Chapter 2: Common Treatment Strategies and Challenges

GLOBAL NOTE: Highlighted passages represent KOL discussion sections that were built into the approved script/discussion guide.

Dr Roger McIntyre: Hello, and welcome back to this clinical consult video series on management strategies for bipolar I disorder, sponsored by Otsuka Pharmaceutical Development & Commercialization, Inc. and Lundbeck Pharmaceuticals, LLC. In the previous video, we explored the prevalence and practical impact of BP-I on patients' daily living. We also talked about the importance of early diagnosis. In this entry, we're going to dive into management strategies for bipolar disorder and two common challenges faced by providers, which are, one, impediments to early diagnosis and treatment, and two, non-adherence. We'll start off with an overview of treatment. Dr. Broder, please review standard therapies, particularly those used to treat manic episodes.

Dr. Todd Broder: Certainly. And I'll preface this by saying that management of BP can be complex as it must treat a range of symptoms that can evolve over time. An effective therapeutic approach should address both acute episodes and maintenance phases of the illness, and it should also work to prevent relapse. Attempts to hit these multiple targets often leads to a rotation through many different therapies and polypharmacy. At this time, clinical practice guidelines such as CANMAT, ISBD, and NICE support the use of traditional mood stabilizers, such as lithium or divalproex, for long-term treatment of bipolar disorder. And we see the term traditional because some antipsychotics meet the criteria of a mood stabilizer as well. As a first-line treatment for acute mania in BP-I, traditional mood stabilizers, in combination with second-generation antipsychotics such as aripiprazole, quetiapine, olanzapine, and risperidone are recommended. Often, patients with BP will initiate therapy with either an antipsychotic or a traditional mood stabilizer, but most of them, up to 70%, will receive some form of adjunctive treatment within a year.

Dr. Roger McIntyre: As we've touched on in the previous video, antipsychotics and traditional mood stabilizer therapy should be initiated early in the disease course to support improved outcomes. However, a BP diagnosis is often delayed. Hara, can you share your insights on this particular topic?

Hara Oyedeji: Yes. So, a timely diagnosis can be very difficult to achieve. So, diagnosis and adequate treatment of bipolar disorder are often delayed, sometimes up to 10 years. The delay can be influenced by a variety of factors, such as initial symptoms can be nonspecific and dismissed, or they can even mimic unipolar depression and even may be misdiagnosed. In addition, racial disparities can lend to a delayed diagnosis. So, for example, African-American, Black, and Hispanic individuals with bipolar disorder can experience a higher rate of initial misdiagnosis with schizophrenia than that of white individuals and their counterparts. 85.7% and 83.3% versus 51.4% respectively. African-American and Black individuals and other historically marginalized populations are underrepresented in bipolar genetic studies. So, this limits the understanding of bipolar biology in this patient population and may contribute to misdiagnosis. Symptoms of unipolar depression are quite common early in the disease course with approximately 50% of patients experiencing episodes of depression as their first symptoms of bipolar disorder.

This is concerning, not only with consideration to delaying an accurate diagnosis, but also because treatment with monotherapy antidepressants can harm patients with bipolar disorder leading to an increased risk for treatment emergent mania, destabilized mood and suicide.

Another challenge with achieving an early diagnosis is related to patients simply not seeking care for their symptoms. Perhaps they have limited access to healthcare resources, or perhaps they fear stigmatization, so they are avoiding care. Patients may even also feel that during a manic episode they feel great, and so they don't see the need to seek out care.

Dr. Roger McIntyre: When facing these challenges to diagnosis, what can providers do?

Hara Oyedeji: Well, providers need to be aware of a patient's risk factors. Risk substantially increases with a family history of bipolar disorder, particularly if it's diagnosed in a parent. For these patients, providers can increase their vigilance for subtle symptoms that may allude to early stages of bipolar disease. In addition, consistently screening for symptoms of mania can support an early diagnosis and treatment initiation.

Dr. Roger McIntyre: Dr. Broder, can you describe the ramifications of early versus delayed treatment?

Dr. Todd Broder: Of course. Delaying treatment for bipolar disorder can lead to compromised functional and social abilities. There are higher rates of comorbidities and an increased risk of hospitalization and/or suicide, for that matter. Once these patients start treatment, they may experience a lower response than if they had initiated treatment earlier. Let's look at this a bit more closely by taking a look at results from a systematic review that evaluated outcomes for patients with BP1 or BP2 who initiated treatment early versus late in the disease course.

