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

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

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

RECOMMENDED MAOI DOSAGE RANGES

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

DIETARY INSTRUCTIONS WITH MAOIs

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.

In our experience, oral adrenergic drugs (e.g., pseudoephedrine) can cause symptomatic hypertensive crises in patients taking MAOIs. Some over-the-counter cold preparations may contain an adrenergic decongestant, but it may not be listed clearly on the bottle. Cough syrup with codeine is preferable to OTC cough syrups that contain dextromethorphan. Patients should be urged to check labels and ask the pharmacist.

Advise patients taking MAOIs to purchase a blood pressure cuff or finger sphygmomanometer and learn how to take their own blood pressure. If they experience a “normal” headache and their systolic blood pressure is not elevated by at least 30 mm Hg, they are not having a “cheese reaction” and do not need to worry. MAOI headaches are typically unmistakable (they feel as if one’s head is splitting apart), and blood pressure is markedly elevated.

We give patients starting on MAOIs 10-mg tablets of nifedipine and advise them that if symptoms suggesting a hypertensive crisis appear, they should bite into one tablet to release the fluid inside and then swallow it. We tell patients to repeat this in 15 minutes if the headache is not receding; if the headache persists, they should visit the emergency ward or the internist’s office for observation.

Although there has been concern about the risk of MI or stroke with the hypotensive effect of nifedipine, we believe it is still the best option for acute severe hypertension in patients who do not have chronic hypertension. Chlorpromazine tablets (50 mg) also will stop the headache and lower blood pressure but will leave the patient groggy for about 24 hours, with possible extrapyramidal symptoms.

In the rare instance that a hypertensive crisis occurs, the “official” labeling recommendation is to give IV phentolamine, but we find emergency rooms either no longer stock the drug or do not remember to do this. Send any patient who is hurting and panicky to an ER, and call to suggest what the attending might do (i.e., IV phentolamine or oral nifedipine or chlorpromazine, or the emergency physician’s preference for hypertensive crisis).

Avoiding other MAOI-related side effects

Orthostatic hypotension is the most common early side effect of phenelzine and isocarboxazid. Clinically significant hypotension is best managed via dosage adjustment. If that fails, add Na Cl, 1 to 2 grams bid with increased fluids. If that doesn’t work, administer fludrocortisone, 0.1 to 0.4 mg/d. If that fails, administer d-amphetamine, starting with 2.5 to 5 mg/d, and observe carefully for hypertension.

An altered diurnal sleep cycle is another MAOI-related side effect. Some patients get extremely drowsy in the late afternoon but then may have insomnia at night.²⁶ Attempts to alter this odd cycle by changing the timing of administration have generally not helped. We add a stimulant—pemoline (18.75 to 35.5 mg), d-amphetamine (2.5 to 5 mg), methylphenidate (5 to 10 mg), or modafinil (50 to 100 mg)—either in the morning or during afternoon sleepiness, with good effect and no hypertensive crises. We supervise the effect on blood pressure of the first few doses. Another helpful alternative has been to administer trazodone at night to initiate sleep.

Box 2

MAOIs are adrenergic agonists, and dry mouth and constipation can occur as side effects; these can be treated with bethanechol. Edema also occurs, mainly with isocarboxazid and phenelzine, and responds in most cases to modest diuretic doses, such as hydrochlorothiazide, 50 mg/d.

The now-recognized trouble reaching orgasm on SSRIs was first reported to us by women on phenelzine, and this side effect is as difficult to treat with MAOIs as it is with other antidepressants. We have found that sexual dysfunction is less likely to occur with tranylcypromine and selegiline than other MAOIs.

