Understanding and Overcoming Negative Preconceptions About MAOIs

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CATEGORY 1 CME

Premiere Date: May 20, 2025

Expiration Date: November 20, 2026

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1. Physicians (CME)

2. Other

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ACTIVITY GOAL

To inform readers of the valuable role of monoamine oxidase inhibitors in many forms of treatment-resistant depression and refractory anxiety disorders.

1. Learn about the concerns associated with this class of medications and how to address them.

2. Describe best practices for prescribing monoamine oxidase inhibitors.

TARGET AUDIENCE

This accredited continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

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Editor’s Note: A subsequent CME article will contain information on MAOIs’ position in a treatment-resistant depression algorithm.

Although clinicians in the field often overlook monoamine oxidase inhibitors (MAOIs) in favor of newer treatment options, international thought leaders, study data, and clinical guidelines over 6-plus decades support their valuable role in many forms of treatment-resistant depression (eg, melancholia, atypical subtype, bipolar depression) and refractory anxiety disorders, notably including social anxiety and panic disorders.^1-3 For example, evidence in a recent state-of-the-art guidelines paper emphasized their clinical value.⁴ Similarly, data from a recent meta-analysis of approximately 6000 patients with depression across 52 controlled studies demonstrated that MAOIs, particularly phenelzine, were superior across a wide range of depressive disorders in efficacy and tolerability.⁵ In intellectual honesty, this latter meta- analysis contained a rather methodologically heterogeneous older group of studies, some with smaller numbers of patients. Nevertheless, what makes their findings valuable is that many of these older studies included inpatients (ie, patients with more severe illness), the lack of whom plagues many of the more recent clinical trials.⁶

Historical Context

MAOIs were discovered in the early 1950s when there was virtually no effective oral treatment for significant depression and anxiety disorders. Researchers noted that select patients with tuberculosis (TB) displayed dramatic changes in mood and vitality when given iproniazid, which was subsequently found to contain MAOI properties. As reported in the media back then, these patients were “dancing in the halls tho’ there were holes in their lungs.”^7,8

With the help of a perceptive cluster of psychiatrists, by the late 1950s, it became clear that iproniazid was an effective antidepressant medication for patients without TB. What followed in the late 1950s was a dramatic uptick in off-label prescriptions of iproniazid to treat depression.⁸

Despite the early clear benefit of iproniazid, as well as the other MAOIs that quickly followed it onto the world market, reports emerged of increasing cases of a syndrome of hypertension associated with a rapid blood pressure increase with pounding occipital headache and, more rarely, a fatal subarachnoid hemorrhage that is considered a hypertensive crisis.^8,9 This reaction was astutely connected to the ingestion of MAOIs in combination with aged cheese or, more precisely, the large quantities of a biogenic amine it contained (ie, tyramine). Although labeled the cheese reaction,^9,10 tyramine is a product of many aging foods, be it in the desired aging or fermentation of foods (ie, as in aged cheese or meats) or undesired aging (ie, in the spoiling or decaying of foods). Research data in the 1960s quickly identified other foods with large quantities of tyramine that also would need to be avoided with MAOIs.^9,10 Nonetheless, this interaction scared both regulatory agencies and practitioners.

Research findings questioning their clinical value beyond atypical depression further reinforced their diminishing use. Specifically, an often-cited study found MAOIs to be ineffective for significant depression, although this study was seriously flawed due to inadequate doses of MAOIs.¹¹

In this context, the initial excitement around MAOIs was replaced by hesitancy and fear.⁸ As time moved forward, the focus shifted first to tricyclic antidepressants and then newer antidepressants. Psychoeducation and research around MAOIs diminished, depriving clinicians of this tool for refractory illnesses.¹¹

Atypical Depression

The term atypical depression was initially used to differentiate a clinical state with preferential pharmacological response to MAOIs compared with either tricyclic antidepressants or electroconvulsive therapy (ECT).¹² This diagnosis included a subgroup of depression with an admixture of anxious and phobic symptoms, personality issues, and some secondary nonmelancholic depressive symptoms such as anergia and reactivity (ie, they do not display features commonly seen in endogenous depression such as guilt, anhedonia, psychomotor retardation, weight loss, and classic diurnal variation with early morning waking and improved mood at night).¹³

Presently, DSM-5 describes the subtype “major depression with atypical features” as requiring mood reactivity and 2 of 4 features—significant weight gain, hypersomnia, leaden paralysis, or interpersonal rejection sensitivity.¹⁴ Ironically, although this subtype was, in essence, created by the unique responsivity to MAOIs more than 60 years ago, the drug class is not the typical first-line treatment for it.¹³

The Cheese Reaction

To challenge and address the concerns associated with this class of medicine, it is important to understand the mechanism of the infamous cheese reaction.