Using pooled data from several trials, the authors of this particular review found that patients who received treatment with either an antipsychotic or a mood stabilizer versus placebo, of course, experienced higher response rates with acute mania and lower rates of manic recurrence when treated, if they had a history of one to five previous episodes compared to those who have had 10 or more episodes. The researchers also noted that compared to lithium, antipsychotics may be associated with greater improvement of manic episodes when administered early in the course of disease. These findings support early treatment initiation overall to help improve overall disease course and outcomes.

Dr. Roger McIntyre: This brings us to a second common challenge associated with bipolar disorder management, which is the high rate of non-adherence to oral therapies used for treatment. Hara, exactly how prevalent is this issue and how does it affect outcomes?

Hara Oyedeji: Well, despite noted challenges in measuring adherence due to variability in methods, available data suggests that medication non-adherence poses challenges to care. It's been estimated that only 41% of these patients are adherent to their prescribed therapy. This is notable because non-adherence considerably affects outcomes. Some experts believe that non-adherence is the number one predictor of a future relapse. In addition with non-adherence patients are more likely to experience a higher number of hospitalizations and a greater risk of suicide. So to add to the challenge, clinicians can have a difficult time detecting non-adherence. In results from a survey of physicians who had expertise in prescribing or studying long-acting injections or LAIs, only 45% reported that they were somewhat confident and 33% reported they were not very confident in determining adherence status to oral therapies among their bipolar patients.

Dr. Roger McIntyre: How can clinicians begin to address these concerns with non-adherence?

Hara Oyedeji: Well, clinicians should be aware of patient characteristics that are associated with an increased risk of non-adherence. These include non-white race, homelessness, greater disease severity, a recent manic episode, incomplete remission, a higher number of hospitalizations, substance misuse, and polypharmacy. Clinicians can also provide education and encourage cognitive behavioral therapy to support patient engagement and adherence to treatment. Patients need to understand the ramifications of missed treatment and early warning signs of relapse. Some clinics go as far as to send patient text and phone reminders and offer financial incentives to encourage therapy adherence. And as you mentioned earlier, Dr. McIntyre, for appropriate patients, clinicians should consider prescribing ALIs, which were developed in part to address the issue of non-adherence among patients with bipolar disorder.

Dr. Roger McIntyre: Great, Hara and thank you. Before we delve into greater detail regarding use of ALIs, I want to hear from each of you about some of your own experiences in practice with treatment of patients with BP-1. So here's the first question, at what point along the bipolar disorder disease course do you typically first see a patient?

Dr. Todd Broder: Interestingly, I would imagine most outpatient providers would say that the depressive episodes, the depressive phase of this illness is probably the first presentation. For me as an inpatient psychiatrist working in a very acute setting, often I will see patients for the first time in that disease state during a manic episode when they become hospitalized for severe manic symptoms.

Hara Oyedeji: Agreed to the point with what Dr. Broder was saying as far as outpatient. Working in an outpatient setting I've been able to see patients generally after they've experienced a depressive episode, and in many cases, they've been misdiagnosed actually with major depressive disorder for example. And so by the time they've come along into an outpatient referral process, or for their appointment many of them might have been experiencing depressive episodes for quite some time. There have been times where they might have been referred into inpatient and admitted, and that's after a manic episode and then come in to be treated for their bipolar disorder. So generally in outpatient we can see patients that are in that depressive episode, but for many of them they've been experiencing that for some time.

Dr. Roger McIntyre: Very helpful indeed. What are your personal strategies for identifying bipolar disorder at an early stage?

Dr. Todd Broder: Bipolar disorder is really a challenging diagnosis to make, at least until you see a true manic episode. And I always say when I'm treating patients with major depressive disorder, I am never 100% certain that my major depressive disorder patient is not going to turn out having bipolar disorder. And I think we all have sort of our own little tricks in doing this. So much of this is in the history. Looking back at how young someone might have been when they had that first depressive episode even. And I think when you see very young patients in their teens or early 20s that really have these quite severe depressive episodes that sometimes could be a clue or an indication. Patients who have obviously, family members who have bipolar 1 disorder, higher risk patients who have comorbid attention deficit symptoms, hyperactivity inattentively earlier on as somewhat of a prodrome to this illness could be a big red flag. And obviously patients who have limited response to antidepressant medications during episodes of a major depressive episode.

