Mood Stabilizers and Anxiolytics PDF

Mood Stabilizers and Anxiolytics Mnmonics Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... Mood Stabilizers and Anxiolytics Mnmonics Speaker 1: We now come to the mood stabilizers, which, if you're anything like me,...

Mood Stabilizers and Anxiolytics Mnmonics Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... Mood Stabilizers and Anxiolytics Mnmonics Speaker 1: We now come to the mood stabilizers, which, if you're anything like me, will be among the most confusing classes of drugs you will ever study. This is because they either have unknown mechanisms of action, like lithium, or work in multiple areas of the body, and thus have unpredictable side e!ects, like the anticonvulsants. Nevertheless, we will venture forward, and I will try my best to break it down for you in an easy to understand form. Just as a quick reminder, you can use the mnemonic DIG FAST to remember the symptoms of mania. Having at least three of these quali"es the patient for mania per DSM standards. Like major depression, the time period is important diagnostically. While having two blue weeks is the criteria for major depression, in mania, the time period is less. In this case, one fun week equals a manic episode. Like psychosis, bipolar disorder should be treated by a psychiatrist. This is largely due to the fact that many of the treatments of bipolar, such as lithium, require close monitoring, as we will discuss soon. While this is a review of psychopharmacology, not diagnostics, this concept is important enough for a quick tangent. Both medical students and clinicians can have di#culty distinguishing bipolar and borderline, as there are many features, such as depression, hyperactivity, impulsivity, suicidality, and occasion psychotic symptoms that are shared between the two. Nevertheless, learning to di!erentiate the two diagnoses is of crucial importance. Why? Because the treatments for the two are completely di!erent. For bipolar, the mainstay treatment remains pharmacology, although therapy may help. For borderline, however, no drugs have been shown to be e!ective at treating the core features of the disorder, although some drugs may be used to target speci"c symptoms. Instead, a form of therapy known as DBT or dialectic behavioral therapy, has been shown to be e!ective. So if you misdiagnose a patient with bipolar or borderline, you could waste years trying to help using the wrong treatments. 1 of 10 6/26/24, 9:06 PM Mood Stabilizers and Anxiolytics Mnmonics Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... So how can we distinguish between the two? There are a few core features that are helpful. First, in bipolar patients, changes in mood tend to happen over weeks and months, whereas borderline patients can switch between their highs and lows in seconds. Second, in bipolar disorder, episodes tend to occur independently of life events, whereas the mood of patients with borderline disorder is often highly dependent on life events, especially interpersonal relationships. Finally, the frequency of the disorders is di!erent, with true bipolar being much more rare, as low as 1% of the population, whereas borderline is up to 10 times more common. Use these key features to distinguish between the two diagnoses. Okay. Now back to the pharmacology of treating bipolar disorders. One complicated aspect of treatment is that the management varies depending on what phase of the illness the patient is in. Chronic management is more straightforward, as it always involves mood stabilizers. In the acute phase, however, mood stabilizers don't work fast enough for management of a manic episode, so antipsychotics are often started to bridge the time before mood stabilizers begin working, usually about 10 days. This is a high yield point and will show up on exams and in the emergency room. One might wonder why antidepressants are not prescribed as part of the picture, especially if the patient is in an acute depressive episode. This is another high yield point. Antidepressants, when given to bipolar patients, are not only ine!ective at treating their depression, but they are now thought to induce a shift into manic episodes and create what is called a rapid cycle type of bipolar. For this reason, antidepressants are to be avoided in patients with known bipolar disorder. The "rst drug we will cover is the oldest mood stabilizer known, Lithium. Originally used in the 180s to treat gout, Lithium was soon noted to have e!ects on mood, and was even incorporated into the soft drink, 7up, for a time, much like cocaine used to be an ingredient in Coca-Cola. It wasn't until 1949 when it was clearly demonstrated to be a mood stabilizer, however, that Lithium began to be used by the medical community at large for the treatment of bipolar disorder. Despite various theories, the exact mechanism of Lithium remains unknown. Lithium is one of the best studied drugs in terms of e!ectiveness for preventing suicide, and current numbers indicate about a seven-fold decrease in the risk of suicide 2 of 10 6/26/24, 9:06 PM Mood Stabilizers and Anxiolytics Mnmonics Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... for bipolar patients on a therapeutic level of the drug. You can see in the graph how the rate of suicide decreases in a way that is directly proportional to Lithium drug levels. Interestingly, the anti-suicide e!ect is independent of its e!ects on mood. There's only one other drug that has been shown to have this much e#cacy at preventing suicide. Can you guess what that is? The answer is clozapine for patients with schizophrenia. So if Lithium is so great, why isn't it in the drinking water, or at least in the 7up still? The problem with Lithium is that it pays for its incredible e!ectiveness with a harsh side e!ect pro"le, including a not insigni"cant risk of death. Lithium has one of the lowest therapeutic indexes known to man, meaning that the dose necessary for therapy is uncomfortably close to the dose that will hurt or kill the patient. Generally the target dose for Lithium is 1.0 to 1.2, which I remember using the neumonic Lithi-ONE. The side e!ects of Lithium are varied and wide spread, but can thankfully be grouped together using the mnemonic LMNOP, L for Lithium, M for movement or tremors, N for nephrotoxicity, O for hypothyroidism, and P for pregnancy problems. We'll go over each of these one by one. As a side e!ect of Lithium intoxication, tremor is incredibly high yield. While not speci"c, a tremor in the context of a patient taking lithium very likely means that their dose is too high, which can show up on boards. N is for nephrotoxicity. There is a classic clinical vignette that you're almost guaranteed to encounter on tests and boards involving an older gentleman who is out mowing the lawn on a hot day. Moments later, he is found passed out in the sun. The question generally will ask what medication is he most likely taking? Since we're in the section about Lithium, the answer is fairly obvious. But let's ask why. This relates to the side e!ect of nephrotoxicity. Lithium is excreted almost entirely by the kidneys, but it is, also, damaging to the kidneys when concentrated. There's a 5% rate of renal insu#ciency in chronically treated patients. In situations where a person gets dehydrated, the lithium can concentrate in the tubules and cause signi"cant damage. This is especially problematic as Lithium can cause nephrogenic diabetes insipidus further accelerating the process of dehydration. Lithium use is, also, associated with a six-fold increase in the likelihood of developing hypothyroidism, which, paradoxically, can induce mood symptoms which can easily be mistaken for depression. The "nal major side e!ect of Lithium is that it causes major problems to the fetus 3 of 10 6/26/24, 9:06 PM Mood Stabilizers and Anxiolytics Mnmonics Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... during the "rst "ve weeks of pregnancy. Most famously, fetuses have about a 10 times higher chance of developing Ebstein's Anomaly, which is a congenital cardiac defect involving low implantation of the tricuspid valve. You can remember this by packing it into the "rst three letters of Lithium, LIT for low implanted tricuspid. You may have noticed that all of these slides had a high yield box on them. Hopefully you're getting the idea that Lithium side e!ects are important to know. So where does that leave us on Lithium? Basically, we have a drug that is one of the few in all of psychopharmacology proven to help prevent suicide, which is one of the worst possible outcomes of mental illness. It, also, comes with no small amount of side e!ects, so Lithium must be used very responsibly. There is a set list of labs that should be drawn on every patient starting Lithium, and if you know the major side e!ects, they should all be no brainers. Take a moment to review them, and connect each one to the LMNOP mnemonic. The next several mood stabilizers that we will cover are all anticonvulsants, meaning that they are, also, used frequently in the treatment of seizure disorders. The "rst, valproic acid, goes by several names, Valproate, VPA, Divalproex, Depakote, Depakene, et cetera. Valproic acid works by at least two mechanisms. First, it inhibits voltage gated sodium channels, which accounts for its anticonvulsant properties. However, it, also, works by increasing the amount of gaba, throwing in a bit of a Benzodiazepine like sedative e!ect. There are two primary considerations you have to make before starting a patient on valproic acid, and both are high yield in term of testable knowledge. First, valproic acid in contraindicated in pregnancy, as it is a known teratogen often causing neural tube disorders, such as spina bi"da. You can remember this with the rhyming phrase valpro at the folate. Folate de"ciency, as you recall, is itself associated with neural tube defects, so you can image valproate eating up all the folate that a mother ingests, leaving known for the fetus and causing neural tube defects. Another