Bipolar Disorder: Pathophysiology

This podcast provides general information, not a substitute or professional medical advice. Please consult your physician for personalized guidance. Hello, hello everyone. Welcome back to PsychRounds. We are going to be continuing on in our series on bipolar disorder. And today we are going to be venturing into the underlying pathology of bipolar disorder, focusing specifically on two elements. The first being the circadian aspect of the illness and as well, the second being the metabolic aspects of this illness. We are joined as always by Dr. Larry Wang and Dr. Bradley Miller. So Larry, let's go ahead and kick this episode off. All right. So I'm really excited to do this episode. And I would say that this is probably one of my favorite topics in all of psychiatry. So the DSM-5 is very useful and I think it does a very reasonable job of describing the symptoms of bipolar disorder. But it doesn't really tell us what is actually going on biologically. Yeah, Dr. Wang, I'll jump in just because I feel like we're going to need some ground territory to start from. So let's begin talking about the circadian rhythm in general. So one interesting fact is the intrinsic circadian rhythm is actually slightly longer than 24 hours. And this means that in the absence of any additional control system, our timeline essentially gets screwed up. It's more and more out of sync with the usual 24 hour cycle. Our body has adapted to this by using various stimuli to entrain the circadian rhythm and keep it in check. The stimuli are called desipkipers, which is a German term. But the most note where these like gibber is light, specifically photoreceptors called melanopsin, which are sensitive largely to different frequencies of blue light or certain frequencies of blue light. These regulate things like melatonin production and communicate with the superchiasmatic nucleus. And this helps regulate time and orchestrate between these different systems. And we'll talk about this more later, but others like a burst can include the timing of meals, exercise, and even socialization. This comes into play with some treatments of bipolar disorder, which we'll probably cover in a further episode. But in summary, this is why it's sometimes easier to conceptualize bipolar disorder as a disorder of a broken clock or the broken clock syndrome. Yeah, I really, I like that analogy a lot. Pratt, it reminds me of zykebergs. I start to think of sleep hygiene when you went through all of the different zykebergs. So that's very interesting that you touched on there, Dr. Miller. We can definitely see the effects of chronic light deprivation. And why am I saying this? Well, for example, Tibetan monks have undergone darkness retreats for spiritual reasons, so they isolate themselves from people, but also as much stimuli as possible, including light for as long as 40 days. So after a while, some of them start exhibiting significant behavioral changes, moods, ability, hallucinations, etc. Almost like a patient who presents with bipolar one disorder with psychotic features. So these disruptions in these zykebergs, such as light, may potentially contribute to the onset of a manic episode. And we see this in clinical practice. So for example, when I was in intern, I remember seeing this very memorable case. It was a 60 something year old patient who had bipolar disorder, diagnosed in her 20s. And by the time she was in her 40s, she had annual manic episodes that occurred like clock work every late March or early April. So this is when there is that change in daylight savings time. And the amount of daylight increases rapidly. And when we look at the literature, this is not an isolated case by any means. So it looks like manic episodes are more common in the springtime. And in addition to this, manic episodes can be also precipitated by things like travel across time zones, which is, you know, a huge disruptor of circadian rhythm, a change in workshop time, or simply taking too many 24 hour calls and residency. Now, I also wonder if there is an association between mania and moonlight, because in many cultures, there's some kind of connection between madness, the supernatural, and the different phases of the moon. Hence the word lunatic. So one example of this, at least in the western world, is the myth of the werewolf, which some have attributed to manic episodes. Now, hold on. And I know I've probably talked to you both individually about this already. But while it's useful etymologically, the idea of making the full moon making things worse is often one of the biggest myths in psychiatry. And I've discussed this where large scale studies appear to debunk this idea when looking at ER visits, hospitalizations, and length of stay. Besides I doubt our patients undergo like anthropic changes during the full moon. Yeah, I will say Brad that that is true, but there does appear actually to be smaller studies supporting this specifically for bipolar disorder. So what's the takeaway from that? Well, sleep time can vary with moon cycles, and it doesn't take much to put people with bipolar disorder at risk for a manic episode. The added light and at nighttime through a full moon could potentially be enough. Again, I'm not sure these are just our thoughts, right? As we're having this discussion. So we can speculate, right? We can speculate that maybe the lunar cycle could contribute to rapid cycling or psychothermia, right? Because of this extra light. So without more studies, it's a heartily speculation in these very niche cases. Well, at the very least, I'm convinced that maybe it's less clear than the broader scale studies may suggest, but regardless, non-medication treatment for bipolar disorder often does focus around tighter control of zeitgebers, which as mentioned, can include control of light, which with things such as phototherapy, dark therapy, blue blockers, and even amber light bulbs. Or even more radical, there's a form of psychotherapy that seeks to control other aspects of circadian rhythms, such as social interactions, meal times, and other such zeitgebers. This one is known as interpersonal social rhythm therapy, or IPSRT, which was developed by Ellen Frank. We plan to examine these non-psychopharmacologic interventions in a future episode. Right. So in conclusion, the hypothesis is that patients with bipolar disorder, whether due to genetic or environmental factors, have trouble