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Module 2—Clinical Queries in Bipolar Depression: How Do You Provide Patient-Centered Care?

  • Authors: Leslie Citrome, MD, MPH; Joseph F. Goldberg, MD
  • CME / CE Released: 11/17/2022
  • Valid for credit through: 11/17/2023
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Target Audience and Goal Statement

This activity is intended for psychiatrists, primary care physicians, nurse practitioners, physician assistants, nurses, pharmacists, and other healthcare providers who care for patients with bipolar disorder.

The goal of this activity is for learners to be better able to integrate patient-centered strategies into the management of bipolar depression.

Upon completion of this activity, participants will:

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    • Risk/benefit profile of available pharmacotherapies for bipolar disorder
    • Individualized treatment approach for bipolar depression


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  • Leslie Citrome, MD, MPH

    Clinical Professor
    Psychiatry and Behavioral Sciences
    New York Medical College
    Valhalla, New York


    Leslie Citrome, MD, MPH, has the following relevant financial relationships:
    Consultant or advisor for: AbbVie/Allergan; Acadia; Adamas Pharmaceuticals; Alkermes; Angelini; Astellas; Avanir Pharmaceuticals; Axsome; BioXcel Therapeutics; Boehringer Ingelheim; Cadent Therapeutics; Eisai; Enteris BioPharma; HLS Therapeutics; Impel; Intra-Cellular Therapies; Janssen; Karuna; Lundbeck; Lyndra; Medavante-ProPhase; Merck; Neurocrine; Novartis; Noven; Otsuka; Ovid; Relmada; Reviva; Sage Pharmaceuticals; Sunovion; Supernus Pharmaceuticals; Teva
    Speaker or member of speakers bureau for: AbbVie/Allergan, Acadia, Alkermes, Angelini, Eisai, Intra-Cellular Therapies, Janssen, Lundbeck, Neurocrine, Noven, Otsuka, Sage Pharmaceuticals, Sunovion, Takeda, Teva
    Stock options from: Reviva
    Owns stock (publicly traded) in: Bristol-Myers Squibb; Eli Lilly; Johnson & Johnson; Merck; Pfizer

  • Joseph F. Goldberg, MD

    Clinical Professor of Psychiatry
    Icahn School of Medicine at Mount Sinai
    New York, New York


    Joseph F. Goldberg, MD, has the following relevant financial relationships:
    Consultant or advisor for: BioXcel Therapeutics; Jazz Pharmaceuticals; Lundbeck; Otsuka; Sage Pharmaceuticals; Sunovion; Supernus Pharmaceuticals
    Speaker or member of speakers bureau for: AbbVie; Alkermes; Intracellular Therapies; Sunovion


  • Clinton W. Wright, PharmD, BCPP

    Medical Education Director, Medscape, LLC 


    Clinton W. Wright, PharmD, BCPP, has no relevant financial relationships. 

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    Associate Director, Accreditation and Compliance, Medscape, LLC


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Module 2—Clinical Queries in Bipolar Depression: How Do You Provide Patient-Centered Care?

Authors: Leslie Citrome, MD, MPH; Joseph F. Goldberg, MDFaculty and Disclosures

CME / CE Released: 11/17/2022

Valid for credit through: 11/17/2023


Activity Transcript

Leslie Citrome, MD, MPH: Hello and welcome to Curbside Consults, clinical queries in Bipolar Depression. How do you provide patient centered care? I'm Dr Leslie Citrome, clinical professor of Psychiatry and Behavioral Sciences at New York Medical College in Valhalla, New York. And I'm joined today by Dr Joseph Goldberg, clinical professor of Psychiatry at the Icahn School of Medicine at Mount Sinai in New York, New York.

Let's review a bit about the criteria for manic episodes and hypomanic episodes. First off, the length of the episode for a manic episode has to be at least 1 week, unless they are hospitalized. A hypomanic episode requires the symptoms to exist for at least 4 days. So that's the length criterion. What about impairment? Is there marked impairment in social or occupational functioning? Well, for a manic episode, yes. But for a hypomanic episode, there is no marked impairment. However, there is a change from when they are not symptomatic, and the change in functioning is observable by others.

