. So let's put this all together in the context of Erin's case now. She has a mild depression and is quite high functioning. Based on that, you propose psychotherapy as a monotherapy. Given that she seems to have a number of negative cognitive distortions and has not really been focusing on the recent Break-Up with her ex boyfriend, you decide to recommend CBT over IPT, You realise NCBT would also not be indicated in Erin's case because she's in the acute phase of illness. Erin has heard about CBT before and is interested in trying it, but she would like to join a group therapy session that is covered by the government. You explain to her the CBT groups available in your area. However, there is a substantial wait time. Erin agrees to be put on the waitlist for these groups, but asks you if she could try a medication in the meantime, as she wants to get better as quickly as possible. She asks how quickly she can expect to feel better on the medications and what side effects she might expect.
Carrol Zhou: [00:28:17] So today, let's talk about four general classes of antidepressants which make up the first line treatments. The first is selective serotonin reuptake inhibitors or SSRIs. That's things like fluoxetine, sertraline, citalopram and escitalopram. Yes. Then we have the serotonin, norepinephrine, reuptake inhibitors or snris, like venlafaxine and duloxetine, for sure. And finally, we have norepinephrine, dopamine reuptake inhibitors or NDRI, which is bupropion and noreadrenergic and specific serotonin agonists or NASSA which is Mirtazapine. Wow. That's a lot of classes of medications. So to summarise, we have SSRIs like fluoxetine, SNRI like venlafaxine and then bupropion and Mirtazapine are on in their own classes. Now how would you choose between all these options?
Carrol Zhou: [00:29:18] Well, like I said, these are all first line, so one isn't necessarily better than the other for treating symptoms of depression. We often end up choosing them based on the differences in their side effect profiles. Side effects.
Lucy Chen: [00:29:31] Maybe you can tell us a bit more about how you would counsel patients who are about to start an antidepressant.
Carrol Zhou: [00:29:36] Sure. So side effects generally fall into two categories. One is serious but uncommon, and the other is non life threatening, but very common side effects. There are very unique side effects associated with each class of medications. And again, for the sake of our brain capacities, I think it may be just wise to talk about SSRIs for today so we can walk away feeling comfortable with prescribing one class of antidepressants. So the serious and life threatening but very uncommon things can include number one, serotonin syndrome.
Carrol Zhou: [00:30:13] It's a cluster of life threatening symptoms that's caused by significantly elevated levels of serotonin in our system. This can happen to individuals taking SSRIs, but it occurs usually only if they're co prescribed with other serotonergic agents. And frequently it happens when you take SSRIs and another class of antidepressants called MAOI or monoamine oxidase inhibitors. Those are not first line treatments for depression. The key here, though, is to always use a drug interaction checker app when you're prescribing antidepressants to make sure that other medications are not synergistically increasing your systemic serotonin in some way. So the second adverse effect to know about is suicidality associated with SSRIs. I think it's at this point important to define what suicidality means. And it can be done in two ways as either completed suicides or suicidal thoughts and behaviours. And we need to know how SSRIs can affect each of these definitions. So basically SSRIs do not increase the risk of completed suicides in adults or children. But research on suicidal thoughts and behaviours is more controversial. This is due to the fact that the physical symptoms of depression often improves before the cognitive and mood symptoms, so people find themselves feeling more restless, yet their mood is still bad. Age seems to be a protective factor, with older individuals being less likely to develop increased suicidal thoughts and behaviours. But studies have shown that there is an increase in those thoughts and behaviours in children and in some studies young adults age 18 to 24 years.
Carrol Zhou: [00:32:02] Although I should add that for those young adults the data did not reach statistical significance. Nevertheless, there is a black box warning for most SSRIs for children and adolescents with the age limit extended to include young adults.
Lucy Chen: [00:32:17] To summarise, beware of serotonin syndrome when prescribing SSRI. As with other serotonergic medications. Also, SSRI can be associated with increased suicidal thought behaviour, especially in children and possibly young adults. But what about some non-serious side effects?
