MAOIs rank high in efficacy and are pretty well tolerated too, as long as you watch for two critical interactions.
CHRIS AIKEN: They are some of the most effective antidepressants around. And they are pretty well tolerated. But to use the MAOIs you’ll need to follow the 6th psychopharmacology commandment: Honor thy MAOI Interactions.
Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report.
KELLIE NEWSOME: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.
CHRIS AIKEN: Psychiatry is a collaborative art. We work with people who have problems with judgment, and we have to meet them where they’re at while making sure that the treatment doesn’t veer too far off the road. That’s what the psychopharm commandments are about. In this series, we are highlighting areas where the line between safe and unsafe is a sharp one and there’s little room for compromise. Let’s recap the first 5, before we get into #6.
1. Do not worsen mental illness with psych meds. So don’t give antidepressants during mania or psychostimulants to people with psychosis.
2. Avoid stopping meds abruptly, particularly benzodiazepines, serotonergic antidepressants, and lithium. Patients rank withdrawal problems as one of their top concerns with psych meds. Unless there’s a dire need to get off the med – like a lamotrigine rash – we recommend stopping psych meds gradually over at least 2 weeks.
3. And that brings us to #3: Stop lamotrigine if any rash develops in the first 3 months of treatment with it.
4. Watch out for lithium toxicity, and prevent it by staying on top of drug interactions, dehydration, and your patients age and renal function.
5. Do not combine benzodiazepines and opioids in patients who have an elevated risk of overdose. Check our November 7th podcast to learn the signs of high-risk, and our September/October 2022 episodes to recap the first 5 commandments.
CHRIS AIKEN: Today we’ll cover another solid line in psychopharm: MAOI interactions. And before you start saying, “I know, hold the cheese, and don’t combine it with antidepressants,” hold that thought – cause we’ve got new research that will change how you use them. And there’s good reason to use MAOIs. These antidepressants can work when other options haven’t, and if you steer clear of these interactions they are actually pretty well tolerated meds, causing fewer problems with weight gain, fatigue, and sexual function compared to other antidepressants. Like lamotrigine – the well-tolerated mood stabilizer that can cause a serious rash – just because a med has medical risks doesn’t mean it’s hard to tolerate.
But before we go further, a preview of the CME quiz for this episode:
1. Which antipsychotic has a potentially dangerous interaction with MAOIs
CHRIS AIKEN: There are two interactions to worry about with MAOIs. Hypertensive crisis and serotonin syndrome. Both are potentially fatal, but for different reasons. In hypertensive crisis, the cause of death is cardiovascular, like stroke. This is the dreaded cheese effect, caused by an interaction with tyramine rich foods like aged cheese, dried meats, and home brewed alcohol. But medications can also cause this hypertensive emergency – like stimulants and cocaine. The main sign is sharply elevated blood pressure and severe headache. Hypertensive crisis can also cause confusion, blurry vision, chest pain, and seizures.
KELLIE NEWSOME: Serotonin syndrome is often talked about with SSRIs and SNRIs, but it’s with the MAOIs that we really need to worry about it. The reason is that serotonin syndrome is much more common – and more severe – when it occurs with MAOIs. It can be fatal, so serious is the reaction that it caused the government to limit resident physician’s working hours in the Libby Zion Law.
CHRIS AIKEN: On March 4, 1984 an 18 year old Libby Zion was admitted to New York Presbyterian Hospital for flu like symptoms. The ED physicians were unsure of the cause and admitted her for observation. The doctors did notice unusual jerking motions in her legs and prescribed an opioid, meperidine, to control it. Overnight, she became more agitated, and the on-call resident ordered restraints and haloperidol. Her temperature spiked to a potentially fatal level of 107, and she died that night of a cardiac arrest. The resident physician, who had been awake for 36 hours at that point, called the family to notify them.
When the father learned about the restraints and the antipsychotic, he suspected something was amiss. He was Sidney Zion, was a prominent lawyer and writer, and the legal case and media attention that followed changed medical training forever.
The problem was that Libby Zion was taking phenelzine, an MAOI, and the opioid she was prescribed is contrainidicated with MAOIs because of its serotonergic effects. The agitation and high temperate that ensued were all signs of serotonin syndrome, in fact she may have had a mild case of serotonin syndrome when she was admitted. Libby had trace amounts of cocaine in her blood, and cocaine inhibits serotonin reuptake among its many other effects, including blood pressure elevation that can trigger hypertensive crisis with MAOIs. The flu like symptoms she was admitted for may have been due to serotonin syndrome, which can cause fever, sweats, and confusion, as well as the muscle twitching that lead to the prescription of meperidine in the first place.