Toward safer MAOIs

Newer reversible MAOIs are in development, and two agents are available (although not in the United States). Delivery systems that reduce the risk of hypertensive crisis also may soon be available (Box 2).^27,28

Related resources

• Amsterdam JD, Chopra M. Monoamine oxidase inhibitors revisited. Psychiatric Ann2001;31(6):361-70.
• Treatment with antidepressants. In: Janicak PG, Davis JM, Preskorn SH, Ayd FJ, eds. Principles and practice of psychopharmacotherapy. 3rd ed. Philadelphia: Lippincott, Williams & Wilkins, 2001:215-326.
• Kennedy SH, ed. Clinical Advances in Monoamine Oxidase Inhibitor Therapies. Progress in Psychiatry Series. Washington, DC: American Psychiatric Press, 1994.

Drug brand names

• Isocarboxazide • Marplan
• Moclobemide • Aurorix, Manerix
• Phenelzine • Nardil
• Selegiline • Eldepryl
• Tranylcypromine • Parnate

Disclosure

Dr. Cole reports that he has served as a consultant to SmithKline Beecham Pharmaceuticals, manufacturer of tranylcypromine, and to Somerset Pharmaceuticals, manufacturer of selegiline in the United States. He also has participated in clinical studies of selegiline.

Dr. Bodkin reports that he has served as a consultant to Somerset Pharmaceuticals and has been principal investigator in several multicenter trials of selegiline.

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

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

RECOMMENDED MAOI DOSAGE RANGES

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

DIETARY INSTRUCTIONS WITH MAOIs

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.

In our experience, oral adrenergic drugs (e.g., pseudoephedrine) can cause symptomatic hypertensive crises in patients taking MAOIs. Some over-the-counter cold preparations may contain an adrenergic decongestant, but it may not be listed clearly on the bottle. Cough syrup with codeine is preferable to OTC cough syrups that contain dextromethorphan. Patients should be urged to check labels and ask the pharmacist.

Advise patients taking MAOIs to purchase a blood pressure cuff or finger sphygmomanometer and learn how to take their own blood pressure. If they experience a “normal” headache and their systolic blood pressure is not elevated by at least 30 mm Hg, they are not having a “cheese reaction” and do not need to worry. MAOI headaches are typically unmistakable (they feel as if one’s head is splitting apart), and blood pressure is markedly elevated.

We give patients starting on MAOIs 10-mg tablets of nifedipine and advise them that if symptoms suggesting a hypertensive crisis appear, they should bite into one tablet to release the fluid inside and then swallow it. We tell patients to repeat this in 15 minutes if the headache is not receding; if the headache persists, they should visit the emergency ward or the internist’s office for observation.

Although there has been concern about the risk of MI or stroke with the hypotensive effect of nifedipine, we believe it is still the best option for acute severe hypertension in patients who do not have chronic hypertension. Chlorpromazine tablets (50 mg) also will stop the headache and lower blood pressure but will leave the patient groggy for about 24 hours, with possible extrapyramidal symptoms.

In the rare instance that a hypertensive crisis occurs, the “official” labeling recommendation is to give IV phentolamine, but we find emergency rooms either no longer stock the drug or do not remember to do this. Send any patient who is hurting and panicky to an ER, and call to suggest what the attending might do (i.e., IV phentolamine or oral nifedipine or chlorpromazine, or the emergency physician’s preference for hypertensive crisis).

Avoiding other MAOI-related side effects

Orthostatic hypotension is the most common early side effect of phenelzine and isocarboxazid. Clinically significant hypotension is best managed via dosage adjustment. If that fails, add Na Cl, 1 to 2 grams bid with increased fluids. If that doesn’t work, administer fludrocortisone, 0.1 to 0.4 mg/d. If that fails, administer d-amphetamine, starting with 2.5 to 5 mg/d, and observe carefully for hypertension.

An altered diurnal sleep cycle is another MAOI-related side effect. Some patients get extremely drowsy in the late afternoon but then may have insomnia at night.²⁶ Attempts to alter this odd cycle by changing the timing of administration have generally not helped. We add a stimulant—pemoline (18.75 to 35.5 mg), d-amphetamine (2.5 to 5 mg), methylphenidate (5 to 10 mg), or modafinil (50 to 100 mg)—either in the morning or during afternoon sleepiness, with good effect and no hypertensive crises. We supervise the effect on blood pressure of the first few doses. Another helpful alternative has been to administer trazodone at night to initiate sleep.