Hara Oyedeji: I agree everything that Dr. Broder mentioned with regards to whether it's the prodromal symptoms or really for me in the outpatient setting getting as much a history as possible. Family history is very, very huge with regards to trying to identify and tease out, are we really looking at what could be a unipolar disorder or is it really truly a bipolar disorder? Especially if the predominant symptoms that are presenting are depressive. And as mentioned in the outpatient setting many times patients don't really understand or don't know and will just say, I've been feeling really depressed. And so some of those trips and tricks are looking at have there been antidepressant misadventures? Have you had a history of being on more than one? And it's just not really working. In addition to getting as much information as possible. I've had an experience with one of my patients where for the longest time she had been diagnosed for years with major depressive disorder until I actually was able to determine she mentioned her mother had what she called manic depression, which back then is how it was referred to. And so what really, we were dealing with was a bipolar disorder.

r. Todd Broder: Hara, would you agree, I find that so often there's somewhat of a reporting bias, right? When I think of depression, I think of it as such an ego-dystonic state. It's very uncomfortable. People come in complaining about it, wanting help, wanting treatment for it, but hypomania or mania sometimes, at least in the beginning, can feel somewhat ego-syntonic. It's not a terrible feeling. And I think retrospectively when patients are reporting their symptoms over time, they're quite ready to report depressive symptoms, but may forget to tell me about those hypomanic or manic symptoms and in the past. And I think sometimes that just takes a little more digging.

Hara Oyedeji: Absolutely. You make a really great point, Dr. Broder. I think it really goes back to stigma. That's a big piece, and you mentioned that earlier. On one hand I've had patients tell me, and we know as clinicians manic symptoms can be productive, so to speak, right? It feels good. And so there's that part of it, but then there's the other piece, right? Society still has a very big bias against a lot of the things that manic symptoms oftentimes incur. And that looks like impulsivity, doing things without thinking or really being, when one is in a very, a manic state it could be detrimental. Whereas with depression we know it's a lot easier for people to just report, I'm feeling depressed. There might still be some stigma there, but it does not hold as many negative views with that. And so oftentimes when we look at mania which can accompany psychotic symptoms, for example, it might be more prevalent that a person is willing to disclose the depressive symptoms versus some of those other manic symptoms that they may have been encountering

Dr. Roger McIntyre: Excellent pearls and insights from both of you. So, thank you. And as a comment, certainly what comes to mind and what emanates and surrounds both of your comments is the need to contemplate the potential that bipolar disorder is the explanatory diagnosis in a person presenting with a depressive episode, first episode, or multiple episodes. Certainly a screening tool for bipolar disorder would not be able to diagnose bipolar disorder, but a screening tool like the mood disorder questionnaire or the rapid mood screener could be considered as a early way to think about triaging the patient's depressive symptoms or their presentation to get us more suspicious or maybe less suspicious that bipolar disorder could be the explanatory diagnosis, but I think it really starts with contemplating the possibility. Another question for both of you. What long-term outcomes have you observed in patients who initiate treatment earlier versus later?

Dr. Todd Broder: You want to start this one off, Hara?

Hara Oyedeji: Sure. No problem. Thanks Dr. Broder. So I think it really depends, but generally when we're able to or when I'm able to diagnose and offer treatments a lot earlier to my patients it definitely has provided more positive outcomes. And I think this, once again, translates to social and daily functioning, right? Am I able to maintain employment? Am I able to maintain my relationships? And so those are things that my patients working in community mental health often really measure their quality of life by. And so I've had patients that have been able to tell me, you know Hara I'm not perfect. Maybe I might have missed my medication here and there, but generally when I'm on my medicine things work out better. And so really just engaging with patients and making sure that they're doing what they need to do to make sure their quality of life or their daily functioning is there. And the small wins, being able to make their appointments even really can in the long term be a positive win in an outcome. So overall it's patient by patient, but daily functioning and being able to do what they need to do.

