So, it's a great pleasure to welcome you all to another session in our clinical updates track of the APA. You know, I'm just going to say something briefly about the genesis of this particular session. Many of us have concerns that some of our really excellent psychopharmacologic tools are not being utilized to their full extent. And we are hoping this year and next year as well to present some refreshers about some important medications that are somewhat underutilized. These include MAO inhibitors, lithium, meclobamide, and I dare say there's still a role for tricyclics in our field. We are doing a pretty good job, I think, as a community in serving our patients with our use of many antidepressant modalities, but I think we can do an even better job. So, we and MAO inhibitors induce a great deal of anxiety in doctors, and we can't help but transmit that anxiety to the patients. And I think there's an understandable history behind that because when MAO inhibitors first came on board, there were many unknown questions and unintended experiences that generated a fair bit of anxiety. I happened to graduate my residency just two years before the advent of SSRIs, so I had the great opportunity to be taught how to use MAO inhibitors, tricyclics, and in our residency program, we look for appropriate opportunities to train our residents in the use of MAO inhibitors because we know that if they don't do so with guidance and training, they may be unlikely to ever do so, which may be true for some of you in this room. So, I will introduce Dr. Stephen Stahl, who will introduce himself, but I should say, in anything less than half an hour, I'm not sure we could list all of the accomplishments and great educational achievements that Dr. Stahl has brought to our community. And afterwards, I will introduce our second speaker, Dr. Jonathan Stewart. Thank you, Ron. Good morning, everybody. This is not a history lesson about a Chinese dictator, Mao. That's in the other room. Some people don't know that's what this is not. So, we're going to talk about MAO inhibitors and my introduction to this was perhaps an interesting one. As a young pre-med, I worked with E. A. Zeller, who actually discovered monoamine oxidase in Switzerland before he came over here after World War II, and he was involved with trying to figure out why some of these people up in the Swiss mountains with tuberculosis in the sanitarium were getting better and why some of them weren't. Long story short, he realized that iproniazid was an antitubercular that inhibited MAO and isoniazid was an antitubercular that did not inhibit MAO. So my first publications were actually on MAO and it's been close to my heart ever since. So the theme of this series, and thanks to Ron for putting it together, is to keep on emphasizing some of the older drugs that have fallen out of favor and are good options. Anybody with no hair or gray hair may know about this, but many of the rest of you may not. So let's have some fun and take a look at this. There are no disclosures for MAO inhibitors, I suppose, unfortunately, because they're all generic, but these are mine if you want to take a look at them. The learning objectives today are to explain the role of MAO in the neurobiology, etiology, and presentation of psychiatric illnesses, including depression, and to identify foods and medications that interact with MAO inhibitors and to implement some safe management strategies when switching between MAOs and serotonin reuptake inhibitors and finally integrate MAOs into your practice with some cases at the end. So why use MAOs? I suppose the answer is because they work. Maybe that's a good reason. But much of the comparative data of MAO and other commonly used options for the treatment-resistant depression are anecdotal since there's no recent head-to-head trials. So in some ways you don't know how to calibrate how well they use. But everybody who prescribes these today, without exception, has seen patients respond after everything else hasn't, including after ECT hasn't. So it maybe shouldn't be left to the end, but it still can work at the end. The barriers to prescriber are mostly unfamiliarity and, I suppose, myths and exaggerations of the problems, which we'll try to debunk in the next few minutes. It's not really the real danger of diet or drug interactions, it's unfamiliarity, and we're going to dispel that in this section. So you can actually augment. You know, nobody in psychiatry with treat-resistant depression is likely to use a monotherapy anymore, and so if you can't augment, you can't use, right? But you can augment. You can augment with stimulants, most atypicals, and the old-fashioned ones, lithium thyroid, even trazodone, mirtazapine, bupropion, and actually, against most people's training, most TCAs, tricyclic antidepressants. Here's an ancient study in which they did omipramine versus two most prominent MAOIs. Placebo is on the left, response rates. Omipramine, that's a tricycle. By the way, tricyclics are not what your little daughter rides. That's a tricycle. So I have to redefine these terms. So omipramine worked about in half the people, and phenylzine worked in three-quarters of the people. But then the interesting thing is they crossed over the omipramine non-responders and found out that... Look at how many responded to phenylzine afterwards, but fewer responded to omipramine after phenylzine didn't work. So it can work after other things don't, and this is some of the better data. But are there head-to-heads against SSRIs and, you know, against maybe atypicals? Not that I know of. So when do you use? Why do you use? They work. When? Well, it's up to you. Most people are going to give SSRI and SNRIs first line because the payers make us do that, and many of us will either augment with bupropion at that stage or an atypical. Some of you may wish to avoid atypicals or do it kind of like, eh, you know, some of the side effects, retardive and metabolic, but you do it anyway because they do work. So I would say at least... I mean, what do you guys and gals do after the atypicals fail? All those other ones, SSRI times 2, maybe an SNRI, maybe bupropion on top of one of them. Now you've given eripiprazole and cariprazine. Now what are you going to do? And so that's probably where you need to consider this and where it often is not. If you look at... Do you know how many SSRIs are prescribed in the United States? Six. Per second. Per minute. Per hour. And MAO inhibitors are maybe 10,000. So there's millions of SSRIs prescribed and there's only a few hundred, actually, MAO prescribers for a few thousand patients. So if you want to consider going to ketamine or escetamine or ECT, you can do it at that point instead of doing those things or right after those as well. You know, the other thing to remember is that in treatment-resistant depression it's not even what antidepressant you use. It has nothing in some ways to do with what antidepressant you use. You know what it has to do with? When antidepressant you use. Nothing works tenth very well, right? Lots of things work third very well. So even if you want MAOs to work, you've got to use them earlier in the algorithm. The other nice piece of news is that Ken Gilman in Australia, who's sort of the current reigning godfather of MAO inhibitors, has a website right there which you can actually consult people and say, oh, my God, you know, the person's got edema, the person's hypertensive, I need to switch from a specific drug, or can I add this specific drug? And until that gets too busy, there's a bunch of MAO GOMs. You know, Dr Stewart's one. I guess, Ron, maybe we'll make him one. You know what a GOM is? Ah, Phil's coming in. A GOM is a grand old man. We need a couple grand old women too, but right now a grand old man, mostly on this website to answer your questions. So the owner's manual for prescribing MAOIs. You have to understand norepinephrine interactions, which are related to the infamous dietary tyramine, but also to drugs that are boosters of norepinephrine. And there's serotonergic, which is the one that everybody's afraid of because serotonergic drugs can be lethal. So let's start with the dietary part of noradrenaline. So the first myth is that you can't eat pizza if you take an MAO inhibitor. You can't drink wine. So you can't go to parties. Your life is over. You basically have to, you know, drink a very limited diet through a straw or something. You know, but the reality is this is a gross overstatement. Actually, Ron's going to show you a simplified diet at the very end on PDF, which is going to be available on the same website that this course is, and I've posted, if you've looked at that site, a downloadable PDF of diets if you want to be more... And so you may have seen this, but the truth is really that there are only a few things to avoid, which are pretty easy to remember. But in practice, the problem with MAO inhibitors is more so