dreaded, but thankfully rare, side e!ect of valproic acid is hepatic necrosis. Valproic acid is one of three drugs that can cause this that you'll be expected to know, the others being halothane and acetaminophen. All of these are important. So to help you remember them, close your eyes and imagine a butler telling you to have a seat at the dinner table. You look at your plate and realize with disgust that liver is being served for dinner. So now you related liver to the phrase have a seat, into which is 4 of 10 6/26/24, 9:06 PM Mood Stabilizers and Anxiolytics Mnmonics Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... packed the three drugs causing liver necrosis, halothane, valproic acid, and acetaminophen. There are other complications of valproic acid use, including a risk of trigonocephaly, as well as protein binding interactions with aspirin and warfarin, but those are beyond the scope of this lecture. Carbamazepine or Tegretol is another anticonvulsant that is approved for use in bipolar disorder, and like valproic acid, it acts primarily by inhibiting voltage gated sodium channels in augmenting gaba transmission. Clinically the three main uses of Carbamazepine are trigeminal neuralgia, mood stabilization and bipolar disorder, and epilepsy. Carbamazepine is sometimes abbreviated CBZ, and we can pack its three uses into that acronym, C for cranial nerve, to remind us that it helps in controlling trigeminal neuralgia, B for bipolar disorder, and Z for zeisures. While e!ective for those three conditions, it must be noted that Carbamazepine, like Clozapine, carries a risk of agranulocytosis. The risk of mortality is not quite as great as for Clozapine, so use of this drug isn't restricted by a registry in the same way that clozapine is, but it's something to be aware of and to counsel patients on before starting the drug. Lamotrigine, brand name Lamictal, is another anticonvulsant mood stabilizer. Lamotrigine is chemically unrelated to the other anticonvulsants, and while it does inhibit sodium channels, it does not act as a gaba receptor like other anticonvulsants. What does this mean clinically? It means that Lamotrigine is better suited to helping bipolar disorder in a patient presenting with a depressive episode, unlike the other anticonvulsants, where the gaba helps to calm patients in the manic phase of the illness. Not something you're likely to be tested on, but helpful for understanding gaba's role in managing mania. A frequently, frequently, frequently tested point about lamotrigine is that one of its most common side e!ects is a widespread itchy rash occurring in about "ve to 10% of patients. This is quite common, so patients should be counseled about what to do if they notice any skin changes. More seriously, these rashes can sometimes progress to Stevens-Johnson Syndrome, a horrifying dermatologic disease, where the epidermis literally sloughs o! of the dermis. If a patient has signs of mucus membrane involvement, you must consider Stevens-Johnson Syndrome in the di!erential. Luckily, 5 of 10 6/26/24, 9:06 PM Mood Stabilizers and Anxiolytics Mnmonics Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... only about one in a thousand patients will develop this. But because of its severity, you must know the side e!ect. You can remember the association between skin disorders and Lamictal by using the mnemonic lam-ITCH-tal. Finally, we'll go over three anticonvulsants that are not, in fact, mood stabilizers. So why are we covering them? Because, despite a lack of documented e#cacy, you are likely to see them being used as mood stabilizers on wards, although hopefully not on boards. In addition, each has some high yield side e!ects that you will see on boards, mostly for neurology, so they're worth going over for general medical knowledge. The "rst of these drugs is Oxcarbazepine, or Trileptal, which is a close relative of Carbamazepine. Unlike Carbamazepine, however, it has not been demonstrated to reduce mood cycling in bipolar disorder. On the plus side, Oxcarbazepine does not carry a risk of agranularcytosis either. That's about all you need to know about this drug. Just be aware that you'll probably see in on wards and in neurology clinics. Topiramate or Topamax is another anticonvulsants that you will see being used clinically for mood stabilization, but similarly to Oxcarbazipine, it is not FDA approved for this purpose. There are several features of the drug that make it particularly appealing for patients, however. Most signi"cant is the weight loss, which occurs in more than 10% of patients, and can help patients lose anywhere from "ve to 15 pounds. This, quote, side e!ect is popular among patients. Yet it must be counterbalanced by the fact that many patients report feelings of mental dulling, and in particular, word "nding di#culty, in addition to a greater risk of kidney stones and metabolic acidosis. These cognitive e!ects have earned Topamax a less than enduring nickname of dope- amax. I like to think of topamax as your classic Miss America, who likely lost a lot of weight but paid for it a bit in the mental compartment. This video illustrates the concept of word "nding di#culty quite nicely. Video: Okay. Recent polls have shown a "fth of Americans can't locate the US on a world map. Why do you think this is? I personally believe that US Americans are unable to do so because some people out there in our nation don't have maps, and I believe that our education, like such as South Africa and Iraq, everywhere such as, and I believe that they should... Our education over here in the US should help the US... Or should help South Africa and should help the Iraq and the Asian countries, so we will be able to build up our future. 6 of 10 6/26/24, 9:06 PM Mood Stabilizers and Anxiolytics Mnmonics Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... Thank you very much, South Carolina. Speaker 1: The "nal drug that we will cover in this category has, also, not been approved for treating bipolar disorder, as it has yet to produce substantial evidence that it works any better than placebo. Nevertheless, it is used o! label for mood stabilization for a variety of reasons. You are more likely to see Gabapentin being used to treat neuropathic pain, such as diabetic peripheral neuropathy, where it does have more evidence. Moving onto the next chapter in our psychopharmacology double feature, we will leave the mood stabilizers behind, and begin talking about anxiolytics and sedatives, which are prescribed for many disorders, from general anxiety to panic attacks. The pharmacology here is fairly straightforward, which should help calm your nerves a bit after having just studied mood stabilizers. The majority of anxiolytics increase gaba's e!ects in some way, shape or form. So let's take a moment to review gaba. As stated before, releasing gaba often makes a person feel relaxed and sedated. Physiologically, muscles unclench and breathing slows down. Benzos are all about relaxing. There are two main classes of anxiolytics, benzodiazepines and barbiturates. They both work on the gaba receptor, but their mechanisms di!er somewhat. Benzodiazepines increase the frequency at which gaba channels open, while barbiturates increase the length of time that the channel stays open. You can remember this by thinking of FRE- nzodiazepines and barbi-DURATE-s. FRE-nzo for increasing the frequency. Barbi- DURATE for increased duration. Not sure how high yield this is clinically, but it has shown up on boards before. We'll go over the barbiturates only very brie$y, as they have largely fallen out of favor in modern medicine. Barbiturate overdoses were directly responsible for the accidental deaths of Marilyn Monroe, Judy Garland, and Jimmy Hendrix, and their use today in the United States includes physician assisted suicide and lethal injections of capital punishment. These are not playful drugs, and should only be prescribed in the most exceptional cases. In contrast, the benzodiazepines, often abbreviated benzos, are very commonly used in 7 of 10 6/26/24, 9:06 PM Mood Stabilizers and Anxiolytics Mnmonics Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... medicine today. Compared to barbiturates, benzos o!er a cleaner pro"le and lower toxicity in overdose. They have, also, proven helpful for their sedating properties, and have found uses throughout the medical "eld, so in treatment of seizures, to relaxing patients before a surgical procedure. When used on a very short term basis, benzos are some of the most helpful drugs ever discovered. Yet, on a long term level, many problems, such as abuse and dependence, begin to emerge. It's helpful to review the "rst rule of neurotransmission in the context of benzos, as they have some of the most clearcut states of intoxication and withdrawal. All of the sedating and antianxiety e!ects get reversed during the withdrawal phase. So cases of rebound anxiety or rebound insomnia are common on these drugs, leading to tolerance and sometimes addiction. As a quick tip, you can recognize the majority of benzodiazepines from the syllables A-Z-E within the name with almost all ending in azepam. One look at this list of benzodiazepines should hopefully convince you of that. This is an A-Z-E thing to remember now. We will not be covering each benzodiazepine individually, primarily because there are too many of them, and they are all fairly similar. However, if there's one clinical distinction to be made between the di!erent benzos, and that is in regard to half life. These di!erences in half life are clinically signi"cant, and account for di!erent indications for each benzo. These are the most commonly used medications in each group. How to remember which class they belong to? We can use the mnemonic short Tom, medium cat, long divorce. Unfortunately, there is some memorization required. So feel free to pause the show if you want to get working on that immediately. Otherwise, feel free to come back later to the list. Moving away from benzos, there are a few other drugs that are used