Carrol Zhou: [00:32:36] There are a lot of common side effects and I will again only touch on the big ones. And for the SSRIs, the reasons SSRIs make us feel better theoretically, is because the increased concentrations of serotonin will bind to a specific subset of serotonin receptors called 5HT1A receptors which are linked to mood. Unlucky for us, though, there are other 5HT receptors in our central nervous system that does not regulate mood, which causes side effects corresponding to increased serotonin levels in their synaptic clefts. For example, the synapses containing 5HT2A receptors are linked to sexual dysfunction. The synopsis containing 5HT2C receptors are linked to insomnia and anorexia, and the synapses containing 5HT3A receptors are linked to increased nausea and vomiting.
Lucy Chen: [00:33:28] So seems like the more prevalent. But non-life threatening of the symptoms include sexual dysfunction, anorexia and GI upset.
Carrol Zhou: [00:33:36] Precisely.
Lucy Chen: [00:33:38] But what if someone experiences these common and bothersome side effects? But and then based on that, they decide to just stop the medications cold turkey?
Carrol Zhou: [00:33:49] I think that's a very good question. It's important to remember that abrupt discontinuation dose reduction and tapering of antidepressants can cause withdrawal symptoms in SSRIs. The biggest culprit for withdrawal symptoms is paroxetine. And the withdrawal symptoms can look like any or all of the following. So some dizziness, nausea, vomiting, chills, insomnia, or even electric shock like sensations down one's back. Visual phenomena, anxiety, agitation. There have even been cases of post discontinuation mania that's been reported.
Lucy Chen: [00:34:27] So based on these side effects, it seems like it'd be important to counsel these patients on not abruptly stopping their medications once you start them so they can avoid these side effects.
Carrol Zhou: [00:34:37] For sure.
Lucy Chen: [00:34:39] Okay. So out of curiosity and we don't have to go to much detail here, but what are some of the indications for using some of the other classes of medications like you mentioned before, like Buproprion and Mirtazapine? Just so our listeners get a flavour for them, get an idea of their clinical utility for sure. So, so to be really brief and again, it's not an inclusive list at all, Buproprion and Mirtazapine generally have less sexual side effects than the other antidepressants. So if someone's really worried about that, it's good to introduce them to these options. However Buproprion, needs to be used with caution and individuals with seizure disorders because it may lower the seizures threshold. So that's something to be aware of. It can also be what we call activating, which means inducing increased anxiety and insomnia. So it's not good for someone who already has issues with that.
Carrol Zhou: [00:35:33] Mirtazapine, on the other hand, tends to be more helpful with sleep. It also comes in a sublingual formulation, so it's helpful for people that have difficulty swallowing, but it can also cause weight gain.
Lucy Chen: [00:35:46] Thanks for touching on those two classes or those two medications Carol. Also, Aaron was wondering how long it takes for these anti depressants to work and what should we tell her?
Carrol Zhou: [00:35:57] It generally takes about 2 to 4 weeks or longer for the therapeutic effects of antidepressants to kick in, especially the mood and cognitive symptoms, whereas physical symptoms such as sleep or low energy may be improved earlier on in the treatment course as early as 1 to 2 weeks. It's really important for us to learn the side effect profile and time lag for antidepressants to start working and to educate the patients on how long it's recommended also to continue medication even after they start feeling better. If people are not informed of this, this can contribute to them not being adherent to the treatment. For example, statistics show that 30% of patients discontinue within 40 days of starting an end depressant and more than 40% discontinue within 90 days. So this is a huge problem with antidepressants.
Lucy Chen: [00:36:49] For sure. Now I really see the value of counselling. But in what ways? Like how would we measure the level of improvement in patients?
Carrol Zhou: [00:36:58] Yes, this is another very clinically relevant question. We need to use validated scales consistently to measure the change in her symptoms instead of just having a general clinical impression every time we see her. There's lots of research to support this, and the CANMAT strongly recommends this as well.
Lucy Chen: [00:37:17] But what if a patient is on a therapeutic dose of an antidepressant? They stay on it for 2 to 4 weeks, but then they don't get a response. Like, what do we do then?
Carrol Zhou: [00:37:27] Right. So there are generally three things you can do when there is no response or only partial response. They are one, optimising the dosage. Two, augmenting or combining with a different medication or three switching to a different class of medication completely. So optimising just means making sure that the dosage that the patient is on is therapeutic. Augmenting means we're adding a new medication that's not classically considered to be an antidepressant in order to improve the antidepressants efficacy. Combining means adding another antidepressant switching just means discontinuing or tapering off of what you currently are on and then starting a whole new different medication altogether.