drug interactions than it is dietary interactions. But if you're going to go and get a gallon of blue cheese, you know, you might be in trouble. So why? Because you can have your blood pressure go up very high. Now, we don't usually see this, but you can see and has been reported, mostly with drug interactions, but fatal reactions with hypertensive crisis. So, you know, most people with a MAO inhibitor might need to have a blood pressure monitor at home. So what is this about? Well, 40 mg of tyramine is considered a high-tyramine meal, which is basically pretty hard to get to in normal diets. But if you take tranylcypramine or phenylzine, those two MAO inhibitors, you don't even need more than 10 mg. You don't need a high-tyramine diet to be in trouble. You need a 10 mg or so. It can raise your blood pressure. So selegiline, you can take a pretty high-tyramine diet. That's why the low dose of selegiline doesn't even have any dietary restrictions. And then you have... If you want to eat in this room 400 mg of tyramine, everybody in the room before you leave, I don't know how you'd do that, everybody's blood pressure would go up. So that gives you a little bit of idea to calibrate. So nobody comes on a package to know how much is 10 mg of tyramine. But we always say if you're aged foods and stuff, that's the problems, pickling and aging. So all the ones on the left that's aged are the ones that are classically... But you can have processed meat, poultry, fish, properly stored pickled and smoked fish, other vegetables, canned beer, alcohol. I guess not Bud Light or something. I don't know if there's something wrong with that beer these days. I guess it's a bad joke. So there's people that are trying to put tyramine in things, mostly that are backyard kinds of breweries and stuff, they can have tyramine in it. But the ones, if you get it out of a can rather than out of the tap, you're pretty much okay. So myth number one, you can take an MAO and eat cheese. So you should be just cautious when combining an MAO, either boost anything greater than 10 milligrams of tyramine because it can raise the blood pressure. How about the other ones? If you get a cold, you're in trouble because you can't take any decongestant, you can't take a cough medicine, you can't do anything. So people who get colds can't take MAO inhibitors, right? So that's everybody, so nobody can take MAOs. But just to put it on the top, you can't take stimulants, so patients who need stimulants can't take MAO inhibitors. Well, the truth is that sympathomimetic decongestants and stimulants, you have to be a bit of a pharmacologist to actually prescribe cold medicines to these patients. We should probably know this stuff anyway. It can be used with caution or not at all, depending on the list I'm going to give you. Monitor blood pressure if there's any question, especially in high-risk populations, older people, frail people, somebody who's already on antihypertensives. The main thing is you're going to use antihistamines, but there's two of them that you shouldn't use or can't use. What's chlorofamiramine, brofamiramine? Why can't you use them? Because they're antihistamines? No, because they're serotonin reuptake inhibitors. See, one of the things that's interesting is that some drugs get characterized as something, and we think that's what they do only, but some of them are also serotonin reuptake inhibitors, so the other antihistamines are not serotonin reuptake inhibitors. You can use them. So you should be cautious when combining an MAO with anything that boosts norepinephrine because this can raise blood pressure. Some antihistamines also inhibit serotonin reuptake, and you should completely avoid those. You know, there's very few things that will kill you in terms of drug interactions in psychiatry, and because this is one of them, anything's reuptake inhibitor plus an MAO inhibitor is potentially, you know, the serotonin toxicity. People are so afraid of that they don't even want to know about it, so they say, we're not going to use that. Well, you know, our specialty is somewhat under threat by other mid-level prescribers. What's going to distinguish us from mid-level prescribers unless we can use clozapine, lithium, MAO inhibitors, we can combine things to treat the sickest patients? Otherwise, we're genericizing ourselves. So this is one of the reasons to know some of this stuff is to be able to have this in your armamentarium where other lesser people who didn't come to Dr. Stull's and Dr. Stewart's course would not know. So here you go. So myth 2 and 3, if you take an MAO, you can't take cold medicines. Probably best to use antihistamines, not decongestants, which are safe, except for those two. Cough medicines are interesting. They have expectorants or codeine are safe. But what's this dextromethorphan? I thought that was a psychiatric drug. Anybody know what happened to that one? Avelity is cough medicine. Did you know that? So it's an NMDA antagonist, which is why it's combined with bupropion, a so-called avelity. Not a good idea to use dextromethorphan with a serotonin reuptake inhibitor. There's another one called Nudextra, which you may or may not use. It's approved for pseudobulbar affect, and it also has cough medicine in it. So don't use that, because that could give you serotonin syndrome, although usually weak. You can use codeine, you can use expectorants. So here's the stuff. Behind the counter you have the FDA, as 10 years ago said you can't use pseudoaffect. You know why? You make methamphetamine out of it pretty well. You just get a bunch of pills, you put it in a bucket, you stir it a little bit, put some heat, maybe, I don't know, salt and pepper, and you can make methamphetamine. Don't use that. You can't get it that easily anyway. You can get some of these other things, but they're best avoided. Some people will risk taking them topically, like Afrin nasal spray and things like that, with the hope that they don't get absorbed systemically and make your blood pressure go up. You can try it, but if it gets systemically absorbed, because what it's doing is the sympathomimetic lead is one of two things. It either releases norepinephrine with MEO that can't eat it, right, because it's been inhibited, or the norepinephrine that's there gets added to sympathomimetic agents that directly stimulate norepinephrine receptors to actually cause your decongestant, but it also can change your heart. So proper stimulants, methylphenidate, modafinil, armadafinil, even amphetamines, may be a little more aggressive when you use amphetamines, are very useful as an augmentation or even a bridging medicine. In other words, if a patient is coming off an SSRI, some of them take a long time. We'll talk about that in a second. What are you going to do in the meantime? You could add a stimulant while they're coming off the MEO inhibitor in anticipation of keeping it on when you add the MEO inhibitor, or just use it as a bridging med. Don't use an MEOI in a known cocaine or methamphetamine stimulant user. No duh. So there's anesthesia interactions. If you're taking an MEO, you can't take anything with a norepinephrine reuptake inhibition, which means you can't have anesthesia. You can't have dental work. You can't get your sutures put in, surgery, nothing. So you can't take an MEO inhibitor. The truth? Be careful when using local anesthetics that contain epinephrine, because epinephrine is a sympathomimetic amine. It usually doesn't get absorbed very far because it's in the needle and it's just a theoretical thing. But generally speaking, dentists use it sometimes. It's probably better to avoid it. They can give the local anesthetic alone. And so presser agents injected intravenously certainly raise blood pressure. That's why they're called pressers. Inhalation anesthesia can cause blood pressure changes both up and down. So what do you do? So if your patient needs local anesthetic, just don't put epi in it. If it needs elective surgery, well, then you can wash out if you want, and you're going to use inhalation and so forth. What if you get hit by a truck? Okay, bleed, and then later we'll take care of you as soon as your MAO washes out, right? No. You can use a benzo, you know, the puroniums, morphine, codeine, all those things can be used without any problem. So in summary, the noradrenergic drug interactions are avoid the decongestants and use stimulants with C, caution. You can use most tricyclics. We'll talk a little bit. There's a couple of exceptions, chloramipramine and omipramine. Otherwise, you can use them. Some people even do it on purpose. You can use bupropion against caution. Watch it. Phentermine, nobody uses that much. That old diet drug is one of the FENs of Fen-Phen, remember that? Local anesthetics avoid, and generally cocaine and methamphetamine avoid. So dispelling myths about the second one, serotonergic interactions, TCAs, pain meds, and other psychotropic