What about psychotic symptoms? They can be present in a manic episode, but they must not be present in a hypomanic episode. Otherwise, we won't call it hypomania, we'll call it mania. What about hospitalization? If it's needed, well then that's a manic episode. Hypomanic episodes are not associated with hospitalizations. So, there is a difference between the 2 and this will define whether or not someone has Bipolar Type I or Bipolar Type II. In Bipolar Type I, there is a history of a manic episode. In Bipolar Type II, there is no history of a manic episode.

Bipolar I versus Bipolar II. It's actually quite simple. We're looking for a history of depressive episodes, manic episodes, or hypomanic episodes. In Bipolar Type I, patients must have a history of manic episodes. And actually, they may or may not have depressive episodes or hypomanic episodes. This is interesting. You can have a diagnosis of Bipolar Type I and only have been manic. These patients are seldom encountered, but it is possible for this to occur.

In contrast, those with Bipolar Type II must have a history of a depressive episode and must have a history of a hypomanic episode but must not have a history of a manic episode. So, it's actually very straightforward. Leads us to perhaps think that Bipolar Type II is a variant of a depressive disorder primarily, and we'll get into that a little later on.

Joseph F. Goldberg, MD: Right, so thanks Les. You were touching on this sort of diagnostic question. And I like the way you were framing this, Les, about whether, especially in Bipolar II disorder, is it more of a variant of predominantly a depressive disorder. And since the symptoms of a major depressive episode, by and large, are pretty comparable in bipolar patients as unipolar patients, it's not hard to imagine that people can get misidentified as having major depression or unipolar disorder. There are a few reasons for that. As you mentioned, patients themselves may not be as aware of the highs as the lows. So, they may be more inclined to report or even over report the downs than the ups. And if you're taking an exhaustive longitudinal history and you're asking about someone's prior times of mania or hypomania, they may not recall that, or at least it may not stand out in their memory.

Another element is that people with bipolar illness often will have a depression before they've ever had a mania. That's a little more common than the reverse. I think it's important to think of depression as a symptom in search of a diagnosis or even a syndrome in search of a diagnosis. You can't assume that polarity is unipolar without looking. And so, for all these reasons, patients may see multiple practitioners and go many years from the time of their initial symptom onset to an actual accurate diagnosis of a lifetime manic or hypomanic episode, which is what you need, as you said, to make the diagnosis of Bipolar I or Bipolar II disorder.

Yet, another complication in diagnostics is comorbidity. So, it's often said that multiple psychiatric diagnosis is more the norm than the exception in people with bipolar disorder. Half to almost 3 quarters will have at least 1 additional psychiatric or substance use disorder, anxiety disorders are common. We think about other conditions such as ADHD, posttraumatic stress disorder, OCD. So, you can have more than 1 psychiatric ailment and that can make it very challenging to parse out the hierarchical approach in someone who has a predominant mood disorder.

And we have also medical comorbidities, obesity, cardiovascular disease, thyroid disease. So, patients can present with lots of different kinds of symptoms, and it really requires a careful clinical assessment to tease out the accuracy of really multiple diagnoses. In fact, we almost want to say what are someone's diagnoses as opposed to what is their diagnosis when we're thinking about these complexities of comorbidity.

And then as final point. A lot of patients in primary care settings who present with prominent depressive features may very well be prescribed traditional monoaminergic antidepressants, although, as Les pointed out earlier, there's actually no database demonstrating efficacy for traditional anti-depressants as having usefulness in treating depression in people with Bipolar I or Bipolar II disorder.

