Stephen Stahl steps down from the industry-sponsored podium to remind us of 3 reasons to use an MAOI: Atypical depression, treatment-resistant depression, and social anxiety disorder.
Publication Date: 06/12/2023
Duration: 26 minutes, 24 seconds
We met up with Stephen Stahl and found something we all agree on: 3 reasons to use an MAOI.
CHRIS AIKEN: 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: Stephen Stahl is not known as a promoter of generic drugs. Between 2014 and 2020 he was the top earner on OpenPayments.com, bringing in 8.6 million in speaking and consulting fees over those 6 years, more than half of which was from Takeda, maker of Trintellix. So we were surprised to find him speaking on long forgotten generics at this year’s APA meeting in San Francisco. He is writing a book on lithium, just finished one on clozapine, and hosted a seminar at the conference whose wordy title is a call to action:
“If you are a psychiatrist, you need to know how to prescribe monoamine oxidase inhibitors: Guide for MAOIs so an effective treatment option is not lost”
Today we’ll bring you some highlights from that talk.
KELLIE NEWSOME: MAOIs are known as a second- or third-line option for treatment resistant depression, but Stahl pointed out their benefits in treatment-resistant cases are not backed by the kind of gold-standard science we have for meds like aripiprazole. He did highlight a randomized, double-blind cross-over trial from 1993 that compared the MAOI phenelzine with the tricyclic imipramine in 89 patients with chronic, non-melancholic, treatment resistant depression. The study was done by one of the founders of psychopharmacology – Donald Klein – and Jonathan Stewart – who was one of the presenters at the talk.
CHRIS AIKEN: This was a much talked about study in the 1990’s, so it was good to see it back in the slide deck. The patients were not truly treatment resistant, as they had only failed one antidepressant, and that’s a common lapse in these kinds of trials. What they did was treat all the patients with either phenelzine or imipramine. They then took those who did not respond to the antidepressant and switched them to the others – so the imipramine failures got to try phenelzine and vice versa. In the end, switches to phenelzine looked more promising, with response rates of 67% vs. 41% when imipramine was the second trial.
KELLIE NEWSOME: Like most studies, this one has problems, and the problem here helps us understand when to use MAOIs. Most of these patients – 80% of them – had atypical features, and none had melancholic features. Atypical depression is known to respond better to MAOIs, while melancholic features favor a tricyclic approach. The features are easy to remember if you think of them as opposite:
Atypical = high appetite, Melancholic = low appetite
Atypical = oversleeping, Melancholic = early morning awakening
Atypical = reactive mood with rejection sensitivity, a mood that tends to worsen as the day goes on and stress builds up.
Melancholic = non-reactive mood that is worse in morning. Patients often wake up with a sense of nameless dread. Their mood is distinct from normal human sadness in a way that puzzles the patient as they try to put it into words, “My insides have died. My heart has turned to concrete;” they feel empty, despondent, and full of despair.
Finally, there’s the psychomotor part. Here they are not exactly opposite, but they are different. In atypical depression, ask about leaden paralysis, “Do your arms or legs feel heavy, as if they are pulled down by lead weights?” In melancholic depression, the motor changes are more visible. They are either lifeless and slowed down, or so agitated it looks like they have akathisia.
Bottom line: This study favored the MAOI, but had they focused on melancholic patients things may have gone the other way.
CHRIS AIKEN: And that is about the best study we have for MAOIs in treatment resistant depression. It’s small, the patients weren’t truly treatment resistant, there’s no placebo control, and the population was biased in favor of the MAOI. Outside of that, Stahl is right: The evidence really is anecdotal, a fancy word for story-telling by experts.
KELLIE NEWSOME: And here are some of those stories. In 1985, psychiatrists at Yale gave the MAOI tranylcypromine to 12 patients on the inpatient unit who were genuinely treatment resistant, having failed at least 2 antidepressants and a course of lithium. They were kept on the lithium, and the MAOI tranylcypromine was added. 8 of the 12 had a meaningful recovery, as judged by a blinded rater.