meds. So TCAs are so dangerous when combined with MAOs that patients on MAOs can't take them or anything even that resembles them. So the package inserts for these drugs say, you know, you can't take carbamazepine or cyclobenzaprine because it looks like a tricyclic. Does it have the pharmacology of tricyclic? No. But it looks like one, and you can't take a tricyclic. It's not even true you can't take a tricyclic, let alone cyclobenzaprine or, you know, that's completely ridiculous. So some of these package inserts say weird stuff. What's the truth? Other than chloramipramine and omipramine, why? They have serotonin reuptake inhibition, which is greater than trivial. The rest of them are mostly, I don't know if you know this, but most TCAs are predominantly norepinephrine reuptake inhibitors. You can use them with caution. The pharmacology is you must avoid MAOs with anything that blocks serotonin reuptake. Most TCAs just increase norepinephrine. So you should be cautious in combining them with norepinephrine once because it can raise blood pressure, but generally not a hypertensive crisis. The owner's manual for the tricyclic interaction is chloramipramine. I should put omipramine there as contraindicated. Other TCAs can be used with caution, and MAO and TCA are combined. The order of combining them, if you're on TCA and want to add the MAO, the MAO, you add the tricyclic. There's different ways of people talking about it. Some people say start them both together. It's not as important as how fast you titrate. So if possible, just start the MAO at the time of the TCA. It's just easier to titrate, but it's not necessary. And alternately, you can raise the tricyclic first, and then you can raise the MAO later, you know, and then the second raising of the tricyclic, and then step up that way. So again, cyclobenzapine, carbamazepine, oxcarbazepine can be used. You should probably do it with caution just because it's in the damned PDR in the package insert, but there's no pharmacology that says that that's a problem. How about painkillers? Oh boy, you can't take them because MAOs will kill you. So patients who have sprained ankles, sore muscles, they've got a tooth taken out, sore, surgery, post-op, you can't take an MAO because you gotta avoid all opiate and non-opiate painkillers. What's the truth? There are a few things to avoid which are easy to remember, and in practice, this isn't really a problem. What you wanna do is say there's no interaction of MAIs with opiate mechanisms. There is no interaction of MAIs with opiate mechanisms. Well, there are opiates that'll kill you, right? Yeah, not because they're opiates. Why? Because they're serotonin reuptake inhibitors. So meparidine is a potent 5-HT reuptake inhibitor. There's famous cases of people going to the emergency room getting a Demerol shot and killing them. Fentanyl, methadone and tramadol are weak and probably should be avoided. I would guess, generally speaking, you wanna avoid fentanyl anyway, but that's another thing. And so pentadol is an orpaniferin inhibitor and probably should be avoided. But so what do you do? So here's you can use with caution. In other words, not really much caution. In other words, just think about that. And sometimes you can use these because they have some norepinephrine effects and never use these. So this is all in your handout. And if you don't get it, you just email me and I'll send you another PDF of my slides. It's not a problem. The psychotropic drug-benefit interaction. You can't take any medications that block serotonin reuptake, and they all do that. You know that, of course. Every psychotropic drug is a serotonin reuptake inhibitor if you've lived through the era of serotonin SSRIs. You know, right, right, they're all, no? Okay, well you can't take any psychotropic drug then. Since patients who are candidates for an MAO all need inconcomitant meds and every inconcomitant med is a serotonin reuptake inhibitor you can't take an MAO inhibitor. Well, besides, in order to start an MAO you gotta stop the other medicines two weeks after the taper. And if you gotta stop an MAO to go back to the other direction, you gotta, ah, ah, ah. That's what keeps people from doing it. The truth, you must completely avoid only agents that block serotonin reuptake. Short list, I just told you. Two of the tricyclics, clomipramine, ipramine, you have two of the antihistamines which are not that commonly available. Anyway, chlorfeniramine and brofeniramine. And the opioids that have serotonin reuptake inhibition, of course, meparidine and fentanyl and a few others. So, you should completely avoid combining MAOs with anything that blocks this because this could be dangerous. You should be cautious when combining an MAO with anything that boosts norepinephrine because this can raise blood pressure. So, serotonin syndrome is one of the most crazy things in psychiatry that I've ever seen. It's completely misunderstood. Did you know that if you have diarrhea after putting buspar on top of an SSRI, that's serotonin syndrome? What if you get a headache on a high dose of an SSRI? Oh my God, serotonin syndrome. No, I mean, it's possible those are serotonin-mediated side effects, but the serotonin syndrome is this. And if you wanna actually make it even simpler, it's this, clonus. So, if you're worried about a patient, I know, feet are smelly, take it and push it up towards the face and see if they beat back down on you. You did that in medical school, it's not that difficult. So, clonus, you're in trouble. Go to the emergency room. But that's the beginning of that. You can induce it, like I said, you have a lot of agitation or sweating, or ocular clonus, a weird look at eyes. So, it's not just diaphragm. If you sweat, you have serotonin syndrome, right? No, it's gotta have clonus with it. And so, tremor and hyperreflexia, high temperature, I mean, the hallmark of serotonin syndrome. And pop quiz, what's the receptor that actually is probably mediating a lot of this? The 5-HT2A receptor. What is the nature of drugs like Trazodone and all the atypicals? They're 5-HT2A antagonists. So, they actually are, in fact, if you have this, I don't know if you ever see anybody with serotonin toxicity we give them something, there are various things, periactin, for example, is an antihistamine with 5-HT2A antagonist actions. And so, the issue is when you have fever and clonus, go to the emergency room, okay? That's serotonin syndrome. When you have diarrhea, take liquids. So, the owner manual for psychotropic drugs to avoid serotonin toxicity is here. You can't take an SS or an SNRI, clonibramine, imipramine, there's even some weird thing about St. John's Wort, I'm not sure that's needed. Ecstasy, ecstasy, what does that do? What's the mechanism of ecstasy? It releases serotonin. So, if you're mild, in fact, everybody in this room has been breathing it. So, we are feeling an affinity for each other. And warm and fuzzy, that's what ecstasy's supposed to do. So, and actually, if your daughter wants to go to a rave party, and you don't want her to get the hyperthermia that you can get with ecstasy, what do you do? Slip her a dose of Prozac. Because ecstasy has to be taken up into the serotonin neuron in order to work. No, don't do that, but if you're on an SSRI, you can't have any fun on ecstasy. So, this is your no-no list. I mean, I think even psychiatrists, as low as we are on the evolutionary scale of medicine, we actually probably can remember this. I mean, I don't know, but I'm hopeful. I'm teasing, of course. So, how about washing out? You need to have, usually taper down, that's the problem is that you can't cold turkey a lot of drugs because they cause a withdrawal syndrome. So, once you're completely off any serotonin reuptake drug, you wait five half-lives. Okay, almost all drugs have a one-day half-life, that means five days. But some of them, like Prozac, have a longer half-life of 72 hours or so, and then they have a long-acting metabolite, which means people will do it for weeks. And then you can start your MAOI. How about the other direction? Pop quiz, is MAO inhibition reversible or irreversible? Irreversible. So, how does your MAO come back? You manufacture new mitochondria, because in the outer membrane of a mitochondria lives MAO. So, it's gotta make new proteins. In fact, not a very good term for us in psychiatry, but do you know what the molecular biologists, enzymologists call MAO inhibitor and drugs like it? Suicide inhibitors. Because virtually, it kills that protein forevermore in that mitochondria, it wipes out all that generation of mitochondria, so you have to make more. How long does it take to replace your mitochondria? About three weeks. So, that's why, and there'll become a time during that three weeks where you've got enough MAO with the new mitochondria to actually start eating monoamines once again. So, sometimes it's just useful to understand why there are