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The Treatment of Bipolar Depression: From Pills to ...
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Hello and welcome, I'm Dr. Amy Cohen, Program Director for SMI Advisor and a Clinical Psychologist. I am pleased that you are joining us for today's SMI Advisor webinar, The Treatment of Bipolar Depression, From Pills to Words. SMI Advisor, also known as the Clinical Support System for Serious Mental Illness, is an APA and SAMHSA initiative devoted to helping clinicians implement evidence-based care for those living with serious mental illness. Working with experts from across the SMI clinician community, our interdisciplinary effort has been designed to help you get the answers you need to care for your patients. And now I'd like to introduce you to the faculty for today's webinar, Dr. Jeffrey Rakofsky. Dr. Rakofsky is the Director of Medical Student Education for the Department of Psychiatry and Behavioral Sciences. In his role as Director of Medical Student Education, he oversees the Medical Student Psychiatry Clerkship and other medical student learning activities. His educational efforts extend into the Graduate Medical Training Arena, where he directs the Emory Residence Psychopharmacology Training Program. He also serves as a staff physician in the Emory Mood and Anxiety Disorders Program, conducting NIMH and industry-sponsored clinical trials of novel pharmacology agents. His clinical work focuses on evaluating and treating patients with refractory bipolar depression, along with other mood and anxiety disorders. Dr. Rakofsky, thank you for leading today's webinar. Well, thank you very much for having me. I'm honored to be here. First, some disclosures. I've received research funding from the American Board of Psychiatry and Neurology. There will be some discussion of off-label uses of medications, and the clinical trials that I'll be discussing do not report results according to socioeconomic status, gender, sexual orientation, race, ethnicity, culture, national origin, language, or religion, nor do they specifically make efforts to recruit subjects based on these categories, except for language. Learning objectives for today include being able to list the conventional psychopharmacologic options for treating bipolar depression, listing the novel psychopharm options for treating bipolar depression, listing the psychosocial treatment options, and then listing the factors considered when developing a treatment plan for bipolar depression. So bipolar disorder basics, first, bipolar disorder is a mood disorder characterized by recurrent manic, hypomanic, depressive, and mixed episodes. It affects close to 5% of the population when you look at the full spectrum of bipolar disorder. It's associated with significant morbidity and early mortality, and treatment must involve pharmacologic management. It can also and should also involve psychotherapy, but pharmacologic management is the cornerstone of treatment for this. Bipolar disorder patients spend a lot of time depressed. This study was a study that followed patients over 10 years and showed that half the time, 52% of the time, patients were not having any symptoms, but about a third of the time, patients were experiencing either depressive episodes or depressive symptoms. So that's a significant amount of time. There's a high degree of functional impairment associated with bipolar depression compared to healthy controls. Bipolar depressed patients have worse functioning in autonomy, occupation, interpersonal relationships, financial issues, leisure time, and the functioning of patients with even subsyndromal depression, meaning not having all the symptoms needed to meet full criteria, is just as problematic as those who meet full criteria for bipolar depression. Suicide risk is a big concern in bipolar disorder. Up to 36% of bipolar patients have a history of a suicide attempt, based on earlier studies. About 15% to 20% of all deaths among people with bipolar disorder is associated with suicide, and then 79% of suicides among people with bipolar disorder are going to occur during episodes of depression. Most suicides occur in cases in which adequate treatment was not received, hence why this talk is so important. It's important to appreciate that bipolar depression is not the same as unipolar depression, even though at times, they can look very similar. Bipolar depression episode duration is shorter than it is in unipolar depression or major depression, as we sometimes refer to it. There are more episodes in bipolar depression than unipolar depression. The male-female ratio is different in the two conditions. Mental health features, such as sleeping a lot and eating a lot, are more common in bipolar disorder than unipolar depression. And there's enduring cognitive impairment that we see as a result of bipolar depression, which we don't always see with unipolar depression. And so because these are two different entities, we can't assume that the treatments we use for unipolar depression can be applied to bipolar depression and vice versa. Bipolar depression is a mixed bag. There's type 1, type 2 bipolar disorder. There's the NOS category. There's rapid cycling variants and ultra-rapid cycling and ultra-ultra-rapid cycling with or without psychiatric comorbidity, chronic depression, mixed depression, anxious depression, melancholic depression, atypical depression. And unfortunately, even though we see these in the clinic, a lot of the clinical trials that I'll be discussing today don't really break it down in terms of these different bipolar depression subtypes, which sometimes leaves us with uncertainty about what to do. The fact that the FDA has only indicated four treatments for bipolar depression also leaves us in a little bit of a lurch, especially when these treatments don't work for our bipolar depressed patients. So what to do? Well, we're going to talk about different options, mood stabilizers, second generation antipsychotics, antidepressants, and novel medication options, and also psychotherapy. What we won't talk about today are things like electroconvulsive therapy, transcranial magnetic stimulation, chronotherapy, and ketamine infusions, all