Bipolar Disorder: Pharmacologic Treatment

This podcast provides general information, not a substitute for professional medical advice. Please consult your physician for personalized guidance. Hello, hello everyone. Welcome back to PsychRounds. We will be continuing on in our series on bipolar disorder. In today's episode, we will be talking about pharmacological treatment for this illness. So we are joined as always by Dr. Larry Wang and Dr. Bradley Miller. And as we begin this episode, I think it's very important to separate from above versus treatment from below. So for listeners, you might be thinking, what did you just say? What do you even mean by this? Well, when I say above, I refer to things like mania and hypomania. And when I say below, I'm referring to things like dysthymia and depression. But of course, there is also an in between or a maintenance phase, right? So this is where always the focus of stabilization and prevention of future episodes can take place. Yeah, so let's start with talking about treatment from above or treatment of acute mania. So medications of choice here often includes mood stabilizers and antipsychotics. So mood stabilizers referring to medications that were traditionally anti-apoelectics, looking at things like lithium and valproic acid. And these are generally thought to treat the underlying cause of the illness, especially lithium. The downside, these are sometimes slow to take efficacy, especially lithium, which can take as long as one to three weeks to begin working. So Brad, why don't we just wait it out until these medications start kicking in? Well, unfortunately, the manic episode is neurotoxic. There's a lot of inflammation going on in the body and it's very bad for your health. When it comes to neural and cardiovascular and pretty much everything. So this is where antipsychotics come in. They work a lot faster and they are particularly good if there's associated psychotic features in the mania. Yeah, so here's a good question, Brad, that my patients asked me. They'll say, "Hey, Dr. Hewitt, do all antipsychotics work for this acute mania? Can I just, I can choose what I want?" So actually, there's quite a lot of variability in the efficacy of antipsychotics for acute mania. Atypical antipsychotics with good evidence includes resparidone, carriperazine, olansapine, quittiappine, and repyprosol, acenapine, zeprazidone, and most recently, iloparidone. All of these are FDA approved except for iloparidone as this is more recently under investigation. And clasapine also has some off-label evidence as well. I know there were a lot above there, but just keep in mind those ones are your go-to choices. But don't forget about the typical antipsychotics as there is good evidence for medications like aloparidol, fluffenazine, and chlorpromazine. Haloparidol specifically appears to have some of the best evidence as an treatment of acute mania, but there is a major downside. And that downside is that it appears to have the highest ray or one of the highest rates of bringing people into a depressed phase after the mania has resolved. Yeah, so Brad, I know I asked you a leading question there, but I will say that we know as psychiatrists that a lot of antipsychotics have different evidence for treatment of acute mania. And there are some that have actually failed multiple large controlled trials. One for example would be Brexpropazole, also known by its brand name, Rexalty, which was pretty surprising because it is similar as a partial agonist to aropropazole, brand name Abilify. So there's also not a lot of evidence for medications that we typically use in other phases of the bipolar illness. So these can be medications like Latuda or even medications like Caplighta. So these can be very useful in certain phases, maybe the bipolar depression phase, but in this stage we're particularly talking about the acute manic phase of this illness. So one of the most surprising ones for myself actually, guys, is this medication that we use frequently, palaparidone, very closely related as the active metabolite of Risperdol, which goes by its brand name of Envega. And this actually had some pretty questionable data for acute mania as well, originally failing two out of three trials for acute mania and having the FDA reject it for acute mania indication. So very interesting for myself because I know this is a medication that we use quite frequently. So again, one of the reasons we have to mention is there is obviously a convenience factor with antipsychotics. And what do I mean by convenience factor is that not every antipsychotic has a long acting injectable available, right? Palaparidone actually has one of the most convenient long acting injectables, which is Envega Sistena, which comes in multiple durations and titrations that are available to you. And what you described Dr. here, it might be actually almost using Envega Sistena there for more maintenance rather than treatment of acute mania. And so this is where why we're breaking down this episode into those different phases. And we could talk about how this applies to mood stabilizers as well as well. A medication like lomoetry gene or lemicdol is very useful for prevention of future episodes in the maintenance phase as well as treating from below in treatment of acute depression, but it is essentially useless for mania. All right, all right. I've stayed silent long enough speaking of lomoetry gene and treating from below. Let's talk about bipolar depression. This is very important because although bipolar disorder is usually associated with the manic phase, these patients actually spend a greater amount of their life in the depressed phase. Now officially the FDA approved treatments are all antipsychotics or at least antipsychotic combinations. So they include quattayapine, coryprazine, lume teperone, loracidone, and cymbax, which is a combo pill of olanzapine and fluoxetine. So just going over these treatments