these things instead of just empirical rules, which don't make any sense, and then they come up with myths. So, how to bridge use of these drugs while waiting to start an MAO or discontinuing one? Benzos are fine. Z-drugs are fine. Even though people don't believe it, trazodone is fine. Trazodone does have some weak serotonin reuptake blockade, but it's not enough to matter. Although, if you're not comfortable with that, don't worry about it. Lamotrigine, valproate, lithium bupropion, okay. Gabapentin, pregabalin, topiramate, carbamazepine, octocarbazepine. Stimulants, especially methylphenidate's a little softer. Ormodafinil, armodafinil. So, you got lots of options, including the same drugs that you augment with wildly today anyway, the atypicals. But there are two of them that are serotonin reuptake inhibitors. So, you don't avoid atypical antipsychotics because they're atypical antipsychotics. You avoid them because they're serotonin reuptake inhibitors and there's two of them. So, in summary, ladies and gentlemen, MAOIs still have a role in modern psychopharmacology. Consult with the people online. If you're timid, you'll get some help. This is how dedicated people, we're not getting paid anything for this. We're just doing it as colleagues to leave a legacy. And distinct and understandable pharmacologic mechanisms account for MAOIs in their therapeutic, drug, and dietary interactions. Bottom line, be cautious when combining MAOs with anything that boosts norepinephrine because that can raise blood pressure and be able to know the list of drugs that are serotonin reuptake inhibitors because combining those with an MAO could be dangerous. So, that took me about 32 minutes and that's basically the only pharmacology you need to know. But I guarantee you that it won't make you prescribe MAO inhibitors unless you have your hand held a little bit. And so, that's what the, find somebody who knows how to do this or go online. And the other way is I'm gonna end with a couple of minutes of cases. So, let's put ourselves in a situation. This is all well and fine. It's all theoretical style. How about Mrs. Jones who has this problem? So, let's find Mrs. Jones. Here's a 60-year-old female with treatment-resistant depression. She's on phenylzine with a good response but dizziness and orthostatic hypotension at doses over 45 milligrams. That should have said phenylzine. So, the question is can MAOs induce hypotension? And if so, what can be done without stopping MAOs? I thought MAOs made you hypertensive. Why are we talking about stop? Actually, hypotension's a bigger problem. So, you can wait. The body gets used to stuff and you know, watch for waiting. In fact, I don't know if you've ever seen my prescriber's guide. It says, what do you do about side effects? Under almost all of them, it says wait, wait, wait. Three waits. Modify your hypertensive meds if feasible. Decrease the MAO dose or split it. Support stockings, hydration, salt tablets. These are all tricks. And then if worse comes to worse, you can use a mineral corticoid which will help you retain water and fill up your capacity vessels when you stand up so that it doesn't all fall into your legs and you don't have any blood in your brain. And finally, some people can use some caffeine or stimulants. This is difficult and touchy. Okay. About a 30-year-old man who's got TRD on an MAOI with good response but worsening insomnia and he failed CBT and melatonin and other stuff. So, can MAOIs be combined with sedative hypnotics? If so, which can be used? Again, doxepin is an antihistamine. It's such a, in fact, doxepin is such a powerful antihistamine, I don't know if you know this. At trace amounts, it's used as a pet tracer for H1 receptors because there's such a separation between the H1 properties and the reuptake properties. So at very low doses, you know, 10 milligrams, five milligrams, one milligram, it's basically a hypnotic. Trazodone is usually the go-to drug. People can also use mirtazapine even though it does raise serotonin by an alpha-2 antagonist. There's a textbook by Stahl that will explain that to you if it went too fast. Sedating second generations, quetiapine, olanzapine, zolpidem, benzos, most antihistamines. What do you gotta avoid? Chlorofamiramine, bromofamiramine, zaprazodone, lumateparone. Yeah, that's okay. It doesn't work. It doesn't work. Yeah. Yeah. Romeltan is a funny drug because it's got like, you know, most drugs have, you know, at least 10, more like 50% bioavailability. Romeltan's like 1%. So it's very variable. So Monday, you take the drug, you get 1%. Tuesday, you take your drug, you get 3%. It's almost vanishingly small, but you've tripled your dose. So it's not a reliable drug. So how about a 61-year-old male with tyranoslipramine, 90, with residual low energy, low concentration, low drive. He failed vagal nerve, ECT, second generation, and lithium. I don't know. I'm done. Can MAOS be prescribed with a tricyclic? And if so, which one? The amitriptyline, nortriptyline, desiropramine. Nortriptyline and desiropramine are some of the favorites of the people who do this. But of course, I say over and over again, just to learn it, not these two buggers. So low starting dose, low titration, adequate dose and tolerability. All right, 60-year-old on phenylzine. Can you give a stimulant? If so, which one? We have to be careful. It's like, you know, they can raise blood pressure. And I've seen, I actually have seen a malpractice case where the person was an elderly person and had a stroke. But the question was whether that was due to the drugs. But you know, always the doctors and the drugs are gonna be blamed in an elderly person. This is kind of like my situation with the atypical antipsychotics, where you give these to elderly patients with dementia. And 80-year-olds are getting death all over the place in America. And do you think it has anything to do with the atypical? I'm not sure it does, actually. But it's a warning, 80-year-olds on an atypical will die. Yes. So what? So some of this is kind of silly. And it's about regulations, and it's not about science or common sense. So methylphenidate is a good one to start with if you wanna start using it. There's a little more presser risk of amphetamines. And again, serotonin release is the case with, again, what did I say, with MDMA. And bupropion is an option. Start low, go slow. Start low, go slow. And nobody ever said that to you in your training? Especially when you're starting a new drug you're not as familiar with. How about a 30-year-old suicidal woman who needs ECT? Oh, you can't get ECT if you take an MAO. No way. So you're optimizing treatment for resistant depression without harming the physical health of the patient. So here's this. If your controversy regarding the concomitant use of MAOs and ECT resolves around the concern over possible hypertensive crisis due to the general anesthesia or sympathomimetic discharge from the seizure. But general anesthesia plus an MAO is not contraindicated. But you can either wash out the MAO for about 10 days if possible, or use a benzo, one of the curoniums, morphine or codeine for your anesthesia. Multiple randomized case series don't show complications with MAO and ECT. This may be your secret weapon. I mean, what happens if ECT's not working? What happens if your MAO isn't working? You're kind of at the bottom of the barrel. And so being able to combine them is important. MAOs and ECT can be combined provided the guidelines regarding MAOIs and ECT and anesthesia are followed. Avoid using ephedrine. If the MAOI has not been helpful then it can be discontinued before ECT. But no washout's required. If the patient has had partial response to the MAO then don't stop it. Likewise, an MAO can be initiated in a patient during ECT. Just watch it. And if you want some help, contact us. A 30-year-old suicidal woman or an MAO, partial response, can ketamine S ketamine be given? Because this is a little more controversial. But I'm relying on people who do this a lot. I haven't done this a lot. But ketamine and S ketamine do have a little bit of serotonin reuptake blockade if you're a good pharmacologist. But many people, I mean I've talked to people who've done this dozens of times. There's no formal drug interaction studies but numerous anecdotes of safe co-administration exist of people who have done this. But don't combine dextromethorphan with MAOIs until we get more information. Right now it's theoretically enough serotonin reuptake inhibition to worry about it. So I wouldn't do it yet. How about a 30-year-old suicidal woman, MAO and only a partial response? And can psilocybin, ayahuasca be given? Can you lick a frog? You know about that? There's certain frogs that make dimethyltryptamine. Actually what you have to do is smoke the frog. Because if you take a frog as in, it's dimethyltryptamine in your mouth, it doesn't get absorbed, you know. What's ayahuasca, by the way? What