-
Jordan: [00:00:14] Welcome to psychEd the Educational Psychiatry Podcast for Medical Learners Biomedical Learners. We're a group of junior psychiatry 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 staff psychiatrists here in Toronto. Our topic this episode is the treatment of bipolar disorder. I'm Jordan Box, your host, and I'm joined by.
Lucy Chen: [00:00:39] Hi, I'm Lucy Chen.
Dr. Raben: [00:00:41] Hi, I'm Alex Raben.
Jordan: [00:00:43] Hi, guys. Thanks for joining me today. Today, we're going to be talking about the treatment of bipolar disorder. And the expert that we have on with us is Dr. Roger McIntyre, who's a staff psychiatrist at the University Health Network in Toronto. By the end of this episode, the listener should be comfortable with information and knowledge on one the treatment of acute mania and depression in bipolar disorder, two preventing relapse in bipolar disorder through maintenance pharmacotherapy. Three. Preventing relapse through non-pharmacological interventions and for how to obtain informed consent for lithium treatment. So before I start asking questions of my co hosts, let's bring listeners up to speed on the case that we first presented in our episode three Bipolar Disorder, Recognition and Diagnosis. This is like.
Lucy Chen: [00:01:43] So. Okay. So you're still in a merge and you've just diagnosed Devin with bipolar disorder in a current manic episode. As reminder, Devin is a 28 year old pharmaceutical rep who had just been brought to hospital by his partner Ben, because he was not sleeping, talking quickly and had become increasingly aggressive through a detailed history mental status exam and some collateral Detective work. You are confident in your diagnosis of bipolar disorder in a manic episode. Devin is waiting on a stretcher in the darkened isolation room of the Emerge department, and you need to make some decisions about how you're going to treat him and the people.
Jordan: [00:02:28] At the front shift. So it's the moment of truth. I feel pretty confident about our diagnosis of bipolar disorder, but I guess I'm curious what my next step should be. Can one of you guys walk me through this?
Dr. Raben: [00:02:41] Yeah, of course, Jordan. So before we jump in, we should let our listeners know that a lot of the recommendations we cover in this episode come from the 2013 canmat bipolar guidelines. These are an excellent resource and we would highly recommend looking into them outside the episode to further your knowledge. Our goal is not to repeat these guidelines, but to touch on the important points and give them some clinical context. These guidelines are Canadian, but the general principles should still be applicable for our international listeners. All right, now that that's out of the way, let's talk treatment to start in a setting like the psychiatric emergency. The first step after attending to acute safety concerns is actually clarifying the disposition. To admit or not to admit.
Jordan: [00:03:31] Okay. So Alex so you mean, like, is this person going to come into hospital or are we going to discharge them from hospital? Yes. So how do we make that decision?
Dr. Raben: [00:03:39] So really, there's two parts to that decision. One is whether or not there are safety concerns. And if there are safety concerns, then the patient should come into hospital. And then if there are no safety concerns, then the question becomes whether or not the patient would benefit from admission anyhow.
Jordan: [00:03:56] I see. And when you say safety concerns, what do you mean by that?
Dr. Raben: [00:03:59] So by this I mean imminent risk to themselves, imminent risk to others, or an imminent risk because they're not able to take care of themselves.
Jordan: [00:04:09] I see. And by not taking care of themselves, that's just like basic needs of living, like a place to kind of keep themselves warm and safe and.
Dr. Raben: [00:04:18] Exactly. So we'll I'll touch on it a bit with Devin and why I feel he fits into that category. So. Remember from last episode that Devin did deny any suicidal or homicidal ideation. So that rules out the first two safety concerns, especially because we corroborated that information with his partner, Ben, which you always want to make sure you do. However, Ben also explained that before Devin came to the hospital, he found him dancing in the streets without shoes, without proper fall clothes. So that prevents a risk to himself. The other piece is that he actually provoked a fight with a much larger man. So that would also present a danger to him if he were to be released from hospital. And so I think it's pretty we have pretty clear evidence in Devon's case that he's not in a good position to care for himself and that he is likely an imminent danger to himself based on that reason. Of course, you're never alone in making these kinds of distinctions, and talking to staff about your disposition is necessary and educational. Both are needed and decided.
Speaker4: [00:05:28] I just. I don't know.
Lucy Chen: [00:05:30] With all this in mind, you review your case with your supervisor who agrees with your provisional diagnostic assessment. And given Devin's risk and illness, together you decide to continue the form one and admit Devin to hospital.
Speaker4: [00:05:43] Don't worry.Just because you. Okay, so that makes sense.
Jordan: [00:05:52] Before we discuss this plan with Devon, I think we should hear from Dr. McIntyre and see what he has to say about the general approach to someone who is manic in the emergency setting.
Lucy Chen: [00:06:03] Good afternoon, Dr. McIntyre.
Dr. McIntyre: [00:06:05] Well, good afternoon, Carol. Nice to be with you.
Lucy Chen: [00:06:07] Yeah. Why don't you first introduce yourself to our listeners?
Dr. McIntyre: [00:06:11] Well, I am a psychiatrist. I'm also a professor of psychiatry and a professor of pharmacology at the University of Toronto and at the University Health Network. Among other things, I head the Mood Disorder Psychopharmacology Unit, and I'm also the executive director of the Brain and Cognition Discovery Foundation. So very pleased to be with you today.
Lucy Chen: [00:06:29] Yeah. And it sounds like you'll provide us with many insightful answers to a lot of questions today.
Dr. McIntyre: [00:06:35] That's my intent. I hope my deliverable meets the intent.
Lucy Chen: [00:06:39] All right. So what are your disposition considerations when you're seeing someone who is likely manic in the emergency room?