There's a second concern with monoaminergic anti-depressants, which is the possibility of potentially destabilizing. That means moving someone from a current depression into a mania or a hypomania in the short run or potentially in the long run and seeing more episodes occur over time. So 1 recent meta-analysis showed that in particular, over the course of the year, patients that have bipolar disorder who were given anti-depressants may be more likely to show more episodes over time than patients that don't get anti-depressants. And if there is improvement in depression symptoms, it's fairly nominal and not that enduring. So, we don't really get a clear advantage for using anti-depressants. We don't clearly see value compared to things that we know may work more effectively.

So, let's now talk about what treatments are known to be efficacious in bipolar depression and carry FDA approvals for bipolar depression. As of now, we have 5. First, the combination of olanzapine and fluoxetine, and this is the one exception perhaps to the rule that monoaminergic anti-depressants are not thought of as being so helpful in bipolar depression. Uniquely, fluoxetine paired with olanzapine, not paired with something else, not by itself, does demonstrate efficacy compared to placebo. It is FDA-approved in Bipolar I depression. Has not been so studied in Bipolar II depression. Does have efficacy in psychotic depression. Has not been approved as an add-on to mood stabilizers such as lithium or valproate. And does carry an indication for pediatric bipolar depression.

Second agent with FDA approval is quetiapine, either the immediate or extended-release formulation, carries an FDA indication for both Bipolar I and Bipolar II depression. Has not been studied in psychotic depression, has not been studied at least acutely as adjunctive treatment in acute bipolar depression, lithium or valproate, and has not been studied or FDA-approved in pediatric bipolar depression.

Third agent, lurasidone, approved in 2013, has its indication in Bipolar I, but not studied in Bipolar II disorder. Has not gotten indication for a psychotic depression. Has been studied as an adjunct to lithium or valproate and is the second drug that carries an FDA indication for pediatric bipolar depression. Lurasidone and olanzapine/fluoxetine would be 2 drugs with FDA approvals for pediatric bipolar depression.

Next, we have cariprazine, approved just in 2019 in Bipolar I depression, but not studied or approved in Bipolar II depression. Has not been tested in psychotic depression or in combination with lithium or valproate, and currently does not have an FDA indication in pediatric bipolar depression. And last but not least, as of December of last year, 2020, we have lumateperone. FDA approved for both Bipolar I and Bipolar II depression, not studied or approved in psychotic depression. Has been studied and is FDA approved as an adjunctive treatment with lithium or valproate and does not have the indication in pediatric populations with bipolar depression. All right well now let's turn our attention to efficacy and safety data. Les, what can you tell us?

Dr Citrome: We need to know are we going to get our patients better? And one way of getting them better is having them be responders, that is a 50% or greater reduction in the rating scale score. Now, we don't use the MADRS generally in day-to-day clinical settings, but we do use the PHQ-9. And you could measure basically very similar symptoms as the MADRS, except the patient answers the questions and they fill out the form. A 50% reduction is considered okay, we're on our way. And in the short term, we can see response rates that are over or very close to 50% for the drug. That's great.

The placebo response is also quite substantial, from 30% to 40%. This is the nature of these randomized controlled trials. When you give placebo, you're not giving nothing, you're giving placebo plus scheduled evaluations, tender loving care of sorts, and you're going to get some response even if people are on placebo.

We're going to calculate the number needed to treat now to see the difference in the clinical trial versus placebo. So, this answers the question, how many patients needed to be randomized to the medicine versus placebo before expecting to encounter one additional responder? Actually, any NNT value that's a single digit is perfectly fine and is consistent with what we use in medicine today, certainly in psychiatry. But the lower the NNT value, the more impressed I am. So, for lumateperone, cariprazine, lurasidone, quetiapine and olanzapine/fluoxetine combination, we essentially have that, with cariprazine at the cusp there with an NNT of 10 versus placebo.

The vertical lines that go over and below the estimate of the number needed to treat represents the 95% confidence interval. And they all basically overlap. So, we would say they're roughly equivalent for response.