CHRIS AIKEN: In 2020 we interviewed Joe Goldberg, who runs a consultation practice for treatment resistant depression. We asked him what treatments he uses for highly treatment resistant cases, the ones who have failed 3-5 antidepressants and psychotherapy. He named ECT, ketamine, pramipexole, and high dose MAOIs. There are case reports of successful treatment with high dose MAOIs, mainly tranylcypromine at doses of 90-120 mg per day, but low blood pressure often becomes a limiting factor in this dose range.
But it’s not all good news for MAOIs. In 2007, researchers from the Netherlands tested trial phenelzine against lithium augmentation in 28 elderly patients with treatment resistant depression. This study was randomized, and it favored lithium, which brought 1 in 3 patients to remission compared to zero – that’s right, zero – who switched to the MAOI.
KELLIE NEWSOME: The latest data is a 2018 study from Brazil that tested a risky MAOI-tricyclic combination in 31 patients who failed to respond to ECT. An impressive 80% of the patients responded within 3 months. We have to be skeptical of numbers like that in an open-label study. For all we know lots of other researchers tried this without success and these were the lucky ones who published. Or maybe these patients briefly perked up when an expert came in with a cutting edge treatment. But, to their credit, the researchers did follow most of the patients for another 9 years and none of them slipped back into depression. So even if it was a placebo, it wasn’t a flash in the pan.
CHRIS AIKEN: That risky combination was tranylcypromine plus the tricyclic amitriptyline. For years, tricyclics have been on the contraindicated page of the MAOI manual, but recent papers suggest they can be used without problems, or at least – if there are problems – they are too rare to show up in the 1 or 200 patients where we have these reports. The risk we are worried about here is serotonin syndrome, something that is theoretically possible with any combination of serotonergic medications, like and SSRI and an SNRI, but is much more common, and much more deadly, when one of those serotonergic meds is an IRREVERSIBLE inhibitor at the enzymes that breakdown serotonin, in other words, the MAOIs.
KELLIE NEWSOME: This risk has led to fears of combining MAOIs with any psychiatric meds, and that is one reason they are neglected. Most of the patients who are candidates for an MAOI are already taking multiple meds. The risk here, is really with serotonergic medications, not with noradrenergics or dopaminergics, although dopaminergics can raise blood pressure on an MAOI.
CHRIS AIKEN: Stahl spent a lot of the talk dispelling these myths about drug interactions. He said that most tricyclic antidepressants can be used with caution with an MAOI except for two: imipramine and clomipramine, which have strong serotonergic reuptake inhibition. In our book Prescribing Psychotropics we are a little more conservative. We recommend sticking with the least serotonergic tricyclics if you’re going to use this strategy, which are desipramine, trimipramine, and doxepin, which is mainly used for insomnia. But both of us agree on using with caution – which means monitoring blood pressure, and only when the benefits outweigh the risk – in other words, the depression is severe and safer options have not worked.
KELLIE NEWSOME: Although amitriptyline was used in that recent case series, it does have mild serotonergic properties so we’re not ready to endorse it yet when there are safer tricyclics to draw from. We also agree with Stahl that bupropion, mirtazapine, and trazodone are relatively safe in combination with MAOIs.
CHRIS AIKEN: And while he opened up the door for those antidepressant combinations, Stahl also closed the door on a few psychotropics that have serotonergic effects but are not antidepressants. These should be avoided with MAOIs: 2 antipsychotics: ziprasidone (Geodon) and lumateperone (Caplyta). The new Auvelty – even though bupropion is OK, the dextromethorphan cough medicine in this antidepressant combo has mild serotonergic effects.
3 of 2000 prescribed an MAOI. Some would add buspirone, lithium, and the ketamines to that list, but the risk of serotonin syndrome is exceeding rare with these and Stahl put them in the “use with caution” category. Another controversial combination is the stimulant-MAOI. Here the risk is more of hypertension. Stimulants – particularly amphetamines – have weak serotonergic effects, but there are no cases of serotonin syndrome on them. Some experts use the MAOI-stimulant combo as a last resort in treatment-resistant depression, and the same precautions apply here as they do with the tricyclics. Stahl made a useful distinction, which is that – if you’re going to tread this rocky path – the methylphenidates are safer than the amphetamines. We agree.