of which have data to support their use in bipolar depression, but because of our time limit, we won't be able to get into those. Let's begin with mood stabilizers. We have four mood stabilizers that fall in this category, lithium, valproate, carbamazepine, and lamotrigine. Let's review the studies. The lithium studies, we'll start out first by talking about a particular meta-analysis. A meta-analysis is when we combine all of the studies that have been performed looking at that medication, and we combine them together to get one summary statistic to tell us, overall, what does the data say? And this is particularly helpful when we have a lot of small studies and we put them all together. So Goodwin and his group put together a meta-analysis of seven double-blind placebo-controlled crossover studies. So first, these patients were given placebo for a couple of weeks, and then unbeknownst to them, they were switched to lithium. There were 81 bipolar patients when they combined all the studies, and 55 major depression or unipolar depressed patients when they combined all of this. The sample sizes of the individual studies were small, anywhere from 10 to 52. And the response rate in the bipolar group was 79%, meaning 79% had a significant amount of improvement when they were on lithium as compared to placebo. That's pretty good. And when you look at the major depression group, only 36% had that same response. So not only did we get a pretty robust response in the bipolar group, but it's pretty specific to the bipolar population. Another study was conducted in Bolden 1, and in this study, the design was a multi-center randomized double-blind placebo-controlled study. So this is really the gold standard of studies, where patients at the very beginning are randomized to either lithium or placebo. In this particular study, there were 800 patients, and there were four different arms of this treatment. There was quetiapine 300, quetiapine 600, lithium, or placebo. We're only going to focus on the lithium and placebo comparison. So in this table in front of you, we have lithium in this first row and placebo in the bottom row. And what we have in this column over here is the change in Madras at endpoint. So the Madras is the depression severity scale that's typically used in bipolar depression studies. And then in this other column, we have response rate, which looks at how many of these patients had a 50% or greater improvement on their Madras scores. And then remission is how many of these patients really had no symptoms by the end of the study. So let's focus on these results. What we see is that in the lithium group, there was a mean change of 13 points, close to 14. And compared to placebo, that's a lot more. Placebo only had 11.8 improvement. When we look at response rate, again, a greater response rate in the lithium group, 62.5% versus 55.8% in placebo, and similar results in remission rate. But unfortunately, the differences were not significant. And so a lot of people look at this study and they say, well, you know, the biggest study that really could have confirmed that lithium was better than placebo did not show it. And therefore, lithium probably isn't good to use for bipolar depression. But here's what I say to that. The difference in lithium efficacy between the Goodwin meta-analysis studies and this last study we just discussed may come down to a couple of factors. One is the lithium levels that were used. These studies that I have in this table here are all the studies that were used in the Goodwin meta-analysis. And you can see that most of them have ranges of lithium levels that begin at 0.8, 0.93. There was one with 0.7, but here's another one with 0.8. And this one was dosed up to 1.5. So those are pretty robust ranges. And in fact, I try to shoot for anywhere from 0.8 to 1.0. Let's look at the Embolden study. In that study, the range of lithium levels was 0.6 to 1.2, and the mean lithium level was 0.61. So most of these patients, in my mind, were not dosed at an adequate enough lithium level. The other thing is that there was a very high placebo response rate in the study. I think we said it was about 55%. And that could be due to the fact that there were four arms, four treatment arms in the study. And we know that the more treatment arms that are used in a study, and also the more clinical trial sites that are used in the study, the greater the likelihood that there will be a high placebo response rate, and then it will make it harder to really show that lithium did do a good job relative to placebo. So I still like to use lithium, and I try to dose it appropriately. Let's move on to Valproate. So here we'll talk about another meta-analysis, and this time it was of four studies. And in total, they had 142 bipolar patients that were depressed. Clinical sizes from 18 to 54, six to eight weeks of treatment with Depakote levels between 62 to 82. I try to get as close to 100 as possible, but this is still pretty good. And then they had low rates of discontinuation from the study due to intolerable side effects, so 4% versus 2.8%, so that's not too bad. Now let's look at the results. So this is what we call a forest plot, and this is what you see in meta-analyses. And it's basically a graphic or visual presentation of the analysis. Over here, you have the four different studies that were looked at, and over here is the graphic representation of their results. So I want to orient you to this first before I show you the results. So down here is going to be the summary statistic, and here are all the individual statistics for the different studies. If these statistics or these graphic, these figures fall on the right side of this vertical line, then that means the results favor divalproate or valproate when it comes to a response compared to placebo. And if it falls on the left side of this vertical line, then it means that it favors placebo as compared to valproate in terms of response. So let's look at what the summary statistics showed. Overall, it showed that it falls on the side of favoring valproate when it comes to looking for a treatment response, so 50% or greater improvement. The other thing I need to point out to you is that it does not