There are 2 isoforms of the enzyme monoamine oxidase (MAO), the most relevant target of MAOIs. These are MAO-A and MAO-B, both of which are located in various brain regions. Notably, peripheral sympathetic neurons, the intestines, and the liver have large quantities of MAO-A; its function in the intestines and liver is to detoxify potentially problematic ingested vasoactive amines (such as tyramine).¹

Several factors come together, starting with an individual who is taking an MAOI ingesting a large dose of aged cheese laden with a high quantity of tyramine.^1,15 In the environment of significant inhibition of MAO-A in the gut and liver, without the catabolism of incoming tyramine, tyramine enters unopposed into the bloodstream and the presynaptic sympathomimetic neurons. These presynaptic neurons already contain elevated norepinephrine levels due to the actions of a nonselective MAOI, which blocks the breakdown of norepinephrine and multiple neurotransmitters. There is also diminished MAO-A at this location, precluding the neutralization of tyramine taken into sympathetic neurons. This induces the rapid release of additional norepinephrine out of the neuron, leading to excessive stimulation of postsynaptic adrenergic receptors with an ensuing sudden elevation of blood pressure shortly thereafter.

Thus, we see that tyramine’s effects are increased by MAO inhibition at various sites in the body and brain. The result may produce an admixture of symptoms: severe dramatic throbbing headache, chest discomfort, palpitations, heart rate changes, sweating, nausea, vomiting, neck stiffness, and/or photophobia.^1,15

This description of the reaction’s biological mechanism is somewhat streamlined; research data suggest other neurotransmitter-related mechanisms may also be relevant.¹⁵ For instance, additional variables play a role in whether a hypertensive reaction will be precipitated. This is illustrated by the inconsistent occurrence of this reaction, even when required dietary limitations are violated.¹⁵ The potential for a hypertensive reaction differs significantly from person to person, partly related to individual differences in tyramine sensitivity, and even in a given person from situation to situation where ostensibly they were ingesting the same amount of tyramine.

Fortunately, the list of potentially problematic foods is small, aided by adhering to a few basic principles.¹⁶ Over-the-counter and prescription medications that possess indirect sympathomimetic actions (the latter are now either known as monoamine releasers or releasers of presynaptic norepinephrine) can also pose a hypertensive risk by potentiating MAOI-induced norepinephrine increase.¹ Nonetheless, the medication list is also quite manageable.⁴

Although the reaction is rather uncomfortable, it is typically short lived—2 to 4 hours—and can be managed at home, perhaps with the aid of short-acting benzodiazepines (eg, lorazepam) to diminish associated anxiety until symptoms dissipate. It does not routinely require heroic measures in an emergency department (ED). When greatly excessive tyramine or a monoamine releaser is ingested, an ED evaluation may be required where it can be safely and rapidly managed.¹⁶ It is worth emphasizing that there have been no (nonoverdose related) fatal hypertensive reactions reported in the literature for decades.¹⁵

Anxious patients may misinterpret any typical headache as being related to the medication. I gently explain to patients that an MAOI headache is typically unmistakable in its intensity and quality and only associated with an elevation in blood pressure. Thus, there is value for patients having an at-home blood pressure cuff to reassure them that there is no hypertensive reaction occurring.¹⁷

Serotonin Toxicity Concerns

Experts proficient in MAOI use may have greater theoretical concern for the risk of serotonin toxicity.¹ Serotonin is one of the neurotransmitters whose breakdown is inhibited by MAOIs, increasing intrasynaptic serotonin. Thus, when added to other agents that increase extracellular serotonin, they may precipitate a dangerous serotonin toxicity with the associated symptoms and potential dangers.¹⁸ This is a dose-related reaction, and its severity is progressive with an increasing elevation of intrasynaptic serotonin.^15,18 Fortunately, observing a few basic practices is preventive (Table 1).

TABLE 1. Types of Agents to Avoid to Prevent Serotonin Syndrome

Challenging the Concerns

Several other concerns have been expressed that prevent clinicians and patients from considering MAOIs as a potential treatment option. Many of these can be addressed and accommodated by allowing the safe use of these agents. Thus, it is crucial to understand the concerns and how they can be addressed.