for anxiety. One drug for generalized anxiety disorder that is probably under prescribed is Buspirone or Buspar. It has a complicated neurotransmitter pro"le, which you won't ever be tested on, but you'll notice that gaba is not involved. Like benzos, Buspirone is e!ective at treating anxiety disorders, but in contrast to benzos, Buspirone does not cause sedation, has not signi"cant withdrawal e!ects, and displays very little addictive potential. The serotonin involvement may even make it better choice for those with 8 of 10 6/26/24, 9:06 PM Mood Stabilizers and Anxiolytics Mnmonics Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... coexisting anxiety and depression, which is honestly the majority of people with generalized anxiety. The large part of the reason why it's not used very often, however, is because, like SSRIs, the therapeutic e!ect can take several weeks before kicking in. It's something to counsel patients on when starting, especially if they have taken benzos before and are used to the immediate relief that they can bring. A mnemonic to remember the use of Busprione is to think of someone who is always anxious about if they will miss the bus. This anxiety about missing the bus can be managed with BUS-pirone. Now we'll move onto sedatives, which are drugs used to help with falling asleep. The "rst one, Temazepam, brand name Restoril, comes from the drug class we just "nished studying. While all benzos are sedating and can help people get to sleep, Temazepam is used more frequently for sleep than anxiety, and has earned its fair share of nicknames, such as vitamin T, tammies, mommy's big helper, et cetera. Just remember that Temazepam is often used for sleep. If it helps, you could think of someone helping a cup of T before bedtime. The next two drugs come from another class, the antihistamines, which we discussed in the "rst lecture, have profound sedating properties. Unlike the other sleeping aids, they are, also, available over the counter. Something to caution patients on, however, is that antihistamines actually mess with your sleep cycle. So while they are helpful for getting to sleep, they do not actually provide a good quality of sleep. Antihistamines are, also, prone to tolerance, and after about three days of continued use, they perform no better than placebos for sleep induction. Nevertheless, their low side e!ect pro"le and ease of accessibility make them a good, inexpensive option for most patients. Doxylamine, brand name Unisom, has been shown to be the single best antihistamine for treating insomnia. Another option is Diphenhydramine, brand Benadryl. While not quite as good as Doxylamine at inducing sleep, Diphenhydramine is a close second, and has been used for years as an over the counter sleep aid to sedate children and pets before long international $ights. One popular prescription option for insomnia is Zolpidem, brand name Ambien. This 9 of 10 6/26/24, 9:06 PM Mood Stabilizers and Anxiolytics Mnmonics Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... drug belongs to a class that is a non-Benzodiazepine hypnotic, which modulate the gaba receptor, but in a way distinct from what Benzodiazepines do. To remind me of its function, I like to focus on the zol part of Zolpidem and think zombie, because you look and act like a zombie if you don't get enough Zs. Some common side e!ects of Zolpidem are anterograde amnesia, meaning that you forget everything that happens in the hours after you take Zolpidem, as well as somnambulism or sleepwalking. There are reports of patients taking Zolpidem and then walking around their house, making a sandwich, or even driving places, and media awareness of this has made it common knowledge among patients. This unique property has even resulted in the creation of a comic character known as Ambien Walrus, seen above and in the next slide. Needless to say, Zolpidem can have some strange side e!ects. Another non-Benzodiazepine hypnotic is called Eszopiclone or Lunesta. It's basically just a clone of Zolpidem. You don't need to know too much about it, except that it is used for sleep and is preferred over Benzodiazepines for this purpose. And that's it for those two lectures. It's time for another break. Print this page 10 of 10 6/26/24, 9:06 PM Mood Disorders Case Study Analysis Lecture Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... Mood Disorders Case Study Analysis Lecture OK, so this is the third and !nal slide set in this unit. We've talked about quite a bit, and now we're going to put it all together in terms of a case study. This case study is a true story. It's one of my patients. It has not been editorialized for dramatic value or editorialized to enhance a teaching point. This is her story. And this is the type of bipolar patient that could walk into your o"ce on any given day. The only thing we will change is her name. Let's call her June. June is !ctitious, but it protects her anonymity. So here's June's story. June is a 57-year-old lady. And she was referred to me by a friend of hers who is someone that I know. Actually, it was a relative, I believe, of hers, who is someone that I know. So she was referred to me that way. Reportedly, she was recently hospitalized for an acute manic episode. She had an interesting story. Now she's 57. And she had not been-- well, I won't say she had not been diagnosed with bipolar. But let's say she hadn't believed it. And, historically, it sounds like that she was diagnosed around the age of 50 when she had another manic episode. But she just didn't really believe it. So she didn't treat it, and she didn't worry about it. So this is the !rst time that she is actually receiving and accepting a diagnosis of bipolar disorder. And this follows an acute manic episode for which she spent several days in the hospital and then a long intensive outpatient program after that. So she's just being started on a medication regimen. And now her hospital piece is over. She's coming back home, which is out of state. And she needs to !nd a provider to manage her ongoing medication care. She had initially just randomly picked somebody out of the-- the insurance companies have a list of providers their directory. 1 of 13 6/26/24, 9:04 PM Mood Disorders Case Study Analysis Lecture Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... And she picked somebody there. But she really wasn't comfortable with the practice or the provider. She said it seemed very like a mill, people in and out. And she didn't feel like anyone was really listening to her. So she went there once, and she wasn't happy. So now she's in my o"ce. So that's the story. So for her !rst visit, she arrives with-- it's her daughter-in-law. Yeah, her daughter-in- law, a friend of mine. And the chief complaint is that she wants to establish care. She is feeling well, she said. Or she felt really well upon discharge from her hospitalization program. Now she's feeling a little bit depressed. I guess when she !rst got home and went to that !rst provider that she found from the insurance directory, she was a little bit depressed then. They prescribed something for her that she felt didn't help. So here she is a month later, certainly not manic, which was the primary problem. But now she's feeling low energy and depressed. And her daughter-in-law asserts that this really is not her. This is not consistent with her normal mood. Now, keep in mind that she probably spent a fair part of her adult life with an elevated mood. So the depression may seem exaggerated. But in any event, this is the way she feels right now. She is not manic, but she is feeling depressed and low energy. And that's really what she wants to talk about today. So with respect to her psychiatric history, she says that she-- decades and decades ago, she had been diagnosed with anxiety and depression just prior to her marriage. She thought that was more just situational with the stresses involved in being married or getting married. She, at the time, was treated with sertraline. And she said she felt like maybe it helped a little bit. But then a year later, she just stopped taking it when she felt like her life had normalized. She really couldn't explain speci!cally. She said, yes, at the time, it did help. But for whatever reason, a year later, she just stopped taking it. And that was it. So that was when she was 29. So she stopped taking sertraline at 30. And she had not had any meaningful psychiatric care ever since, and now she's 57. So as we go through the rest of the history, from the time she was 30 and stopped taking sertraline till after she was 50, she really didn't have anything to report. She did not feel that she had any psychiatric history or diagnoses. Then six years ago, she was diagnosed with bipolar disorder following a manic episode. She didn't go into any great 2 of 13 6/26/24, 9:04 PM Mood Disorders Case Study Analysis Lecture Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... deal about the manic episode. But she does say that now, upon re#ection, she believes that her mania, in general, began with menopause, which was early onset. And it had happened 15 years prior in her early 40s. She feels like her mood elevations began to start about them. Finally, six years ago, there was some acute episode. But like I said, she was seen for it. She just didn't really accept her diagnosis then. And that's the psych history. She does report a remote history of substance abuse. She was in rehab many years ago. But now, that is not an issue for her. She does report that she smokes marijuana on a daily basis. But it's not be high or to feel good. It's basically to help her sleep. She has perpetual trouble sleeping. So that is the psychiatric story as we know it to this point. In terms of medical history, she has a diagnosis of hyperthyroidism, for which she takes levothyroxine. She's diagnosed with osteoporosis. And she's on a bisphosphonate from her primary care provider. She has a diagnosis of dyslipidemia, but I don't believe she was taking any medications for that. She