touch the vertical line. If it touches the vertical line, then no matter what side it falls on, it's considered not statistically significant. And if it's not statistically significant, then we can't really believe the results. So here, it does not touch the line, so it is statistically significant, and we could believe that it is better than placebo at treating bipolar depression. Here they looked at remission, and basically they found the same thing, that the summary statistic fell on this side of the vertical line, so it favors valproate, and it doesn't, it kind of looks like it gets close to the line, but you can see that one does not fall into this 95% confidence interval. So again, we can trust that valproate does increase the rate of remission or the risk of remission compared to placebo. Carbamazepine. So this study comes from the National Institutes of Mental Health. It was a double-blind, placebo-controlled, off-on-off study. There were 24 bipolar patients and 11 unipolar or major depressed patients who were all treatment resistant. Blood levels were targeted at around 9.3, which is pretty good. I try to aim for anywhere between 8 to 12. Median length of treatment was 45 days, and let's look at the results. They looked at marked response rates. How many had a significant response in their scores? Well, in the bipolar group, about 42% had that marked response, and in the major depression group, only 18%. So again, we're seeing an effect that's specific. It's not too robust. I mean, we would love to see higher than 42%, but let's not forget that these were treatment resistant patients. And if we look at how their depression scores changed over time, we see that the bipolar group score went from an average of 7.9 down to 5.6, and it was statistically significant. In the major depression group, although they also had a reduction in depression score, it was not found to be statistically significant. And here's a graphic representation of the scores in patients when they were on carbamazepine. So initially, they were on placebo, or they were off the carbamazepine, and then they were put on carbamazepine, and their scores came down, and then once they were taken off the carbamazepine and put on placebo, unbeknownst to them, their scores shot back up, and then put back on carbamazepine, their scores came down, and then the same thing. So when you see a pattern like that, the off-on-off pattern, it really does add evidence and credibility to the result. Another study was conducted in China, and it was a randomized double-blind placebo-controlled study. So it was the gold standard of design. And here they looked at carbamazepine plus a supplement, an herbal supplement, versus carbamazepine alone versus placebo. It was bipolar type 1 in two patients, doses about 800 milligrams, study duration of 12 weeks, and let's see what the results showed. So here, we have a graph, and on the y-axis, we have HAMD, which is the Hamilton Depression Scale, and it's a little different than the MAGRIS, but it's also used in depression studies. And what we see here is that the group with circles represents the placebo group. The group with squares represents the carbamazepine alone group, and the triangle group represents the carbamazepine plus herbal supplement group. And what we see is, at the end of the study, over time, we see that the carbamazepine plus the supplement did better than the placebo group, but unfortunately, carbamazepine alone did not. However, when they looked at a different outcome, the Clinical Global Impression Severity Scale, what they saw was both the carbamazepine alone group and the carbamazepine plus the supplement group were both better than placebo. And then when they looked at response rates, meaning the number of patients who had a 50% or greater improvement on the Hamilton D, what they saw was more than 60% of the carbamazepine group and more than 80% of the combined group responded as compared to less than 40% of placebo, and those differences were considered statistically significant, again, supporting the use of carbamazepine in bipolar depression. Some side effects were things like dizziness, headaches, rash, fatigue, blurred vision. Let's move on to lamotrigine. The studies here are part of a qualitative summary of the five randomized double-blind placebo-controlled studies. Type 1 and 2 patients were included. The study duration was anywhere from 7 to 10 weeks, which might have been part of the problem that they went on for so long. Sample sizes were pretty robust, 128 to 249, and the doses were fixed or flexible, meaning that they can be changed over time during a study. Let's look at these results. So what you have in front of you are three different figures. The first one represents the Hamilton D scores for all the five different studies. The second one represents the MAGIS scores, again, for the five different studies, and the third one represents the CGI, clinical global impression scores, for the five different studies. Now, the Hamilton was the primary outcome. That's the outcome that everything was designed for in this study, and unfortunately, none of these studies, none of these five studies, showed a significant separation between the lamotrigine groups and the placebo groups. The lamotrigine groups are in gray. The placebo groups are in white. However, in only one of five studies were they at least able to show a MAGIS separation, but that's still not great. And then when they looked at the CGI outcome, there were two studies that did show a separation, but still, this is a bit concerning, and again, may have to do with the fact that the study duration went on for so long. That usually gives the placebo groups time to improve. In another study looking at lamictal, the design was different, and they said, well, let's actually consider adding lamictal to a mood stabilizer and look and see how effective it is in that scenario. And that's what they did. They looked at 124 patients who were already on lithium, and they had been in it for at least two weeks, and they were dosed to 200 milligrams by week seven. The duration was eight weeks, and let's see what the results showed. So they looked at the MAGIS score, and the blue line that