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Evidence-Based Reviews

MAO inhibitors: An option worth trying in treatment-resistant cases

Fears of hypertensive complications, drug-food interactions, and other side effects discourage many psychiatrists from prescribing MAOIs. The authors urge readers to rediscover these drugs, especially for treatment-resistant depressions and related disorders.

Vol. 1, No. 6 / June 2002
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Many fully trained psychiatrists, even psychopharmacologists, have rarely prescribed a monoamine oxidase inhibitor (MAOI), afraid of the possible consequences. One Boston-area psychiatrist who plans to retire soon has 12 patients who have been doing well for years on MAOIs. Before he called us, no psychiatrist in the area was willing to accept these patients who intended to stay on MAOIs.

Despite their potential side effects, the older MAOIs (phenelzine, tranylcypromine, isocarboxazid, and selegiline) have all been proven effective in depression; some studies have found them more effective than tricyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs).1,2 In our experience, MAOIs succeed in at least one-half the depressed patients who have failed on other antidepressants, and they are highly useful in treatment-resistant depressions and related disorders. Further, hypertensive crises are rare, and dietary restrictions are often exaggerated.

Drawing from the evidence and from our nearly 50 years’ experience in the use of MAOIs, we hope to acquaint or re-acquaint you with how to use these agents safely and to maximum effect.

When to use an MAOI

Reviews, meta-analyses, and more than 250 controlled studies have addressed MAOIs in psychiatric conditions.

The bulk of the literature reports a response rate of about 70% in various types of depression and anxiety.3 Unfortunately, because of the absence of major federal or industry funding, the findings are difficult to integrate, with most investigators testing different MAOIs on different subpopulations. This type of fragmented research, however, is not unique to MAOIs.

We at McLean have found MAOIs useful as second-line agents—and occasionally as first-line agents—in treating depression. We also use them as third-, fourth-, or fifth-line agents because we see many patients who have failed to respond to or tolerate several other antidepressants or whose response to other antidepressants has faded.

MAOIs are effective for a range of clinical presentations in inpatients and outpatients—depressive disorders (endogenous and atypical, unipolar and bipolar, neurasthenic and phobic), anxiety disorders (panic disorder and social phobia), and conditions as far afield as borderline personality disorder and the negative symptoms of schizophrenia.4

In controlled trials, many investigators have shown an MAOI to be more effective in some clinical conditions than a tricyclic and than a placebo.5 For example:

  • A group at Columbia University studied phenelzine in various permutations of atypical depression (rejection sensitivity, overeating, oversleeping, mood reactivity, severe lack of physical energy).6
  • Davidson et al studied isocarboxazid in anxious depression.7
  • Thase and Himmelhoch studied tranylcypromine in anergic and bipolar depressions.8
  • Liebowitz followed up with studies of phenelzine and tranylcypromine in social phobia.9
  • At Yale, early studies were done with phenelzine in posttraumatic stress disorder (PTSD).10
  • The British have generally argued for use of MAOIs in mixed anxiety and depression.11
  • The magisterial text Manic Depressive Illness recommends MAOIs as first-line treatment for bipolar depression.12

All of these studies yielded clinically and statistically substantial results with modest adverse effects.

Box 1


The enzymes MAO-A and MAO-B were identified in the 1950s. MAO-A occurs mainly in the intestine and brain, and the enzyme preferentially oxidizes (inactivates) serotonin and norepinephrine. MAO-B occurs in the brain and in platelets as well as in other tissues, and it inactivates phenylethylamine and benzylamine. Both enzymes metabolize tyramine and dopamine. The older MAOIs (phenelzine, tranylcypromine, isocarboxazid and high-dose selegiline) are irreversible MAO A and B inhibitors and block the actions of both enzymes from 14 to 28 days while new MAO enzymes are being resynthesized.

The actions of all MAOIs are presumed to be mediated by the blocking of the metabolism of intra- and extraneuronal biogenic amines, leading to increased brain levels of serotonin, norepinephrine, and dopamine.13 Even in the 1950s, when work with MAOIs was just beginning, these biogenic amines were suspected of being low or underactive in depression.