Lucy Chen: [00:38:14] So it seems like if something's not working, we have a few options, one of them being optimising the dosage, another one being augmenting or combined with another antidepressant or completely switching to a different depressant. Cool. When would I do each of these things?
Carrol Zhou: [00:38:32] The CANMAT provides a really great diagram to try to tackle this issue in a systematic and algorithmic way. So basically, after four weeks of antidepressant therapy, a few things can happen. Either you, a improve and go into full remission, which is what we all hope for, or b you improve, but only partially by as evident by a validated depression scale. And three, the patient does not improve at all, or they're just totally intolerant physically to the treatment.
Lucy Chen: [00:39:08] So if the patient goes into remission, you know, it's intuitive for them to stay on this medication. But if they don't improve or they can't tolerate the treatment, they can clearly be switched.
Carrol Zhou: [00:39:20] Yeah, that's right.
Lucy Chen: [00:39:22] But what if they they don't completely improve. They only partially improved the medication.
Carrol Zhou: [00:39:28] Right. So that's the time that we would consider either augmenting or combining the existent therapies with another medication, because residual depressive symptom is a risk factor for relapse into another major depressive episode. Our goal of treatment is always for the patient to achieve complete remission.
Lucy Chen: [00:39:49] But what if augmenting, combining, doing all these things still doesn't work,
Carrol Zhou: [00:39:54] Then it may be time to switch. We would taper the patient off of their current medication safely and then start them on a different class of medications. The Star D trial, which is the landmark trial that everyone sort of quotes in psychiatry, shows that 28% of individuals achieve complete remission with their first antidepressant and then 25 additional percent of patients achieve that with their second antidepressants. So 53% of patients should be expected to achieve full remission after two sequential treatments. And hopefully, in our case, Aaron falls into that group. But unfortunately, there's really no way to tell how she's going to respond to each kind of treatment.
Dr. Sid Kennedy: [00:40:47] One of the most important comments of this, Discussion is that it would be very naive to think we have only one type of depression and only one dysregulated brain mechanism so that everybody should naturally respond to the same treatment. It doesn't help. It doesn't happen with hypertension. It doesn't happen even with diabetes. Doesn't happen clearly with infections. So why should we expect that one treatment will help everybody with depression? So I think the problem sometimes is identifying who would the key responders be. And that's where the whole pursuit of biomarkers, where the whole question of better defining subpopulations within a group of depressed people might well help us to say you're the group who would do best with our teams. But there's another group over here who actually are excellent candidates for behavioural activation, and that's the that's the next challenge, I think.
Lucy Chen: [00:41:51] I see. But how long should people go on antidepressants for?
Carrol Zhou: [00:41:56] Yeah. So you can tell them that once they start getting better, if they're a low risk adult, generally, you put them on for 6 to 12 months after that. And if they have risk factors like older age or recurrent episodes or really severe disease, then we think about putting them on this medication anywhere from two years to longer.
Lucy Chen: [00:42:19] All right. Thanks, Carol. So now I just want to kind of start applying some of this newfound knowledge of pharmaco pharmacology to Erin's case. So we discuss with Erin the common side effects, which include sexual dysfunction, GI, upset, insomnia and anorexia, as well as some of the more serious side effects such as serotonin syndrome and suicidality. We've explained to her that it will take about 2 to 4 weeks before she notices any changes to her actual mood. We explain that we'll make these recommendations to her family doctor and that this will be a one time consultation and that she'll need follow up with her family doctor regularly after starting the drug and should follow up sooner if she experiences any suicidal thoughts. But what drug will we actually recommend to her family? Doctor, to start with.
Alex Raben: [00:43:13] If you were just starting an antidepressant and someone for the first time, which drug would you go with? I know that the 2009 guidelines point to some drugs having superior possible superiority. Does that come into play?