Dr Citrome: Let's talk about remission. Remission is better than response. You can get a 50% reduction in your symptoms, but you may not necessarily be well. The definitions for remission approximate what we want for our patients. Now, the problem is the different medications used different thresholds for the definition of remission, but it's close enough for our purposes. We can take a look at the remitted rates for the different agents that we have available and they're fairly substantial. The rates for placebo are also up there.

And again, we're going to go through our exercise of calculating the number needed to treat, how many patients needed to be randomized to the medication versus placebo before expecting 1 additional remitted patient. Here we see that lumateperone had an NNT estimate of 16, which was not statistically significant, even though the NNT for response was perfectly okay. This may be a vaguery of how the clinical trial was conducted or the characteristics of the patients here or the high placebo response that was evident.

Cariprazine, NNT of 11. And the others, the NNT was less than 10. When we take a look at the 95% confidence intervals, they actually overlap. And although I just said that the number needed to treat for lumateperone was not statistically significant, another statistic was used and published called the odds ratio, and that was statistically significant. So, it's a matter of how you look at it. But I would say overall, I'm fairly confident that using any of these choices, lumateperone, cariprazine, lurasidone, quetiapine or olanzapine/fluoxetine combination will get you generally to where you need to go with response and hopefully remission.

Dr Citrome: So, what's the difference amongst all these different choices? Well, it's tolerability. Evidence-based practice requires us to take into account not only our clinical experience and our patient's values and preferences, but also the literature and what evidence is out there regarding the different choices. And here, we can actually apply that principle and looking at number needed to harm. We know the number needed to treat was roughly equivalent. The number needed to harm is all over the place for the outcomes that some of us are very concerned about and some of our patients are quite concerned about too.

But this varies. Some patients are very worried about weight gain, others are not. Some patients are very worried about somnolence, others are not. Same with an akathisia, same with nausea. However, when these occur, they can be a deal breaker for some patients. So, I like to get an understanding from my patient as to what adverse events they've experienced in the past and that will help guide me as to what choices to look at. I've calculated number needed to harm for the outcome of weight gain of at least 7%, the existence of extrapyramidal symptoms as an adverse event, somnolence adverse events, akathisia adverse events, nausea adverse events, and the overall discontinuation from the clinical trial because of an adverse event.

And I have columns for cariprazine, lumateperone, lurasidone, olanzapine/fluoxetine combination, and quetiapine. I've divided the doses for cariprazine and lurasidone because we do have fixed dose studies available or fixed dose range studies available that help us try to figure out a dose response when it comes to adverse outcomes. In general, number needed to harm values, that is how many patients do you need to treat with one agent versus placebo before expecting to encounter the outcome you'd rather avoid. Here, we want high numbers. We don't want low numbers. If you have a number needed to harm of at least 20, well that's going to be lower risk. I'm not generally going to be worried about that outcome for that agent. In yellow is number needed to harm between 10 and 19, and that's intermediate risk.

I'm going to pay some attention to it, but I'm really going to pay it close attention to the red, number needed to harm values less than 10. Let's take a look. Where do we see the red? Basically, the older agents generically available, olanzapine/fluoxetine combination, weight gain of at least 7%, had a number needed to harm of 6, which means for every 6 people randomized to OFC versus placebo, you would expect to encounter 1 additional patient to gain that amount of weight in a relatively brief period of time. And that's pretty close to the number needed to treat value for the outcomes we want. So, we can say we'll probably encounter weight gain as often as response or remission. So that's a thought that's kind of unpleasant to think about.

With quetiapine, the red is for somnolence, with a number needed to harm of 3. That means actually, somnolence is twice as likely to occur than response or remission. So, I'm gravitating towards cariprazine, lumateperone and lurasidone because there I see a sea of green, so to speak, particularly for the lower doses of lurasidone and cariprazine. But there is some yellow involved. For example, lumateperone, the number needed to harm for somnolence, is 10. And for cariprazine, for akathisia, at 3 milligrams a day, the number needed to harm is 13 versus placebo. And for lurasidone, we have akathisia for both dose ranges in yellow and in yellow for extrapyramidal symptoms, somnolence and nausea. Nothing is perfect. How do we match treatment goals with evidence-based options for bipolar depression?