real quick, coryprazine is kind of the odd one out because although it is FDA approved, the effect size is actually pretty bad. So its number needed to treat is around 11. And I'm actually surprised it even got this FDA indication. The other ones are kind of similar. So they have number needed to treat of around four to five. And remember with number needed to treat, the lower the number of the better. Anyway, the other ones have a number needed to treat around four to five, but either have significant adverse effects, so things like quattayapine or cymbax, or are really new and expensive, something like lume teperone. So generally my preference is loracidone, brand name latuda, which balances efficacy, tolerability, and cost. So Larry, I know you were going over some of the antipsychotics there, but for the sake of mood stabilizers, I noticed you didn't say or touch on lymotrogen. And I thought that Brad said this works pretty well for treating bipolar disorder from below. Actually is right. So although lymotrogen doesn't hold FDA approval for this indication, and this might actually be due to the way the original trials were designed, it actually has pretty good off-label evidence for this. And other medications that also may work well include things like lithium, and actually surprisingly, preme pexol, so brand name mirror pex. It was very, very surprised by this, because we don't really use this much in psychiatry. It's mainly reserved for restless leg syndrome, but it seems to work on the D3 receptor preferentially. And while there are risks, the effect size is actually quite large. So studies range from about 0.6 to 1.1, so potentially one standard deviation above placebo. And actually this effect has not seen so much with something like rolepeneral, which is another dopamine agonist. All right. So we've talked about treatments from above, aka our manic like phases of bipolar disorder and our treatments from below, aka our depressive phases of this illness. But let's talk about prevention of future episodes, basically the maintenance phase. So two medications really stick out here, lithium and limotriging. In general, lithium looks to be better at preventing future manic episodes, whereas limotriging seems to be better at preventing future depressive episodes. So theoretically, the question that I've been asked before is, could these work really well together. Well, antipsychotics also have evidence here, with medications like aeropryproposol, ziprazidone, quityapine, and a landsapine showing good effect. What's interesting is that a large 2005 paper, Lieberman at Al, showed that a landsapine brain-aimed Cypraxo might actually be more effective than lithium in the maintenance phase of bipolar disorder. Any comments on this, Brad? Not to be the eternal skeptic, but that study was funded by Eli Lilly, the maker of a landsapine. There was another large non-industry-sponsored study in the UK comparing lithium, Valproate, a landsapine, and cateyapine from maintenance treatment of bipolar. And this found that lithium was well ahead of the pack on multiple measures, and this seems to be consistent with the general impressions and the rest of the literature we see as well. And I think that this raises another point that I want to talk about, which is the limitation of rating scales. So while symptom rating scales like the young mania rating scale or the YMRS scale is useful, it's useful at telling the condition about reduction of symptoms. They don't necessarily tell you about how the patient is doing overall. And these are the scales also used in research as well for reference. When compared on these rating scales, lithium and anacocytis can look somewhat similar, but where they can differ is looking at something called psychosocial functioning. And in fact, this is what often patients care about. So what is psychosocial functioning? These can include things like, you know, is the patient able to take care of themselves independently? Can they go to school? Can they volunteer? Can they work? Are they able to have meaningful social relationships with friends and family? And are they able to, you know, have romantic relationships as well if they desire one? And this is where I'd want to jump in and say that mood stabilizers like lithium and the motro gene appeared a win for benefit to patient and this domain in the improvement of their psychosocial functioning. And so it's no surprise that when a group of bipolar patients were surveyed about what they thought most beneficial to them, the top two medications that popped up on that list were the motro gene and lithium. In fact, this has been known for a very long time. Papers even as far back as the 1970s have shown that lithium appeared superior to anti-psychotics, such as chlorpromazine, haloparadol, and flufenazine when it came to psychosocial functioning. And even more recent studies in the early 2000s looking at lithium versus quattitapine showed that the former lithium was far superior for quality of life measures. In fact, longer term use of quattitapine and bipolar patients actually showed worse psychosocial functioning than patients who were not on medication. So the ones who were not adherent with their anti-psychotic did better in terms of psychosocial functioning. So is there a big difference between lithium and the anti-psychotics for psychosocial functioning as a class? Because what it sounds like to me, Brad, is that what you're saying is that the psychosocial functioning is pretty much impaired with these anti-psychotics. But we have a less of an impact when we're choosing things like the moods, stabilizers, like lithium, and limotrogen. Yeah, that is essentially what I'm saying. But for those anti-psychotics study, we cannot treat all anti-psychotics equally and the mechanism can be quite different. So waters can get a bit murky. For example, there's some evidence that a lyrazodone may actually improve psychosocial functioning and