KELLIE NEWSOME: To remember the symptoms of Serotonin Syndrome, think “Shaking, Sweaty, and Confused”
Shaking: tremor, restless, twitching
Sweaty: fever and sweats
Confusion: delirious, unresponsive
CHRIS AIKEN: The father sued for murder, but in the end the resident was charged with 38 counts of gross negligence and/or gross incompetence. As part of the trial – which was broadcast on court TV – the defense lined up several medical school chairs who testified that they had never heard of this MAOI interaction. It was not widely known at the time, so it’s not clear that sleep deprivation caused the error. But it caught the attention of the state health commissioner, which lead New York to pass the first law limited residents working hours in 1989 – to no more than 24 hours in a row and 80 hours in a week.
KELLIE NEWSOME: That law went national in 2003, and was further tightened in 2011, limiting on call hours for PGY 1 residents to 16 hours. We’d like to think that makes a difference for patients, but oddly most studies of mortality rates before and after the change have found little to no difference. Some say it’s because the laws did not go far enough, restricting work to just 36 hours. Staying up for 30 hours pulls down cognitive performace in physicans by a whole standard deviation, according to a meta-analysis of 60 studies.
CHRIS AIKEN: Today, the interaction that took Libby Zion’s life is well known and prominently posted on many medication information sheets. Google MAOI drug interactions and it can seem like nearly every medication causes problems. But some of those warnings may be unwarranted. Some meds got warnings early on, based on theoretical risks, meds like carbamazepine – whose resembles a tricyclic antidepressant - and the tryptans for migraines. The tryptans are serotonergic but do not act on the serotonin receptors involved in serotonin syndrome. Large epidemiologic studies have not found increased rates of serotonin syndrome with these combinations.
For our book Prescribing Psychotropics we gathered an up-to-date list of meds to avoid with MAOIs. It’s on page 145 if you have the book, and we’ll summarize it here. It includes all the SSRIs and SNRIs, the MAOIs, vortioxetine, vilazodone, the tricyclics – mainly clomipramine and imipramine; possibly trazodone and nefazodone; ketamine, esketamine, and possibly lithium and buspirone.
KELLIE NEWSOME: We have to say “possibly” on some of these because clinical studies are not exactly possible to conduct here.
The list also includes and antipsychotic – ziprasidone – which is a serotonin 1A agonist with a track record for triggering serotonin syndrome in case reports.
CHRIS AIKEN: Stimulants are included – these meds not only raise serotonin but like cheese can also cause a hypertensive crisis. Then there are some opioids with serotonergic effects, a few odds and ends like fenfluramine, and other-the-counter meds like L-tryptophan, SAMe, St. John’s wort, and decongestants containing phenylephrine, pseudoephedrine, dextromethorphan, or chlorpheniramine; as well as recreational drugs like cocaine, amphetamines, LSD, MDMA, ecstasy, and bath salts.
KELLIE NEWSOME: The bulk of those medicines are antidepressants, which presents a challenge when starting MAOIs cause you have to get them off their old antidepressant first to avoid these drug interactions. Technically, it takes 5 half-lives for a med to clear the system, but just because it’s out of the blood stream doesn’t mean it’s pharmacodynamic effects in the brain have settled down. So add a little buffer. For most meds, 5 half lives is 5 days, so we’d wait at least 7 days after stopping it before starting the MAOI. The two with longer half lives are fluoxetine (Prozac) and vortioxetine (Trintellix). For fluoxetine the wait is 4–5 weeks, and for vortioxetine it’s 2–3 weeks.
CHRIS AIKEN: This next part is for the highly skilled pharmacologist, who can gauge with adept precision the risk-benefit of every decision. In other words, don’t try this unless you’re real experienced and your patient has failed ECT. Some antidepressants may be safe to combine with MAOIs – specifically those with no serotonergic effects. That is, desipramine, trimipramine, and doxepin – all tricyclics, and bupropion. And Jan Fawcett reports success with the dopaminergic pramipexole. These meds have been successfully combined with MAOIs in case series, but that doesn’t mean they are safe – we’d need a lot more published data and real-world experience to back that up. And you also have to wonder if its’ even effective. It’s difficult – after all – to show much additive benefit when two antidepressants are combined together. Rather than combining meds, I’d recommend maximizing the MAOI dose – there is evidence of a dose response relationship with MAOIs.
KELLIE NEWSOME: And which MAOI do you start with Dr. Aiken?