also, interestingly, reports chronic nausea and vomiting, for which she takes ondansetron, 8 milligrams BID, which is not an insigni!cant dose of ondansetron. This particular piece of her history has always fascinated me. But I am not her primary care provider in this scenario, so it's not really for me to get into. But remember, I think we probably talked about this in an earlier unit. She does have a remote history of anxiety. And she has bipolar disorder-- not sertraline-- serotonin really is a neurotransmitter that is implicit in both of those. And so I wonder if there's not some sort of serotonin imbalance that is making her GI tract perpetually hyperactive. And that's what accounts for her nausea and vomiting. But I don't know. That's just speculation on my part. That's the domain of her primary care provider. So that's the story up until this episode. So what happened was four months ago, she started to develop a sense of sleeplessness. Her insomnia exacerbated. And, !nally, she got to a point where she was awake for 114 hours in a row. So even though she didn't feel like she needed to sleep, she knew something was wrong. She went to a local emergency department. And they gave her a sleeping pill 3 of 13 6/26/24, 9:04 PM Mood Disorders Case Study Analysis Lecture Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... and discharged her. So she tried to sleep with her meds. What she did actually was rent a hotel room that she could have complete quiet. Her adult son came with her just to be there to make sure that she was safe. And she tried to sleep, and she could not. And so then she got up after this 114 hours of no sleep. She got up, and she drove by herself over 300 miles to a major medical center psychiatric unit that was in an adjacent state. She was admitted there. She was an inpatient for nine days. She was controlled. Her acute mania was controlled on a combination of medications. Once she was reasonably well-controlled, she was discharged, but she stayed there. She stayed locally in a hotel so that she could attend a partial hospitalization program. And so she did go in every day for this four weeks of intensive therapy. And then she was discharged from the outpatient program and instructed to return home and go home and !nd a psychiatric provider that can maintain your care in a long-term basis. So that's when she came home. She connected with her family. She found that local provider in the directory. She went to see the person once, but she didn't really feel comfortable with it. And that really is the story right up until now. So the thing now is that she needs ongoing stability. She needs maintenance care. She needs to be prevented from going back into a manic episode. And she's also complaining of depression or depressed mood, which is not all that unusual after you come down from a real manic episode. Sometimes the patient really is depressed. And sometimes they just feel depressed because they've spent a signi!cant part of their history being perpetually elevated. So it's a !ne line there. But that's her complaint right now, and that's what we have to manage. So she was discharged from the partial program on Depakote. Remember, valproic acid 750 milligrams at HS, that was clearly for her mania. She was also discharged on Seroquel, which was at 200 milligrams HS, de!nitely higher than your classic sleeper, although it certainly has a sedative property. But Seroquel at 200 milligrams is really-- sort of hugs that line between e$ective for mania and e$ective for depression. So maybe whoever put her on that dose was thinking about both. And then she was also discharged on metformin 500 milligrams a day, which we very commonly used to try to attenuate the weight gain that often happens with Depakote 4 of 13 6/26/24, 9:04 PM Mood Disorders Case Study Analysis Lecture Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... and Seroquel. So she's not diabetic. She's on the metformin to try to prevent the weight gain. And you do see a lot of that. I mean, the evidence on it is equivocal, but it's very commonly done. I guess the thinking is it won't hurt. It might help, so let's try it. So that's where she was when she got out of her hospital program. And then she went to that !rst visit with the other local provider. She described for them symptoms of depression. And that person put her on sertraline. And so remember we talked about antidepressants in the last slide set. They are absolutely not the !rst choice for patients or the monotherapy for the patient with bipolar disorder. But they may be used sometimes as an add-on for depression that is part of the disease as long as they are already on mood stabilizers. So it's not entirely out of the question. I don't know that it would have been my !rst choice. We'll talk about that in a minute. But I mean, it's a reasonable approach because she's already on the mood stabilizers. So that's what the person gave her. So now today, in my o"ce a month later, she presents to change local providers. Her medications currently are the Depakote, Seroquel, metformin, and now the sertraline at 75 milligrams a day. That's what she's on right now. She's still complaining of depression. So as we go through the history of present illness, today, she admits to depressed mood, low energy, lack of motivation, a sense of guilt, guilt about her disease, about what it's doing to her family, how they're having to make so many adjustments, how they're worrying about her. She also admits to constant worry. And she admits to the occasional anxiety attack, although she was really, really clear that the anxiety attacks like that is not her concern today. She doesn't want to talk about that, but she wants to talk about is her low energy and lack of motivation. But they're here for you to see. And they're in my note with asterisks next to them because they are those two core features of an anxiety disorder. So she's got an anxiety disorder. Whether she wants to talk about it right now or not is, well, that's something else. We honor her wishes, of course. But it is necessary to include in her record that there is clearly some sort of anxiety disorder going on. But for now, her primary goal is the depression business. So that's what we're going to talk 5 of 13 6/26/24, 9:04 PM Mood Disorders Case Study Analysis Lecture Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... about. So as we go through the bipolar assessment, clearly, she has symptoms of depression. But it's important also to make sure that her mania is not breaking through, especially since she's been on sertraline for a month. So she is speci!cally worried about symptoms of mania. And here, they are. She denies. She denies any problem sleeping. She is doing that. She denies any sense of grandiosity, no hallucinations, no periods of excess energy, no swings of mood. She doesn't report any extremes of anger or racing thoughts. And these are the things that we want to look for because like I said, that antidepressant, it's not unreasonable in combination with a mood stabilizer. But we're always on the lookout for it to precipitate a manic episode. And at least right now, it's not. Further, she goes on to deny other things that are important to assess. No extremes of anger, which you do sometimes see with mania. She denies alcohol use and the recreational drug use. We've discussed that a little bit. Those two things always have to be part of any mental health assessment because they themselves can be causing symptoms. You'll notice when we get to the diagnostic courses, every mental health diagnosis carries the caveat that it is not caused by a substance of abuse, it's not caused by an underlying medical condition or medication. And hers does not appear to be. She does not drink. And she does use marijuana. Like I said, she uses it at night to help her sleep. She does not see it as recreational drug use. And I really don't, either. You might. We all have di$erent interpretations of this. I know marijuana actually remains very controversial. And for people that use it constantly or use it through the day, there are some concerns about long-term e$ects of it. But in a lady like this, I see her using that at night rather than a sleeping pill, frankly. And we'll talk about, is there another option she can use for sleeping? But at this point, that's what she's doing. She denies any suicidal thoughts. She has never had suicidal thoughts. She denies any homicidal ideation, which, although unusual, you may encounter it someday. 6 of 13 6/26/24, 9:04 PM Mood Disorders Case Study Analysis Lecture Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... And, socially, she lives with her husband. She is typically very active. Her daughter-in- law, who was with her for this visit, also asserts that she usually-- she's very active with family. She has grandchildren. She's always the !rst one to help take care of them. She's always the one to have people over or want to meet for lunch or that kind of thing. And she just is not interested in any of that right now. Her depressed mood and low energy are signi!cant. That's the assessment of both the patient and her daughter- in-law. So that's the history. OK, in terms of physical examination, I mean, it is normal. She appears her age. Her hygiene is attended to. She's done her hair. She's got makeup on. She appears normal in terms of gait. Her conversation, its content, volume, the way she interacts with others, all very normal. And this is an important part of the mental status assessment of any patient, but especially bipolar disorder. More to come on that in your !rst clinical course. She describes her mood as depressed and a little bit of anxiety. Her a$ect is appropriate to the interview. Remember, mood is how the patient tells you they feel. A$ect is what you observe on the patient. And they're not always congruent. Sometimes people who are depressed, they look very happy, and they look just !ne. And sometimes people who are happy look depressed. So the two aren't always the same. In her