even cognition by a fair bit. I agree with Dr. Miller and what I'm about to say is more theoretical and anecdotal and more speculative, so take it with a grain of salt. But from my experience, I find that the strong D2 blocking agents, such as Hallopardol and Fluffenazine, were the highly sedating agents. So medications like Olanzapine or Quattayapine appear to have a worse effect on psychosocial functioning compared to some of the "milder" anti-psychotics like lyrazodone or air pipersol. So for reference, patients I've seen go into remission from these strong "andesticotics" are often glad that they're not having a lot of the symptoms anymore, but some of them complain about feeling diminished or blunted or even the more extreme cases of feeling like a zombie. I rarely share these comments from patients on medications like lyrazodone or air pipersol. That was a great discussion. I do want to say that one of the last things I want for us to at least talk about is the treatment of mixed mania and rapid cycling, which may be a little bit different than the classic euphoric mania that we're talking about. Now the textbook answer is that lithium may be less effective than the prog acid or tegrotal. Is this true? Not exactly. While it's true that lithium tends to be more effective for a classic euphoric mania you're talking about, when there is a clean break between manic and depressive symptoms, it doesn't appear to be inferior to the other mood stabilizers for mania with mixed features. Where the confusion might be from is that compared to euphoric mania where lithium is significantly better, there doesn't appear to be much difference between it and Valproate or carbamazepine as all of these medications appear to be less effective for mixed mania. So lithium is still a reasonable option in these scenarios along with the other antipsychotics that we mentioned above as well. Because one of my last thoughts for the day, I just wanted to talk about the antipsychotic aeroproprysol, brand name Abilify. It's often referred to as a weak antipsychotic and although yes it appears to have relatively weak data for positive symptoms of psychosis, it actually has some of the strongest data for bipolar disorder in both the manic and the maintenance phases, which begs the question, is this even right that we refer to it sometimes as a quote unquote weak antipsychotic? Additionally, Abilify or Purposeol is typically well tolerated. It has a good side effect profile and does have long acting injectable formulations available. So it's definitely one of the antipsychotics high on my list for bipolar disorder. Any thoughts on these speculative opinions, Larry, or Brad? Well, I agree. I think Abilify or Aeroproprysol is actually one of the strongest antipsychotics for acute mania. So like yourself, it is one of my go-to's for that indication. Before we close, I also wanted to mention that another important consideration with bipolar disorder is sleep. So some of the medications given for bipolar disorder like Olanzapine are already very sedating, but otherwise it's often good to start other medications to help your patient sleep. So for example, there's some decent evidence and adjunct of remeltion. You can try some of the histamine one antagonists. And even sometimes the benzodiazepines are z drugs, although that is a little bit more controversial. Speaking of benzos, they are quite useful early on in acute mania for symptomatic benefit as a rescue medication. They probably don't address the underlying cause of bipolar disorder, but they can act as a hypnotic for sleep, as well as addressing potential agitation and aggression so you can keep your nursing staff safe and let the antipsychotics and mood stabilizers do their work in the meantime. It's definitely not something that I would want to keep on the patient long term, however, and ideally I would want to taper and discontinue the benzoprior to discharge. Yeah, I also want to cut in before you go ahead and wrap up, but I know this episode's already very detailed. I just want to give a theoretical final thought where if you have a patient who's maintained on lithium for mania over a limotron gene for depression and they're doing well in the medication, but then they have a breakthrough episode of mania or depression. This does not mean that the medication is not effective for them. They may have had this breakthrough episode for any number of reasons, but trying to switch the medication because of this is not necessarily the go-to-right option. You may have to consider it, but it sometimes is more useful to think about these as prolonging the time to next relapse of the illness. Ideally it goes forever, but that may not always be the case. Keep this in mind that just because they had a manic episode with them or whatever medication was working for them may not need to be changed. Yeah, and Brad, I think that's a really great point because a lot of times we will have a patient on a good medication regimen. It might be the best medication for them, right? But maybe the patient has a dual diagnosis of a substance used as order and is under the influence of methamphetamine, etc. And then this can cause some of these breakthrough episodes. So I think that's a really good point. You may have there about with these pharmacotherapies, a breakthrough episode is not necessarily mean treatment failure. There may be something else going on. And Larry, I think too, that was a great touch on sleep as a consideration that really tied in with our last episode talking about the circadian rhythm and some of the theories of bipolar disorder. However, that will bring this episode to an end. So thank you everyone for listening. We will continue on with our last episode on the bipolar series next week, looking at some of the non-pharmacological treatments. So we will see you next time. Have a great weekend, have a great rest of the week. And thank you for listening to PsychRounds.