you see up top here represents those patients who were just given placebo in addition to the lithium, while the red line represents those who were given lamotrigine. And you see that at the end of eight weeks, the MAGIS scores for both groups came down, but they came down much more so for the lamotrigine group, and the difference was statistically significant. When we look at responder rates, we see more responders in the lamotrigine group than in the placebo group. So certainly, this is good data to support using lamotrigine in addition to a mood stabilizer like lithium. And of course, the lamotrigine monotherapy is debatable. All right, now we're going to talk about antidepressants, and I use this graphic here because this has been and continues to be controversial in the bipolar disorder treatment world. You need to be familiar with the classes of antidepressants to appreciate the nuances here. We have first-generation antidepressants, which include tricyclics and monoamine oxidase inhibitors. Second-generation include SSRIs, SNRIs, and the atypical ones, mirtazapine, bupropion, nifazodone, and trazodone. So people who have studied this have looked at the studies and separated them into those that look at short-term use of antidepressants in bipolar depression and those that look at long-term. So we're going to look at a couple of meta-analyses that just focus on short-term and then look at the long-term use meta-analysis. So in this meta-analysis, they looked at clinical response. And just to orient you, if the graphic falls on this side of the vertical line, then the result favors antidepressant over placebo. And if it's on the left side of the vertical line, then it favors placebo over antidepressant. Here are the different studies that were looked at. And the summary statistic falls on the side of favoring antidepressant, but look at this. It does touch the line. The value of one is included in this 95% confidence interval. So you can't trust the results. So this would suggest that there's not enough data to say that antidepressants are better than placebo and bipolar depression in the short term. In the same study, they looked at affective switch, which means the risk of becoming manic when given an antidepressant. This is always the concern with bipolar disorder. And what they saw was the summary statistic fell right on the line. And so it suggests that there isn't enough data to say that antidepressants do cause mania relative to placebo, which is probably surprising for a lot of people to hear. Another meta-analysis included studies where mood stabilizers or second-generation antipsychotics were required for all patients receiving antidepressants, but they could not have taken any of those first-generation antidepressants. And here's what their results showed. They looked at clinical response. And again, looking at the summary statistic, it falls right on the line. So not enough data just to argue that antidepressants are better than placebo in bipolar depression. When it comes to affective switch, again, same conclusion, not enough data to show that antidepressants truly are, you know, or increase the risk of becoming manic. Let's move on to long-term use now and take a look at what that shows. So this came from one study, but they did several meta-analyses within the study. And we'll go through those together to make sense out of this. So in this first analysis, they were looking at long-term use of more than four months of antidepressants versus placebo. And they looked at those studies where it was used as monotherapy, so no mood stabilizer, or those where it was used with the mood stabilizer. And just to orient you, if it falls on this side of the vertical line, it means it favors the antidepressant. If it falls on this right side of the line, it favors placebo or mood stabilizer, whatever the comparison group was. And what we see is for depression, in terms of, you know, reducing the risk of depression over the long run, we see that antidepressants do have some benefit, whether they're used on their own or with the mood stabilizer. So that's promising. So you can see none of this, none of the confidence interval line touches this vertical line. The next analysis was looking at antidepressants versus placebo in terms of preventing new manic symptoms or new manias over time, over four months. And what you can see is all of these results, all of them hit the vertical line. So even though this is the main summary statistic, these lines represent the 95% confidence interval, and they all cross over the vertical line. So there's not enough data to suggest that antidepressants over the long run compared to placebo increased the risk of mania. But there are some interesting signals here, though. If we look at this particular analysis, which only looked at the first-generation antidepressants, the summary statistic falls pretty far on the side of favoring placebo over antidepressants, meaning antidepressants are going to be more likely to induce mania over time. But again, that line crosses over, so you can't trust it 100%. But on the other hand, when you look at the analysis looking at second-generation antidepressants, you see that the summary statistic falls further on the side of favoring antidepressants. But again, you can't really trust it. And then this last analysis, this looked at antidepressants versus mood stabilizers over the long term, so more than four months. And what you see is very clearly, those patients who are on antidepressants, they were much more likely to have more manic symptoms, more mania over the long run than if they were getting placebo. And the same wasn't true for the second generation antipsychotics. So the key here is the mania risk may have a lot to do with the antidepressant that's being used, whether it's first generation or second generation, and also whether or not there's mood stabilizer protection to go along with it. So this is all very confusing, I understand. And so the ISBD, the International Society for Bipolar Disorder put together a task force to give recommendations on antidepressant use. And here's what they came up with. Overall evidence is limited and weak. Non-antidepressant treatments should be