is ayahuasca? I actually did this. I went to the Amazon with my wife on a, what's that? Yes, and so people don't know, there's two routes. And so I went to the witch doctor. And the witch doctor was brewing on these two kettles next to each other. Route one and route two. And route one has the frog stuff in it, the dimethyltryptamine, DMT. But you can't just give it DMT because DMT won't get absorbed. So what's in the other one? Harmine and harmaline, which are alkaloids that do what? Inhibit MAO. So if you inhibit the MAO, then it doesn't get eaten by MAO. And so the DMT gets into your brain. So I didn't take any of it. But I was watching her on, and she takes a cigarette, and she blows it in my face. It was part of the ceremony, I guess. It was very interesting. But, and the way in which they cook, the relative balance between pot one and pot two depends on, you know, Nike's versus Hoka's shoes, you know, whatever. So she had a brand of her own. So no formal studies, but I would proceed with very extreme caution because serotonin toxicity, and especially the fever, is thought to be mediated by the 5-HT2A receptors. And so silo, silo, and pop quiz, how does it work? It stimulates 5-HT2A receptors. How does LSD work? Same way. So we don't really see a lot of problems yet, but I guess you could potentially get a serotonin syndrome with these drugs on an MAO inhibitor. So, but even ayahuasca already contains one, and so we'll see what's gonna happen. Magic mushrooms plus an MAO inhibitor, you need to caution your patients to probably not do that. So it's very interesting. Few more and we'll be done. A 44-year-old single woman with debilitating social anxiety disorder. This is the secret of the day. If you leave here and don't know anything else, if you're gonna use MAO inhibitors, I got a great secret for you. They are bitchin' drugs for social anxiety disorder. But bitchin' means powerful, by the way. So if you wanna have, you have a terrible social anxiety patient who just isn't responding to SSRIs, isn't responding to therapy and so forth, I dare you to try this. In fact, you can try it in panic as well. And you know what? I don't know if I got it on the slide or not, but so is MAO a reasonable choice? And so it's not ever proved for that, but what do you do? So, okay, it's not here. Do you know phenylzine is a weird drug? It is an MAO inhibitor, and it therefore raises what? Serotonin, dopamine, norepinephrine. So there's no other drugs that we have that raise all three neurotransmitters in one drug. But there's a dirty little secret you should leave here with. It raises GABA. Why? Because a metabolite of phenylzine is a GABA transaminase inhibitor. And if you actually have experience with MAO inhibitors, it's pretty remarkable. If you have anxious depression, phenylzine is pitching. So, pop quiz, who didn't get better in STAR-D? Who had half the response rates of the other group? Anxious depression was nothing. You could get half or less of the response rates of citalopram. You take citalopram, it's great for non-anxious depression. For anxious depression, it doesn't work. So what are you gonna do in anxious depression? Give a Benzo in today's world? Ever try to give a Benzo in the marketplace today? You get shouted down and say you're some sort of heroin prescriber. So, you know, you have to use Benzos when you need them. But what is a secret is that this is good for anxious depression, which is a type of depression that will be visited upon us when we have our treatment resistance because the other drugs don't work. And that's one of the reasons why we use so many of the atypicals because they're the only other drugs that treat the anxious subtype. You can call it anxious distress via, you know, DSM-5. You can call it whatever you want to. Or just anxiety disorders that are terrible without depression like this. So this is another clue. And that is worth the price of admission. We'll collect the offering at the end of the lecture here. As a 35-year-old man with TRD on MEO calls you, I did not realize the food had mozzarella cheese on it, doctor, but I didn't drink the wine. And at home, I'm monitoring blood pressure for two hours. It's not increased, but I'm worried. Do you have any symptoms? No. What am I supposed to do? How much time means too much? What to do? So you will have more calls from patients and actually even more calls from other doctors, dentists and anesthesiologists on MEO inhibitors than you'll ever have on any other drug. There's so much mythology out there. So nothing's happened to reassure. So, you know, lots of reassurance. But if you've got to say, because you don't really know this and you're a MEO rookie, you still got your rookie T-shirt on, you go, well, you know, I think you'll be okay, but you know, yeah, yeah, you're gonna be okay. You know, if that's the way you reassure, it's not gonna work. So here we're trying to put a steel rod up your backbone and say, you know, let's get some confidence in there because if it comes across, that's half of it. But certainly get a blood pressure monitor, tyramine sensitivity, varies in that range of 20 to 40 milligrams of tyramine. So, you know, restrictions, but 25 grams of tyramine containing cheese, which I don't know how much 25 grams is, but it's a fair amount, might have six milligrams of tyramine. You have to leave a lot of cheese. So you say, have another slice. Go home, measure your blood pressure, get relaxed. You're gonna be okay. So part two, American mozzarella, cream cheese, processed cheese slices, chain pizza, really do have acceptable levels of tyramine. And of course, what you want to do is test that out in the patient. They should tentatively go out on their own, check it, you know, and use it and see what happened. Measure the blood pressure, you know, get reassurance, and they find out that they can eat this stuff. Pasteurized canned or bottled domestic beers in low quantities are low in tyramine, but avoid tap and these specialty beers. Small quantities of wine, including reds, are low in tyramine, so always provide diet information. And Ron has some more for you to give out if you want to, and there's others online, and some of them that I put in your app. And who should go to the ER? There's an old myth about giving nifedipine and use it sublingual. People don't do that anymore, but they do go to the ER. Hypertension, of course, you know, you know the parameters, systolic and diastolic, and sustained systolic is really a problem. It's interesting, for reasons that are not exactly pharmacologically clear to me, there's been some interesting people who are still interested in MAO inhibitors, and what they're finding is mitigating the blood pressure change as a beta blocker, not nifedipine. We haven't gotten to that point yet, but I'm looking at the possibility of actually having some people with a beta blocker to rescue some of these symptoms in the long run. But the calcium channel blocker, nifedipine, probably is not a good idea anymore. So here, take-home points. Look at the partial list of what you can combine with MAOs. Second generations, ECT, TMS, VNS, ketamine, nesketamine, most stimulants, most tricyclics, a set of hypnotics, most pain, most antihistamines. So there's a whole community of MAO experts willing to help field questions to new MAO prescribers. Includes the authors of those MAO guidelines. I also put up there, I edited a journal called CNS Spectrums, we put together about, God, what was it, 30, 50 people? It was an unbelievable number of people who all put that together. It's only a few months old. Free downloaded PDF in the app, and then you can go online. And so to finish, we can't end without having a little fun. And to remind you, I'm hoping this tune stays in your mind for the rest of the day, and I will torment you until you sleep. You know this one? ♪ Young man, there's no need to feel down ♪ ♪ I said, young man, pick yourself off the ground ♪ ♪ I said, just cause all the drugs let you down ♪ ♪ There's no need to be unhappy ♪ ♪ Young man, there's a drug that I've seen ♪ ♪ I said, young man, pick yourself off the ground ♪ ♪ There's no need to be unhappy ♪ ♪ Young man, there's a drug that I've seen ♪ ♪ I said, young man, it's allegedly you can take it ♪ ♪ And I'm sure you will find many ways to have a good time ♪ ♪ Oh, good time ♪ ♪ You can wear a beer cap, I say, just stop ♪ If it's beer from a tap, I say, young man ♪ Don't eat the kimchi ♪ But you can have a raspberry ♪ Bottle of minoxidase ♪ And time ♪ And we block it in place ♪ We just do it ♪ With an M-A-O-I ♪ And then you'll be feeling just fine ♪ It's fun to take me up ♪ M-A-O-I ♪ It's fun to take me up ♪ M-A-O-I ♪ You can eat lots of things ♪ That's a many issues ♪ You can eat any veggies ♪ It's fun to take me up ♪ M-A-O-I ♪ It's fun to take me up ♪ M-A-O-I ♪ You can eat big fish ♪ Fresh poultry or eel ♪ But none of the world ♪ Can have no eel ♪ M-A-O-I ♪ It's fun