Dr. Sid Kennedy: [00:43:26] So that's a good question. If we think about first drug selection or first antidepressant choice. There was a very influential meta analysis around 2009 that looked at both the dropout rate and the response rate across more than 12,000 people where there had been head to head trials. The author was Cipriani. And what he showed was that if you took a composite of response and dropout, escitalopram and Sertraline looked better than the other agents. Now, there were limitations, of course, in that not all trials used the same measures. A dropout is a fairly crude measure of whether you tolerated a drug or you didn't. It only captured the, if you like, the tail end when we looked at this for the 2016 guidelines, we probably took a broader, slightly more conservative position and we recognised that there tended to be not so much difference across most of the current SSRI as entry agents. And in general, we didn't recommend one SSRI or snris over another.
Lucy Chen: [00:44:49] So it seems like it's really about choosing the right drug for the patient. Aaron expresses a desire to minimise sexual side effects and also doesn't want to feel tired at work. So we recommend starting her on Buproprion, which she actually agrees with. So that covers the basics of pharmacology for depression. Let's switch gears now to neurostimulation therapies. Alex focuses his research on these therapies and can give us an overview.
Alex Raben: [00:45:27] Thanks, Lucy. So again, I'll just cover the basics here. Neurostimulation therapies are therapies used in depression and other illnesses that apply electrical currents or magnetic fields to stimulate the brain. The one that our audience will most likely be familiar with is the tried and true electroconvulsive therapy or ECT.
Lucy Chen: [00:45:54] Yeah, I've heard of ECT and also I think most people are familiar with it in one clue. One Flew Over the Cuckoo's Nest, where they shock Jack Nicholson when he didn't behave. But what exactly is it?
Alex Raben: [00:46:08] Yeah. I think it's good that you bring up One Flew Over the Cuckoo's Nest. Because it is. Depiction in many of our patients mind, and it's actually quite inaccurate. So in the movie, it's depicted as something that's involuntary, it's used as a punishment, but in reality, it's actually a very helpful therapy that doesn't involve a lot of these negative aspects.
Lucy Chen: [00:46:34] Yeah, in the movie it seemed like it was really painful and highly debilitating, but what is ECT actually like in reality?
Alex Raben: [00:46:43] So modern ECT involves anaesthesia and it involves muscle relaxants to prevent discomfort and to prevent seizure movements. So the patient doesn't actually feel anything that's happening. Once the patient is under anaesthesia, that's when the psychiatrist will apply the electrodes to the scalp and induce the seizure through the electrical current.
Lucy Chen: [00:47:08] It seems like it's pretty much just like any other procedure, but it's still pretty involved. So why do we use it when we have antidepressants?
Alex Raben: [00:47:19] It's a good question. And the reason is that it's highly effective. So response rates are between 80 and 90% in general, depressed patients and 50 to 60% will respond if they're treatment resistant. Nothing else in our armamentarium comes close to it in terms of effectiveness.
Lucy Chen: [00:47:41] So it sounds like it works better than antidepressants. Now, kind of flipping my previous question, why do we use antidepressants instead of ECT?
Alex Raben: [00:47:50] Yeah. So ECT is not perfect either. It comes with side effects and the most important being memory loss. This is the most common side effect of ECT, and it's both anterograde and retrograde. So both before and after the ECT treatment and it can be up to months before and after that the patient has trouble remembering or it's fuzzy for the patient. And patients will often complain about this after ECT. Because of this, ECT is generally reserved only for certain clinical situations. In the CANMAT guidelines, it's a first line treatment for life threatening depression, which includes depression with psychosis, severe suicidal ideation, or those depressed patients who are catatonic or unable to care for themselves. It is also used for depression resistant to other treatments, and for those patients who have done well on ECT or in the past or have a preference for trying ECT.
Lucy Chen: [00:48:49] So ECT seems like a lost measure of sorts. It seems like it's a very safe therapy and actually our most effective treatment of depression and therefore is first line in really difficult cases despite the amnesia may cause. Do I have that right?