considered as monotherapy before going to antidepressants, whether you're looking at Liftium or Lamotrigine or some of the antipsychotics we'll talk about in a moment. If you do use antidepressants in bipolar disorder one, they should be prescribed with the mood stabilizer. And I completely agree with that. Antidepressants in bipolar two are well tolerated, meaning probably less likely to induce mania, but may or may not be as effective. And the evidence for long-term prophylaxis is poorly studied. And there's little evidence to suggest one type of antidepressant is more or less effective or dangerous, except TCAs, which represent those first generation antidepressants. And then the faxing they also mentioned here as well. I would say that anecdotally speaking, there are some patients for whom antidepressants are a necessary part of their regimen, but it's usually not the first medicine I start with. I always use a mood stabilizer first. But even though the data shows that there isn't enough evidence, there clearly are people that do need antidepressants. And we know this because when we try to wean them off, which is usually the recommendation, the depression just comes back. All right, moving on to second generation antipsychotics. So there are a number of second generation antipsychotics on the market, but not all of them have been proven to help with bipolar depression. Those that have include quetiapine, olanzapine, lorazodone, cariprazine, and those that have negative studies include aripiprazole, risperidone, zoprazodone. So let's talk about those. And we'll go through the important things you have to appreciate with those studies. So we'll start first with quetiapine. There were a number of studies that were conducted looking at quetiapine versus placebo. And they all have these wonderful names like bolder and boldened. And they all share the same thing, which is that quetiapine is superior to placebo in each study. So that's great. However, there are a number of adverse events that occur with second generation antipsychotics, especially with quetiapine. Those include things like dry mouth, sedation, somnolence, dizziness. And you can see how much more common they are in those who receive the active drug versus placebo. And why this matters, oh, and there were no clinically relevant differences in vital signs, EKG, clinical chemistry values. But why these differences matters because in clinical trials, we want the patient and the person rating the patient in terms of their improvement to be completely blind to whether or not the patient is receiving the active drug or placebo. But when patients start having side effects, then it becomes pretty clear that the patient is likely to be on the active drug. And that could subconsciously lead the rater to inflate the improvement. Or it can lead the patient to get excited about possibly getting better. And so they then report improvement to the rater. This was addressed in a commentary, assuring that double blind is blind. And the authors of this commentary put together this great analysis here. And what they did was they looked at the change in MAGIScore in bolder one. And they looked at the quetiapine group and the placebo group. And they divided the results based on who reported sedation and who didn't report sedation. And then what happened with their MAGIScore. So if you were in the placebo group and you reported sedation, you had a 19 point improvement, which is similar to the quetiapine group. But if you didn't report it sedation, then you only had an 11 point improvement. So the point here is for clinical trialists to understand the importance of maintaining that double blind all throughout the study, but also for us to realize that maybe some patients, you know, maybe some of the benefit that we saw in these studies might have been due to, again, raters and patients being unblinded. Olanzapine, this is another antipsychotic. This study was a large randomized double blind placebo controlled study, 800 patients type one and two. There were three arms to the study. There was the placebo group. There was the olanzapine group on its own. And then there was the olanzapine group used in combination with an antidepressant fluoxetine. Study duration was eight weeks. Let's look at the results. They looked at MAGIS improvement over time. The squares at the top represent those patients who are on placebo. Triangles represent those who are given just olanzapine and circles represent those who are on the olanzapine and fluoxetine combination. And we're looking at the MAGIS changes over time. And what we see is that both treatment groups did better than placebo and the result was statistically significant. And there was no difference in risk of mania. So that's all good. And of course, the response rates looked pretty good. Olanzapine 39%, OFC 56% response rate compared to placebo 30%, all very promising. But here's the thing. When you drill down on the items on the MAGIS, that's where these results become a little more clear. What you have here on the left are all the items that you'd find on the MAGIS scale. And in this first or the second column here, we have the comparison between the placebo group versus the olanzapine group with regards to that particular item on the MAGIS. And here's the placebo versus the OFC group for that particular item on the MAGIS. And the only thing that was statistically significant when we looked at the olanzapine alone versus placebo group were these three. Tension, reduced sleep, reduced appetite. And I'm sure many of you know that two of the very common side effects of olanzapine are increased sleep and increased hunger. So it could have been that the improvement that was seen between olanzapine and placebo on the total MAGIS score might have been related to these three items and might have artifactually made it appear as though olanzapine was very helpful for bipolar depression. And I say artifactually because, look at the placebo versus OFC group and look at how all of these more core features of depression were statistically significantly different than placebo. Reported sadness, apparent sadness, lassitude, inability to feel. And then when you look at the MAGIS score, the mean change