Dr. Daniel Knoepflmacher (Host): Welcome to On the Mind, the official podcast of the Weill Cornell Medicine Department of Psychiatry. I'm your host, Dr. Daniel Knuffelmacher. In each episode, I speak with experts in various aspects of psychiatry, psychotherapy, research, and other important topics on the mind.

Our focus today is on bipolar disorder, one of the central diagnoses in Psychiatry, and a condition that affects approximately 45 million people across the world. Bipolar disorder is characterized by episodes of mania and depression, with a wide variety of clinical presentations between these two poles. It manifests as a spectrum of illness appearing in variable ways in different individuals, which reflects the intricate mix of biological and psychological factors behind the core mood instability.

While the extremes of mood instability can have life-altering consequences, there are well established treatments that manage symptoms effectively and allow many living with bipolar disorder to maintain high levels of functioning and achieve a fulfilling quality of life similar to those who don't have the diagnosis.

In this episode, we'll delve into the key facets of this condition, discuss strategies for effective diagnosis, and review the leading evidence-based treatments. To help us tackle all of this today, I'm thrilled to welcome our guest, Dr. James Kocsis, who is an esteemed professor of Psychiatry at Weill Cornell Medicine. He's had a storied career here at Weill Cornell, having led influential clinical research trials on the treatment of bipolar disorder, depression, and other mood disorders. For me personally, he's been a generous teacher, mentor, and colleague. Someone who always seems happy to answer whatever challenging clinical question I throw at him. And I hope to throw some of those at him today. Jim, thank you so much for joining us.

Dr. James Kocsis: Daniel, thank you for having me. It's an honor to be here.

Dr. Daniel Knoepflmacher: Well, I'm really excited to get our discussion going. And as I always do here, I'm going to begin by asking you about your story. How did you become an expert in bipolar disorder and other mood disorders?

Dr. James Kocsis: Well, Daniel, I don't know whether you're aware of this, but Cornell Medical School actually played an interesting role in the development of lithium for the treatment of bipolar disorder in the 1950s, '60s and '70s. Lithium was first described as a treatment for mania by an Australian psychiatrist named John Cade in 1949. But in that same year, there was an article in JAMA from the Cornell Medical School describing deaths from lithium toxicity. Lithium was being used as a salt substitute in the 1940s. So, some people died from lithium toxicity.

As a result of that, American psychiatrists were not very eager to start giving lithium to their patients. And it was not until 1971 that lithium was actually approved for the treatment of mania in the United States. Importantly, there was a psychiatrist here at Cornell named Peter Stokes. Peter Stokes was one of the few people who had the guts to do inpatient trials of lithium versus placebo for the treatment of acute mania right here at Payne Whitney on our inpatient unit in the 1960s. I came along as a resident. I was chief resident in 1974, and Peter Stokes was my mentor. And I actually worked with him on studies which looked at the relationship between blood levels and clinical response in the treatment of acute mania.

And also, we had a lithium clinic. This was one of the few places in the early 1970s in the United States where you could get lithium treatment. We had dozens of patients on lithium here in our lithium clinic during the time when I was chief resident early on in my career. So, that's it, that's how I became interested in bipolar disorder and the treatment of bipolar disorder.

Dr. Daniel Knoepflmacher: But then, you went on to do more studies yourself. Is that right?

Dr. James Kocsis: Yes. Well, I was involved in the study that looked at the relationship between blood level and clinical response in the treatment of acute mania. We did go on to do more studies on maintenance treatment of bipolar disorder and also studies on the pharmacology and biology of how lithium works.

Dr. Daniel Knoepflmacher: I want to get back to lithium as we talk about this, but also focus a bit on the bipolar disorder diagnosis itself. And as we know, this is something that has been described going back to at least the time of the ancient Greeks and the ancient Greek physicians had characterized states of mania and depression as linked in the same condition.

And then, moving forward, thousands of years to the European psychiatrists in the 19th century, they also recorded observations of the cyclical mood disorder and that was most famously identified by the German psychiatrist, Emil Kraepelin, who described it as manic-depressive insanity, a term manic-depressive that existed certainly into our lifetimes. So, I'm wondering if you can share how some of these earlier conceptions of bipolar disorder that came out of the 19th century crystallized and evolved in the 20th century into the clinical diagnosis we use today.