to take me up Very quickly, not to take any more time, we've been trying to cram a bit of information into your head, but we're not expecting you to remember all of this right now. We're wanting to decrease your anxiety, knowing this is not that hard to do, these drugs are not that scary, and there's lots of information available. The slides will be posted on the app in the session. They're not yet, they will be. There are already, like, seven or eight things posted that are deeper references. We're looking and hoping some of you may be teaching residents, you'll want some deeper references, and there's some very good stuff that's already online. And also, there are a lot of pearls we haven't really been able to get to, like questions of doses. Doses that were originally recommended, I would dare say, were too low. Stop topping off at 40 milligrams of phenylzine or 60 milligrams of channeled subramines, often not going to be enough for people. There's still, you know, stuff to learn, but it is all learnable. Well, forget that. You'll see it online. We have a simplified three-page version of the diet that lists in three columns things that are allowed, things that are not allowed, and things that just, you know, think about. It's much simpler... It's much simpler than it seems. And one comment I want to make, I hope you all use interaction checkers very frequently. We have lots of reasons to do so because of metabolic interactions. Probably the word I see most frequently on my interaction checker is MAO inhibitor, even for drugs that have nothing to do with it. Any time the word serotonin comes up in a mechanism of action, it seems to come up in the interaction checkers, at least some of them. Trazodone, which can protect you against it. It comes up as a contraindication, so be very careful. And I think it's one of the things that further induces fear every time we see MAO inhibitors on our interaction checkers. I come from a tradition that has taught me to honour those people who have been my teachers. I feel very honoured today to be on the podium with Jonathan Stewart and Phil Muskind, who have been two of my great teachers at Columbia University in psychopharmacology. Jonathan, professor of clinical psychiatry at Columbia University for decades, was one of the leaders of our depression evaluation service, which did extensive, extensive research on clinical application of antidepressants. He's the man who taught me and still teaches me. I still call him when I have any ornery questions about MAO inhibitors. And he was one of our leading experts in their clinical application. He's going to follow up with some more material for you before we get to our question and answers. Thank you. Well, thank you, Ron. Steve's obviously a hard act to follow. So, no current conflicts of interest. What I'm going to do, I just did the first of it. Okay. So I did the setting of the scene. I'm going to give you a cookbook recipe for using the MAOIs. I'm going to talk about adverse events and what to do about them, although Steve has covered those quite well. And I'm going to show you a few studies of how likely your treatment refractory patients are to benefit. So I've already covered you need to have the stepwise algorithm. You need to push each to the hilt. And then we finally get to MAOIs. And first I review current medications, particularly looking for the presence of recent SRIs, MAOIs including St. John's wort and some of the other things that Steve outlined. I review the tyramine-free diet. I use the diet that Ron is going to post for you and go through the do's and don'ts of the diet carefully. I review the potential adverse events, and particularly that most of them we can do something about and assure people that most of them we can help. Now how do I use MAOIs? I start with one pill a day. Every three to seven days I increase the dose, if tolerated, to two-thirds PDR max, which for all the marketed in the U.S. MAOIs is four pills a day. I leave them at four pills a day for two weeks, and for insufficient response and good tolerability, I raise to five and then a full dose of six pills a day. Channel cipramine, I'll get to why, I divide the dose in half, part first thing in the morning, part noon or early afternoon. And the treatment goal is full remission, not just getting better. Getting better is not good enough. Why? Because even mild depressive symptoms convey considerable psychosocial dysfunction, and it's not until we get the patient without depressed mood that we get full return of functioning. So if remission is obtained, I continue that dose of that drug for six months. If they have a history of frequently recurrent episodes or very chronic depression, and I see a lot of chronic depressives, I'll likely continue that dose indefinitely. If remission does not obtain, I raise the dose further above PDR max doses. I may augment with the standard augmentators combined with other antidepressants or switch to alternative treatment, which for me is ECT or transcranial magnetic stimulation. Now, this is a list of the common side effects we see with MAOIs. Post-dose hypertension is peculiar to tranalsipramine and why I split the dose. Pyridoxine deficiency, on the other hand, is peculiar to the two hydrazines, phenylzine and isocarboxazid. The others occur in all MAOIs, including selegiline. But orthostasis, and particularly troublesome orthostasis, is most common and most severe with tranalsipramine, as is insomnia. The others, weight gain, sexual dysfunction, peripheral edema, and hypersomnia, more common with phenylzine, with isocarboxazid somewhere in between. So managing the hypertension induced by tranalsipramine, this can be of hypertensive crisis proportions and occurs exactly as if you gave 100 milligrams of tyramine. So we get a pre, and it goes away in about 90 minutes. So a random blood pressure usually will not discover its presence. I have the patient skip their afternoon dose of tranalsipramine when I go from 20 to 30 milligrams at a shot, and I take the blood pressure, immediately have them take 30 milligrams of tranalsipramine, and 45 minutes to 60 minutes later, I get a second blood pressure. If that second blood pressure has raised less than 30 millimeters mercury systolic or 20 milligrams millimeters diastolic, I continue the dose raises, but with each subsequent dose raise, I'll repeat the blood pressure testing. If, on the other hand, the blood pressure rises more than this, I will either institute three times daily medication to bring the individual doses below the one causing significant blood pressure increase, although three times daily is difficult for patients to adhere to. I use counteractive treatment. I do use beta blockers. Propranolol has a relatively short half-life. This is a short-duration problem, so you don't want to use a long-acting beta blocker. 10 to 40 milligrams typically does the trick, and I get pre-post once I institute the propranolol blood pressures to make sure it's working and to titrate what dose works. If the patient is doing quite well, I sometimes might continue the same dose, but usually we get here because they're not doing well enough. Pyridoxine deficiency is peculiar to hydrazines, and so I encourage patients taking these drugs to increase their dietary B6 intake. If they still get peripheral neuropathy, I give pyridoxine B6 pills up to 300 milligrams three times a day. It's very water-soluble, so you've got to give multiple doses. Orthostasis, usually time takes care of it. We don't need to do anything but delay the next dose raise. If we need to do something, I give salt. I also warn them to get out of bed slowly and notice whether this is happening. And particularly a sauna, getting out of a sauna, your blood pressure's liable to drop anyway, and more so with an MAOI. I've virtually never had to go to a mineralocorticoid, but I do know some people who use that counteractive mechanism. Weight gain is very difficult. You can tell them not to eat, but people on particularly phenylzine just can't do that. They have to eat. Occasionally not buying fattening foods can help, but they have to go to the grocery store after having eaten, not when they're hungry. Metformin, topiramate can be helpful, but sometimes you do need to switch to a different, less weight-gaining MAOI. Peripheral edema, support stockings are terrific, and usually that's all you need to do, although you could prescribe diuretics. Switching from phenylzine to tranalsipramine can be helpful with that. It's less common, less intense with tranalsipramine. Sexual dysfunction is particularly difficult. That takes the form of anorgasmia, so the erectile dysfunction drugs generally aren't very helpful, and you need to either put up with it, and I've had plenty of patients who are willing, in exchange for good effect, to put up with it, or you can try a different MAOI. It's worse, again, with phenylzine. Daytime sleepiness is a big