at end point, placebo versus olanzapine was 3.1. So that was statistically significant and versus OFC it was even higher. But what's missing here would be an additional arm where they look at just fluoxetine versus placebo. Because without it, we don't know if there's better performance by the OFC group relative to the olanzapine group is related to the combination, like some synergy that happens between olanzapine and fluoxetine, or if it's just the fluoxetine on its own that's responsible for this benefit. And just like quetiapine, there are a lot of side effects that could potentially unblind the rater and the patient. And whether it's somnolence or weight gain or increased appetite. Let's move on to some newer atypical or second generation antipsychotics, lorazodone. So lorazodone has 5-HT7 receptor antagonism and 5-HT1A receptor partial agonism, which makes it kind of unique. This study is also placebo controlled randomized. This only looked at bipolar one depressed patients. Three treatment arms, placebo, a low dose 20 to 60 milligram and a high dose 80 to 120 milligram group. Episodes had to be for more than four weeks, but less than a year. And they cannot have failed more than three antidepressants. And so let's look at the results. The purple line represents the placebo group and the orange and green lines represent the treatment groups or the lorazodone groups. And we're looking at the change in MAGIS score over time. And what we see is at the end, both lorazodone groups were statistically significantly better or had greater improvement on the MAGIS, so that's good. And then when we look at the individual MAGIS item scores, like we did for olanzapine among the three different arms, we see that for all of them, all of these core features, we tend to see a separation with placebo for both of the treatment arms, the low and the high dose. So that's very positive. But there's no perfect medicine. And there are side effects that could have unblinded the rater and the patient, but also things that patients have to contend with if we do prescribe this medicine. Things like nausea, akathisia, sedation, vomiting, extraparameteral symptoms. And because this is a newer antipsychotic, sometimes insurance companies aren't willing to pay for it. This is a nice piece though, the fact that there are minimal changes in weight and metabolic parameters. It does make it a little more tolerable in that regard. Co-representing another new second generation antipsychotic, this one has D3 and D2 and 5-HT1A partial agonist receptor activity. Again, another randomized, double-blind placebo-controlled study. Also just looked at bipolar I patients. Also had three arms, a low dose and a high dose, 1.5 versus three milligrams. Episode also had to be more than four weeks but less than 12 months. But here's something different. Patients enrolled in this study cannot have failed potiopine, the olanzapine fluoxetine combination, or latuda or two antidepressants. So what we're doing here is we are recruiting a very narrow group of bipolar depressed patients. Because usually bipolar depressed patients have tried lots of different things. And so we have to keep that in mind when you see the results because you have to ask yourself, well, how generalizable are these results? Generalizable to other bipolar depressed patients? Well, let's take a look at the results. This top figure looks at the change in MAGRA scores. The orange group represents placebo and the blue and green represent the two coriprazine doses. And we see that both were statistically significantly better than placebo. When we look at the other outcome used, the clinical global impression scale, we see the same thing. So that's very positive. But there are also adverse events that could have unblinded and also could be a nuisance to deal with. In the low dose group, 1.5, there was a lot of akathisia, where people are restless and they have to move around a lot. It's very uncomfortable. And then in the three milligram dose, we saw even more side effects, nausea, headache, insomnia, restlessness, and again, akathisia. This too has been shown to induce very minimal weight gain. So again, makes it more appealing to a lot of patients. But on the other hand, because it's new, it can be sometimes hard to access from the insurance companies. There were negative studies, as I alluded to before. So aripiprazole. But here the caveat is that, well, maybe the study duration was too long because all along the way, aripiprazole was beating placebo until it got to the eight-week mark, and then the placebo group caught up. In the risperidone study, there was a small sample and there was a really treatment-resistant population. And in the zeprazidone study, when they looked back at the study, it turned out the ratings were of poor quality, there were inappropriate patients who were included in the study, and there was overall low confidence in the diagnosis. So even though they were negative, there are these caveats you have to appreciate. Now let's move on to novel medications. So these are the treatments you think about when nothing else is working. Pramopexil would be an example of one. This is a medicine that's used in the treatment of restless legs and Parkinson's. There have been two small double-blind randomized controlled trials that showed positive results. You do, however, have to look out for the risk of manic induction and impulsive behaviors like gambling. Thyroid hormone is another option, T3 or T4, with or without thyroid disease present. And you could use standard or superphysiologic doses, superphysiologic meaning we're gonna dose until that TSH is below 0.01. And then finally, armodafnil or modafinil, there's been a meta-analysis of five studies that do show a modest effect with no increased risk of manic induction. All right, now let's move on to psychotherapy. So in psychotherapy, we have some evidence-based psychotherapies for bipolar depression, but there aren't too many. Cognitive behavioral therapy, family-focused therapy, and interpersonal and social rhythm therapy. So let's review the basics of those, and then we'll talk about the data. Cognitive behavioral therapy, the underlying theory is that depression is