Alex Raben: [00:49:05] Yeah, that's exactly it. ECT not the only available neurostimulation therapy, though. Nowadays we also have rTMS or repetitive transcranial magnetic stimulation. As the name suggests, it uses magnetic fields to induce electrical currents in the brain. The major difference here from ECT is that rTMS can target specific areas of the brain and therefore does not cause seizures or memory impairment. Unfortunately, another difference is that so far it has not proven to be as effective as ECT or other therapies for that matter, that are used for treatment resistant depression. The response rate is somewhere in the ballpark of 25 to 30% of patients. However, rTMS is growing every day. It's a hot area of research and so we may see changes in this area. It also has a relatively benign side effect profile, and so it's certainly a good option for the right patient. Again, CANMAT recommends it as a second line treatment for treatment resistant depression, and a more recent European guideline made similar recommendations. Finally, I should also mention deep brain stimulation as well as vagal nerve stimulation. However, these therapies are rarely used and are experimental, and so we won't go into detail here.
Lucy Chen: [00:50:33] Cool. That's really exciting. It seems like there's a lot of growth happening in neurostimulation therapy and the research involved. Let's hear what Dr. Kennedy had to say about the future of neurostimulation in depression treatment.
Dr. Sid Kennedy: [00:50:46] So what do we mean by neurostimulation treatments for a person with depression? 30 years ago, we talked about electroconvulsive therapy. If it was the media, you talked about shock therapy. You had Jack Nicholson and The Cuckoo's Nest, and you scared everybody away from the treatment. Today, we would say our rTMS transcranial magnetic stimulation is probably an entry level, if you like, to neurostimulation. It's a matter of choice. Some people would go there before they would have pharmacotherapy. Usually people have had some pharmacotherapy. They've become aware that rTMS is an available treatment and so they've stayed on the antidepressant and perhaps the rTMS has given them a boost. And I think about 50% of people who get rTMS do get a boost from the addition to existing pharmacotherapy. Many people do not respond and they either go back to pharmacotherapy or they begin to look at the two forms of seizure therapy. So electroconvulsive therapy or magnetic seizure therapy, ECT, ironically has a very robust evidence base of efficacy, but it also has a relatively high level of side effects, particularly the memory issues. And frankly, it has one of the worst public relations officers, I think, of any treatment. So it has a very bad public perception. Over the years I've had people come and say, Don't waste my time with other treatments I had ECT eight years ago. It worked very quickly and I was back at work in four weeks. That's all I want. Don't give me anything else, but that's the minority opinion. So ECT today may or may not require inpatient hospitalisation. It may be able to be given on an outpatient basis as long as there's somebody to accompany a person back home.
Dr. Sid Kennedy: [00:53:04] And again, the evidence of efficacy is very good. Magnetic seizure therapy is an alternative that may have less side effects in terms of memory, still will require anaesthetic. And so many of the issues relate to recovery time from anaesthetic for for many patients. Now if we go and I should say that more recently, while rTMS has been an approved technique in Canada for a number of years, one of the limitations has been whether as a treatment service it's actually funded for physicians to build their health insurance scheme so that that has become a recognised billing code in Ontario quite recently. So the limitation of access, of course, remains an issue. You won't have trouble getting RTMs in Toronto, but you might have trouble in Oshawa or some smaller centre. So that's an issue there. Now the final neurostimulation treatment is deep brain stimulation treatment, which is undoubtedly the most invasive procedure in psychiatry. If you talk to a neurosurgeon, he or she would say, Well, it's a very specialised procedure, but it's not a very invasive procedure because we're not actually cutting any circuitry. We're inserting these fine wires under MRI guidance. And so this specificity and the reversibility of the treatment is quite remarkable. But that's an experimental treatment. We happen to have used it probably more times in Toronto for depression than anywhere else in the world. But it's far from an evidence based treatment at this stage. It's still an experimental treatment.
Lucy Chen: [00:55:16] I see neurostimulation as something that's important to that's important to depression treatment, but likely will not be something that we would try right away with Aaron's case.
Alex Raben: [00:55:26] Yeah, exactly.
Lucy Chen: [00:55:28] Let's go back to Carol now and wrap up our treatment modalities with complementary and alternative medical treatments or CANMAT treatments.
Carrol Zhou: [00:55:36] Sure. So essentially, in the 2009 guidelines, only one complementary and alternative sort of treatment has first line evidence, and that's light therapy for major depression with a seasonal pattern like therapy is basically daily exposure to bright light, either with a fluorescent light box or in some cases LEDs. I think it could be very helpful for people who don't want any therapy.