problem when it occurs. It's iatrogenic narcolepsy. People just suddenly fall asleep, and if they fall asleep when they're driving, that could be catastrophic, so I warn patients to watch for this. If it occurs not to drive at the time of day, which is typically mid to late afternoon, they can't drive at that time. As with standard narcolepsy, stimulants are very helpful, but you can also pay attention to sleep hygiene, and if they get better sleep at night, they're less likely to have afternoon sleepiness. Again, I've not seen this yet with tranalsipramine, so you can switch MAOIs. So I'm going to show you two studies of prescribing MAOIs in highly treatment refractory patients. First is Willem Nolen from Netherlands. He systematically treated over 200 depressed patients, most of whom had already had at least one good antidepressant trial. He randomized them to tricyclic or SRI. Non-responders got crossed over to the other agent, and he ended up with 47 who weren't doing well. He randomized them to tranalsipramine versus a comparator, and the bottom line is half got better, and 80% of the responders maintained that response at the six-month follow-up. Our own study of 28 patients who had a history of poor response to two or more means four differently acting, adequately used antidepressants. We gave them tranalsipramine initially to PDRmax of 60 and non-responders to 120. Again, half got better, and 80% of those maintained their response at six-month follow-up. So in conclusion, I think we can say that MAOIs are effective agents even in highly treatment refractory subjects. They can be used safely, as Steve elegantly outlined, and we do our patients a disservice if MAOIs are not on our algorithm. Thank you. I just, once again, want to mention that we will be loading onto the app Dr. Stoltz's slides. Dr. Stewart's slides are already there, and a number of other references are already there. We also will load the link to that group that will provide advice regarding using MAOIs. I want to introduce my co-moderator, Dr. Phil Muskin, who will take questions from the audience. Please line up at the microphone, and we'll alternate with questions from our remote audience. Because this is a streamed session, there are people online. We want to give them a chance as well, so we'll alternate back and forth. To the point questions, please, and speakers, to the point answers, please, so we get to hear from everybody. And we really did a great job. Please don't take five minutes praising them. Let's get right to the point. I'll get straight to the point. Firstly, thank you so much for a very reassuring lecture. I've been prescribing MAOIs for some time, very happily, until 2020. Prior to that, just out of habit, phenylzine was my MAOI that I was prescribing. From 2020, with the sudden fall-off in phenylzine availability, I switched patients to tranylcypramine, started new patients on tranylcypramine, and was disappointed to see, admittedly, a smallish group of people, but quite a strikingly obvious increase in intolerability tranylcypramine compared to phenylzine, and quite a significant drop in efficacy. Fortunately, phenylzine's gone back onto the market, but in my country, in New Zealand, it's remarkably expensive, and it's not been put back on the government fund when it was funded previously. Phenylzine is between $500 and $1,000 per month now, which is equivalent to the minimum living wage. It's a very expensive option for people, and I'm caught in a dilemma. Should I try and encourage people to press on with tranylcypramine because I'm just not that experienced with it, because previously, phenylzine was my go-to, or should I think about something else entirely? Okay. John, Steve. John? Well, one thing I think you hinted at, Steve, is that we do get people who do better on one MAOI than another, as you just anecdotally documented. It's not surprising to me. Out of 100 patients, I'll get more tolerating tranylcypramine well than phenylzine, but there are certainly people who are going to tolerate phenylzine better than imipramine, and it sounds like you had funneled your phenylzine responders down to those who were tolerating it well and only had the possibility of tranylcypramine doing worse for the sake of argument. Maybe the GABA enzyme inhibition of phenylzine accounts for some of this. The chemical structure of tranylcypramine looks on paper virtually like amphetamine, and it does seem to me to have amphetamine-like qualities, so maybe that accounts for the other direction. I do agree with Steve that phenylzine is much more anxiolytic than tranylcypramine, and so you didn't say, but possibly your people who did worse on tranylcypramine were your anxious depressives in the first place. Shoot us an email, and your Down Under colleague, Ken Gilman, and we'll try to maybe put some pressure on the government. It's ridiculous. We're working with the WHO to put it on the list of, you know, what do they call it, vital medicines or something like that, and so if there's nobody, as we're trying to seed advocacy in this crowd, if there's no advocates, they'll go away. They're almost gone now, and so nobody wants to manufacture them. So let's work together. Shoot us an email after this, and we'll see if we can't put some pressure on and say it's ridiculous. Thank you. Let's take something from the people at home. I'm going to paraphrase one of the questions. Those of you who work in Canada are probably familiar with meclobamide. Those of us in the United States don't have it available, although I used to bring it in for some patients. And there is a question about whether or not the diet is necessary and does it work as well. Dr. Stahl, would you like to take that one? Well, I get some of my information from a colleague that you probably know well, Roger McIntyre, and he said when it first came in in Canada, we don't have it in the United States. He said he loved it. He said he gives it very high doses, and it's the only drug that he said with no side effects. I don't know if that's an exaggeration, but I think it probably doesn't have much of a dietary restriction thing. You know, there's always too much of a good thing is too much of a thing, so it's probably within limits. But it was also not thought to be quite having the punch of efficacy, particularly at the regular doses. Now, Roger blasted people with doses and thought it worked better. So it's probably, you know, not as effective. I don't know. I guess I'm the only one on this panel who's actually prescribed it, which I have. I haven't in a number of years. My clinical impression has been that not as effective as oral MAO inhibitors. We haven't spoken about MSAM, transdermal selageline. Again, my own personal impression is, well, it's excellent for some patients, not as reliable as the oral irreversible MAO inhibitors. Leucobomide is a reversible MAO inhibitor, which is why it doesn't present the same problems for the diet. However, Roger McIntyre pointed out yesterday that, however, in the doses that he finds are optimally effective, it starts to become irreversible and, therefore, may not be an advantage over the oral ones we have in this country. I have not commonly, but used, leucobomide as well. And my strong feeling is with Ron that it's not, while it's effective, it's not as effective as the pill MAO. And I find the MSAM similarly. There are certainly patients who respond to these drugs, but it's like giving 30 milligrams of tranalsipramine or 45 of phenylzine, maybe 40 and 60. Certainly you get people better. Those are well-tolerated doses of the pill MAOIs. It's really not until you get up to 5 and 6 milligrams a day that you really get hit by the side effects. And that's my impression of these other MAOIs. Thank you. I will make one comment about transdermal. I'm a CL psychiatrist. And we have a population that they don't have intestines. And so it's very hard to give them oral drugs. And one option is the patch. It's not on formulary at the hospital, but we do it, and it works. So if you have people who don't have intestines or have a very short, small intestine because they've had bowel disease or they've had surgery, you're kind of left with what are we going to give them? Okay. Please. I have three questions. I'll try to be fast. I've heard that you know if you're having a hypertensive crisis that it's unmistakable. Don't worry about it happening without noticing. My second question is what about carrying a rescue medicine, for example, if you're traveling or in a rural area and can't get to an ED quickly? And then thirdly, literature about using maximal doses above the 60 milligrams, say, of channel ciproamine. Thank you. Go ahead. Okay. Well, I no longer, I used to have people take along counteractive medication. But by the time they get that pounding occipital headache, and that's what they need to look for, and find the counteractive medicine, get it into themselves, get it into