Rethinking Treatment Goals in Bipolar Depression and Mixed Episodes

Bipolar depression and mixed episodes remain among the most difficult—and highest-risk—conditions in psychiatry. Even when mood symptoms improve, many patients continue to experience significant cognitive and functional impairment.

On NYU Insights on Psychiatry, Dan Iosifescu, MD, explains why standard treatment approaches so often fall short. Dr. Iosifescu argues that symptom suppression is frequently mistaken for recovery, that short-term improvement does not equal durable treatment, and that bipolar mixed episodes expose the limits of one-size-fits-all care.

The discussion focuses on the clinical dangers of mixed episodes, the challenge of recognizing them, and the importance of acute stabilization followed by a deliberate transition to sustainable long-term treatment. Dr. Iosifescu also explores how emerging biological research—including metabolic interventions and personalized experimental models—may eventually help clinicians better match patients to treatments.

Rather than offering quick fixes, this conversation reframes how clinicians think about success, recovery, and personalization in the treatment of bipolar depression.

Guest: Dan Iosifescu, MD, Director of Clinical Research at the Nathan Kline Institute and Director of the Mood Disorders Clinical and Research Program at NYU Langone Health.

Watch Insights on Psychiatry on YouTube
Senior Producer: Jon Earle

Transcript

[00:00:00] Dan Iosifescu, MD: Because healing in the brain involves making new connections between cells—what we call neuroplasticity—being able to produce energy for that construction phase is extraordinarily important. If you are unable to do it, that could hamper your ability for either resilience or improvement with treatment.

[00:00:33] Charles Marmar, MD: Welcome to Insights on Psychiatry. I'm your host, Dr. Charlie Marmar. I'm the Chairman of the Department of Psychiatry at NYU Grossman School of Medicine, and it's my great pleasure to welcome my guest today, Dr. Dan Iosifescu, who is an internationally recognized leader in the understanding, treatment, and research in mood disorders.

[00:01:00] He is the Director of Clinical Research at our affiliate Nathan Kline Institute, a New York State Institute. He also directs the Mood Disorders Clinical and Research Program in our faculty practice here at the medical center. Welcome, Dan, it's a great pleasure to welcome you to our podcast.

[00:01:22] I thought today you and I could have a conversation about perhaps the most vexing and highest-risk disorder in all of psychiatry: bipolar depression. Tell us a little bit about a typical challenging case you get and how you're thinking about how we can do better, given the tremendous pain and suffering these patients experience.

[00:01:52] Dan Iosifescu, MD: When people think about bipolar disorder, they think about mania, which is flamboyant, but in fact, we have ways to treat it relatively well, whereas bipolar depression is extraordinarily difficult to treat. The only FDA-approved interventions for this phase of the illness are antipsychotic medications, which have a lot of downsides and only work partially well. That really makes it extraordinarily difficult for a lot of patients to get to a resolution.

[00:02:39] One very important piece of the burden of bipolar depression has to do with cognitive deficits and with the toll it's taking, not just in terms of mood and sadness, but inability to function cognitively.

[00:02:58] So I just want to give you some examples of clinical problems that some of our patients can have. In the interest of protecting confidentiality, this is not going to be any particular individual, but essentially a composite of several such problems. So imagine a person who would have been an extraordinarily successful teenager academically, even valedictorian in their high school, and who by the time they reach college experiences a series of bipolar mood episodes, which essentially make them completely unable to function. A series of manic episodes during which they present in very odd ways to their peers and to their teachers, and then profound periods of depression when they are barely able to function. After a few years of such repeated episodes, they are unable to continue with their academic work.

[00:04:11] They have to leave college despite their previous level of excellence and are now completely disabled. They are seeing perhaps some doctors that treat them with the commonly prescribed medications for bipolar depression, such as the antipsychotics that I was telling you about, but ultimately the level of sedation that is triggered makes our imaginary patient, in fact, barely able to stay awake.

[00:04:51] And while they're no longer experiencing any mania, they're still completely unable to function and to return to work. It's a matter of addressing all these symptoms and thinking about the person in global terms, and also thinking about relatively novel ways of treating bipolar depression. There is an entire body of research about glutamate abnormalities in depression and in bipolar disorder in particular.

[00:05:29] In this particular case, one such strategy would involve, in an acute sense, perhaps interventions such as intravenous ketamine, but then that's only a short-term improvement and it's not really an ideal treatment in the long run. So combining that with lithium, which is a fantastic mood stabilizer that is actually used much less than it should be, because it's one of our best treatments in bipolar disorder.

[00:06:07] Then combining with some glutamate modulators such as memantine, which is a weak NMDA antagonist that has some procognitive effects. For our imaginary participant, it serves its place of extending the response to ketamine, so they only need these more acute interventions at larger intervals.