associated with maladaptive thoughts. So those distorted maladaptive thoughts then drive negative feelings, which then lead to maladaptive behaviors, which reinforce those negative thoughts. The goal then of this therapy is for the patient and therapist to agree on short and long-term goals to address the problematic thinking and the behaviors. The first phase is spent providing psychoeducation about bipolar illness and the CBT framework. The second phase is where the coping skills are addressed. The patient is helped to become more aware of cues that will trigger mood shifts. There's cognitive restructuring to change the negative thinking patterns. They're encouraged to engage in positive behaviors and within regular routines, and to keep the medication compliance high. And as is the case in all of CBT, there is homework, which is important in order to reinforce the learning that happens. Family-focused therapy, the underlying theory here is that bipolar disorder is associated with high expressed emotion. So it's yelling, criticizing, and high expressed emotion in families, and maladaptive interpersonal interactions. The goal then is to increase the positive interactions within family, and engage the patient support network in treatment and relapse prevention. The first phase, just like CBT, is devoted to psychoeducation about bipolar disorder, but also about the family communication style and how that could be a maintenance, or how that can maintain the symptoms of depression. The second phase is spent teaching communication style. So teaching patients and their family members how to actively listen, how to make eye contact. And then the third phase is spent problem solving, and trying to anticipate problems in the future, and how will the family mobilize to help the patient and prevent things from getting worse. And then we have interpersonal and social rhythm psychotherapy. So here are the underlying theories that disruptions of circadian rhythms, the sleep-wake cycle, or social rhythms can lead to mood episodes. So the goal then is to try to maintain consistency in biological and social rhythms, and then try to improve interpersonal relationships. Because those, when they go sour, can then impact the social and biological rhythms. First phase also is spent with psychoeducation, but then they also try to identify an interpersonal target, meaning an individual or relationship with whom the patient is having trouble with, and causing problems. And then they're also taught to monitor social rhythms. So keeping track of when they're going to sleep, when they're waking up, when they're having their meals, when they're exercising. Second phase includes teaching strategies to maintain those daily rhythms, to manage mood changes, and then improving those target interpersonal relationships. And then the third phase is spent preparing for future social rhythm disruptions, like maybe anticipating an exam that's coming up that maybe prior to this therapy would have led the patient to pull an all-nighter. Well, now they'll try to prepare so that there won't be that interruption to the social rhythm that's required. And then also crisis management will be provided as needed during this phase. So unfortunately, there's really only one study that has sufficiently and adequately studied these psychotherapies, and it was part of the STEP-BD psychosocial treatment study. It was sponsored by the NIMH. There were 293 patients who were at the same time receiving protocol pharmacotherapy, and they were randomized to one of these three different psychotherapies that we just discussed, or to collaborative care. If it was one of the psychotherapies we discussed, they received 30 sessions over nine months, and if it was collaborative care, they received six sessions over three weeks. In the analysis, they combined all three psychotherapies into one group, and they called it psychosocial treatments, and they compared it to those receiving collaborative care. And here's what they showed. At the end of the year, if you were receiving psychosocial treatment, then there was a greater likelihood that you would be in recovery than patients who just received collaborative care. So 64% in the psychosocial group versus close to 52%. And then, if you received psychosocial treatment, you would recover much more quickly, 113 days on average versus 146 days. And here's a graphic representation. So this is what we call a survival curve. And here at the beginning, everyone starts off depressed, and then over time, there are fewer and fewer people in both groups who are depressed. But what you can see is that at the very end, the red group, which is the collaborative care, still has more people that are currently depressed at the very end than those in the blue group who received any kind of psychotherapy that I mentioned before. So the thinking here is that if you have a patient who's depressed, doesn't matter which therapy we're talking about here, they really should have some psychotherapy to supplement the medication treatment that they're receiving. But there are non-evidence-based psychotherapies that I often refer patients to, things like psychodynamic psychotherapy, supportive psychotherapy, couples therapy, group therapy. And when I say non-evidence-based, what I mean is non-evidence-based in terms of helping bipolar depression. There's clearly evidence for the use of these psychotherapies in other areas. And some of those other areas apply to our bipolar patients. So maybe we have a bipolar patient who has significant personality pathology and would benefit from psychodynamic psychotherapy. Or maybe we have a bipolar patient who's having problems with his spouse. And so it would make sense to refer them to couples therapy. And then there are a number of psychological themes that I've picked up on and heard over the years that I've been running my bipolar clinic. And what I've learned about those themes is that if you don't address them in one way or another, they will either perpetuate the depression the patient is currently experiencing, or they will serve as a trigger for future episodes of depression. So I just wanna list out those themes and just so you're aware of them. Themes like