Dr. James Kocsis: I mean, manic-depressive insanity in its prototypical form is very dramatic. And it's pretty easy to recognize for not only clinicians, but also for the lay public. I mean, when somebody is in a full-blown manic episode, that's a pretty dramatic thing. And the person is obviously very much different than their normal self. So, it's kind of easy to recognize that something is going on.

So, what Kraepelin described as manic-depressive insanity I think is very similar to what you and I today would think of as bipolar I disorder, where patients have clear-cut episodes of mania and episodes of depression. However, in the ensuing years and in recent decades, first of all, we realized that bipolar disorder is more complicated. And there are more subtypes of bipolar disorder than the old-fashioned manic-depressive insanity. So for example, we now make a distinction between what we call bipolar I disorder and bipolar II disorder. The main distinction there is that bipolar I disorder involves severe manic episodes that are most often psychotic and require hospitalization, whereas bipolar II disorder involves episodes of major depression, but also episodes of a milder form of mania called hypomania, which is usually not psychotic and which usually does not require hospitalization.

And then, also, we've come to recognize something called bipolar mixed states. Bipolar mixed state is, for example, if you are in a manic episode, you can have days or hours where you have depressive symptoms mixed in, so to speak, with the manic symptoms. If you are in an episode of major depression, you can have hours or days of manic symptoms or hypomanic symptoms mixed in with your major depressive symptoms. And those distinctions, the bipolar II distinction, the mixed features distinction are important in terms of our thinking about what we are going to do for treatment, because the recommended treatments or the evidence-based treatments for bipolar I disorder, bipolar II disorder, and mixed states are different. So, those distinctions become important.

Yeah. So, there's a lot under the term bipolar disorder, and I think it's better to use the word diagnoses rather than diagnosis when discussing this. And you really hit on bipolar I, bipolar II, and mixed states in what you were just describing. I'm wondering if you can just walk us through some of the hallmarks that are distinguishing factors between those identifying states and also, if you could comment on cyclothymia or what is also called cyclothymic disorder.

Let me give you an example that patients with bipolar I disorder often have grandiose delusions, right? "I am the next coming of the Lord," or "I am--" I don't want to say this-- "the next coming of the president of the United States." So, manic grandiose delusions. Whereas people with bipolar II disorder by definition, they do not have delusions. They are not psychotic. They do not require hospitalizations. They may have grandiosity in the sense that they think that they're a great poet, or they think that they're a great writer, or they think that they are very sexually desirable, which may lead them to undesirable outcomes in terms of having affairs or in terms of making a fool of themselves at work or at a public meeting or something like that. So, that's the main distinction between bipolar I and bipolar II.

Dr. James Kocsis: Cyclothymia is something that gives me a problem even after all these decades that I've been dealing with bipolar disorder. Have I ever actually met someone who's cyclothymic? Because the definition of cyclothymia, if you look in the DSM-5, for example, for at least the last two years, there have been numerous periods with hypomanic symptoms that do not meet the criteria for a hypomanic episode, and numerous periods with depressive symptoms that do not meet the criteria for a major depressive episode. Have you ever met a patient like that? I'm not sure I have. So, this is a diagnosis that I've never really endorsed, and I'm not really sure that it's very useful. To me, the clinical diagnosis of bipolar disorder applies to those who do meet the criteria for bipolar II disorder, bipolar I disorder, or bipolar disorder with mixed features.

Dr. Daniel Knoepflmacher: It's a great point, Jim. And I feel as the further you get away from a bipolar I diagnosis, the fuzziness increases to the point at which at some of the cyclothymic descriptions, you wonder where is this within the range of somebody's natural state, their traits, even their personality? Perhaps it gets a lot harder in my opinion.

Dr. James Kocsis: It gets murky, doesn't it?

Dr. Daniel Knoepflmacher: Yeah.

Dr. James Kocsis: I mean, while we're on this topic, we should address the issue of how do you distinguish between bipolar disorder and borderline personality disorder.

Dr. Daniel Knoepflmacher: You took the words right out of my mouth. Let's do it.

Dr. James Kocsis: One of the important things about the diagnosis of bipolar disorder is duration. So, for example, for a diagnosis of a manic episode, the duration, if you look at the DSM-5, the duration is at least one week. What that means is that you need to have the symptoms persistently every day for at least one week. If you take a look at the criteria for major depressive episode, the duration is two weeks. So, you need to have your syndrome of depressive symptoms day in and day out for at least two weeks. And if you look at the diagnostic criteria for hypomanic episode, it's four days. You need to have your hypomanic syndrome symptoms persistently day in and day out for at least four days.

