“The sooner you can recognize and diagnose bipolar, the sooner you can institute effective evidence-based treatments.”
Adherence, comorbidities, and treatment efficacy in bipolar I disorder (BDI) were the themes discussed by Vladimir Maletic, MD, MS, and Andrew J. Cutler, MD, in a recent PsychView custom video series.
Both Maletic, a clinical professor of psychiatry and behavioral sciences at University of South Carolina School of Medicine in Greenville, and Cutler, chief medical officer at Neuroscience Education Institute in Carlsbad, California, and an associate clinical professor of psychiatry at SUNY Upstate Medical University in Syracuse, said much has has changed since they were in medical school.
“When we trained, we were taught there was a part of the brain that was responsible for depression and there was something wrong with this part of the brain,” said Cutler. “But we now know it’s much more complicated.”
“As we elucidate some of the pathophysiology underlying bipolar disorder, we are realizing that symptoms of bipolar illness map more easily on dysfunction of a functional brain network, and their communication, than they do to transmitter systems,” Maletic added.
“In addition, there are issues with increased motoric activity in mania,” Maletic continued. “These individuals are restless and agitated and often pacing. On the other hand, salience network also seems to have heightened activity and, therefore, there is possibly a relationship with grandiosity….The so-called default mode network, which in part has to do with self-reflection of monitoring, seems to have decreased activity in mania.”
Adding to the Challenge
Psychiatric comorbidities can complicate the diagnostic process and the treatment selection. The 2 most common comorbidities with BD are substance use disorders and anxiety, Cutler said.
Attention-deficit/hyperactivity disorder (ADHD) is the third most common comorbidity in patients with BD, he added. “Even if patients don’t meet full criteria for ADHD, most of them have some aspects of it, especially problems with sustained attention and working memory.
The fourth most common comorbidity is binge-eating disorder, Cutler said. “I do think that there’s an element of dopamine dysregulation that goes on. And, if you think about it, ADHD, substance use disorder, binge-eating disorders, these are disruptions of the dopamine system, especially motivation reward. And that may be why some of our effective medications seem to stabilize the dopamine system.”
In individualizing treatment strategies, it is important and safe to address psychiatric comorbidities in addition to BDI, Cutler and Maletic said.
For comorbid ADHD and BD, for example, using stimulants can be considered, Cutler said, citing 2 large meta-analyses supported their use.
“What the researchers found was that as long as the patient is adequately mood stabilized—either with a traditional mood stabilizer or atypical antipsychotic—not only does adding the stimulant not hurt the patient, it actually improves their mood, their attention, and various other issues,” he explained. “Of course, they have to be adequately mood stabilized, and I have to be comfortable that they are not going to be actively abusing the medication.”
Similarly, comorbid anxiety disorder might influence Cutler’s treatment decisions. “I tend to use atypical antipsychotics now as a foundation, and then I’ll add either lithium or lamotrigine, perhaps divalproex,” Cutler said. “Some of the atypical antipsychotics appear to be better than others for treating comorbid anxiety.”
Cutler added that he also considers selective serotonin reuptake inhibitors (SSRIs). “One place where I think there may be a role for SSRIs is somebody who has a real obsessional anxiety picture,” he said. “A little serotonin may help with obsessionality. But, in general, I do try to avoid what I call traditional antidepressants or non–mood stabilizing antidepressants.
“The bipolar brain is just not well buffered,” Cutler said. “So if you flood it with monoamines, it’s going to go off the road...You’ll go off into a mood episode.”
Addressing Bipolar Depression
Maletic and Cutler both agreed that it is important to start with an FDA-approved medication when developing a treatment strategy for bipolar depression because that status indicates that the drug is both efficacious and safe. However, they noted that there is confusion around what is and is not FDA approved.
“What’s interesting is when you poll audiences, they get [the answer to] this question wrong all the time: What are the approved medications for bipolar depression? Well, it turns out there are 5 of them, and all 5 of them are atypical antipsychotics,” Cutler said. “Lithium, divalproex, carbamazepine, and lamotrigine are not approved for acute bipolar depression.”
Although not all antipsychotics are approved for mania, Cutler believes all would work for mania.
In terms of choosing medications, Cutler said his “whole thinking has changed.” He noted, “I still like lithium, and I like lamotrigine. Divalproex hasn’t worked as well for depression for me, so I reserve that for somebody with a real troublesome mania or frequent manias. It’s a good antimanic. But I tend to use the atypical antipsychotics.”
Cutler said the majority of patients have recurrent depressions, with depressions lasting longer, and an increased impairment associated more with a depressive state than with the manic state. Thus, he looks for an agent that can address and possibly prevent the depressions. He finds lamotrigine to be a good choice. He also likes lithium for maintenance. However, if there is an element of anxiety, he considers quetiapine a “go-to medication” if the dose can be adjusted to minimize weight and metabolic issues.
Although the American Psychiatric Association BD treatment guidelines previously advised the use of antipsychotics acutely only, “the thinking has absolutely changed,” Cutler said. “We have several [antipsychotics] that are FDA approved for maintenance treatment of bipolar disorder. Very often what I find is if a medicine works acutely for a patient, it usually continues to work if they continue to take it. So I’m more likely to stay with the medicine that helps them in the acute phase.”
Cutler cautioned that the FDA requires monotherapy trials but admitted that the majority of patients are on more than 1 medication. “Bipolar disorder is difficult to treat with just 1 medication,” he said. “We have 2 medications now that are FDA approved for bipolar depression in combination with either lithium or divalproex.”
It is also important to consider associated or breakthrough symptoms, Cutler added. “You might be dealing with insomnia or anxiety or... ADHD.”
Maletic and Cutler noted that clinicians seem to be drawn to antidepressants as a tool, even though there are issues with doing so.