feeling defective because of the illness, feeling hopeless about having a romantic partner or family, fears of passing on the illness to offspring, guilt and shame for behaviors during manic episodes, fears about relapse, concerns about who to reveal their illness to, believing that they will become like their bipolar parent who might've had a terrible course of illness, feeling infantilized by their partner, guilt about their unreliability, missing the highs, or grieving loss of their potential. So again, if these aren't addressed in some way, either by you or by a therapist that you refer the patient to, then trying to get them out of their depression, trying to prevent future depressions is really gonna be an uphill battle. All right, now let's put all this together. So when it comes to selecting medication, we have to do this very carefully. And so what I've laid out is this table, and here we have the four mood stabilizers, lithium boproate, carbamazepine, lamotrigine, and then antidepressants and second generation antipsychotics. This first line represents antidepressant efficacy, and it's just a summary of the data and how I've scored it. And then the second line here represents prophylaxis data and a summary of the data and the way that I've scored it. Now, we didn't go over prophylaxis data because that would require another hour of lecture. But suffice it to say that this is how I've scored it. And when you pick a medication for someone with bipolar depression, you have to think not just about short term, but also long term efficacy. And that's where the prophylaxis data comes into play. And when you put that all together, what you see is that the mood stabilizers are the ones that really have the best antidepressants, acute efficacy and prophylaxis data. But you also have to consider other things like short term and long term tolerability. Some medicines will have side effects that come on right away, and others will have medicines that come on over the long run. So like lithium over time could lead to reduced kidney functioning or thyroid problems. But you also have to consider additional advantages that some of these medicines provide. Like with lithium, there's really good data to support its anti-suicidal benefit, regardless of what impact it has on mood. And for valproate, there's data to suggest that it's helpful for migraines, which plagues a lot of our bipolar patients, unfortunately. All right, so here's my algorithm. I'll run through it with you all. So stage one, I'm gonna start with a mood stabilizer, and it's usually gonna be lithium or valproate. And if that doesn't work, I add. So even if it doesn't work or works partially, I keep that medicine on board and I add to it. And I'll either add whichever one I didn't use in the first step, or I might add lamotrigine or carbamazepine. If that doesn't work, then I might go towards antidepressants, especially if there's some anxiety that's present along with the depression. And I might move through some different antidepressants over time. Or maybe I'll go to second generation antipsychotics, especially if there's no risk of diabetes, or the patient doesn't have diabetes or they're not obese. And I may run through some of those second generation antipsychotics. And over time, I might switch between those two classes. And if none of those are working, then we move towards novel treatments, like I mentioned before, or even something like electroconvulsive therapy. In psychotherapy, I try to make sure my patients are receiving from the very beginning of treatment. All right, so in conclusion, there are lots of treatment options available for bipolar depression, but there are variable levels of evidence supporting their use. And one needs to select medicines that have the perfect balance of short-term efficacy, long-term efficacy, but also good tolerability and accessibility from insurers who aren't always willing to pay for these medicines. Adjunctive evidence-based psychotherapy should be part of a bipolar depression regimen. Sometimes it's hard to find local providers who can do IPSRT or family focused or CBT. And if that's the case, then think about the other therapies, whether it's supportive or psychodynamic, but there should be some psychotherapy on board. And finally, always leave your bipolar patients with hope. There are so many treatment options out there and so many combinations of treatments, and there are new medicines on the horizon. And hope is just so important if we wanna help our patients through what could be a very painful experience as they wait for these medicines to finally take effect. And with that, I will stop for questions. Thank you.
Video Summary
In this video, Dr. Jeffrey Rakofsky discusses the treatment of bipolar depression. He begins by introducing the various psychotherapies available for bipolar disorder, including cognitive-behavioral therapy, family-focused therapy, and interpersonal and social rhythm therapy. Dr. Rakofsky then delves into the pharmacological treatment options for bipolar depression, such as mood stabilizers, second-generation antipsychotics, and antidepressants. He provides an overview of the research supporting the efficacy of each medication, as well as the potential side effects and considerations when prescribing them.<br /><br />Dr. Rakofsky emphasizes the importance of personalized treatment plans and discusses the relevance of individual patient factors, such as comorbidities and treatment resistance. He also highlights the need to address psychotherapy and psychosocial support as part of a comprehensive treatment approach for bipolar depression.<br /><br />Overall, Dr. Rakofsky's presentation provides a comprehensive overview of the current understanding and treatment options for bipolar depression.
Keywords
bipolar depression
psychotherapies
pharmacological treatment options
efficacy
side effects
personalized treatment plans
comorbidities
psychotherapy
Funding for SMI Adviser was made possible by Grant No. SM080818 from SAMHSA of the U.S. Department of Health and Human Services (HHS). The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement by, SAMHSA/HHS or the U.S. Government.
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