Now, that's not typical of patients with borderline personality disorder, as you know, patients with borderline personality disorder have what is described as mood reactivity, frequent mood swings, and the mood swings are generally related to what's going on in their life at any given moment, right? If they are feeling admired, then they may look hypomanic for a few hours, or if they are feeling rejected or something bad is happening in their life, they may go into a dive into a major depression that lasts for a few hours or a day. So, the distinction between the bipolar diagnosis and the borderline personality disorder has to do with the persistence and the duration of the symptoms that appear, and also the context, right? Episodes of bipolar disorder generally do not occur in relationship to a life event.

Dr. Daniel Knoepflmacher: It's complicated, because there's overlap here. I mean, I have had patients who I think would meet the criteria for borderline personality disorder, but clearly also had an underlying bipolar diagnosis as well.

Dr. James Kocsis: I agree. I mean, there is obviously an incidence of comorbidity. Sometimes these people are called borderpolar. And yes, I've certainly seen that.

Dr. Daniel Knoepflmacher: The way I've always kind of formulated it is the two together, you can imagine how having the mood instability and the relational difficulties that come with bipolar disorder, how that would exacerbate borderline personality disorder.  

Want to ask you about another,

Dr. Daniel Knoepflmacher (Host): and

Dr. Daniel Knoepflmacher: this is okay. Also, I'll disclose speaking from experience, my clinical practice in the past where I've had situations where there was substance use at a high degree. And I thought I was treating primary substance use disorder and then, once was able to achieve a state of sobriety, that I realized there was underlying bipolar disorder.

Dr. James Kocsis: Very important point. And I absolutely agree with you. I mean, again, I have the DSM-5 in front of me at the moment, so I'm cheating.

Dr. Daniel Knoepflmacher: Do you carry it with you wherever you go?

Dr. James Kocsis: Never. Only for this meeting today. But if you take a look at Criterion D for a manic episode, it says, "The episode is not attributable to the physiological effects of a substance." So, it's very important, I think, if we know that a patient has current substance abuse, that we defer our diagnosis. We defer our diagnosis of mania. We defer our diagnosis of major depression, whatever is presenting itself to us. And we addressed the substance abuse issue first. We really would like to see what does this person look like if they are no longer using cocaine, or if they are no longer getting drunk on alcohol every day. So, that's a very important point that manic or depressive episodes in the setting of substance abuse. We should have caution about making a bipolar diagnosis.

Dr. Daniel Knoepflmacher: And the two can often be comorbid. I mean, there's a higher propensity among people with bipolar diagnoses.

Dr. James Kocsis: Obviously, there can be comorbidity. I mean, one of the important symptoms of mania sometimes is substance abuse. There are individuals who don't abuse substances generally, but the only time they abuse substances is when they're manic. So, that's another issue.

Dr. Daniel Knoepflmacher: I want to talk about another, I think, challenging aspect in diagnosis when it comes to bipolar disorder. I think about this as somebody who trains residents that often there are patients who present with depression in our line of work, and sometimes depression that is difficult-to-treat. So, the question is when and how do you, as a very experienced psychiatrist working with mood disorders and bipolar disorder, how do you think through depression that you wonder whether it might be bipolar depression when there isn't a clear history of mania in that patient?

Dr. James Kocsis: First of all, I do pay attention to family history. So, let's say we have a patient with so-called unipolar depression or recurrent unipolar depression. And let's say they have a first-degree relative who has bipolar disorder. That would be one clue that perhaps there could be an underlying diagnosis of bipolar disorder going on.

The other thing is something which I call hypo-hypomania. I asked about this in my unipolar depressed patients. Have you ever had a period where you've been on the upside, you've been euphoric, you've been grandiose, you may have lost your judgment a little bit in terms of things like overspending or doing other things that reflect a loss of judgment, but never have fully met the criteria for a hypomanic or a manic episode.

So, in my experience, I mean, one of the reasons why I want to ask about these things is because I'm thinking about lithium augmentation. I'm thinking about which patients with unipolar depression would be the most likely to benefit from lithium augmentation? So in my experience, those two things that I just discussed are the clues that helped me to figure out that this might be an individual who would respond to lithium augmentation.