circumstance, she reports feeling depressed and anxious, as we've discussed. But her a$ect-- I mean, her range of emotion and expression is appropriate in the encounter. Her memory appears intact. And she attends to the topic at hand. Her concentration is good. On physical examination, so here are her vital signs, which not every psychiatric practice checks, but I do. My practice is a little bit di$erent. I do also have an FMP component. And so I mean, I do like to check these things, especially for brand new patients. So those are her vital signs. And as I say, the content of her thought is normal. She's not having any hallucinations, which I know may sound a bit of a stretch. But patients with mania do sometimes hallucinate. And you don't know it until you ask them directly about it. So in terms of diagnosis, well, she clearly has bipolar I disorder. Based on her history, 7 of 13 6/26/24, 9:04 PM Mood Disorders Case Study Analysis Lecture Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... we know that she cycles up and down. And, today, based on her assessment, she is depressed. We know that she has a history of hypothyroidism. And she is on thyroid hormone replacement. And you might be thinking that her thyroid levels are important to her overall assessment here. Could her hypothyroidism have anything to do with her depressed mood? And you would be right. And I did get records from her primary care provider. And her TSH and 3t4 were within normal limits. And so in terms of management, we do come back to the fact that the bipolar disorder is the primary problem, and the depression is the symptom that is presenting at hand. So when we start to think about considerations in pharmacotherapy, there is a structured approach to decision making of the drugs just like there's a structured approach to assessing a patient. We do a history !rst and then physical exam and then laboratory assessment if appropriate. When we think about what and how to prescribe, there is an approach. There is a systematic way. And the !rst consideration of pharmacotherapy is, what is she already taking? What medication is she already on? If the meds she's on are helping but not getting her where you want to be, not getting her to remission, then we increase the dose of the medication she's taking. If her medications aren't helping at all, then we need to consider whether or not we have to change it. So we have to think about the meds she's taking. The other consideration is, what exactly are we trying to do today? What is the primary treatment target? This may sound like a no-brainer. But believe me, it's really easy to get lost in this. When you have a patient with multiple issues, it's really easy to lose track of them and just re!ll the things that they're on or start making changes without having a really good reason for doing so. So we're going to look at what she's taking. We're going to consider the primary treatment target today, which is both improving the depressed mood and maintaining stability with respect to the mania. And then we have to consider the non-pharmacologic considerations. What else is going on in her world? Does she have a therapist? Can a therapist help her? Is there 8 of 13 6/26/24, 9:04 PM Mood Disorders Case Study Analysis Lecture Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... anything going on to exacerbate her symptoms like we would consider sleeplessness, for instance? So these are the meds. She's taking we've already established. That she's on valproic acid, Seroquel, metformin, and sertraline, keeping in mind that we are considering these in light of the primary treatment targets today. So that's what she's on. The primary treatment target today-- she's depressed. She has all of these symptoms of depression. So we de!nitely want to try to improve her depressed mood. Remember, she also has constant worry and the occasional anxiety attack. But like I said, she is absolutely crystal clear that these are not her primary concern today. Today, she wants to improve her depression, manage her depressive symptoms. And we, of course, want to make sure that she doesn't become manic again. And so her treatment of the acute manic episode included Depakote/valproic acid, Seroquel. And we know that her manic episode stabilized on these. But the depressed mood emerged. We know that the sertraline was not part of her stabilization regimen. She was prescribed that by an outpatient provider after she completed the partial program. And so you might want to think about, was that a good option? Should we consider a dose increase? What about the sertraline? Remember, when we think about how to manage medications, consider what the patient is already on, consider what the treatment target is. Can we reach the treatment target with some change of the existing medications? Or do we have to change them? So what about the sertraline? We know that they're not-- antidepressants are not indicated as a monotherapy for depression. But we know that they may be used in combination with mood stabilizers and antipsychotics. So it is in combination. Is a dose increase appropriate for her? That's one thing to think about. She's also on quetiapine. So quetiapine in bipolar mania is usually in higher doses, used for bipolar depression, usually up like 200, 300 milligrams a day. So one option we have is to increase her Seroquel to 300 milligrams. Maybe she's just not on enough of it. So think about the pros and cons of that. I mean, if we increase the quetiapine to from 200 to 300, maybe we will improve 9 of 13 6/26/24, 9:04 PM Mood Disorders Case Study Analysis Lecture Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... depression control. Or maybe for her, we start to encroach in the level of mania control, which could actually make her depression feel a little bit more pronounced. So think about it. Then we consider an antipsychotic. Perhaps that's a better option. Remember the mnemonic quetiapine, lurasidone, olanzapine-- quietly lift out of depression. These are antipsychotics that we know are used for bipolar depression. They're indicated for it. So is this something we want to use? And when you think about adding an antipsychotic, they are e$ective. That's true. It's just that antipsychotic adverse e$ect pro!les are something to think about. It's just one of the things to consider. At this point, I'm not advocating for or against it. I want you to think about that. Does her symptom presentation warrant the addition of an antipsychotic? And then, of course, we have the only mood stabilizer antiepileptic drug. But it's used as a mood stabilizer that is commonly used for bipolar depression. And that is lamotrigine. Remember, lamotrigine is not FDA-approved for acute bipolar symptoms. So it would be o$-label to use it to treat bipolar depression. But it is very commonly used for that reason. And so like I said, it's a favorite of the primary care provider because primary care providers like it, because it's easy and safe and doesn't have a huge side-e$ect pro!le in the scheme of things. It is also not a heavy-duty drug. It's for a more mildly symptomatic patient. So it's not as profound symptom control, but it is also much better tolerated. So in this circumstance, do we want to increase the sertraline? Do we want to increase the quetiapine? Or do we want to discontinue the sertraline and introduce an antipsychotic or a lamotrigine? I mean, if we're not going to increase the sertraline, it's because we think it's not helping. We think it's not helping, and we don't see any particular value in going any further with it. So get rid of it. Find something else to treat her depression with. That's the situation. That's the question we have here-- increase the sertraline or increase the quetiapine, or d/c'd the sertraline and begin an antipsychotic or lamotrigine. That's it. That's the choice in front of us. 10 of 13 6/26/24, 9:04 PM Mood Disorders Case Study Analysis Lecture Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... So my choice was to d/c'd the sertraline. At 75 milligrams, I felt like if it wasn't demonstrating any level of improvement, it wasn't worth increasing. And I was really worried about precipitating a manic episode because mania was her primary problem and because it was so profound. I mean, being awake for over 100 hours and then getting in the car and driving 300 miles is unsafe. I mean, not only did it attend to-- speak to the wakefulness. But, clearly, her judgment was impaired because she really didn't realize that it was a bad idea to do that. So I was very concerned about precipitating mania. Didn't think the sertraline was helping, so we got rid of it. And while her depression is disturbing her, it wasn't severe. I mean, she's getting up. She's getting dressed. She's washing her hair and brushing her teeth. And she's putting her makeup on. And she is getting out and about. She is seeking care. It's just that she feels more depressive symptoms than typical. So in this scheme of mild, moderate, to severe, I was comfortable with mild. And because she was starting to get concerned about the adverse e$ects of Depakote and Seroquel, primarily, the weight gain, I didn't really want to increase the Seroquel. Was not convinced it would be all that helpful anyway. So we talked about it, and we added the lamotrigine. Remember that lamotrigine and valproic acid have this relationship, where valproic acid interferes with the metabolism of lamotrigine. So the lamotrigine has to be maintained at lower than normal doses. And we talked about that, and we talked about the business of itch. And if you notice an itch or a rash or both, that we need to hear about it because that's an adverse e$ect. So patient education is important when you use those two meds together. And that's what we did. And the patient was advised to return in one month. So she did. And one month later, she was put on-- I think it was 25 milligrams of lamotrigine BID, which is very, very low. 50 a day is nothing compared to, oh, the patients that are maintained on 200 and 300 a day. So it was a low dose, but things were de!nitely better. The patient reported less extremes of mood. Again, no manic symptoms, which is always a concern in these circumstances. Her appetite was normalizing. She was starting to have some nocturnal awakening, which is a bit of a concern. And we're going to be aware of that. But no overt manic symptoms. 