KELLIE NEWSOME: After drug interactions, the other reason people avoid this renowned antidepressant class is the MAOI diet. No one wants a case of hypertensive crisis on their hands because their patient could not resist a tyramine-rich chunk of aged cheese. Drs Stahl and Stewart pointed to the updated MAOI diet, which is based on modern, post-2000’s methods of measuring tyramine, and is much more liberal and easy to follow than the stodgy old version. Their dietary guidelines were right in line with the ones we reviewed in our March 20 podcast. It’s also on page 142 of Prescribing Psychotropics.
KELLIE NEWSOME: In this podcast, we’ve covered 4 reasons to use an MAOI, let’s recap:
1. Atypical depression
2. Treatment resistant depression
3. Social anxiety disorder, and possibly panic disorder
This podcast is not a full MAOI prescribing guide – turn to our July 2018 online issue for that – but we will round it out with that most important question: Which MAOI to start with. There are 4 in the US, and the choice matters, so let’s get to know them.
1. Phenelzine. This of this one as the sleeper – fatigue is the main side effect – and you can remember that by its brand name Nardil which sounds like Narcolepsy. It also causes more weight gain and sexual dysfunction than the others, and unlike its competitor tranylcypromine it can cause vitamin B6 deficiency. Besides its MAOI base, phenelzine produces a metabolite with gaba-ergic properties, which may be why this one is the best studied MAOI in social anxiety disorder. Stahl called it a secret weapon there, actually he called it “bitchin.” And we agree. In multiple controlled trials, phenelzine has about double the effect size in social anxiety as an SSRI. Phenelzine also has small studies in panic disorder, and Stahl gave it the “bitchin” status for anxious depression, an anecdote that finds some support in small controlled trials from the 1970’s.
CHRIS AIKEN: 2. Tranylcypromine, brand name Parnate, the upper. This one is more activating and has dopaminergic properties, so some call it a triple-reuptake inhibitor. Unless your patient has insomnia, this is the MAOI to start with, if only to spare the weight gain, fatigue, and sexual dysfunction from phenelzine. But there’s a catch: Tranylcypromine is the most expensive of the MAOIs. These meds are prescribed so rarely. Even in the populations that need them most – complicated, chronic depressions in public mental health centers – only 1 in 1,000 take an MAOI. That has caused supply and demand bottlenecks that jack the price up.
KELLIE NEWSOME: Those are the top two, to recap: phenelzine for depression with anxiety disorders, and tranylcypromine for its favorable side effects. Otherwise, there is no difference in efficacy, and that has been tested in a head-to-head study. The third MAOI is isocarboxazid (Marplan). This one is third line. Why? Because there aren’t many studies in it. Not even anecdotal reports. So we just don’t know how it stacks up in treatment resistant depression.
CHRIS AIKEN: The same holds true for the fourth MAOI, selegiline, EMSAM. Many are drawn to this patch because it lacks food interactions, at least in the low dose of 6 mg. It also has the luster of a branded med – in other words, there’s a myth that it is better tolerated. But from experience I can tell you there little difference in the tolerability of EMSAM and tranylcypromine. Both are slightly activating and, that’s about the only side effect I’ve seen, although EMSAM patch causes skin irritation in most people and tranylcypromine causes hypotension at high doses. Dr. Stahl barely mentioned EMSAM, and he did not endorse it, for the same reasons I would steer away from it. First, MAOIs have a dose-dependent response, and if you’re moving in the MAOI direction you’re probably dealing with difficult to treat depression that’s going to need the higher dose. So while EMSAM is friendly to start out with, most patients need to march up to the 9-12 mg level where they’ll need to watch out for dietary tyramine. Second, EMSAM has no studies in treatment resistant depression, which is usually why you turn to an MAOI. Oral selegiline does, but only in high doses, like 30-60 mg/day, which is equivalent to 9-18 mg/day of EMSAM. So it may work – you can get to 12 mg with the patch – but it doesn’t go up to 18 mg and it is expensive.
KELLIE NEWSOME: At the Carlat Report, we do have a bias. We try to cover stories that aren’t getting covered by the main stream psychiatric press. Those unsponsored wonders like lightbox and ECT, exercise and psychotherapy, lithium, clozapine, and the MAOIs. We were pleased to see Dr. Stahl join the crusade, and we asked him drew him in. “The APA education committee asked me to put together a session on MAOIs. I see it as a way to give back to the meeting, and there will be future sessions on “old” meds like lithium and clozapine.” There was no honorarium, and he paid his own travel and registration.