Dr. McIntyre: [00:06:48] In the emergency room, a person presenting with mania is the clarion call for emergency. This is an acute medical emergency. The first objective is to assure safety of that individual. And, of course, health care providers and those around this individual. The second is, is to offer relief to this individual for the incredible distress that this experience is for the person. There's a canard, a false story that unfortunately is still pervasive not only in psychiatry, but in medicine, that people like being manic. That's generally untrue. And most people do not like being mad. They find it horrifying, in fact, and they require immediate effect stabilisation. So safety first and beginning to, in fact, thinking about approaches that can offer that individual immediate symptom resolution. As is always the case in medicine, when we're in fact confronted with someone in such an acute situation, we always need to make sure that we are removing any aggravating factors to the acute manic episode, often complicated by psychosis. And we need to identify what are some of the more adaptive or some of the more therapeutic or salutary factors. For example, it's not uncommon for us in the acute setting to see people who are manic, who are taking an anti depressant medication. Well, clearly that medication must be discontinued. Is an example, very simple, axiomatic example of a aggravating factor. We also know that emergency rooms can, in fact, be very active and very busy and very stimulus prone type environments. And very often we need to create an environment that's much more settling for the individual. And that requires, in fact, obviously the appropriate infrastructure in the emergency room. But to the extent that we can control this, being cognisant of environmental factors that could be activating that particular individual. So our objectives in the acute phase are safety. Secondly, to offer immediate symptom relief through the appropriate pharmacological treatment avenues. And thirdly, to do the best that we can to engage those factors that enable acute anti manic responses and to in fact make sure we're mitigating any aggravating or provoking factors.
Jordan: [00:09:07] All right. That makes a lot of sense. So just to summarise Dr. McIntyre's main points, first, we tend to safety and then we make sure we can reduce some of the aggravating factors by keeping the environment as calm as possible. So when a patient who is acutely manic, they might be really distractible, They're really sensitive to aggravating factors outside other people getting upset, people walking by their room, then we want to try and reduce those sort of external factors as much as we can in an emergency setting that has an isolation room, then that can be an appropriate sort of place to put someone like this to try and reduce the amount of external distractors and stimuli that are can be upsetting or provoking for them. And then next, we want to try stopping anti depressant medications as soon as possible because we know that anti depressant anti depressant medications can worsen mania. Finally, we want to offer the patient medications that may help reduce some of their symptoms. And that's something that we're going to discuss in quite a bit more detail next. So before we get into that, let's check back in with Devin.
[00:10:16] About finally about targets. And we have to get them today so much more.
Lucy Chen: [00:10:24] Now that you've put together a plan with your supervisor, it's time to talk to Devin again in order to be as safe as possible. You stand just outside the door and have asked security to accompany you to Devin's room as you anticipate he might get agitated. The news of having to come into hospital. You explain to Devin your provisional diagnosis of bipolar disorder and how he was currently in a manic episode. You further explain that in order to help him, you'll be continuing the form one and admitting him to hospital. Devon shouts, I'm fine. Why are you guys trying to keep me here? Why don't you just lock me up in a jail? Devin gets up from his gurney with his hands in fists. You attempt to calm him down using a soft tone of voice to explain that you're concerned about his safety. We are quickly interrupted by more shouting. He continues to advance towards you and you realise this has become an unsafe situation that is beyond verbal de-escalation and quickly back away from the door while security moves in to confront Devin. Devin lunges for the door and is stopped by security. You call a code white. Your allied health colleagues spring into action and Devin is placed in physical restraints. You offer him oral medications to help him relax, but Devin refuses.
Jordan: [00:11:48] Okay, let's press pause. Before we move on, I think we should point out to our listeners some of the excellent things that were done by the staff in this situation because it would be easy to skim over them. So one of the things that jumps out to me when I'm hearing about this case is when you see that Devin is getting up from the gurney with his hands in fists, there's an immediate recognition that there is a risk here, that there's a sort of an emerging violence risk based on his physical behaviour. And the immediate response is an attempt to calm him. And one of the nice things about that is using a soft tone of voice, and it's very tempting when the patient's being loud to try and be louder than them. But we know that in emergency settings that often actually escalates people. So it didn't work in this case with Devin. But using a soft tone of voices is important for that. Then when he continues to advance to wards that the staff, the staff backs out of the situation, recognising that it's continuing continually unsafe. And then there's the bringing in allied health, because you never want to be alone in these situations. And then there's also the offer of oral medications. It's tempting when someone is this upset to just go right to giving medications by needle, but it's an important act of respecting a patient's autonomy to offer them an oral medication first. So now that we've kind of gone over that a little bit, how do we approach a situation like this and what should we do next?
Dr. Raben: [00:13:15] Yeah, Jordan, I think that's exactly the right approach. Just as you said, you want to first start with verbal de-escalation. You then want to offer oral medications and then if all else fails, you need to get the team in there to physically restrain the patient and give them IM medications for restraint. But speaking specifically about agitation in bipolar disorder, severe agitation, the CANMAT guidelines make some recommendations around this. First of all, they point out you want to start with oral medications. These include risperidone, olanzapine, or quetiapine. These are all atypical antipsychotics. If this is not an option, then you want to go to your anti psychotics which include olanzapine, Ziprasidone OR aripiprazole. Or haloPeridol combined with lorazepam. Now. Benzodiazepines like Lorazepam, are often given alone for severe agitation in the emergency setting. But keep in mind, the CANMAT guideline suggests that for mania you should not do this. You should always combine it with an anti psychotic like Halopeidol.
Jordan: [00:14:30] Thanks Alex, for going over the list of medications and making everything explicit. Now, Lucy, bring us back to the case and talk about what actually we would do in this scenario.