CHRIS AIKEN: Usually phenelzine. It is the least sedating of the bunch, possibly because it has unique dopaminergic effects. In that sense, phenelzine is the holy grail of antidepressants – the fabled triple reuptake inhibitor that the industry has long toiled to device – raising serotonin, norepinephrine, and dopamine. You know, we talk about using MAOIs in treatment resistant depression and atypical depression, but they also work really well in anxiety disorders. Phenelzine had a large effect size – much larger than SSRIs - in several trials of social anxiety, some of them large, and Tranylcypromine has trials in panic disorder.
70% of psych meds are prescribed in primary care, which means the pool of SSRI and bupropion responders is likely dried up by the time the patients get to us. We are secondary and tertiary care, so ought to be well versed in using MAOIs, not to mention clozapine, lithium, and ECT. Yet I’ve sat in conferences where the audience is asked who is prescribing MAOIs and very few hands go up. Let’s change that – think of how many patients you see with treatment resistant depression, panic or social anxiety disorder. Try an MAOI.
KELLIE NEWSOME: And I doubt it’s the drug interactions that scare people away. Those are easy; just avoid them. It’s the food interactions where things get dicey, because we’re depending on the patient not to eat that pepperoni pizza.
And here’s where we have an update that will make it easier for you. The internet is awash with warnings about tyramine-rich foods to avoid on MAOIs, but you can cast most of that aside. We really didn’t have the technology to measure tyramine in foods until around the millennium – year 2000. Since then, the dietary restrictions have relaxed a bit, most importantly with that fan favorite: pizza. In 1999, researchers at the University of Toronto measured the tyramine content in pizzas from popular chains like Pizza Hut and Dominos. They didn’t hold back, ordering double cheese and double pepperoni and considering half of a medium pizza as a single serving. All were safe.
CHRIS AIKEN: The foods you have to worry about are those that are aged or fermented, like aged cheese or meat – charcuterie board stuff; sauerkraut, fermented tofu, homemade beer or wine. These foods have bacteria in them that convert proteins into tyramine, and it’s that tyramine that causes the dreaded hypertensive crisis. Sourdough bread and specialty soy sauces also count. But most commercialized, processed products are usually OK – all those preservatives keep the bacteria and the tyramine down. Most grocery stores keep the inexpensive cheese in the dairy section – wrapped in plastic with a Kraft logo – and the expensive, aged cheese somewhere else, with an artisanal display.
KELLIE NEWSOME: Now that we know how much tyramine is in each food, we can advise our patients more clearly on which foods to avoid completely and which are safe in small quantities. Bananas, avocados, commercially produced beer and wine and kimchi, even a Vegemite sandwich if you come from down under are all safe in normal portions. Microbrewed beer or beer on tap is safe in small portions, like one standard drink. And some foods have no restrictions: yogurt, pepperoni, prosciutto, smoked fish, and soft cheese: mozzarella, American, ricotta, cottage cheese, and cream cheese.
Get the full list of all that’s edible and inedible on an MAOI in our page 142 of our book Prescribing Psychotropics. Or, if you’re a subscriber, find it in our double issue on treatment resistant depression from July 2018.
KELLIE NEWSOME: And now for our study of the day. The impact of age on antidepressant response from Jeffrey R. Strawn and colleagues in the Journal of Psychiatric Research.
This study gathered together data from 3 large NIMH sponsored trials to figure out whether age influenced antidepressant response. This participant level data included over 1,000 patients from adolescence to old age from the TORDIA, TADs, and COMED studies.
The graph is very telling. Adolescents had a very low rate of responding. Not surprising, considering only about 10% of antidepressant trials in children and adolescents are positive. Responses get better in the 20’s and peak at age 30, then start to fall in each succeeding decade, particularly after age 50, which is the new cut off for geriatrics.
CHRIS AIKEN: There are a lot of reasons why older adults may not respond as well to antidepressants. Medical illnesses – particularly inflammation and vascular disease – are known impediments. Changes in fat and water affect the clearance and distribution of drugs. Older patients are more likely to suffer chronic depression, which is harder to treat, and more likely to be isolated and unemployed, factors that hinder response. For the young, the reasons are less clear. Early onset depression may have a different biology. The brain doesn’t fully major until age 25, and that’s also the age when antidepressant induced suicidality fades away.
KELLIE NEWSOME: Dr. Aiken posts one research update each day on his twitter and linkedin feeds - @chrisaikenmd. Earn CME credits for this episode through the link in the show notes. Your support helps us remain in the ranks of Consumer Reports, Practical Farm Ideas, Motorcycle Consumer News, and the few publications that operate free of commercial support.