“I think our brains just want to go to an antidepressant,” Cutler said. “This is a problem with nomenclature.... It’s very unfortunate that we have a class of drugs called antidepressants and a class of drugs called antipsychotics. It’s just not the way they work.
“I like to distinguish between what I call the traditional non–mood stabilizing antidepressants, which are predominantly reuptake inhibitors, and what I call the mood stabilizing antidepressants, which are, in fact, some of the atypical antipsychotics,” Cutler said.
“Another interesting fact is that all of the antipsychotics, whether first generation or second generation, work pretty well for psychosis and probably for mania, but they don’t all have as strong an antidepressant signal,” he added. “That’s what I find fascinating because several of the newer atypical antipsychotics have been studied either as adjunct for unipolar major depression or for bipolar depression, and there have been some failures. Then there are some that have had very robust antidepressant signals in that setting.”
A New Look at LAIs
What about the long-acting injectable (LAI) antipsychotics? Cutler and Maletic are impressed with how well they work and how well they have been accepted by patients.
“I’ll never forget when I was first contacted to be an investigator on a study of long-acting risperidone, [there was] microsphere preparation with every 2-week injection for bipolar disorder for maintenance. I just thought that was kind of out there,” Cutler said. “I guess I’d always associated the LAIs with schizophrenia and psychotic disorders.
“I thought I was going to have trouble recruiting for this study,” he shared. “I thought patients with bipolar disorder tend to be higher functioning. Are they going to want to have a shot? I was surprised how many people with bipolar disorder, when given this option, accepted the option.”
Those studies eventually led to the FDA approval of risperidone long-acting microsphere preparation. “We also now have an aripiprazole long-acting injectable, aripiprazole monohydrate,” Cutler said.
“That experience really changed my thinking,” he explained. “Sometimes I love when I’m proven wrong. I kind of love when I’m kind of flat-footed like that and just don’t consider the options.”
Another benefit of LAIs is their impact on adherence. According to Maletic, studies show that between 40% to 60% of individuals with BD do not adhere to treatment.
“If we ask our audience, ‘What is one of the biggest challenges you face in managing bipolar disorder?’...near the top is going to be adherence,” Cutler explained.
“[BD] works on parts of the brain that have to do with insight and judgment,” he added. “I think people with bipolar disorder often are not very self-aware.... They don’t always have the best insight and judgment.... So they may think, ‘Well, it’s not that bad. I don’t need to take medication.’”
Thus, Cutler shares the LAIA option with patients because they may prefer it for all the same reasons patients with schizophrenia prefer it: Patients do not have to go see the doctor as often, they do not have to remember to take or think about a medication, and it is discreet—nobody will “catch” them taking a pill.
Plus, Cutler said he believes tolerability is better with LAIs compared with oral medications. “If you think about the pharmacokinetics of an oral drug, the medicine has a lot of peak-to-trough variability, whereas the LAIs tend to have a much smoother blood level with less peak-to-trough variability,” he explained.
That, in turn, impacts the adverse effects. “We all know that at peak levels, you can have more side effects,” Cutler said. “There is some evidence that there may even be less risk of movement disorders with [LAIs].
Based on the schizophrenia literature, LAIs also may be better at preventing deterioration and preserving the brain, Cutler said. “I tend to think of bipolar now a little more than I used to as a potentially neurodegenerative or neuroprogressive disorder,” he explained. “I had a professor years ago who said to me, ‘Never let anybody stay manic or psychotic because it is bad for the brain.’ There is now evidence that that may be true. As we know with subsequent manic or subsequent depressive episodes, you can see a decrease not only in brain tissue but also in cognitive performance. Use of a long-acting injectable may not only prevent clinical relapse—it may be disease modifying.”
Although Cutler said it is not realistic to see LAIs as first-line treatment, the option may rise to the top of the list for patients who “are vulnerable to relapse with oral medications, either due to the illness itself or to their difficulty with adherence.”
Still, he likes the idea of starting the LAI conversation and detailing out how it might be beneficial when the patient is struggling or finds themselves in difficult situations, like in jail or in the hospital. Peter Weiden, MD, a schizophrenia expert and colleague, put it succinctly to him, Cutler said. “Andy, you offer them LAI, the first time they’ll say, ‘No.’ You offer the second time, they say, ‘No.’ You offer the third time, they say ‘No.’ The fourth time, they’ll say, ‘Why didn’t you tell me about this before?’”
It is all in the presentation, Cutler noted. “You don’t say, ‘Would you like an injection? Do you want a shot of your medicine?’ You would say, ‘Are you interested in a modality that has been shown to prevent relapse and the consequences of relapse and that you only have to take, for instance, once a month or only have to think about once a month? By the way, the way it’s delivered is by an injection—a long-acting injection.’ I found I get better success that way.”
Maletic and Cutler emphasized that it is important to screen every depressed patient for BD and to make the correct diagnosis as early as possible. “The sooner you can recognize and diagnose bipolar, the sooner you can institute effective evidence-based treatments,” Cutler said.
The next step is to be thoughtful about the treatment choices. “As we have more options, it’s really important to think about individualizing treatment not only for the mood state or the mood episode you might be treating or the type of pattern that the patient has with respect to manias versus depressions, but also various comorbidities and patient preferences. It’s very important to offer—and get comfortable with—all of the different options,” Cutler said.
“I like to say that if I only had a 5 iron in my golf bag, I don’t think I’d be as good a golfer as I am with my full set of clubs. The more different tools—the more clubs you have in your bag, so to speak—the better outcomes we’re going to have for our patients.”
To watch this Around the Practice program, visit https://www.psychiatrictimes.com/psych-view/expert-perspectives-on-the-clinical-management-of-bipolar-1-disorder.