Lucy Chen: [00:14:53] So Devon is given an anti-psychotic and a benzodiazepine. He's given IM Haloperidol, five milligrams and lorazepam, two milligrams and slowly settles and sleeps through the night. He eventually is moved to the inpatient ward where a new team takes over his care.
Dr. Raben: [00:15:20] Okay, So I'm going to take over hosting because I know, Jordan, you did some background research on how to treat someone with mania when they're on the ward. So let's say that now you're on Devon's care team. What do we do now?
Jordan: [00:15:35] Yeah. So the purpose of this episode is not to do a detailed review of mental health law, but it's important to cover just the basics here because based on Devon's current manic presentation, his impaired insight and judgement at this time and his inability to contract for safe behaviour, we would place Devon on a Form three and issue a Form 33 respectively. These forms are to keep Devon in hospital for up to two weeks and also to declare him incapable to make treatment decisions whereby his decisions are made by his SDM or his substitute decision maker. The nature of these forms is a matter of legislation that's based on provincial or national guidelines, and in Ontario we have special legislation for them. So you'll have to refer to your local legislation for the Local Mental Health Act that would have to do with involuntary detention and also incapacity to make decisions. In this case with Devon, his husband, Ben, would be his substitute decision maker in this scenario. Now the CANMAT guidelines break down the management of bipolar into three categories. First, the acute treatment of mania. Secondly, the acute treatment of depression. And third, maintenance treatment, which means preventing relapse of manic or depressive episodes in the future. Right now, Devon is experiencing an acute manic episode, so he needs treatment for acute mania. Here are a few things we consider in line with our general thinking about medications and psychiatric disorders.
Jordan: [00:17:04] First off, we go with the best evidence. This is why it's nice to have something like the CANMAT guidelines available where we can look at the level one, two, three, etc. evidence for different medications because we want to use medicines with the most evidence. Number two, monotherapy when possible, or using the least medications possible to minimise possible side effects. Three, we want to match side effect profiles to patient preference when we have an option of multiple different first line agents. It can be difficult to know how to choose. So one of the ways we can choose is by asking patients what sort of side effects would be particularly troublesome for them. Because we know if we put somebody on a medicine that the side effects really bother them, they're more likely to discontinue that medicine. And lastly, we can watch for special features. And in bipolar this treating patients with bipolar disorder. This is something we think about a lot. So we look for a family history of response to an agent. For example, if there's a family history of responding to lithium, then we might be sooner to use lithium because we think that maybe this patient has some genetic or biological predisposition to responding favourably to an agent like that.
Dr. Raben: [00:18:16] Right? Yeah, I think that's a great general approach. Jordan, You mentioned at the beginning that you go with the best evidence and you mention the CANMAT guidelines. So what does the CANMAT say about your approach to Devon?
Jordan: [00:18:29] So CANMAT has quite a few options for a first line monotherapy for bipolar mania. Number one is lithium. Number two is Divalproex or valproic acid. Number three would be an atypical anti psychotic. Almost all of them have evidence except for lurasidone. Some of the more common ones that you probably hear or see in psychiatric settings are olanzapine, risperidone, quetiapine, and aripiprazole. And for some sort of combination of a mood stabiliser like lithium and Divalproex and you combine that with an anti psychotic. So the algorithm in terms of choosing medications can be simplified as follows. If they are not on a first line therapy, they should be switched to a first line therapy if they are already on a first line therapy and it's not working because they're in acute mania. We should switch to a different first line therapy. So if the patient is on a classical mood stabiliser like lithium or valproic acid, then we should be they should be switched to an atypical anti psychotic or have one added or vice versa. If they're on an atypical antipsychotic and they're manic, then they should be switched to lithium or Divalproex or have that agent added. If they fail three different first line therapies, then we got to think about going down to second line agents. And also we should be thinking about ECT,the gist of it is that it's kind of complicated and it's really nice to have a clear algorithm, which is why we'd recommend looking at the CANMAT guideline that has a really clear decision tree for how to select an agent in these scenarios.
Dr. Raben: [00:20:09] For sure, Yeah, you should always look look that up before you do anything. And that's that's kind of a lot to take in. Jordan So but let me get try and get it straight, so. If they're coming in manic and they're already on a mood stabiliser, you would switch to an anti psychotic or add one if they are on an anti psychotic, atypical anti psychotic to begin with. You would switch to a mood stabiliser or add a mood stabiliser. And if they weren't on a first line therapy to begin with, you would initiate a first line therapy.
Jordan: [00:20:40] Yeah, I mean, the gist of it is that we want to put people on an agent with the best evidence. So that means trying to get them on some sort of first line therapy and sometimes a combination thereof. And all this sort of talk of switching or adding basically just means that if somebody comes in and they're manic and they're on an agent, it means that they have sort of failed that agent or they have had symptoms despite being on that agent. So that means that we need to sort of do something about that, which means either switching or adding something on.
Lucy Chen: [00:21:10] So just to emphasize, I mean, when you say failed therapy, what does that exactly mean?
Jordan: [00:21:16] Yeah. So when we talk about medication failure, usually we mean that somebody has symptoms despite being on a therapy. But I think what you're getting at is that we need to be careful not to jump to the conclusion that a medication is not of some benefit to a patient. So when somebody is having symptoms despite being on a medicine, the first question we always have to ask is, is the person taking this medication as we prescribed it? And we know that medications are actually quite hard for patients to take, especially if they have complicated dosing regimens, which many of the mood stabilisers do. So we absolutely do need to ask people how compliant or how often they've been taking their medicine and if they've been missing doses and stuff like that makes sense.
Dr. Raben: [00:22:01] And so assuming they're taking it and they've failed a number of medications, then just like with depression, we're we're heading down the path towards ECT or more experimental treatments.