Dr Goldberg: Right. So, you heard information about what's FDAs and information about dosing, about efficacy, about tolerability. Let's spend our final moments just talking about how you might think about what we can consider the pros and cons of one option relative to another from among all of these appropriate options. And then when you think about a particular kind of patient and their given characteristics, how can you best match up a given patient's characteristics given the profile of medication? So, let's just go through these.

Lurasidone has its efficacy for bipolar depression with mixed features as well as with baseline anxiety. Lurasidone does not worsen mania symptoms and is actually efficacious in that setting. Baseline anxiety is very tough problem to treat in all of mood disorders. Lurasidone does have anxiolytic effects. There's some interesting research looking at lurasidone in euthymic bipolar disorder patients with cognitive complaints. And actually, did formal testing and showed some greater degree of improvement compared to placebo with lurasidone in terms of global cognitive functioning. And lastly, as we kind of saw with the NNH heat map, it's a well-tolerated drug. On the downside, has not been formally studied in mania or hypomania. And we don't have data in Bipolar II depression. So that would require extrapolation. And there is 1 maintenance study with lurasidone, which failed to show a benefit with lurasidone compared to placebo for prevention of relapses over the course of time in people with Bipolar I disorder.

Let's turn now to cariprazine. One of the few drugs with bimodal efficacy. This is the compound that is FDA approved to treat not just bipolar depression but mania as well. It's a strong partial agonist at the D3 receptor and we think that there's a very enriched supply of D3 receptors in reward pathways. So, when we think about, gee, is there a way to jumpstart that mechanism, a D3 partial agonist might actually have some nice value. On the con side, as Les showed with the heat map, akathisia is dose related. We don't have maintenance data at this time either in Bipolar I or Bipolar II disorders. So those are 2 shortcomings with cariprazine. But again, nothing is perfect.

Lumateperone, newest of these compounds. So, as you heard, has efficacy in both Bipolar I and Bipolar II depression. Actually, had about twice as much efficacy in Bipolar II depression as Bipolar I. So, a large effect size, compared to a medium effect size, in Bipolar II depression, makes it a very compelling molecule to contemplate in someone for whom Bipolar II depression is especially prominent. Very well tolerated, is a drug with a much stronger binding affinity at the serotonin 5-HT2A receptor than the D2 receptor. Makes clinicians sometimes think if a patient is prone toward EPS or someone for whom we really want to steer clear of the dopamine blockade that this molecule may have some value. We await maintenance data with this drug. Don't have it yet. And I should say also, there are other data in combination therapy with lithium or valproate, with lumateperone.

Quetiapine does have bimodal efficacy. It does treat mania or depression. Quetiapine, like lumateperone, does have data in Bipolar II depression. So technically, in Bipolar II depression, any drug other than quetiapine or lumateperone would be considered an off-label use for Bipolar II depression. We have maintenance data with quetiapine as well as the acute efficacy data. On the con side, as Les mentioned previously, the sedation and the weight gain both have a rather not so favorable number needed to harm. But, as I indicate here, one person's sedation is another person's soporific effect, and we sometimes capitalize on an adverse effect. If a patient has insomnia or sleep problems, there may be some value and capitalizing on that side effect.

And last but not least, olanzapine/fluoxetine does have a large effect, does have demonstrated anxiolytic properties, but does have on the con side, the sedation, the weight gain. We don't have long term data. So olanzapine has long-term maintenance data, but not the fluoxetine part. So, at what point if a patient responds to OFC should I remove the F and keep the O? We don't know. And Bipolar II has not yet been studied with this molecule.

Dr Citrome: Well thanks Joe and thank you to our viewers. We hope that this has been helpful to you, and we hope that you'll listen to more Curbside Consults.

This transcript has not been copyedited.

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