Lucy Chen: [00:56:03] Wow. That's pretty interesting. How long does it usually take for it to work?
Carrol Zhou: [00:56:07] The response usually occurs within 1 to 3 weeks.
Lucy Chen: [00:56:11] Hmm. And are there any side effects of using a light box?
Carrol Zhou: [00:56:15] Yeah. So with any intervention, there are potential side effects. For light therapy, these are usually mild and include headache, eye strain, nausea, agitation. But they really lead to people wanting to discontinue their treatments. However, one thing we have to be aware of is a serious adverse effect of triggering a hypomanic or manic episode in someone with a bipolar disorder. So therefore, it's really important to rule that out in your history, like we discussed in our first episode.
Lucy Chen: [00:56:47] Mm hmm. So it was the light box only for depression with a seasonal affective pattern.
Carrol Zhou: [00:56:53] Actually, since the publication of the CANMAT almost seven years ago, there has been lots of other studies that suggest that light therapy could work for depression without a seasonal pattern, either by itself or in combination with something like Sertraline as an antidepressant. The newest CANMAT guidelines in 2016 have reflected this change in level of evidence, as according to Dr. Kennedy.
Lucy Chen: [00:57:20] That's interesting. It's really nice to know that there's alternatives to medications as well. But what about more kind of simple therapies, sort of like exercise and diet?
Carrol Zhou: [00:57:30] Aside from light therapy for seasonal depression, there are no alternative therapies that are noted as first line. And this excludes exercise and dietary like nutraceuticals like omega three and folic acid. Given the poor level of evidence with potential benefits, how do you approach this topic with patients as a recommendation?
Dr. Sid Kennedy: [00:57:54] Well, I think the key point is that we value the benefit of exercise, whether you're depressed or not. So if you are depressed, presumably we should value it even more. The problem I would have is to say when somebody would come in, I don't want to take any other treatment. I feel I can hardly get out of bed. I have suicidal thoughts, but I just want exercise. It's not a very practical and there's no evidence to say for a severe form of depression that that would be an adequate monotherapy. Most of the studies that have been done have actually been done in universities with college kids where the level of depression would be at best mild to moderate. And there's no doubt exercise is good. It's good for everybody. So you you find it hard to generalise. And one of the biggest issues when you look at complementary and alternative medicines in a guideline document compared to pharmacotherapy and magnetic stimulation is that it's almost certain the population studied differed quite significantly across these. So how do you apply the same standards? We try because we look for evidence of the severity of the disorder. Was there a structured clinical diagnosis even to start with? Because in some cases the CAMS have been used for depressive symptoms rather than syndromes. But I think that light exercise, folate and omega three are probably among the most robust in terms of being adjunctive treatments that could be recommended. Methyl folate, for example, had a number of studies that looked quite promising. And then in other cases, they were not replicated. So but that's no different than some pharmacotherapy, some drug treatments that you might get one promising, uh, trial. And then another one is less promising.
Alex Raben: [01:00:22] Okay, now that we've gone through the various treatments, let's go back to Aaron's case. You inform Aaron of the importance of diet and exercise as contributing to an overall feeling of well-being and that these interventions can help her depressive symptoms in conjunction with her medication. After wishing her all the best, you go to speak to your family medicine colleague about your recommendations for Aaron, and he agrees with your plan and is happy to follow up with her. One month later, you run into the same family doctor and he gives you a brief update on Aaron. It seems as though she is tolerating the bupropion well and having been on this medication for months now, she's starting to feel like herself again. You are glad Aaron is doing better and that you were able to meaningfully contribute to her care. Thanks for listening to PsychEd. We hope that you enjoyed our second episode as we're new to this. We'd really appreciate your feedback. You can find us on Twitter at Psyched Podcast Or you can email us at info@Psychedpodcast.com This episode of Psyched was written and produced by Lucy Chen, Bruce Fage, Lu Gao, Alex Raben and Carrol Zhou. This podcast was made possible by the support from the Department of Psychiatry at the University of Toronto. We would like to especially thank Dr. Sid Kennedy, who took time out of his busy schedule to speak with us on the treatment of depression. We'd like to also thank Dr. Elise Hall, our staff psychiatrist editor. Thank you once again for listening.