Jordan: [00:22:13] Yeah, exactly. And we asked our expert, Dr. McIntyre, to elaborate on this. Let's hear what he had to say.
Dr. McIntyre: [00:22:20] Well, electroconvulsive therapy is the most effective treatment for depression and the most effective treatment for mania. And electroconvulsive therapy is the quintessential mood stabilizing therapeutic modality. I would, in fact, consider electroconvulsive therapy in any patient who because of. The severity, but usually the duration and the resistance to existing pharmacotherapy. The person's general health is in fact being compromised. I recall vividly not 20 years ago a patient who was pregnant actually who had very severe mania and consequently was not caring for herself. And there were risks, obviously, to herself and the unborn fetus. And in that case, because of the acuity and the emergency here, ECT was chosen. In fact, it was very safe and very effective. So ECT would be a consideration of acute mania after the sequential and algorithmic failure of conventional first, second and third line treatment modalities. We also would consider ECT in a situation where the person's physical health was being jeopardized because of severe mania. And or in the case of that person, I saw where the health of the fetus was being jeopardized. And in many cases as well, what we're learning, CarRol, is that patient preference matters, and there are many patients who prefer to in fact have electroconvulsive therapy.
Jordan: [00:23:50] Now there is some debate about whether special features such as mixed features, psychotic symptoms, or rapid cycling constitute special clinical entities requiring specific pharmacological therapies. And we asked Dr. MacIntyre for his opinion on this as well.
Dr. McIntyre: [00:24:06] I think, in fact, the message is we need to be aware of what it is that we are treating conventional therapies like atypical antipsychotic agents. Lithium and develop Divalproex reasonable first line agents for a patient who has mania with or without psychosis. As many of our participants would be familiar with the DSM five, which was launched in May of 2013, in fact removed mixed states as a Nosllogical entity and supplanted mixed states with a new entity known as mixed features specified. Simply put, if a patient has mania in three or more opposite polarity symptoms, that is depressive symptoms, that person would have mania with mixed features. Then what we're learning is, is that perhaps in that phenotype, mania with mixed features, atypical are the most studied and seem to be the preferred agents. Now, we said earlier, Carrol, that depressive symptoms and episodes dominate the course of bipolar illness. And very often we'll see patients who have a full-blown depressive episode have some syndrome of hypomania. Again, using the DSM language, that would be a depressive episode with mixed features. And these folks often end up in emergency settings agitated, anxious and suicidal. In those cases, we have good reasons to believe that treatments like atypical or even Lamotrigine could be a reasonable first line treatment option. Unfortunately, Lamotrigine, because of the need to start low and go very slow and titration because of cutaneous syndromes linked to that particular drug. Lamotrigine is not ideal in the acute symptom resolution phase. Nonetheless, it is a treatment we would consider in a more ambulatory outpatient setting where the acuity may not be as severe.
Jordan: [00:26:17] As alluded to earlier, since we have so many possible agents with good efficacy for treating acute mania, one of the things that we can do is to try and use family history as a shortcut to predict response. But in Devon's case, we don't have one. So the next thing we can do is try and see if there are specific side effects that should or could be avoided based on medical comorbidity or patient preference. So with this in mind, let's return to the case of Devon. And remember that we're actually having this discussion with his substitute decision maker, Ben, who is acting as sort of a communicator of Devon's preferences, values and interests.
Lucy Chen: [00:27:00] When discussing the side effect profiles of some of the first line agents with the SDM Ben. He admits that he's somewhat hesitant about lithium and valproic acid because of their possible liver and kidney side effects and all the blood work that it's going to require knowing that Devon doesn't like needles. He also states that physical fitness is actually quite important to Devon. With this in mind, he chooses Arirprizole as the best agent for Devon to start with, since it's less likely compared to the other atypical antipsychotics, with the exception of Ziprasidone known to cause weight gain and other metabolic side effects.
Jordan: [00:27:37] So now the CANMAT guidelines gives many first line monotherapy options. But from clinical practice that I've been involved in, I've often seen patients on two or more drugs in the short term to try and bring a more rapid resolution of mania. So we went to our expert. We asked Dr. McIntyre about this practice. Is there an evidence base to support this? We wanted to know his opinion on early and aggressive polypharmacy in the treatment of acute mania.
Dr. McIntyre: [00:28:06] Well, in acute mania, we do have replicated evidence indicating that the combination of a conventional mood stabilising agent such as lithium with an atypical anti psychotic agent, the two together appear to have a slightly greater overall effect. That is the reduction of manic symptom severity and possibly, Carrol, to your point, maybe hasten the onset of clinically relevant symptomatic improvement. Now, the reality is most people don't like to take more than one medication, and most clinicians would not be inclined to give more than is needed. That being said, is that in the acute manic situation, these patients are often but not always hospitalized or suddenly brought into acute care type of settings or ecosystems. I do think that the initiation of polypharmacy in such cases is not just warranted, but it's evidence-based supported. I also include Carrol, to our our comments moments ago. We can't forget that hypnotics or medications and benzodiazepines are medications, and so that counts in the polypharmacy count. What we become very concerned about, Carrol, is when patients are taking two and three antipsychotics or, as I said moments ago, taking two and three benzodiazepines. This is, in fact, simply not justified. One of the challenges that we do have is when a patient's manic episode resolves. Is there, in fact, the need to keep that person on the combination treatment? And again, the responses are it depends on each individual case. There is no prescription that is tailor-made for every individual patient, but there are guiding principles. And the guiding principles are if the patient is tolerating the treatment, well, that is the acute treatment. Well, generally speaking, with some exceptions, but generally speaking, we tend to stay the course. So that maxim, what got you well is what keeps you well, generally speaking, seems to ring true.