their system, enough into their system that it's going to do anything, it's gone, the blood pressure's dropped anyway. So I think it's too little, too late. Second, even if they're in very rural area, if they experience that pounding headache, they've got to get to the nearest emergency room, they could have had a bleed. If it's a mild bleed, they may not know it till the next day, and they really need to get evaluated for having had a bleed. I don't know about the other doctors on this panel, but, and I'm the child on this panel, but I've been prescribing these drugs for 40 years, and I have had only two episodes ever decades ago. One was intentionally inflicted by a self-injuring, very sophisticated person who knew exactly what they were doing. And the other, I went nuts tracing a particular turkey breast back to its packing plant in Missouri and found that you can lyophilize a cooked turkey breast, put it at room temperature on a shelf for 90 days. The FDA, at least at that time, would call it fresh, but it may be free of bacteria, but it created lots of opportunity for the tyramine to develop in the turkey breast. So one of the pearls we haven't talked about is what is fresh meat, right? What is fresh poultry? What I tell my patients, and if anyone here has a different comment, I say, you want to know that that bird or whatever it was, was cooked within the last 72 hours. So based on that one experience, if you get the fresh turkey breast sandwich in a deli, ask if it was cooked on the premises. Any other comments about how long? I saw it once with orange juice. It was the only thing I could identify for the hypertensive crisis. The patient had had nothing to eat all day except, as the patient said, it was very sparkly. For those of you who keep orange juice until you should really get rid of it, it gets sparkly. You have orange juice jack. And by the way, just wanted to have you glance at this. It will be posted online. This is the short and very simplified version of the diet. Goes on for three pages. I just want you to glance at it. It is very, very user friendly. Again, it will be posted at some point on the session app. I'll just add, I've also only had, I think, three hypertensive crises in 45 years of practice. They are rare events, but they really upset your nerves when they occur. And I think the infrequency of it, with both Ron and myself, argues that we can train our patients not to have this happen. Online. We have a question about whether or not you would use MEO inhibitors with a patient who has psychotic depression. Well, just like anything else, you probably need a neuroleptic along with it. So it's not gonna treat the psychosis very well. And as others have said, each of these drugs is two drugs. Adrenalcypromine is amphetamine plus an MEO inhibitor, which probably would not be the greatest things to give to a person with psychosis. So I'd probably go to phenylzine, which is a GABA-T inhibitor plus an MEO inhibitor. But give any one of those atypicals along with it, perhaps. The older people here will remember the debates of psychotic depression, high dose antidepressant versus the combination of antidepressant and antipsychotic. The high dose antidepressant really never worked for psychotic depression. You needed an antipsychotic, okay? So you came up later, so I'm gonna go to someone in the back first, but I'm not gonna ignore you, I promise. Well, thank you all for your enormous contribution to the field. It's an honor to be here and hear you all speak after reading your texts for all these years. My question is about obsessive compulsive disorder and the role of MAIs in the treatment of that. I think there's some case reports of it being useful, but no studies I know of, right? They date from the 1960s. So there are studies, actually, in almost all, including PTSD, what they call it, combat sickness, something like that. There are studies of many different psychiatric disorders, and except for the psychoses, there are studies from a long time ago showing MAI efficacy, and they just treat everything, especially phenylzine. We have a question as to whether or not one would ever use an MAI as a first line treatment, and what about any data of safety for individuals under 18? Probably not. I mean, I don't know, I don't think it's a bad thing, but I think realistically, no. I'm not sure it has any official studies under 18. Have you actually treated people under 18? I don't think there's any reason why you wouldn't, but what do you think? Well, we used to allow people 17 and a half, rounding it off to 18, into our studies. I can only anecdotally say I don't remember any difference between them and the true 18-year-olds, nor would one expect it. I guess the biggest problem is frontal lobes aren't totally developed yet, and so you have a little more trouble with impulsivity. I got a secret, which is that maybe in your bulimic women, you can try it, because there's anecdotal evidence that it can be useful in eating disorders. Kim Walsh had a nice study with Phenylzine that was positive. And some of those kids are under 18, and so if you're desperate enough, I think a teenager with bulimia nervosa or anorexia nervosa could be considered candidates. You might think of differentiating the drugs, because, as you pointed out, Phenylzine and Trenilcipromine derive from different places. And so given the concerns about amphetamines for ADHD, particularly in youth, that might be a place where you would use one over the other with an abundance of caution. There's zero data that supports that, but it's just an interesting idea. Not quite zero, Phil. From the 1960s, there were a number of studies In the 1960s, there were studies of Trenilcipromine for what was then called minimal brain dysfunction. We've now started to call it attention deficit disorder. And those were positive studies, and I would say the amphetamine look to the chemical structure of Trenilcipromine ought to have predicted. No, I agree, but there is that concern with amphetamines that the FDA has. So if you had to pick one for a youth. I would still pick a standard stimulant. Me too. You're making a good point. I mean, I don't know if you know this, but amphetamines are reversible MAO inhibitors. That's one of their mechanisms. So they have a lot of different, they're not just releasers, like you say, there's other things to do. And so Trenilcipromine actually is a cyclic side chain, and it opens up and it suicide inhibits the MAO, whereas the other amphetamines come in and out reversibly. The question of whether or not it would be first line use does raise the question of where does it enter into your algorithm of treatments for a patient. And because of how long it's been since MAO has been included in most clinical research, we haven't really seen studies that compare them in a way to other agents that would really tell us. And there are some disagreements, I suspect, on this panel about where it enters. How much do you want to avoid the risk of an atypical and its side effects? Or are they going to be that so likely to be effective and in many ways otherwise safe, which would come first? So this has still to be worked out, either. I think we're on the line next, if I recall correctly. Okay, another question. Did we comment on whether or not, what we would think about using it in MDD in combination with symptoms of PTSD, any special precautions or thoughts about that? Well, again, the studies from long, long ago would suggest they'd be good treatment for such people, Ron. I still wouldn't make it first line. And the only time I would start somebody up on an MAOI without other agents would be if they came with a history of good response to MAOI. You'll virtually never see that today. I used to, but that's extremely rare. But that's the only time I would first consider it. I just wanted to make one more general comment. Steve kept mentioning drugs that raise the blood pressure. With virtually all of them, the tricyclics, the amphetamines as examples. It's the same without the MAOI as it is with the MAOI. It's not a drug-drug interaction. It's a general action of those other drugs. And I don't see an increase in the hypertensive effect of amphetamines or tricyclics if they're combined with MAOIs. So we are officially out of time. That doesn't mean people have to leave. I don't think there's something in this room next, because I don't see anyone crowding. But, so I encourage people to come up and- If anyone wants to come up, come up. But we are officially out of time. I want to thank both these people. They have been mentors to me for many years. Thank you.

American Psychiatric Association

psychopharmacologic tools

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tricyclic antidepressants

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treatment-resistant depression

Dr. Stephen Stahl

hypertensive crises

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