Dr. Daniel Knoepflmacher: Well, we've just gone through this complex range of unstable mood states that are all characterizing bipolar disorder in different ways. And, as is the case with schizophrenia or major depressive disorder in Psychiatry, we have diagnostic criteria that have emerged from years, sometimes hundreds of years of extensive clinical observations that then later we discover more about the brain and the underlying biological factors that create these clinical scenarios.

So, I'm wondering if you could give us a brief overview of what we know in terms of neuroscientific research, and how that's taught us about the underlying biological mechanisms that create bipolar disorder.

Dr. James Kocsis: Yeah. You know, at your recommendation, I actually watched the podcast with Dr. Lopez on schizophrenia. And the answer that I'm going to give is very similar to the answer that he gave you about schizophrenia, which is there's really not a lot we know. There are lots of unknowns. But what we do know, I mean, first of all, important is genetic inheritance. I mean, we do know that there is an important genetic inherited component to bipolar disorder. There's no doubt about that. It's genetic rather than environmental.

And the other thing we know is pharmacologic response. So, what does it mean? I have patients in my practice who their only treatment for the last 20 years or 30 years has been being on lithium. They have not been in psychotherapy. They have not had other treatments. So, they've had a history of manic episodes, a history of depressive episodes, you put them on lithium and it keeps them well. What does that mean? I mean, I think what it means is that there must be a biological underpinning that the lithium is addressing. And these are the things that make us know that there is an important biology, so to speak, in the brain for people with bipolar disorder. But having said that, I don't think we know an awful lot on that.

One thing that has attracted a fair amount of interest is an enzyme called GSK-3, glycogen synthesis kinase 3, which is an enzyme that mediates the addition of phosphates to some amino acids and some research has supported the idea that GSK-3 is upregulated in patients with bipolar disorder. It's overactive in patients with bipolar disorder. And there is also evidence that lithium acts as a mood stabilizer by inhibiting GSK-3. I'm not going to go any further with this, because there are a few other maybe neurobiological clues out there, but I don't think that the evidence is all that interesting or all that good, so I'm not going to go any further.

Dr. Daniel Knoepflmacher: Yeah. We have a lot more work to do in that area. And the fact is, though, we do have treatments that work, which is not the case with all medical conditions. So, let's turn to treatment. Given the inherent course of this condition, it's helpful, I believe, to think about treatment at two distinct times.

There's the acute phase, when you encounter somebody, probably, hopefully, in the inpatient unit who is in the midst of a severe manic or depressive episode versus a maintenance phase, perhaps when someone has achieved a fairly stable mood state and your goal then is to prevent a recurrence of a major mood episode. So, let's start with the acute phase. Can you give us an overview of the standard approaches to treatment?

Dr. James Kocsis: For what I'm calling a typical manic episode with euphoria, grandiosity, and the associated manic symptoms, and particularly as is typical that the patient has delusions, has grandiose delusions or paranoid delusions or other kinds of delusions. I mean, the standard treatment on our inpatient services is a mood stabilizer plus an antipsychotic drug. And ideally, the mood stabilizer would be lithium. But there may be reasons why it can't be lithium or it shouldn't be lithium.

Let's say an example would be somebody who has a kidney disease or something like that and cannot be on lithium. Then, the alternatives are some of our anti-epileptic drugs, such as divalproic acid, Depakote. And the choice of the antipsychotic drug is variable. I mean, I think probably, one of the most popular and effective antipsychotic drugs for the treatment of acute mania right now is probably olanzapine, Zyprexa. But in the long run, in long-term treatment, if a patient needs to be on a long-term antipsychotic drug, oftentimes an effort will be made to take them off olanzapine and start them on an alternative antipsychotic drug that doesn't have some of the longer term side effects, such as weight gain and metabolic issues that are associated with long-term treatment with olanzapine. So, bottom line is that, for the treatment of acute mania, it's choosing a mood stabilizer and also choosing an antipsychotic drug.

One other additional piece I would add to that is I think it is important. There are patients who are admitted to an inpatient unit in a mixed state. In other words, if it's a complicated picture of mania with depressive symptoms as well, lithium does not do as well in those patients as it does in patients with pure mania. So, actually, an anti-epileptic drug like divalproex is preferred as the mood stabilizer in patients who are admitted with a mixed state.