CHRIS AIKEN: These days, it’s rare to see a psychiatrist of Stahl’s stature at the APA meeting, and pharmaceutical funding – or lack thereof – is part of the reason. In 2008 the APA completely cut ties with the pharmaceutical industry. Before that, the highlight of every meeting was the evening dinner symposium, where top researchers gave talks as audiences of over a thousand dined on 3 course meals. The industry paid for the set up, but the APA choose the speakers independently. At least, that’s how it was supposed to be. In reality, I’ve heard of pressures at such meetings to – say – feature a talk about pain because the maker of Cymbalta is funding it. But on the positive side it incentivized people to submit their best talks, and drew move talent in for talks in the daytime, lifting the quality of the conference overall.
Sadly, as the money dried up, so did the experts. Stahl is one of the last ones standing. But we can turn this around. I’m going to submit a talk for next year, and if you have an area of expertise I hope you will to. We’ll be true to the original Hippocratic Oath, where young doctors pledged to teach the art of medicine without reward or payment.
KELLIE NEWSOME: Stahl may have spoken without honorarium, but he was not without disclosures, and among the 3-dozen companies that reported relationships with one stood out to us that is worth mentioning. He is the Chief Medical Officer at Neurawell, a Florida-based pharmaceutical company that is developing an extended released MAOI and a combination MAOI and norepinephrine reuptake inhibitor.
CHRIS AIKEN: And now for the study of the day…. Reporting of harms in clinical trials of esketamine in depression: a systematic review, by Tanguy de Laportalière and colleagues from the journal Psychological Medicine.
The time before the was the wild west of clinical trials. Try reading those early papers. Often it’s unclear how the treatments were delivered, the diagnoses made, and the ratings assessed. Then in 1996 30 scientists came together to create the CONSORT guide, basic out standards for conducting and reporting on trials that are with us today. A year later, in 1997, the National Institutes of Health launched ClinicalTrials.gov, a public registry of clinical trials.
The registry started as a way to improve access to investigational drugs for patients with terminal illnesses like HIV and cancer, but it grew into a way to keep research honest. When trials are registered in advance, researchers can’t hide negative results or move the goal posts to fit the data. It also gives everyone a chance to look at the raw data, which is what the investigators in today’s study did for 10 trials of esketamine.
Using CONSORT as a standard, they compared the raw data on ClinicalTrials to the published studies for this anesthetic turned antidepressant. Here’s what they found. Only about 40% of adverse events in the raw data were reported in the published studies, including 179 serious adverse effects. Among the undisclosed were 49 serious adverse events including delirium, confusion, depression, 2 suicide attempts and one completed suicide, as well as medical events like cerebral hemorrhage, hypertensive crisis, and symptoms of inflammatory renal and urinary disease.
The studies largely missed on the CONSORT standards, failing to write down how the decided if an adverse event was related to the drug or not. On a positive note, the long term open-label study of esketamine – which was intended to detect adverse effects – had the highest CONSORT rating.
Why did they skip on the data? One possibility is that they only reported adverse events at the start of the treatment. But really, there’s no good excuse for this, especially when most of the unreported events occurred in the medication arm.
This is not to say that all of these were side effects to esketamine. Just that the data was missing. Esketamine was fast-tracked through FDA approval, allowing it to enter the market without the usual high standards we’re accustomed to for a new medication. Those standards, it now seems, are even lower than we knew.
KELLIE NEWSOME: Dr. Aiken posts a study a day on his LinkedIn and Twitter feed, the Daily Psych, @ChrisaikenMD. Earn CME for this podcast through the link in the show notes. Want more? Try one of our online journals in special editions of Child, Addiction, Geriatric, Hospital Psych, and, for the generalist our flagship Report.
Carlat CME Institute maintains responsibility for this program and its content. Carlat CME Institute designates this enduring material educational activity for a maximum of one quarter (.25) AMA PRA Category 1 CreditsTM. Physicians or psychologists should claim credit commensurate only with the extent of their participation in the activity