Dr. Raben: [00:30:14] It's great answers like that that make our staff contributors so invaluable. There is evidence to support polypharmacy in acute mania, and that includes benzodiazepines. As long as we are using them judiciously. Now. Jordan, bring us back to Devon. The decision was made to start him on ASrirprizole
Jordan: [00:30:34] Yeah, that's. That's right. Thankfully, in our scenario, Devon had a robust response to Arirprizole treatment, and he ended up settling at 20 milligrams taken by mouth every day. If he had not had a good response, we would be fully supported by the evidence to add a mood stabilizer like lithium or valproic acid. And let's say if he had failed multiple medications, we could have used ECT. Many people know ECT exists as a treatment for depression, but it's somewhat less commonly considered for mania and it's important to keep that in mind.
Dr. Raben: [00:31:06] Well, that's good to know that Devin responded to Aripiprazole and also that we had other options if that didn't work out. Let's fast forward now in our scenario.
Lucy Chen: [00:31:30] A few weeks pass and thanks to Aripiprazole, Devin is no longer manic. Ben, who has been visiting regularly, remarks that Devin is himself again. Ben and Devin are both wondering when Devin can leave the hospital. You and your supervisor both agree that discharge now seems reasonable, given how much better Devin is doing. You sit down to go over the discharge plan and take a minute to evaluate Devin's medication with the goal of maintenance therapy in mind.
Dr. Raben: [00:31:58] So I'll give some of the background on this. So unlike in unipolar depression, where a course of treatment can in many cases be self-limited. Bipolar is always considered a chronic illness and requires long-term treatment. This does not mean that a patient will spend their entire life unwell. Patients with bipolar cycle between high, low and normal mood episodes and classically the entire episode functioning of bipolar patients is considered to be quite good. If you're interested in hearing more about this, please go back and listen to our episode three, where we go over the natural history of bipolar illness and more detail.
Jordan: [00:32:36] Okay, so we need a maintenance phase of therapy in order to prevent the symptoms from coming back or in other word, relapse. So what are our options in Devon's case? Are they different?
Dr. Raben: [00:32:47] The pharmacological options for maintenance therapy are very similar to those used for acute mania. The exceptions are mostly that the Doane anti psychotics, that is Ziprasodine,paliperidone, and risperidone are not as effective. The first two cannot be used as a monotherapy and only the long acting injectable risperidone is an acceptable first line treatment. The odd one out is Acenapine, and it's also dropped from that list of maintenance therapy. Interestingly, Lamotrigine is a first line maintenance therapy, despite CANMAT making it quite clear that it is not as good at preventing manic episodes as the other drugs on the list. Dr. McIntyre helped clarify its role in treatment for us.
Dr. McIntyre: [00:33:43] Lamotrigine is an anti depressant in bipolar and we refer to it as an anti depressant mood stabiliser. Some agents are better at mitigating from below the baseline. Others are better at mitigating from above the baseline of normal. In other words, most of the atypical antipsychotics, with a few exceptions, are what we call anti manic mood stabilisers. They have some anti depressant properties, but they're more effective in mania. Lamotrigine is more effective in depression and as you are correct in highlighting its ability to forestall and prevent manic return is less impressive for the number needed to treat perspective than would be its ability to forestall and prevent depression. So it is in fact a frequently used treatment, and it's also a treatment that patients like to take. It doesn't cause weight gain. It doesn't cause sexual dysfunction. It doesn't cause cognitive impairment. And these are three reasons patients often mentioned that they are not satisfied with other treatments. So it's well tolerated. Notwithstanding, some people may get a rash. That doesn't happen that often, but it's a well tolerated medication and it's a medication that has a fairly good effect size at mitigating and preventing the return of depression. It's important, Carrol, for folks to be aware that the gene does prevent manic return. It does have anti manic prophylactic properties, but the anti manic prophylactic properties are not as robust as the anti depressant prophylactic properties. And when the United States Food and Drug Administration approved it as a mood stabilising agent, that's exactly what their position was.
Dr. Raben: [00:35:19] Great. So according to Dr. McIntyre, we should not be hesitant to start someone on Lamotrigine for maintenance, as it does have antiemetic properties and is generally well tolerated. Luckily, in Devon's case, the Ariprizole, all which was started for acute mania, is also a valid first line maintenance therapy, and so no changes are required from a pharmacological point of view.
Jordan: [00:35:43] That makes sense. So we have his medications figured out. But I know, Lucy, you did some reading around sort of non-pharmacological management of bipolar. And maybe you can take a break from your narration role and tell us a little bit about the psychosocial piece of bipolar treatment.
Lucy Chen: [00:36:00] Thanks, Jordan. So despite significant strides in pharmacotherapy, recurrence rates are really high for patients with bipolar. The average is about 40 to 60% within 1 to 2 years of an episode. So either a depressive or manic episode. Even with medication, there's a ceiling for the effectiveness of pharmacotherapy, which has prompted research into the role of environmental stressors and the corresponding role of psychosocial measures such as psychotherapy to help delay relapses, stabilise episodes and reduce the episode length. Many reviews have established the importance of the role of PSYCHOEDUCATION, bipolar illness.
Jordan: [00:36:40] And Lucy by Psychoeducation. That's just talking to somebody about bipolar disorder.
Lucy Chen: [00:36:47] Yeah. So basically it's talking about what a manic episode or depressive episode could look like, help kind of anticipating what those symptoms are and kind of triggers for them, including stress, including like stimulants, including sleep deprivation. So it's all of the factors that sort of entail what the what the episode would look like and how to prevent it.
Jordan: [00:37:10] Oh, and so sort of by helping them understand what their illness looks like, maybe they can catch it at earlier phases. I imagine that bringing family members into that discussion might be useful too.