[00:06:40] What eventually happens is that this person starts being able to function and then slowly regains not just their cognitive prowess, but also their self-confidence, which was shattered.

[00:06:55] Charles Marmar, MD: Amazing. And do so maximizing their mood regulation, minimal sedation, and paying close attention to functional capacity, not just mood control.

[00:07:07] Dan Iosifescu, MD: Absolutely. We are talking about these as being mood disorders, but in fact, they impact the person as a whole, and we need to keep into our attention all these different aspects and especially their functional abilities.

[00:07:23] Charles Marmar, MD: One of the phases of bipolar illness, including those with some depression, that are the most difficult for us as practicing psychiatrists, especially in outpatient settings, is bipolar depression as part of a mixed episode, where there is some mixture of overactive hypomanic-like features and mood disorders. Can you describe briefly what characterizes a mixed episode, why they are so dangerous, and how we can manage them?

[00:08:01] Dan Iosifescu, MD: This is an extraordinarily toxic mix. The mixed episodes are, in fact, presentations where the individual has both symptoms of depression and symptoms of mania at the same time. So imagine someone who's very depressed, but actually agitated and very irritable. The problem is that most of the traditional antidepressant treatments don't work.

[00:08:32] Actually, they can make the situation much worse. Other approaches that we have for these mixed episodes, which are primarily antipsychotics and anticonvulsants, do work, but there are strings attached in terms of side effects. It's a very difficult-to-treat mix of symptoms, and there is no one single way of addressing it. I can't give you a recipe. I think this is a particular area where we need to think in terms of personalized medicine, both using clinical features and, hopefully, as we are researching now, finding specific biological markers that would steer us in the right direction, because I absolutely do not think that there's a one-size-fits-all answer to this very complicated clinical question.

[00:09:37] Charles Marmar, MD: And why is the risk so great? If we think of bipolar disorder carrying the highest lifetime risk of suicide, probably of any psychiatric disorder, within bipolar disorder, the risk of imminent suicide may be greatest in mixed episodes. Say a little bit about that and how we should at least try to mitigate that risk.

[00:10:03] Dan Iosifescu, MD: In some ways, it's not surprising. When people look at the clinical risk markers for suicidal behavior, for attempts and actual completed suicides, some of the clinical features include agitation, irritability, anxiety—all these are present in these mixed episodes of bipolar disorder. So you are already having all these different characteristics of high risk, and the person is profoundly disabled and profoundly unhappy, and, not surprisingly, some of them have this urgency to act on their distress.

[00:10:54] So what to do about it? It involves first recognizing it, because that's one of the most important issues—to not essentially just treat someone who says, "Oh, my anxiety is worse as well, let's give him a classic anti-anxiety medication," but actually recognize that this is a bipolar mixed episode.

[00:11:22] That step is already quite hard because of the protean, very complex presentation, where people can miss one or the other facets of this. So recognition, and then second, trying to both have an initial aggressive treatment that calms down this very toxic situation, and at the same time, not letting that be the long-term treatment, because what helps in that immediate moment to calm down may be way too much for that person to continue treatment with.

[00:12:03] Unfortunately, if you just leave things on at the level where they were required in the acute moment, people will be unhappy with the side effects of such aggressive treatment that they would typically stop it, and then the cycle would restart. It's a very sophisticated approach where we need to ensure that soft landing of a very acute crisis into a relatively good level of functioning.

[00:12:40] Charles Marmar, MD: So would this be a fair summary also? The first thing is it's hard to recognize, and we have to maintain a high level of vigilance for it in anyone with a personal or family history of bipolar disorder, particularly since we do not yet have a blood test or a brain imaging test that says you have bipolar disorder, mixed episode, for example. Second, treat it as a real psychomedical emergency—that bipolar mixed depression with suicidal ideation and high levels of agitation is as dangerous as having a myocardial infarction. And third, we have to treat it in a safe setting with a very high intensity level of treatment, but plan an appropriate step down from that when the patient is stabilized.

[00:13:33] Dan Iosifescu, MD: Absolutely. But I fear that longer-term view is, unfortunately, too often missing.

[00:13:44] Charles Marmar, MD: As a leader in the understanding and treatment of complex mood disorders, including bipolar disorder, what are you excited about that we're doing at NYU and the field is doing so that five years or ten years from now, when you and I have the pleasure of sitting down and talking about bipolar disorder, we will have fresher approaches, more effective and safer approaches, and that more of our patients with bipolar disorder can have meaningful and enjoyable lives?

[00:14:21] Dan Iosifescu, MD: Our field in general, and NYU Psychiatry in particular, are developing a lot of very interesting and promising treatments for severe psychiatric disorders.