Dr. Todd Broder: Yes. I have just been on a mission to treat chronic mental illness more aggressively earlier on in the disease state. And this concept really drove me into the world of long-acting injectables many years ago. I think once I finally let go of the fantasy that my patients in particular were extraordinarily adherent to medications because they wouldn't deceive me. Once I finally realized how much of an issue non-adherence became, I started using long-acting injectables very early on in the course of schizophrenia and now bipolar disorder. And I had moved, I was living in Gainesville, I was at the University of Florida, and I was in a large academic setting, and we had all sorts of community support. We had assisted living facilities, we had ACT teams. And when I moved to St. Augustine, where I live now, a much smaller community with significantly less community support, I started to realize that patients were relapsing and they were coming back in with a manic episode, with a psychotic episode. And every time I saw them back in the hospital something was lost. They lost their job, they lost their housing, maybe they were arrested, some part of their freedom was lost. And I looked back, and I had this feeling of helplessness very early on in my career. And I said to myself, why am I waiting for patients to lose so much before I started looking at long-acting injectables or more aggressive interventions earlier on with social interventions and getting families involved and whatnot. So this has just been a mission for me in my career over the last 10 to 15 years, early intervention and preventing that social degradation over time.

Dr. Roger McIntyre: So well articulated. That's just fantastic. I certainly agree with all of that. One of the other aspects that you mentioned was fantasy. I'm guilty of fantasy and magical thinking myself. And one of the fantasies that I had is that somehow long-acting injectables were only for people who were late stage, multiple episode, lacked illness literacy because of a variety of reasons. Often these patients have cognitive impairment or comorbidity, too often these patients are very chronically ill, and certainly that patient would be a candidate for an LAI. But what I did was I didn't intend to do this, but it sort of blocked the opportunity to think maybe I should be thinking broadly. In other words, LAIs are a consideration for a patient anywhere in the patient journey not just mid stage, late stage, but early stage. Early in illness, in young in age. And we know that the arc of the illness trajectory is most malleable early in the illness course. I think it's part of shared decision making, having patients empowered with information to participate in the shared decision-making process hence I do think LAIs should be part of the discussion with any patient diagnosed with bipolar 1 disorder anywhere in that illness journey. Final question for this section in your clinic, what are your strategies for improving therapy adherence for patients living with BP-1?

Hara Oyedeji: So if I might, I think these are some wonderful points that both you, Dr. McIntyre and Dr. Broder have brought up. And really your point of having this fantasy. I agree. I think we really do a disservice to our patients when we don't start the conversation earlier on about offering an LAI. And to your point, Dr. Broder, I was kind of coined in my previous clinic, the long-acting injection queen, because I complete, it's something that if it is an option we're discussing it even at the first appointment. And one of the things that I try to tell when I am either precepting nurse practitioner students or working with nursing students is this, you may not get a yes on the very first try, but that doesn't mean that your patients don't deserve you to offer that up. And I've seen it many times where patients down the line have even come to me and said, maybe we need to look at a long-acting injection because I've introduced it earlier on. And the reality is this, LAIs really provide freedom. I think there's a misconception that, oh, I don't want to offer something or have a patient reject me and say no right away. Or even a patient may say, oh, I don't want something in me that I'm not going to be able to get out. But we really have to shift the conversation, and we are shifting it as we know that long-acting injections provide freedom, right? Freedom from having to take a pill every day. And it doesn't mean that other oral medication or agents are not going to be on board, but I've had many patients tell me, I may miss some of my oral meds, but one thing is for sure I won't miss my injection because we know that it provides a level of protection as well as maintenance for treating the symptoms as we know of bipolar disorder.

Dr. Todd Broder: Absolutely. And Hara, I think you used the magic word offer. And I think this, and we can get into a multiple hour conversation about this. As a forensic psychiatrist I'm so squarely focused on the concept of informed consent. And I really do think that there is an obligation, a duty on the part of clinicians to offer to our patients known effective treatments. And there were landmark, legal cases that really drove this conversation dating back into the late 70s, early 80s. So offer really is the magic word here.

Dr. Roger McIntyre: Good word. And I agree with all of that. And certainly as they say, no decisions about me without me. And so patients should be informed and be part of that shared decision-making process. It's been truly a light bulb moment for me as a practitioner for many years that that many people are open to taking LAIs. Dr. Broder you referred to some of your patients who take their medications orally. I also had magical thinking just like you. I thought all my patients took all their medications all the time. But in reality, I'm obviously being a bit facetious, but we know that the non-adherence rates are much lower even than our best guess. And I also then come to realize that many people who do take their treatments on a fairly regular basis would elect to take a treatment less frequently, once a month, every two months, whatever the case may be. So this is part of informing people, keeping them informed. And I think the forensic psychiatry perspective is certainly a wonderful vantage point, reminds us of not only is the right thing to do, but I think it's also a good medical legal right thing to do.

Now, with respect to our discussion, I thank you both. In this final entry of this series we'll have an in-depth discussion about long-acting injectables. Stay tuned.