Lucy Chen: [00:37:20] Yeah, most definitely. Dr. McIntyre elaborates on what psychoeducation really entails.
Dr. McIntyre: [00:37:26] People, in fact, need to hear that it's a common illness. They need to hear that it is an illness that doesn't imply you can't live a healthy, happy quality of life, satisfactory life. It doesn't mean you can't have family if that's part of your life narrative. It doesn't mean you can't finish your schooling and pursue a normal career trajectory. So I think many people also come to us who have bipolar, who have a family member who's affected because this is obviously an illness which is not just heritable, but highly familial. Right. And it's quite common, Carrol, for me to meet people who have bipolar, whose mom or dad or brother had bipolar and had a devastating illness. And people are alarmed, understandably, that perhaps that's what's in store for them. And I think people also need to be educated, that there's heterogeneity in bipolar, not just in the phenotype of the illness, but in the illness trajectory and in the type of medications people, in fact, need to get better.
Lucy Chen: [00:38:24] So in addition to telling people about their illness, we need to emphasize the importance of staying on medication and adhering to the treatment plan, and also really maintaining their sleep in order to stay well for longer periods of time. Recognizing prodromal symptoms. So basically the symptoms that precede a manic episode or depressive episode and developing a relapse prevention plan are really important parts of management. Prominent prodromal clinical features include anxiety, hypomania, anger and irritability, and disturbances in sleep and attention. Recognizing and managing these symptoms early on can prevent relapse and the dysfunctional sequelae. It's also important to explain the importance of abstaining from recreational drugs like cannabis and stimulants that can also trigger an episode.
Dr. McIntyre: [00:39:19] Cannabis exposure in bipolar disorder. Almost all the studies are very clear results in a very negative outcome. And for those who are at risk of schizophrenia and bipolar, it may even hasten the onset of the condition younger populations. So I think the taketh away of excess alcohol, the taketh away of marijuana. Of course, illicit substances are illicit, so they shouldn't they shouldn't use them anyways. These are obvious concerns. I think in everyday clinical psychiatry, antidepressants are still being used too frequently and bipolar patients and that can in some people destabilize. And finally, what I just will mention is that there are some medications that we do give patients who have bipolar that are used for other medical purposes like steroids that could also destabilize people with bipolar.
Jordan: [00:40:05] So there's a lot to think about. I can see why education about the disorder is so important as part of the treatment.
Lucy Chen: [00:40:13] Yeah, you definitely need to take your time with this, with your bipolar patients.
Jordan: [00:40:18] Good to know what other psychosocial interventions can we use outside of just educating people.
Lucy Chen: [00:40:24] So there are actually mixed results regarding the role of some therapies like CBT in bipolar illness. It's thought that it could be helpful in both phases of illness. So I'm talking about the depressive phase and the manic phase and the depressive phase. You can often have pessimistic thoughts and negative thinking and that are overly distorted. In manic phases, people can be overly optimistic and have unrealistic expectations. So basically, CBT can work on these sorts of distortions and thinking in both of these states. However, trials have yielded inconsistent results. Cbt seems to be more effective in less severe illnesses, so less recurrent patients and less severity of illness. The effects of CBT on depressive outcomes also appear to be more robust than in mania.
Jordan: [00:41:18] So CBT seems to be better for the depressed side of the illness and also for people who have sort of a less severe type of illness. I'm just thinking about linking some of this back to our earlier episodes on the natural history of bipolar. And, you know, I think it's then important to keep CBT on the table because we know that patients with bipolar disorder, especially type two, spend a lot of time in depressive episodes. So CBT has a role. Is there anything else, any other type of psychotherapies that we've developed that may have other use?
Lucy Chen: [00:41:49] Yeah, definitely. There's a lot of strength in the evidence for a form of therapy called interpersonal and social rhythm therapy. It's basically an adoption of interpersonal therapy for depression and derives from the fact that bipolar is often associated with poor interpersonal functioning, really, especially during the depressive phases, when there's often disruptions in the relationships with other people. And that can elicit a lot of conflict and can trigger a manic episode or a depressive episode. Also, in bipolar, there are clear disruptions in sleep wake cycles, which can also precipitate an episode. So interpersonal and social rhythm therapy essentially strives to address these triggers for episodes. So basically conflict and relationship problems and also disturbances in sleep. It's typically initiated during the post episode period. So when patients are starting to get better, patients are instructed to track and regulate their daily routines and sleep wake cycles and identify events that could provoke changes to these routines. The results generally support the efficacy of this therapy in the sense that people who received it stayed well for longer during acute phase, during their acute phase compared to patients that just received treatment management alone.
Dr. McIntyre: [00:43:09] It's so essential that we really communicate to patients the relevance, the importance, the therapeutic offerings of some of the psychosocial interventions. There's no question that normalization of daily rhythms is highly effective and salutary in bipolar disorder. There is a manual based psychosocial intervention referred to as interpersonal therapy, social rhythm therapy, and this is a more monualized attempt to really, I think, take a common sense approach to try and set the circadian rhythms back to normal. Having a normal daily rhythm, daily schedule because we know the keepers of the day. In other words, the events around us that remind us of what time of the day it is are highly affecting the brain and highly affecting the actual behaviour of the individual. So I do think that attention to sleep, sleep hygiene and circadian rhythms is essential. I think in fact a whole attention to a more organised day. In many cases, Carol, patients would be candidates for cognitive behavioral or mindfulness based approaches in large part because Carol, this is a chronic illness. We know we're emphasising mania and depression, but most people who have bipolar are not floridly manic or depressed. They have substance trouble, depression, they've got interpersonal affective instability, they have comorbidity, they've got cognitive problems, they've got sleep problems. Many of these types of difficulties are targets with cognitive behavioural therapy and mindfulness based approaches. Bipolar doesn't affect individuals, it affects families and in many cases we'll have either couple or family type therapeutic interventions that can be critical as well as a psychosocial intervention. Our group is particularly interested in what is the role of aerobic exercise. I think it's been emphasised in this population also in major depression and I think in fact there is plenty of evidence preclinical and clinical, convergent and convincing and highly reproducible that there could be something very beneficial beyond the generic feeling good of exercise that could in fact be very helpful. Finally, cognitive remediation. Cognitive remediation is a psychosocial intervention that targets cognitive functions, depressive symptoms and cognitive problems are the principal mediators of psychosocial impairment and workplace impairment amongst people with bipolar.