11 of 13 6/26/24, 9:04 PM Mood Disorders Case Study Analysis Lecture Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... For the next three months, she reported good symptom control. She was seen in follow up monthly at this point. For the next three months, she did well. But then she started to complain about the weight gain associated with the valproic acid and the quetiapine. And she had always had weight gain. But she was just becoming more aware of it, and it was continuing. So this was a lady, remember, who was very petite. And so she had gained something like-- I don't remember precisely. It's something like 10 pounds. But for her, that was almost 10% of her starting weight. And it wasn't getting any better. So I started to get the sense that now that she was feeling better, she was feeling stabilized, what happens, often, is that people, the more distant they get from their acute symptoms, the harder it is for them to convince themselves they really need the meds. And I was concerned that she was going to stopped taking one or both of these. And so we had a long conversation about it. She was cross-titrated to cariprazine. Remember that cariprazine is marketed as Vraylar. We talked about it in the last PowerPoint presentation. It is newer in the scheme of things. I mean, it's a couple of years old, but it is indicated for all aspects of bipolar disorder, mania, depression, and stabilization. And the adverse e$ect pro!le is much more tolerable. You don't see all of that weight gain that you see with older drugs. So after a long discussion and a careful discussion and the agreement to monitor closely, she was cross-titrated. The cariprazine was started. First, the quetiapine was slowly weaned o$. Then the valproic acid was weaned o$. We stayed on the lamotrigine just because it's just so safe. We stayed on the lamotrigine. The metformin was d/c'd because she didn't need it anymore. And that was the new plan-- the cariprazine and the lamotrigine. And for the next six months, she did well. Now, what this slide set doesn't mention-- and I probably should have included it here-- is she does have perpetual nocturnal awakening and early morning awakening. And so a sleeper was added for that. She was put on eszopiclone, Lunesta, for sleep because keeping her asleep is so important. So she was on Lunesta. But for her bipolar, she was on cariprazine and lamotrigine. 12 of 13 6/26/24, 9:04 PM Mood Disorders Case Study Analysis Lecture Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... And for six months she did really, really well. We did increase the dose of the lamotrigine because she was no longer on valproic acid. So it was being metabolized more quickly. So we titrated up her dose a little bit. Her depressive symptoms began to break through. In those visits, the visits went anywhere from one to three month intervals depending on how she felt. But then there developed a persistent presence of the depressive symptoms despite elevating the lamotrigine. And so we had another conversation. Ultimately, the sertraline was reintroduced. And this time around, with the lamotrigine and with the cariprazine, it really did normalize those depressive symptoms. And she was really doing well. She was sleeping. She was stabilized. She was not depressed. She wasn't cycling. So she was stabilized on those three meds for a long time. And then the !rst of the year, her insurer renegotiated their contracts, which they so often do. And we got a notice that they would no longer cover her cariprazine, which was really catastrophic. I was so worried about her not being able to take it. The insurer required that we try aripiprazole. And so when I put her back on the aripiprazole, Abilify, I really expected that what we would have to do is tolerate ine$ectiveness of the aripiprazole and then repetition to pay for Vraylar. But check it out. The aripiprazole did the trick. I mean, it controlled her bipolar just as well as the cariprazine did. So now, for, oh, many, many months now, she remains very comfortable and well- controlled, stabilized, no cycling in either direction on a regimen of aripiprazole, lamotrigine, and the sertraline. So she's on the antipsychotic, the mood stabilizer, and the antidepressant. And that's what it took for her. So news to follow, she's been stable on that regimen for, gosh, well, I guess seven months now. So we continue to cross !ngers. But always, always pay attention at regular intervals because the thing about bipolar I is it does cycle. So there's the case study. And like I said, it's going to be the foundation of one of your assignments for this week. Print this page 13 of 13 6/26/24, 9:04 PM Pharmacodynamics of Moood Stabilizers Lecture Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... Pharmacodynamics of Moood Stabilizers Lecture OK. So after that brief introduction to what we know about the physiology of mood disorders, which isn't as much as we know about the physiology of some other mental- health disorders, but it's what we know-- and so based on that now, we're going to look at the pharmacodynamics of mood stabilizers: particular drug choices, how they work, and how we select among them depending upon what the patient's primary symptoms are in the mood continuum. So with that brief intro from video 1, let's take a look at some of the medications. So we have established that even though the understanding is ambiguous, we do know that there are manic symptoms. There are depressive symptoms. And we also know or you do now that there are drugs that are clearly targeted to one or the other. This isn't a case of, oh, you have bipolar disorder. Here's your medication. Once we deduce that somebody has bipolar disorder, the next question is where are they in the symptom spectrum? Are they acutely manic? Are they acutely depressed? Or are they stable? They have already been stabilized and now we need to select a drug therapy that will maintain stability. There really are di!erences. Of course, there are many drugs that cross over. But there are those that have a particular treatment target, and that's what I want to talk about here. So we have drugs that are referred to as manic-minded. They reduce acute manic symptoms, a.k.a. stabilize the patient from above. We have other drugs that are depressive-minded. They stabilize from below or they improve symptoms from below. And then, like I said, once the patient is stable, we have medications that prevent relapse to keep them from cycling again. And the reason that that's signi"cant is that sometimes the medications that have to stabilize them, especially the manic-minded drugs, they're very e!ective in controlling 1 of 22 6/26/24, 9:04 PM Pharmacodynamics of Moood Stabilizers Lecture Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... mania. But they have a pretty signi"cant side e!ect pro"le. So people really struggle with being on them for the long haul. In the short term when it's necessary, they can do it. But then when they start to feel better and realize that this is a chronic illness and they're going to be on medications chronically, they "nd that they just can't tolerate some of the adverse e!ects of those more powerful drugs and will stop taking them if we can't "nd something that's a little bit more palatable. So it is important to recognize that we have a spectrum of medications that can help with all of those things. So not all drugs used to treat bipolar disorder are appropriate at all points in the spectrum. So like I said, when we make the diagnosis of bipolar disorder, the next question in decisioning drug therapy is where are they? How active is their cycling? Are they going from manic to hypomanic like every day or a few times a week? Or is this something that is more subtle? And then the other question is about the adverse e!ect pro"le. Many of these medications do have adverse e!ects. So it's not like we can just pick the drug that has no adverse e!ects. Unfortunately, that's a rare drug. But what we can do is try to pick the drug that has the symptom pro"le that is least o!ensive to that particular patient. And that's what it really comes down to with meds for bipolar disorder. What is the primary treatment target? What are we trying to treat? What side e!ect pro"le can the patient tolerate best? And then we try it. So I know I've mentioned this before. And I'll say it a whole lot more as we go through the course. Antidepressants are not indicated as "rst-line therapy even when depression is the presenting pole which it often is, especially in bipolar II. People don't come in when they feel good. They come in when they are depressed. So once we ascertain by way of good history that it is bipolar depression, we know that antidepressants are not what we're going to treat the patient with. We have other medications for that. It's an important point, and I keep repeating it, that antidepressants are not the "rst-line therapy. They are never monotherapy in the bipolar patient even if the bipolar is presenting as depressed. Sometimes in the more complex patient and the mixed episode patient, we may have to use it as an add-on therapy. But even then, we do it carefully in carefully selected patients, but never as a "rst line and always as a considered adjunct. 