adjusting their circadian clock. And as a result, their day/night cycle becomes a mess. And as a result, one of the first signs of a manic episode is when a patient stops sleeping at night and has an irregular amount of energy and arousal. If you want to learn more about the effects of light on both mental and physical health, I think neuroscientist Andrew Cuperman, he has an amazing podcast of his own, and he is an expert on this topic. So that's our quick discussion on the circadian rhythm. Why don't we shift gears and start talking about the metabolic side of things now? All right. And as an introduction to this topic, let me ask our audience a common board question. What is the most common cause of death in a patient with bipolar disorder? Is it suicide? Is it death during a manic episode? Well no, the answer is actually cardiovascular disease. Now some of us ask things like this due to treatments that we have for bipolar disorder. Why am I mentioning this? Well because some of the medications that we use for bipolar disorder can be things that can be pretty taxing on the heart, right? We think of second generation anti-psychotics and metabolic syndrome. We think of medications like olanzapine brand names, hypoxia, or quityapine brand names, seroquil, which can cause this metabolic dysfunction. However, studies have shown that this appears to be independent of pharmacological treatment. This was noted by clinicians long ago before modern psychopharmacology even came into play. So in fact, a recent 2024 study from Sweden, Najar et al, showed that patients with bipolar disorder had significantly higher BMI to controls across all stages of life. So this is where I want to focus our attention as we can begin to conceptualize bipolar disorder or at least some subtypes as a disorder of energy metabolism. Yeah, and one area of focus in particular has been the mitochondria, which is highly involved in the production of energy. And there is actually quite a fair amount of literature on this. So they found that bipolar patients have abnormalities. abnormalities in things like glucose metabolism, pH, ATP, and lactate, which are all measures of metabolism. So abnormal and damaged mitochondria have also been detected in living and deceased patients. Mutations in mitochondrial DNA polymerase have been found as well, and defects in mitochondria can also cause inflammation, oxidative stress, and even changes in neurotransmitters, which are all highly implicated and not only bipolar disorder, but all of the mental illnesses. So that's pretty interesting. Do we have treatments that act directly on mitochondria or target these otherwise? And if so, do we like C&E efficacy in symptoms of bipolar when these are added? Actually yes. And for some of these treatments, you may be actually using them without realizing what they're doing. So medications like Lomotrogen and Lithium may be directly acting on the mitochondria and stabilizing it. And there are actually two of the best medications for bipolar. Additionally, other interventions such as exercise, fasting, and the ketogenic diet, these all improve mitochondrial mass as well as functioning, and actually all of them have pretty good evidence for bipolar treatment as well. Yeah. That's very interesting, Larry. We should definitely make an episode of that in the future with some of the other medical uses for that. But now let's switch gears here. I want to focus in on insulin resistance because we've known for a long time that insulin resistance from type 2 diabetes is bad for the kidneys, bad for the heart, which is kind of our basic med school education, right? Diabetes is not great for those organs. But what about the brain? So I'm asking this because based on what I've read, it seems like type 2 diabetes is about three times higher in the bipolar population. I also mentioned this because a prominent bipolar researcher, Dr. Roger McIntyre, has even theorized bipolar disorder as a "metastasis of diabetes" to the brain. Yeah, I'm glad you asked because I was just about to get to this. So there's a couple of reasons why insulin resistance is thought to be linked to bipolar disorder. So we associate insulin with glucose regulation, but it's actually also highly involved in the modulation of neurotransmitters. It affects cognition, neuroplasticity, neuroplasticity, and reward as well. And with insulin resistance, some of these functions can be disrupted. What's really cool actually is some of the recent work by Dr. Cynthia Culkin. So she's been looking at the effect of insulin resistance disrupting the blood brain barrier in bipolar patients. So I want to study is actually about 28% of the bipolar patients had blood brain barrier leakage. And this was compared to 0% of controls. And normally the blood brain barrier regulates what can and can't go to the brain. And impairing this can cause significant neuronal dysfunction. All right, Dr. Wang. I'm going to jump in because I know you could probably talk forever about these different topics. But I want to ask kind of a similar question as before, but with insulin resistance. Are there any current treatments that act directly on insulin resistance and show improvement in bipolar symptoms? And once again, the answer appears to be yes, although the studies are still developing. So medications like GLP1 agonists, pyoglyzone, have some evidence in bipolar oppression. And actually one of the coolest studies I've seen is the Trial BD study. And it's actually one of the 2023 best paper in the Journal of Clinical Psychiatry Award. So it actually found that metformin, which is one of the most common diabetes medications. And this medication also improves insulin resistance was found to be effective for bipolar depression with a very large effect size. Yeah, Dr. Wang and Dr. Huay, I think this has been a great discussion. I know we're excited to see where the future literature takes us on this one. But this episode has just been a brief overview of some of these potential etiologies that are documented, but also still being investigated. So we do have to move on and look towards the future horizon. So what do we have coming up next, Dr. Huay? Yeah, so next up we are going to be zeroing in on the pharmacological treatments for bipolar disorder. So we are very excited to continue on with this series. We will see you all next time and we will see you next week. Thank you for tuning in to its Site Grounds.