Lucy Chen: [00:45:35] In essence, psychotherapy and lifestyle modification can serve as an effective adjunct to pharmacotherapy in relapse prevention and episode stabilization in bipolar illness. Patients that receive it can have better functional outcomes than those who just receive pharmacological care, which is the ultimate goal of management.
Jordan: [00:45:54] Well, that's good to know. It's nice to know that we have something that we can do for patients outside of just prescribing medications. Now, Lucy, do you mind taking your role back on as narrator and bringing us up to speed on where Devon is as an outpatient?
Lucy Chen: [00:46:08] Yeah, sure. Six months later, Devin is followed up as an outpatient, but now he's severely depressed. Your gut reaction is to start an antidepressant medication. But you remember the classic warning that antidepressants can flip patients into mania and you decide to look into this further.
Dr. Raben: [00:46:44] Although they look the same, it's important to think of bipolar depression as a separate entity from regular or unipolar depression. Antidepressants alone are not the answer. Certain modern antidepressants can be used for the short term treatment of bipolar depression, but always in combination with a mood stabilizer. The antidepressants, which can be used, include the SSRIs. Except for paroxetine, it doesn't work. And bupropion. That's it. Older antidepressants and snri carry a clear risk for inducing mania and should not be used so unopposed.
Jordan: [00:47:25] Antidepressants for bipolar depression are just right out. So what are we left with? What should we do to stabilise Devin's mood?
Dr. Raben: [00:47:35] It's a good question. Interestingly, there are only three first line mono therapies for treating bipolar depression, so it's different from mania. The three that you can use are Lamotrigine lithium, which you can remember because it does everything in bipolar, and quetiapine. One way to remember these three is using the acronym LLQ, which every med student knows for also standing for left lower quadrant. So if you remember LCU, you can remember Lamotrigine lithium quetiapine. The other first line treatments involve adding the antidepressants that we already talked about the SSRIs and bupropion to boost the effects of two made to mood stabilisers which aren't effective alone as antidepressants. These are olanzapine and Divalproex or valproic acid. So for instance, one combination might be olanzapine and fluoxetine, which would be a first line combination for treating bipolar depression. Finally. Lithium again, being a jack of all trades and bipolar can be combined with antidepressants or even combine with Divalproex and all of those would be considered first line treatments for bipolar depression.
Jordan: [00:49:03] So, Alex, the drugs that you just mentioned, those would be suitable as monotherapy for bipolar depression, and that was lithium seroquel or quetiapine and lamotrigine. Yes, but we could also use one of the antidepressants that you mentioned earlier, like fluoxetine or Sertraline. As long as we had another mood stabilising agent on board to sort of protect from the the flip into mania.
Dr. Raben: [00:49:34] Exactly. And then again lithium can be combined with those as well.
Jordan: [00:49:38] Okay. So the treatments for bipolar depression are somewhat different than for mania. What does the algorithm say we should do for Devin?
Dr. Raben: [00:49:47] So it's similar to acute mania. If the patient is not on a first line treatment, they should be switched to a first line treatment. And if they are already on a first line treatment and it's deemed as failing, they need to be switched to a different first line. However, for bipolar depression, which switch you make depends on what you started with. So it quickly becomes much too convoluted for us to discuss over the podcast. The much better advice that we can give to our audience is if you're faced with this clinical question review the CANMAT guideline, look at the algorithm they've put out for you, and that will allow you to make the right choice.
Jordan: [00:50:36] So you're saying just go back to the guidelines.
Dr. Raben: [00:50:39] Yeah, essentially. I mean, the principles are the same as mania. You want to make sure they're on a first line treatment, but the algorithm is a bit more convoluted for depression. And so I don't think it's going to be helpful for us to discuss the details, But simply remember to go back to CANMAT, or if you're an international listener, then whatever guideline you're just jurisdiction uses. If we go back to Devin's case, Aripiprazole is not a first line treatment any longer because we're talking about bipolar depression. So in Devon's case, you're going to need to switch him to a first line treatment. And so one of these possibilities, as we discussed, is lithium. So now let's transition to talking about that. Okay.
Jordan: [00:51:42] So, Alex, if you don't mind, I'll take over here because I did some reading around lithium, and I think it's something that our team definitely wanted to bring into the podcast because lithium is one of the best agents that we have for bipolar disorder. It's been around the longest, so we have a lot of good evidence for the treatment and prevention of both the manic and the depressive poles. And it's got a growing reputation as an agent that also decreases incidence of self injury and suicide. It's not without its challenges, though, and every medical student and resident should be familiar with the side effects of lithium therapy. And those rotating through psychiatry should be familiar with the monitoring protocol.
Dr. Raben: [00:52:24] So what kind of side effects do we look for then.
Jordan: [00:52:27] So we can break it down into a couple of domains of side effects? We can think about nuisance side effects, and that would be things like weight gain, sedation or people feeling kind of cognitively dulled on lithium. Some people will develop a rash. Sometimes the rash will be acne or another skin change like that. And another common nuisance side effect is polyurea and subsequent polydipsia. So lithium stimulates increased urine production. So you're being more and the also needing to drink more to sort of compensate for that.