I will move on to your question about a long-term maintenance treatment. So, there are a few issues about long-term maintenance treatment. Number one, we aim for higher lithium levels for the treatment of acute mania. Usually, we're looking for lithium levels in the range of about 1.0 to 1.2 for the treatment of acute mania. But when we go to the patient is discharged, the patient is no longer manic, and we want to convert them to maintenance treatment, long-term maintenance treatment, at that point, we are usually going to bring down their lithium dose and try to get their lithium level into the range of 0.6 to 0.8.

And then, we need to make a decision. Are we going to continue the patient on the antipsychotic drug, or can we take the patient off the antipsychotic drug and maintain them on monotherapy with lithium alone? And that is variable. And usually, particularly with a younger patient who maybe they've just had their first episode or they've only had maybe a couple of episodes, I'm usually going to try to take them off the antipsychotic drug and maintain them on monotherapy with lithium alone. But I have to be alert and I have to involve the patient and the family in psychoeducation about what are we looking for, what are the first signs if this person is going to go back into a manic episode? And if they go back into manic episodes while they're on lithium monotherapy, then that may be a patient who's going to need to be on both a mood stabilizer and an antipsychotic drug. In the long run, that's just sort of an empirical issue. It's trial and error. You have to see whether the patient can be maintained on a mood stabilizer alone, or do they need to be on a combination of a mood stabilizer and an antipsychotic drug.

The other issue in long-term maintenance treatment is and you know, I think maybe, as we go along here, we'll talk more about psychotherapy for bipolar disorder. But one of the important matters is involvement of the family. I do not like to treat bipolar disorder patients in my practice unless I have a significant other or a spouse involved in the treatment. And oftentimes, I have them involved in the sense that they come to every meeting with me and the patient.

One of the things that I want to do is I want to educate the significant other, the spouse, the family member what to look for; when to call me up on Saturday night because the patient is going into a manic episode; what are they supposed to look for; and obviously, what that involves is educating them about the symptoms of a person going into a manic episode or a person going into a depressive episode.

And if that happens, then what do we do? We need to probably increase the dose of the lithium, get the blood level up. We need to increase the dose of the antipsychotic drug. And that needs to be done quickly because, believe me, patients can go very quickly into a full-blown manic episode and need to go back into the hospital. So, this becomes sort of a psychiatric emergency and you need to really step on the gas. And by handling it that way, for the most part, I've kept a lot of patients out of the hospital.

Dr. Daniel Knoepflmacher: I just really want to highlight that point about, first of all, the therapeutic alliance with your patient. Having gone through all of these experiences with them and having a level of trust there and then extending that to the family is so crucial in these treatments. Because while the medications are really crucial, if let's say medications get missed or for whatever reason something breaks through, that's when you really want to draw on that trust and those relationships.

I want to actually turn though to depression because we were talking a lot about the acute and maintenance phases of treatment, in the midst of mania, avoiding mania, but bipolar depression is its own beast that you have to think about and you're going to have patients coming to you with depression and that takes different steps. So, could you speak to that?

Dr. James Kocsis: So again, here the distinction between bipolar I and bipolar II becomes very important. The reason being, if I have a patient who's been hospitalized for mania in the past, and let's say they come to me, they come into my office, they're in a depression, they're not on any medication at all, and I'm thinking about what to do to treat them. If they have a history of bipolar I and they've been hospitalized for mania, the first thing I want them to do is to be on a mood stabilizer with an adequate blood level. Depending upon the situation, that could be lithium or that could be an anti-epileptic drug like Depakote, divalproex, but I'm not going to just slap a bipolar I patient onto an antidepressant medication without first having them on a adequate dose of a mood stabilizer.

On the other hand, if the patient has a history of bipolar II and they've never been hospitalized for mania, they've never had a full-blown manic episode, then I feel more comfortable treating them with an antidepressant and counseling them about switching into a manic phase and observing them to see whether they switch into a hypomanic or a manic phase.

And then, there are specific other treatments, mainly some of the atypical antipsychotic drugs such as Seroquel, quetiapine, Latuda, lurasidone, and Caplyta that have actually been studied in either as adjunctive treatments along with mood stabilizers for bipolar depression or as monotherapies for bipolar depression.