2 of 22 6/26/24, 9:04 PM Pharmacodynamics of Moood Stabilizers Lecture Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... And so "rst up is the treatment of mania. The big three that control mania are referred to as the toxic trio. Doesn't sound very appealing, I know. But that's what we call them, the toxic trio. We have lithium, valproic acid, which is marketed as Depakote or Depakene. And then we have carbamazepine, which is marketed as Tegretol. Sometimes I "nd myself using those terms interchangeably. So I'll try not to. But I may say valproic acid or Depakote because they're the same thing. It's just generic and brand. Carbamazepine and Tegretol. And lithium is just lithium. I mean, there are brand names for lithium. But everybody just calls it lithium. It's kind of funny. Anyway, speaking of lithium, let's look at lithium "rst. So lithium is the classic mood stabilizer. It is the prototype mood stabilizer. I mean, it can treat any aspect of bipolar disorder. It is used for mania. It can be used for bipolar depression. And it can be used to maintain a stable state. It can be used to keep patients from cycling. It's just that this is one of those medications that has a pretty signi"cant adverse e!ect and safety pro"le. So we only want to use it when we have to. And many times once the patient has stabilized, we will try to switch it for something else that doesn't require as intensive monitoring. But it is a bomb drug. I mean, most drugs-- and I probably said this before too. That the more e!ective the drug, the greater the safety pro"le. I mean, that's just always the way it is. Drugs that are really, really safe with no adverse e!ects, they're just not very e!ective clinically. They're very mild drugs. Drugs that have a really powerful clinical e!ect will very often have a very powerful adverse e!ect pro"le too, which is why we evaluate the risk-bene"t ratio. And when we need to use them, we just monitor them closely in the appropriately selected patient. So I mean, lithium is awesome. It is an awesome drug for mania. It is also one of only two medications in all of psychiatry that has been correlated with the decrease in suicidality and suicidal ideation that appears to be independent from its e!ect on mood. I genuinely don't know how anybody studies this. But it is a commonly held tenet of psychiatry that lithium can reduce suicidal ideation. 3 of 22 6/26/24, 9:04 PM Pharmacodynamics of Moood Stabilizers Lecture Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... That doesn't mean that we give it to everybody who is suicidal. It is an added bene"t. Like it's a value added that if we have a patient with bipolar disorder who has some challenging symptoms to control, if we're considering lithium versus say a valproic acid, if the patient is suicidal or has a repeated history of suicidal attempts, that's one of the things that might weigh in favor of using lithium even though it does have a powerful adverse e!ect pro"le. And so I mean, that's the "rst thing to say about lithium. It is a great drug. So lithium's mechanism action-- you see the "rst bullet point, which is always a challenge. Lithium's mechanism of action is poorly understood. But like with many older drugs, "rst, somebody realized that they worked. So we just prescribed them. And then the scientists start to try to "gure out why they work or how they work. And so we are still in that phase of we're not exactly sure how lithium works. But, boy, do we know it works. So we keep using it. But it is theorized to o!er several levels of protection in the patient with mania. Neuroprotection is the "rst one. And I know it's kind of a nebulous word. But patients with bipolar disorder have a tendency to demonstrate structural changes in their neurons that's linked to chronic worsening of symptoms, di#cult to treat symptoms. Patients with mania are-- typically, they demonstrate increased white matter, decreased cortical and subcortical volume. And lithium is believed to actually help protect from that. Lithium is generally believed to help-- like the earlier you start it, the better. And so not wasting time or not delaying but getting lithium on board right away can actually prevent structural deterioration that is associated with bipolar disorder and worsening of symptoms. So there is an argument to be made for starting lithium early because of this potential level of neuroprotection. Lithium is also theorized to normalize brain-derived neurotrophic factor that we talked about when we talked about the theoretical foundation of depression. And the physiology of depression is believed to be due to an exaggerated stress response and like a dysregulation of that hypothalamic adrenal pituitary axis that leads to decreases in BDNF. Lithium can actually help preserve that. So neuroprotection-- there's a lot of support for that as a bene"t of lithium. Lithium also modulates dopamine, gamma aminobutyric acid, and glutamate. These are really important neurotransmitters with respect to expansive mood. Dopamine, 4 of 22 6/26/24, 9:04 PM Pharmacodynamics of Moood Stabilizers Lecture Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... remember this is the feel good neurotransmitter. This is the happy neurotransmitter. And it stands to reason that manic patients have excesses of these in some neural pathways. Gamma aminobutyric acid is the primary inhibitory neurotransmitter in the sympathetic nervous system. And perhaps patients with mania have a de"ciency of that or a dysregulation that results in not enough GABA activity. Glutamate is the most abundant excitatory neurotransmitter in the brain. So all of these are targets of lithium, which explains why it's so helpful. Downregulation of NMDA receptors, N-Methyl-D-Aspartate receptors. Remember that those are the receptors to which glutamate binds in lots of neurons. And glutamate is excitatory. So if you down regulate these, you will presumably have less excitation which may be bene"cial in trying to manage the manic patient. Modulation of cellular signaling is just really a fancy way of saying regulating dysregulated pathways. And that's something that all of our psychotropic drugs do. But lithium appears to do several things. And like I said, it is one of the most powerful antimanic drugs that we have. Let's see. It is useful, yes, for a stabilizing mood after the acute mania is managed. I mean, it's a very useful drug. The only problem with lithium is there are signi"cant safety issues and monitoring requirements. So for sure to stabilize the manic patient, the bene"t absolutely is outweighed by the risk. And in the patient who will be adherent to follow-up and someone with whom you're not especially worried about adverse e!ects of lithium, there is no reason not to keep using it for stabilization. You just have to be on the lookout for these things like the potential very serious and lethal adverse e!ect pro"le, that combined with the narrow therapeutic margin. There's a real "ne line between minimally e!ective concentration and minimally toxic concentration. In other words, you have to exceed a certain serum level to even be e!ective. But you have to stay below a threshold of toxicity. And with lithium, the range in between isn't too wide. So it's always a challenge. And it needs frequent monitoring. You have to have lithium levels regularly. So here's the lithium toxicity meter. And it shows you the ranges. So you can use it for the depressed patient. And the therapeutic range is comparatively low. 5 of 22 6/26/24, 9:04 PM Pharmacodynamics of Moood Stabilizers Lecture Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... So it is fairly safe for the patient for whom you're managing depression as long as we can stay on top of the levels and make sure that they don't climb. You can see that a therapeutic level for a depression is anywhere between 0.4 millimolars per liter and 0.8 millimolars per liter. So that's "ne. The challenge is in the patient who needs to have acute mania controlled. You have to get to at least that 0.8 millimolars and very often upwards of 1 millimolar. And you can see that at about 1.2 it becomes acutely toxic. The risk of toxicity starts as soon as we get above 1. So there is a very "ne line between helpful or therapeutic versus toxic in the manic patient. Now if they're like in the inpatient setting, if they're hospitalized for their acute mania, no problem. We can keep very close eye on them. But if you're treating somebody as an outpatient and you decide lithium is the drug to use, you really have to be sure that they will come in for follow-up, they will come in for their labs, that they are reliable. If not, then lithium is not the drug for them. And then, of course, we do have a maintenance phase in the middle where we have the patient who's either-- either their mania or depression is controlled. And now we are just trying to keep them from cycling. And the balance is really kind of middle of the road. So the problems with lithium, the adverse e!ects I keep referring to-- they span multiple body systems. One of them is that lithium will almost always make a patient hypothyroid. Lithium is an iodine-containing element. And every piece of iodine that goes into the human body gets pumped into the thyroid gland. The thyroid gland is the only gland in the body that uses iodine. And so we have really aggressive active transport pumps that pumps iodine into the gland so that every little mole of iodine that $oats around the body gets pumped into the gland, which is "ne, because we don't usually have that much of it. In fact, we have to iodize salt so that we have it. So it's "ne. We only have a little, but only one gland needs it. And everything is perfect. But then if you start taking basically iodine boluses, which is what lithium is-- lithium is full of iodine. So now there's much greater serum concentrations of iodine $oating around the body. And it all gets pumped into the thyroid gland. So for like a minute, your thyroid glands like having a party. It's like, wow, we have all this iodine. But very quickly, the gland realizes that it is being overburdened. And it will start to down regulate its thyroid or its iodine receptors. 