Draconian Dietary Restrictions

The likelihood of a significant hypertensive reaction has dropped significantly since MAOIs came to the market in the 1950s and 1960s. Only a limited number of foods contain potentially risky tyramine levels. The commercial food industry is working diligently to diminish the potential development of tyramine from its own perspective, as it may reflect poor food safety standards and hygiene. Tyramine is formed from the enzymatic decarboxylation of tyrosine in food by certain bacteria strains.^15,16

As a prominent psychopharmacologist recently wrote, adhering to a few basic rules is “90% of achieving a proper (MAOI) diet,” and thus the actual diet and medication list is rather modest.¹⁹ These rules include eating only foods that have been properly refrigerated. Most hypertensive reactions over my decades of use of these agents resulted from individuals eating spoiled foods. I tell my patients, “If in doubt, throw it out.”²⁰

Another useful guide to minimize hypertensive risk is to educate patients to limit themselves to healthy portions of foods, particularly those that may contain tyramine, which will help reduce the quantity of ingested tyramine or other pressor agent.^16,19 For example, although soy sauces may contain varying amounts of tyramine, ingesting smaller quantities is not likely to be problematic. When ordering at a Chinese restaurant, patients should request the soy sauce on the side so they can monitor the amounts. Similarly, there are reports of decreased tyramine in many cheeses, the original problematic culprit. Thus, we can confidently say that fresh cheeses, processed cheese, cheese spreads, and commercial pizza products (without problematic toppings such as hard salami and aged cheeses) are safe to ingest. Even some older cheeses, with portion control, are safe to eat.¹⁶ Cheeses that require particular care due to aging and fermentation processes are strong-smelling or -tasting hard cheeses, including those that are smear or mold ripened (eg, blue veined or hard and crumbly).¹⁹

Research has shown that alcoholic beverages in proper moderation are not problematic. Exceptions are tap, unpasteurized, artisanal, or home-brewed beers. There is reported variability in tyramine content in dry-cured or fermented aged meats. In contrast, fresh meats, fish, and poultry products are not problematic. Other products of possible concern include homemade (not commercial) sourdough breads, fermented fish sauces, some fermented soy products (eg, stinky tofu, sufu), sauerkraut, and overripe bananas.

In general, instruct patients to be on the lookout for deliberately fermented or matured products that may develop significant tyramine concentrations. At the initiation of an MAOI trial, verbally review the diet while searching for any potentially problematic foods that the patient tends to eat in large amounts. Also, provide them with a written copy of their diet (Tables 2 and 3).

TABLE 2. Dietary Guidelines

TABLE 3. Foods to Avoid

Risky Drug-Drug Interactions

Some medications need to be avoided, but they are specific and limited. They include medicines that have indirect sympathomimetic actions—in other words, monoamine releasers—such as over-the-counter decongestants (eg, pseudoephedrine), ephedrine, and any medicine that either releases or blocks the reuptake of serotonin.¹⁵ Table 4 lists other medications to be careful about; review these with your patient and give them a written copy of this information when treatment starts.

TABLE 4. Medications/Drugs to Avoid

Stopping MAOIs Before Surgery

Findings from a recent review showed that MAOIs do not need to be stopped weeks before or even days prior to surgery as previously mandated, as a competent anesthesiologist can work around them safely.^1,21 The 2 potential historical concerns in the perioperative setting for patients receiving MAOIs are, firstly, serotonin toxicity and, secondly, the potentiated hypertensive effects of vasoconstrictors, notably indirectly acting sympathomimetic amines. Anesthesiologists and other involved doctors can avoid these by not prescribing a small group of potentially problematic serotonergic-releasing agents (these include a few analgesics), similarly not utilizing indirect monoamine releasers such as ephedrine or metaraminol, and slowlyand judiciously titrating directly acting adrenergic agonists such as epinephrine or norepinephrine, dobutamine, or isoproterenol.^1,21

Adverse Effects

Like all medicines, MAOIs have adverse effects, but many diminish over time. Study data have not shown MAOIs’ adverse effects to be more problematic than newer antidepressants.² The adverse effect profile differs between the various MAOIs (Table 5).^16,22

TABLE 5. MAOI Adverse Effects and Treatment

Clinical experience and prevalence data involving transdermal selegiline and tranylcypromine reflect that sexual dysfunction occurs notably less often with MAOIs (except perhaps phenelzine) than with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).^23,24 Weight gain, another potential long-term burden of newer antidepressants, is generally minimal with MAOIs, again with the exception of phenelzine. On the other side of the adverse effect burden spectrum, transdermal selegiline, although potentially activating, appears to be the best-tolerated MAOI.²⁵

The most common MAOI adverse effect is not the hypertensive reaction discussed previously but orthostatic hypotension, which tends to improve with time.^26,27 If necessary, it can be treated with a few simple rules such as getting up slowly, wearing compression stockings, or adding salt tablets, 1 to 10 g per day. Extra caution is warranted in geriatric patients regarding this adverse effect. Interestingly, for unknown pharmacologic reasons, it has been observed that orthostasis is a good correlate of whether there is adequate MAOI inhibition for potential treatment response.²⁶ I frame its occurrence as a positive indicator providing a measure of hope as a patient awaits therapeutic response.