So, those are other options that we have. I mean, I'm not afraid of using antidepressant medications and there is a long history of the utility or usefulness of antidepressant medications in patients with bipolar depression with the caveat, as I mentioned, if they're bipolar I, that they need to also be on an adequate mood stabilizer.

Also, I mean, historically, it's interesting that back in the days before we had SSRIs and SNRIs, we had two different kinds of antidepressants. We had tricyclic antidepressants and we had MAO inhibitors. And actually, there were studies done back in the day that showed that bipolar depression responded preferentially well to MAO inhibitors and not to tricyclic antidepressants. So, that's another little secret that many people may not know about, that if you have a patient with bipolar depression who's not responding to your standard treatments that we usually use here, that maybe putting them on an MAO inhibitor could be the secret.

Dr. Daniel Knoepflmacher: That is some advanced psychopharmacology that I think people want to make sure they have some consultation around that. But that's very good knowledge to convey about that past study. My understanding-- and correct me, Jim, because maybe I have this incorrect-- is that the efficacy of SSRIs for bipolar depression in bipolar I patients is not robust.

Dr. James Kocsis: Yeah, no, I agree with that. I mean, that on the average, we're not usually going to choose. But on the other hand, for various reasons, patients with bipolar depression do get put on SSRIs. They might even be put on their SSRI by their primary care physician or something like that. And sometimes it works. I mean, it's not forbidden, but not generally the first choice. 

One other thing that I should mention, we shouldn't get off the topic of bipolar depression without talking about Lamictal, lamotrigine. Because, for the maintenance of patients with bipolar II disorder, lamotrigine is an important treatment, it works well. It doesn't work well as an antidepressant, but it does work well for the prevention of depression in people with bipolar II disorder. Lamotrigine, Lamictal, is an important medication in my practice for the maintenance treatment of patients with bipolar II disorder.

Dr. Daniel Knoepflmacher: Jim, I remember you helping me with a difficult case of bipolar depression. And if I'm not mistaken, what I tried was pramipexole, which is Mirapex, a totally different medication that's often used for Parkinson's. Can you speak a bit about that?

Dr. James Kocsis: Yeah. Thanks for bringing that up. I mean, this is something that we've learned in recent years. There is a small literature on it, actually, in the psychiatric literature. Mirapex, pramipexole is a dopamine receptor agonist, and it is FDA approved for the treatment of Parkinson's, which is a dopamine deficiency disease. But for patients with bipolar depression in particular, who are not responding to our standard mood stabilizers or atypical antipsychotic drugs, adding Mirapex, pramipexole can be effective and can get them over the hill into remission. I have had several cases in my own practice where that has been an effective strategy.

Dr. Daniel Knoepflmacher: I want to present a scenario that I think is pretty common. So, we treat anxiety disorders primarily with SSRIs. If you have somebody who has bipolar I disorder and is struggling with anxiety that is not part of mania, that is not part of depression, but they have primary generalized anxiety that you want to treat, what do you think about the efficacy of SSRIs in that bipolar I individual?

Dr. James Kocsis: I mean, not terribly enthusiastic, it's worth a try, but I think you and the patient need to be mindful that this could switch them into a manic phase. And if they have a diagnosis of bipolar I, they should be on an adequate blood level of a mood stabilizer before you put them on the SSRI.

I mean, there are other alternatives for trying to manage anxiety in patients with bipolar disorder. That would include some of the anti-epileptic drugs such as gabapentin or pregabalin. it would include buspirone. Buspirone can be effective as an anti-anxiety agent.

And also, the newest antidepressant on the market in the United States is a drug called gepirone, which has a trade name, E-X-X-U-A, Exxua. And that's the most recent antidepressant, but gepirone is a chemical cousin of buspirone. And one of the things that they're advertising is that this may be a particularly effective antidepressant for anxiety. I have not prescribed it yet myself, but that's something I'm keeping in the back of my mind.

Dr. Daniel Knoepflmacher: So, thank you, Jim. We've covered a lot of pharmacology here. You identified psychotherapy as an important part of treatment as it is in Psychiatry. So, can you speak to that specifically when it comes to patients who have bipolar disorder?

Dr. James Kocsis: Yeah. I mean, there has been a lot of good research on some forms of psychotherapy for bipolar disorder. Two that I'll mention, one is called interpersonal and social rhythm therapy that was developed by Ellen Frank at Pittsburgh. And another is family therapy for bipolar disorder by a psychiatrist named David Miklowitz.