Research offers no real clues as to which enzyme is more important to inhibit or which of the various brain chemicals increased during MAOI therapy are crucial to clinical improvement. Two small studies suggest that decreasing the synthesis of brain serotonin will produce a temporary return of symptoms in patients clinically improved on MAOIs.14,15

The hypertensive crisis caused by tyramine has been shown to result from the inhibition of MAO-A, not MAO-B. More recent studies show effects of most MAOIs on receptors as well as enzymes. The basis or bases for MAO inhibitor actions may be more complex or different than anticipated.16

Characteristics of each agent

In the United States, a psychiatrist interested in using an MAOI for depressed patients can choose from among four agents. These older MAOIs are irreversible blockers of the enzymes MAO-A and MAO-B (Box 1).13-16

Tranylcypromine has been found effective in patients hospitalized with endogenous depressions.17 Most clinicians experienced with MAOIs prefer this agent because it triggers weight gain to a much lesser degree than other MAOIs. Tranylcypromine can cause insomnia and a greater increase in tyramine sensitivity than other MAOIs, which therefore brings a greater risk of hypertensive crisis.

Phenelzine has the advantage that the effective dosage for depression is probably now known—more than 1 mg/kg body weight—although in three earlier large negative controlled studies, the effective dosage was not known and too little was given for too short a period. Weight gain and hypotension may be more common with this drug than with other MAOIs.

Isocarboxazid is the least studied but has been shown to be effective, with an average 41% drug-placebo difference in two studies.16 One of us (JOC) preferred it for several years, based on good responses in a handful of treatment-resistant patients.

Selegiline is used in low dosages for parkinsonism. At higher dosages (more than 20 mg/d), selegiline is a good antidepressant but is no longer MAO-B selective—inhibiting both the MAO-B and MAO-A enzymes and thus requiring the usual dietary restrictions. One of us (JAB) routinely maintains bipolar patients with mild baseline depression or lethargy on a mood stabilizer plus a low dosage (5 to 10 mg/d) of selegiline. With this combination, patients are more satisfied and compliant with the mood stabilizer regimen and require no dietary restrictions.

Overall, there may be a special clinical benefit to phenelzine in the more anxious, easily distressed patient and to tranylcypromine or selegiline in the more sluggish, lethargic patient. But probably the soundest way to choose MAOIs is if other, more standard treatments have not worked.

Combinations with other antidepressants

We have found all antidepressants that do not involve significant serotonin reuptake inhibition (e.g., bupropion, trazodone, and tricyclics other than clomipramine) can be safely administered with MAOIs. Combination therapy is worth considering because it may be effective when other approaches have failed.

For a patient switching from an SSRI, a trial of one of these other antidepressants may be appropriate before undertaking MAOI therapy, simply because it avoids the SSRI washout period. Normally, patients should be off fluoxetine for 5 weeks, other SSRIs or clomipramine for 2 weeks, and venlafaxine for 1 week before starting an MAOI.

With the exception of clomipramine, TCAs generally are safe with MAOIs, although the Physician’s Desk Reference warns against adding a TCA to an MAOI. We know of one death and one case of delirium when parenteral imipramine was given to a patient who had been on a MAOI for some time unbeknownst to the MD giving the injection. Both amitriptyline (and by extension, nortriptyline) and trimipramine have been given along with an MAOI in controlled studies with no special adverse effects.18 Both drugs, and probably doxepin, are good hypnotics and seem safe in combination, although one should begin with a low dosage (e.g., 25 mg hs) if the patient is improving on an MAOI but is bothered by insomnia.

Table 1



Dosage range


20 to 80 mg/d


300 to 900 mg/d


30 to 90 mg/d


15 to 60 mg/d


20 to 100 mg/d

* Available in Canada but not in the United States

Trazodone is frequently employed as a remedy for MAOI-induced insomnia. 19 Mirtazapine can be used safely in combination with MAOIs, and the agent has been reported to acutely treat serotonin syndrome.20

Determining dosage

Failure to understand the required effective dosages of MAOIs led to many early treatment failures and fueled clinicians’ perception that drugs in this class were ineffective. The senior author had to hospitalize a depressed man who had failed to improve on 30 mg/d of phenelzine for 10 days. The author later learned that a dose of more than 1 mg/kg per day for 3 to 4 weeks was necessary for response.