Dr. Raben: [00:53:11] Right. So as you say, those are sort of the nuisance common side effects. What about the more severe side effects we need to worry about?
Jordan: [00:53:20] Yeah, so we can think about these in three broad domains. First is we need to be concerned about lithium impact on thyroid function. We need to think about lithium's impact on heart conduction. And we can think about lithium impact on the kidneys. So that actually leads us really nicely into how we monitor lithium in patients who are taking it. So first off, we want to get an EKG at baseline and then after initiation and then yearly for monitoring hypothyroidism. We're going to want to do TSH at the beginning and then also every 6 to 12 months. We're going to also want to monitor kidney function by doing creatinine levels and creatinine clearance and checking that every six months after initiation. And also, we need to heighten our frequency of blood work if we're changing the dose.
Dr. Raben: [00:54:24] Sure, that makes sense. Yeah. So we can think of the severe side effects almost anatomically. So the thyroid, the heart, and the kidney.
Jordan: [00:54:33] Yeah, that's right. And then also, we shouldn't forget that if the patient is a woman, that we need to do a pregnancy test before starting lithium because there are teratogenic effects of lithium. Now, another important thing that we need to think about when using lithium therapy is in lithium toxicity. So lithium in high dosages will result in kidney damage and also can result in neurological damage. So we always counsel patients who are starting lithium on what lithium toxicity looks like and the importance of lithium toxicity and the need to come to a healthcare provider if that's happening and usually emerge. So the nice thing, though, about lithium is that we have a readily available blood test to monitor the levels and that the level of lithium, with the exception of the geriatric population, we feel very comfortable about what levels are safe for patients.
Dr. Raben: [00:55:35] And so what levels are we looking for and when are we taking these levels?
Jordan: [00:55:40] Okay, So we can just like other parts of managing bipolar, we break it down into acute and maintenance phases. So in an acute treatment, we aim for the blood lithium level to be in Canadian numbers between 0.8 and 1.2. And for maintenance, we're aiming for a little bit lower. Between 0.6 to 1 levels over 1.5 are concerning for toxicity. A person is at quite high risk of toxicity and over 2.5 it should be associated with severe toxicity and that would be a medical emergency. An important thing as well to remember about getting a lithium level from a patient and having it be accurate is that the level should be drawn 12 hours after the last lithium dose. Otherwise you're dealing with artificially high or low levels.
Dr. Raben: [00:56:31] I see. And so you may use this early on while you're titrating up the dose to figure out what range you're in. And then presumably when you're making dose changes or you're not sure if someone is compliant with medication.
Jordan: [00:56:45] Yeah, exactly. So when we're initiating somebody on lithium, we're going to be doing lithium levels very frequently to make sure that our dose is appropriate. Of course, you're going to want to be using clinical judgement here as well. So if you have a patient that's responding really well on the low end of what you think the lithium level should be, for example, somebody who's had an excellent clinical response for several weeks, but their lithium levels only 0.5, You may actually discuss with that patient staying at that level as opposed to going up further because you're giving yourself a bigger sort of cushion, protecting them from some of the toxic effects of lithium.
Dr. Raben: [00:57:29] Sure. So just like any other drug in medicine, people have individual reactions to it. And some people may respond to a lower dose of lithium than others.
Jordan: [00:57:38] Yeah, absolutely. And then we should also, I think, mention here that in the geriatric population, so that's individuals over the 60 age of 65, these numbers are less we can be less comfortable. So let's say we have a 75 year old come in and they look lithium toxic. There's tremor, they're slurring their words. They have a bit of nystagmus and their lithium level is 0.8. If we should still be very concerned about lithium toxicity in that case. And so in people over the age of 65, we should probably be more conservative in these numbers. And I've heard some clinicians say that in people over the age of 65, if there's somebody on lithium, their lithium is toxic until proven otherwise.
Dr. Raben: [00:58:24] That's good to know. And thank you for providing some of the clinical aspects of lithium toxicity as well for our listeners. Or is there anything else, Jordan, we should know about lithium before we wrap up the episode?
Jordan: [00:58:37] Yeah, with chronic therapy, patients can develop a lithium tremor. So this is like a relatively fine tremor. It's about 8 to 12 hertz. And it's noticeable most often when someone's hands are outstretched or when they're trying to do a really fine motor movement. Patients can be very self conscious about tremor and practitioners. Practitioners should know what to do to address the patient's concerns. Because if somebody is concerned about a side effect, as we mentioned earlier, they're more likely to discontinue the medication so we can help deal with lithium tremor by dividing the dose into separate daily doses. So instead of giving it all at once, we can divide it up and do it in two doses or even three doses. And we can also use beta blockers like propranolol to help reduce the tremor.
Dr. Raben: [00:59:28] Great. Thanks.
Jordan: [00:59:33] All right. So that concludes our episode today. I hope you guys enjoyed listening. Thanks for tuning in to the PsychEd Podcast, an educational podcast on psychiatry. If you have any questions or comments, we highly encourage you guys to reach out to us. You can find us on Twitter at Psyched Podcast. We'd love to hear from you and we'll do our best to answer any questions in future episodes. Take care. We'll see you guys next episode.
Dr. Raben: [01:00:17] This episode of PsychEd was written and produced by DR. Lucy Chen, Bruce Fage, Alex Raben, Jordan Bawks, and Carrol Zhou. This podcast was made possible from the support of the Department of Psychiatry at the University of Toronto. We'd like to especially thank Dr. Roger McIntyre. Who took time out to share his incredible wisdom, both clinically and academically, with us in his interview.