[00:14:39] There are quite a few that are either already here, such as neurostimulation strategies and ketamine, but others that are in development, like psychedelics or other novel ways to modulate circuits with neurostimulation and even metabolic interventions. So the promise is enormous, and we see things that work much faster than our traditional treatments and that work for people where traditional treatments did not work in the past, so that's great.

[00:15:23] However, I think that each of them will have their blind spots. They will be absolutely fantastic for some people and not necessarily so good for others. This efflorescence of novel treatments needs to be paired with a personalized medicine approach and a very good understanding of the biological changes that these treatments work on and are meant to address.

[00:15:57] So that we are able ultimately to pair the right patients with the right interventions, rather than just throwing darts at a wall and hoping that some of them stick.

[00:16:09] Charles Marmar, MD: And among these novel treatments, tell us a little bit about the ones you're currently involved in developing and testing.

[00:16:18] Dan Iosifescu, MD: For a long time, my research has been related to changes in metabolism, mitochondrial abnormalities. Mitochondria is the power plant of the cell, and we know that in a series of psychiatric conditions, there is a deficit. Because healing in the brain involves making new connections between cells—what we call neuroplasticity—being able to mount an energetic response and to produce energy for that construction phase is extraordinarily important.

[00:17:03] If you are unable to do it, which is true for some people, that could hamper your ability for either resilience or improvement with treatment. It won't be everybody who would benefit, but there will be a great number of people who would benefit from these energetic interventions.

[00:17:25] We are testing two different ways of improving that system. We are currently in the last year of two very large studies testing a near-infrared laser, which actually shines through the skull into the brain and interacts with the mitochondria. We have biological proof that it actually produces this energetic response.

[00:17:58] We are also testing its effects in depression and in mild cognitive dysfunction, in early stages of Alzheimer's disease, and I'll be able to share results from these studies in less than a year. It's really wonderful.

[00:18:16] Charles Marmar, MD: One of the challenges in our field, which has kept us behind oncology or GI work or cardiology, is that we're not able to easily biopsy the organ of illness, right? We are always looking downstream and far away for biological markers of what's actually happening, where the illness is being actually mediated. Any thoughts about how we can get closer to a proxy for a biopsy? Otherwise, it seems to me like the person who lost the keys in the dark and is looking under the lamppost because that's where the light is, but not where the keys are.

[00:19:04] Dan Iosifescu, MD: I absolutely agree with you. Simply testing whether treatments work or not, without a very serious and sophisticated understanding of their mechanism, doesn't really help us enough. It's still good to know that we have a good treatment, but knowing why this is a good treatment actually allows us to further improve it and find other things that may be even better.

[00:19:34] Also, at the same time, what I was alluding to earlier, which is finding the right patients who would be most likely to succeed in their treatment cycle with these particular interventions. So I absolutely think that anything we do in terms of treatment discovery has to be grounded in biology.

[00:19:59] We have several novel ways to do this brain biopsy that you are talking about, either using sophisticated neuroimaging or using interventions—those pioneered by one of our colleagues, Carla Nasca—looking at exosomes and little snippets that can be detected in the plasma, which have been discarded from the brain and can be analyzed and give us insights into what actually is happening at the brain level. These are just two examples. There are others of ways in which we can actually interrogate the brain in a way that meaningfully advances our understanding of the illness and our ability to deploy treatments in a more thoughtful way.

[00:20:58] Charles Marmar, MD: Great example of neuronally derived exosomes. They give us a window into brain functioning in psychiatric illness. I think postmortem studies have limitations but are interesting and important, and the new field of growing brain organoids, so we can look at the brain in addition, manipulate it for an individual patient.

[00:21:20] Dan Iosifescu, MD: Which we are actually doing in some of our research studies right now.

[00:21:24] So I was telling you about our interventions to improve mitochondrial functioning. In a group of patients with bipolar disorder, we are essentially taking biopsies from their skin to grow organoids and test not just whether the interventions themselves help at the brain level, but also how this intervention would interact with this brain in a dish that we are growing, which allows us a lot more manipulations than the actual living brain would.

[00:22:04] Charles Marmar, MD: So you can take a skin cell, reprogram it backwards to a stem cell, program it forward to grow out a brain organoid—even a structure in the brain like the basal ganglia or the hippocampus, potentially—and then manipulate that. So we actually have a living model of a single patient's brain function that we can study. There's great hope with all this potential. Thank you for your wonderful work in leading this area: infrared work, brain organoids. It's really the cutting edge, and the deep commitment I think we share, and our department shares with the field, is a very serious attempt to personalize psychiatry and to also develop objective understanding of the specific molecular and circuit problems that underlie psychiatric illness, so we can offer greater hope to our patients who, up till now, unfortunately, many times have struggled with a lifetime of suffering.

[00:23:13] So thank you for your wonderful work, and it was a pleasure speaking with you.

[00:23:17] Dan Iosifescu, MD: Thank you.