A rule of thumb is to start with one MAOI pill the first day and increase the dosage by one pill every 4 to 7 days until these levels are reached:

  • 1 mg/kg/d for phenelzine;
  • 40 mg/d for tranylcypromine and isocarboxazid;
  • 45 mg/d for selegiline.

Reduce the dosage if side effects occur, or increase it if improvement is not noted in 1 to 2 months. We’ve tried starting patients on the 1 mg/kg dose of phenelzine the first day and elicited rapid and severe insomnia. Other intolerable side effects can also emerge from too-rapid dosage escalation. Clinical experience suggests the dosage ranges shown in Table 1.

Avoiding MAOI-related hypertension

We believe two factors have contributed to disuse of MAOIs by U.S. psychiatrists and slow development of new MAOIs here. These are the fear of severe hypertensive crisis and often vastly inflated MAOI dietary restrictions. In our practice, we provide patients receiving MAOIs with a reasonable list developed at the University of Toronto that explains foods to be avoided and alternatives that are allowed (Table 2).21

Table 2


Several foods and beverages contain tyramine and may interact with your medication. You MUST follow the dietary instructions below, from the day before you start taking the medication until 2 weeks after you stop taking the medication.

Note: All foods must be fresh or properly frozen. If you are not aware of the storage conditions of a particular food, AVOID that food.

Food to avoid

Food allowed


All matured or aged cheese
All casseroles made with cheeses (i.e., pizza, lasagna, etc.)

Fresh cottage cheese, cream cheese, ricotta cheese, and processed cheese slices. All fresh milk products that have been properly stored (i.e., sour cream, yogurt, ice cream)

Meat, fish, and poultry

Fermented/dry sausage (pepperoni, salami, mortadella, summer sausage)
Improperly stored meat, fish, poultry
Improperly stored pickled herring

All fresh packaged or processed meat (e.g., chicken loaf, hot dogs), fish, or poultry. Store in refrigerator immediately, and eat as soon as possible

Fruits and vegetables

Fava or broad bean pods (not beans)
Banana peel

Raspberries up to a maximum of one-quarter pound at one time
Banana pulp
All others


All on-tap beer

Alcohol: No more than two bottled or canned beers or 4-fl. oz. glasses of red or white wine per day. This applies to nonalcoholic beer also. Red wine may produce headache unrelated to a rise in blood pressure


Marmite-concentrated yeast extract
Soy sauce and other soy bean condiments

Other concentrated yeast extract (e.g., brewer’s yeast)
Soy milk

Reprinted with permission of the department of pharmacy, Sunnybrook and Women’s College Health Science Center, North York, Ontario, Canada. Copyright 1994

In experience, tyramine-associated hypertensive crisis in patients receiving the older MAOIs is rare, often very painful, and time-limited. Data on incidence of hypertensive crises with any MAOI is inadequate, except for a negligible incidence with low-dose selegiline and moclobemide (a reversible MAOI available in Canada but not in the United States). Most reported cases have involved tranylcypromine,22 which causes the greatest increase in sensitivity to tyramine, the basis of the dietary interaction with MAOIs.23 Specifically with tranylcypromine, transient hypertension can occur in the absence of dietary indiscretion or drug interaction.24,25

Food-associated hypertensive reactions are more common but unpredictable. A patient at McLean who had eaten cheese without trouble for 4 years while taking tranylcypromine in Europe mysteriously developed a severe headache after one bit of cheddar in the United States; she never tried an MAOI again. Another patient who took tranylcypromine for months at dosages exceeding 100 mg/d (but never took the tyramine restriction seriously) suffered a frightening pulsatile headache after a Chinese restaurant meal with soy sauce.

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