6 of 22 6/26/24, 9:04 PM Pharmacodynamics of Moood Stabilizers Lecture Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... And then it begins to hypofunction, which is why anybody on lithium therapy needs to have their TSH monitored every 12 weeks. And as soon as that TSH goes above 4, and it will if they're on it long enough-- as soon as the TSH goes above 4, then they have to be put on thyroid hormone replacement. They need levothyroxine. I mean, the only other option is to stop the lithium. But, presumably, if somebody is on lithium, they really need it. And you can't just stop it. So we just have to monitor the thyroid. Also, lithium can have GI e!ects all along the continuum from vomiting to diarrhea and every level of unpleasantness in between. This is usually when the levels get to be a little bit elevated. But some people will feel some of these symptoms at a therapeutic dose or a therapeutic level. Neuro symptoms are also a concern. Neurologic symptoms of lithium can range anywhere from mildly tired, mild sedation, all the way up to loss of coordination and really $at out confusion and psychosis. Lithium also like many psychotropic can lead to weight gain. And the reason that tremor is here-- it's one of the neurological "ndings. But tremor is an important physical "nding. It is very often one of the "rst physical "ndings that's apparent in the patient who is lithium toxic. So anytime you have somebody on lithium when you see the patient for your o#ce visit, observe and document the presence or absence of a tremor. If you start to see a tremor that hasn't been there before, now it's time to stop the lithium. Stop the lithium. Check the level, and "gure out what else you're going to do to control the patient's mania. As if that wasn't enough-- excuse me. As if that wasn't enough, lithium can also be extremely nephrotoxic. And so we have to be regularly monitoring renal function of BUN creatinine and eGFR. And be on the lookout for things that can precipitate volume loss or dehydration in patients that work out and like that are landscapers or work outside in the summer, patients that work in any kind of environment where it gets hot or they don't have access to adequate hydration. Like I know it seems very subtle. But these things absolutely can make people-- as you become volume contracted, your renal function is less e#cient. And the next thing you know you're lithium toxic. Lithium can also precipitate nephrogenic diabetes insipidus. Remember when the renal 7 of 22 6/26/24, 9:04 PM Pharmacodynamics of Moood Stabilizers Lecture Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... tubules become unresponsive to ADH and you just start losing volumes and volumes of water. And, of course, this will exacerbate lithium toxicity as well. So you really do need to keep an eye on those renal function tests. I've seen people-- thank goodness I didn't do it because that's what we always look for on the chart when something goes wrong. Did I do it? Did I write that note? But I haven't done it yet. I've made other mistakes but not this one. But I have seen patients that have wound up on dialysis, $at out renal failure, because of lithium therapy that didn't appear to be monitored. Another thing about lithium is it is highly teratogenic. We don't want to give this to pregnant women. And unlike many drugs, it tends to be the greatest problem very, very early in pregnancy. Most things that are teratogenic it's almost like they allow for the fact that the mother doesn't have any good reason to know she's pregnant until after she misses period. So most things that are teratogenic usually don't become a problem until after that till after the "rst period. But lithium can be highly teratogenic very, very early on. So this should not be given to somebody who is contemplating pregnancy, or trying to get pregnant, or even somebody who is not trying but not using any form of contraception while they're sexually active. It's a judgment call. But lithium is pregnancy category X. And we do not want pregnant women taking it. And the very earliest weeks of pregnancy are the worst. This can precipitate lots of cardiac anomalies like the slide says. So that's the story on lithium. If you really, really feel like a patient needs to be on it, try to get them on some form of birth control. So here's a mnemonic that can help you remember all the wonderful things that lithium can do. So I don't think there's any big surprises there. If you decide to start lithium therapy for your patient, there is a laboratory panel that needs to be done before starting. It should all make perfect sense. The basic metabolic panel ensures that there is no undiagnosed renal dysfunction. The CBC ensures that there is no undiagnosed infection or immunosuppression. The TSH we want as a baseline because we're going to have to be watching this because as soon as it goes above 4, we're going to have to replace levothyroxine. Of course, an hCG because you want to ensure that the patient is not pregnant. And lithium levels will be monitored in regular intervals when you start it. I mean, when you "rst start putting somebody on lithium, you should have levels weekly or at the very 8 of 22 6/26/24, 9:04 PM Pharmacodynamics of Moood Stabilizers Lecture Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... least biweekly as your titrating therapy. When the lithium levels stabilize, then you can back o! to every three months really is the longest that we should go. Anytime you make a change in lithium dose, you should check the lithium level within "ve days. And check it at the nadir. Check it at least 12 hours after the last dose. There's some dosing guidelines here. I'm not going to read it to you because it really, really varies with what you're trying to do. If you're trying to control depression, if you're trying to control acute mania, or if you're just trying to stabilize the patient. So, logically, the doses are going to be di!erent depending on what you're trying to do. And that's lithium in a nutshell. I'm sure you'll learn more about it when you go into clinicals and see people prescribe lithium. Now the next group-- the remaining two of the toxic trio are two anti-epileptics medications. Remember valproic acid and carbamazepine. So they all target the same neurotransmitters, although not so much dopamine. These target GABA and glutamate. And while they are both anti-epileptic, there is variability among them. I mean, they're not necessarily interchangeable. And the anti-epileptics has a big class of drugs. I mean, there are many of them. It's interesting that more and more anti-epileptics are developed and marketed. And then it turns out that a lot of them aren't really all that useful for seizures, but they have other utility in brain and nervous system disorders. And a few of them have distinct utility in patients with mood disorders and mania. So we have a couple of anti-epileptic drugs that are manic-minded. We really only have one that's depression-minded. And then many have no usefulness in the patient who has bipolar disorder at all. There are certainly things that people try to use o! label because the patient has access to it or for whatever reason. But there's only a few that actually seem to really be helpful in the patient with bipolar. And there are two manic-minded anti-epileptics, valproic acid and carbamazepine. And there they are, valproic acid and carbamazepine. So why would you use them like instead of lithium? What's the pros? What's the cons? Well, the "rst one is that overall they are safer than lithium. They are less likely, I guess, 9 of 22 6/26/24, 9:04 PM Pharmacodynamics of Moood Stabilizers Lecture Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425020-dt-... to shut down your kidney or cause central nervous system toxicity. Not that they do not have issues in their own right. But, comparatively, they're a little bit safer. They certainly don't require the aggressive monitoring that lithium does. And especially for patients who are manic, I mean, it's very hard to get them to follow up. So it's a consideration. I mean, from a textbook perspective, we say, oh, you're manic. Let's put you on an antimania drug. And the patient says, OK, that's wonderful. And they take their meds, and they all live happily ever after. But in real life, that's not the way it is. In real life, we give people drugs. And sometimes they take them, and sometimes they don't. Or they forget or they skip them because, I mean, after all, they are manic. And then they don't come back to follow-up. And then they might decide they need to take it, and they just start taking it. And nobody's checked their blood for a while. And it can be a bit of a challenge. So you do have to give some thought to how aggressive the patient will be with respect to their follow-up. Valproic acid and Depakote, believe me, they have their own issues too. But they are generally considered safer than lithium. So "rst up is valproic acid. And this really is the number two go-to. This seems to be the next thing that we use in the patient for whatever reason we don't want to use lithium. So valproic acid is a manic-minded anti-epileptic. It is believed to work by way of potentiating GABA. Remember GABA is an inhibitory neurotransmitter that actually calms the sympathetic nervous system. And the belief is that that's what valproic acid does. And it too like lithium is appropriate for stabilization as well as control of acute mania. The problem is where lithium is a pain in the butt because of safety, valproic acid is more of a pain in the butt because of the massive weight gain that it can produce. And people just don't like to take it. But either way, I mean, it's good for both stabilization and control of acute mania. Its e#cacy for depressive episodes not so much. Valproic acid almost seems to be like a bit of a depressant. And so actually helping depressive episodes, not so much. But with a manic patient, controlling mania is the primary treatment target. Once we get the mania under control, then we look at what we could do to stabilize them and minimize their depressive episodes as well. So valproic acid is a little bit safer 10 of 22 6/26/24, 9:04 PM Pharmacodynamics of Moood Stabilizers Lecture Transc