So, interpersonal and social rhythm therapy focuses on an issue, which is very important in patients with bipolar disorder, and that is maintaining your daily rhythms. So, sleep is one important example. We definitely want our bipolar disorder patients to try to be regular in the time when they go to sleep and the time they wake up and to pay attention to that. For example, when they travel to Europe or something like that, because we do know that upsetting or disturbing circadian rhythms can be a trigger for a manic episode. So, that's one of the reasons why helping patients to regularize or normalize their social and circadian rhythms is one important issue.

Family therapy, I mean, I've already talked about this a little bit. And, I mean, I think it's very important, as I say, to involve the family in treatment of your bipolar patients. And the things that you're going to do with the family are pretty obvious. I mean, number one, you want them to be involved in, is the patient taking their medication, right? Hopefully, the family member can help either to remind them to take their medication or to monitor and make sure they are taking their medication.

And the other issue is educating them about symptoms, what are the early symptoms of going into a manic episode? What are the early symptoms of going into a depressive episode? And don't be afraid to call me. Don't be afraid to contact me if you see that your husband who's bipolar is going into one of those. So, those are some examples.

Dr. Daniel Knoepflmacher: So when you survey the literature and the work and research that's going on out there right now related to bipolar disorder, what are some of the recent developments or, hopefully, future developments that you think may help us in the diagnosis and treatment of this condition?

Dr. James Kocsis: So, there are a couple of interesting things I'll mention. There is a group, a large group in the United States of bipolar disorder researchers who have formed an organization called pharmacogenetics of bipolar disorder study group. And they've developed an induced pluripotent stem cell technology for human bipolar disorder. So, they take like a piece of your skin or whatever, and they develop in the test tube. They develop stem cells from patients with bipolar disorder and patients who don't have bipolar disorder. And they have developed certain brain-like neurons, dentate gyrus-like neurons, and they have found that they are hyperactive in patients with bipolar disorder, but not in patients who do not have bipolar disorder. And that this hyperactivity of the stem cells is selectively reversed by lithium, only in bipolar patients who were lithium responders and not in bipolar patients who were not lithium responders.

So, I mean, this is an example of an interesting, relatively new scientific development that I think could potentially be helpful, both in diagnosis and, you know, can we test out medications in a test tube that will reverse the hyperactive dentate gyrus-like neurons and help us to find out what could potentially be an effective mood stabilizer.

If I have time, I can mention one other thing. So, this is interesting. There's a new technology being developed by some small biomedical research company called NanoLithium. NanoLithium is an investigational product, which involves a novel cell penetration mechanism, if you will, a novel way of getting lithium into cells that enables pharmacologic activity at very low doses.

So, think about that. I mean, you know, one of the problems obviously forever that we have with lithium therapy is the narrow therapeutic index, right? I mean, there's not a lot of difference between a therapeutic blood level of lithium and a toxic blood level of lithium. That's always been one of the important issues as clinicians in pursuing lithium therapy. But with this NanoLithium, if it's real, I mean, if it pans out as something that they're trying to develop, it could be that you would be able to have therapeutic activity with very, very low lithium levels, very low lithium blood levels. And that would be very beneficial because then you would not be so much at risk of lithium toxicity if, let's say, you took a few extra pills.

Dr. Daniel Knoepflmacher: Wow. As always, Jim, it was a pleasure speaking with you. And I really want to thank you personally for the work you've done in your career to advance our treatment of mood disorders and psychiatry, but also personally for the individual supervision you've given me over the years. It was really a pleasure to have you on this podcast and have you sharing your knowledge, experience, and wisdom with our audience. So, thank you.

Dr. James Kocsis: Thank you very much, Daniel, for your invitation and your very good questions. And as I say, it's been an honor.

Dr. Daniel Knoepflmacher: Well, an honor for me as well. And thank you to all who listened to this episode of On the Mind, the official podcast of the Weill Cornell Medicine Department of Psychiatry. Our podcast is available on many major audio streaming platforms that includes Spotify, Apple Podcasts, YouTube, and iHeartRadio. If you like what you heard today, please give us a rating. Subscribe, and that way you can stay up to date with all of our latest episodes, and maybe even leave a review because we love those and they help other people learn about us. So, please tell your friends. We'll be back again next month with another episode. And until then, wishing you good health in body and mind.