Insomnia has been associated with these agents and sometimes requires an additional agent to address the problem, including trazodone, mirtazapine, or doxepin. Tranylcypromine tends to be the most activating.²²

Brief periods of paradoxical daytime fatigue are not uncommon with MAOIs. If problematic, treatment options include a dose of caffeine or the use of a prescription medicine, such as modafinil or low-dose methylphenidate.²⁸

Switching to an MAOI From a Newer Antidepressant

The concern that MAOIs require an excruciatingly painful washout period can be addressed through the clinical use of bridging,^4,29 which refers to giving a patient another agent that is not problematic as they taper and discontinue an SSRI or SNRI in preparation for an MAOI trial. This medicine’s role in the interim washout period is to minimize the discomfort, or anticipated discomfort, in waiting to initiate and titrate up an MAOI trial. There is a long list of safe medication options that can be used, including a benzodiazepine; other antidepressants, such as bupropion, mirtazapine, or nortriptyline; or an atypical antipsychotic. Anecdotally, if the bridging medication is a potent antidepressant (eg, nortriptyline), occasionally there is a surprising clinical benefit that negates the need for the MAOI trial. A newer, interesting bridging option, supported in anecdotal reports and case series, is the use of esketamine or off-label intravenous ketamine.^4,28,30

In terms of the specifics of the washout between an SSRI, SNRI, or other serotonin-releasing agent before initiating an MAOI, the consensus is that a washout period of not less than 5 half-lives of the serotonergic agent is required; for most antidepressants that is approximately 8 to 10 days.⁴ Exceptions include fluoxetine, which requires at least a 5- or 6-week washout, particularly at high doses, and vortioxetine, with its longer half-life requiring a 14-day washout.⁴

In terms of washing out in the other direction (ie, discontinuing an MAOI), 2 weeks are required to regenerate new MAO enzymes. The MAOIs available in the United States are all irreversible in nature; once they inactivate the MAO enzyme, new MAO enzymes need to be generated.⁴

Fear That MAOIs Cannot Be Used if a Patient Has Hypertension

Decades ago, some MAOIs were used to treat hypertension.³¹ Therefore, a patient taking an MAOI whose hypertension is well controlled is at no greater risk than they would be with other antidepressants while taking these medications. Some patients might require a downward titration in their hypertensive medication regimen due to the MAOI’s antihypertensive effects. If blood pressure is not yet controlled, waiting to initiate an MAOI trial until it is controlled is recommended.⁴

Fear That Stimulants Cannot Be Prescribed With MAOIs

The combination of stimulants and MAOIs has been labeled by the FDA as contraindicated since the early days of MAOI use due to fatal case reports in the 1950s and 1960s.³² The reality is that this absolute contraindication does apply to concomitant high-dose amphetamine use, both because of its monoamine-releasing effects and its reported serotonergic reuptake blockade properties.^1,4,32 Methylphenidate is much less of an issue because it has no such serotonergic reuptake blockade properties; the same is true for lower-dose amphetamine.³² When combining these medicines, apply a rule of good psychiatric practice: Start low, go slow, and make one medicine change at a time.^28,32 Because this can be a delicate process, the clinician should have experience with MAOIs in general before trialing this combination.

There is literature suggesting MAOIs have efficacy in treating attention-deficit/hyperactivity disorder (ADHD) symptoms.^33-35 Anecdotally, the concomitant use of an MAOI and a stimulant has helped minimize the need for prior or more standard doses of ADHD medications.

Concluding Thoughts

MAOIs can be a useful agent when treating depression, but there are some issues that must be considered. A subsequent article will discuss additional considerations, including efficacy and MAOIs’ position in a treatment-resistant depression algorithm.

Dr Feinberg is an associate clinical professor of psychiatry at Montefiore Medical Center, Albert Einstein College of Medicine of Yeshiva University in Bronx, New York.

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