Box 2

MAOIs are adrenergic agonists, and dry mouth and constipation can occur as side effects; these can be treated with bethanechol. Edema also occurs, mainly with isocarboxazid and phenelzine, and responds in most cases to modest diuretic doses, such as hydrochlorothiazide, 50 mg/d.

The now-recognized trouble reaching orgasm on SSRIs was first reported to us by women on phenelzine, and this side effect is as difficult to treat with MAOIs as it is with other antidepressants. We have found that sexual dysfunction is less likely to occur with tranylcypromine and selegiline than other MAOIs.

Toward safer MAOIs

Newer reversible MAOIs are in development, and two agents are available (although not in the United States). Delivery systems that reduce the risk of hypertensive crisis also may soon be available (Box 2).^27,28

Related resources

• Amsterdam JD, Chopra M. Monoamine oxidase inhibitors revisited. Psychiatric Ann2001;31(6):361-70.
• Treatment with antidepressants. In: Janicak PG, Davis JM, Preskorn SH, Ayd FJ, eds. Principles and practice of psychopharmacotherapy. 3rd ed. Philadelphia: Lippincott, Williams & Wilkins, 2001:215-326.
• Kennedy SH, ed. Clinical Advances in Monoamine Oxidase Inhibitor Therapies. Progress in Psychiatry Series. Washington, DC: American Psychiatric Press, 1994.

Drug brand names

• Isocarboxazide • Marplan
• Moclobemide • Aurorix, Manerix
• Phenelzine • Nardil
• Selegiline • Eldepryl
• Tranylcypromine • Parnate

Disclosure

Dr. Cole reports that he has served as a consultant to SmithKline Beecham Pharmaceuticals, manufacturer of tranylcypromine, and to Somerset Pharmaceuticals, manufacturer of selegiline in the United States. He also has participated in clinical studies of selegiline.

Dr. Bodkin reports that he has served as a consultant to Somerset Pharmaceuticals and has been principal investigator in several multicenter trials of selegiline.

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

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

RECOMMENDED MAOI DOSAGE RANGES

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

DIETARY INSTRUCTIONS WITH MAOIs

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.

In our experience, oral adrenergic drugs (e.g., pseudoephedrine) can cause symptomatic hypertensive crises in patients taking MAOIs. Some over-the-counter cold preparations may contain an adrenergic decongestant, but it may not be listed clearly on the bottle. Cough syrup with codeine is preferable to OTC cough syrups that contain dextromethorphan. Patients should be urged to check labels and ask the pharmacist.

Advise patients taking MAOIs to purchase a blood pressure cuff or finger sphygmomanometer and learn how to take their own blood pressure. If they experience a “normal” headache and their systolic blood pressure is not elevated by at least 30 mm Hg, they are not having a “cheese reaction” and do not need to worry. MAOI headaches are typically unmistakable (they feel as if one’s head is splitting apart), and blood pressure is markedly elevated.

We give patients starting on MAOIs 10-mg tablets of nifedipine and advise them that if symptoms suggesting a hypertensive crisis appear, they should bite into one tablet to release the fluid inside and then swallow it. We tell patients to repeat this in 15 minutes if the headache is not receding; if the headache persists, they should visit the emergency ward or the internist’s office for observation.

Although there has been concern about the risk of MI or stroke with the hypotensive effect of nifedipine, we believe it is still the best option for acute severe hypertension in patients who do not have chronic hypertension. Chlorpromazine tablets (50 mg) also will stop the headache and lower blood pressure but will leave the patient groggy for about 24 hours, with possible extrapyramidal symptoms.

In the rare instance that a hypertensive crisis occurs, the “official” labeling recommendation is to give IV phentolamine, but we find emergency rooms either no longer stock the drug or do not remember to do this. Send any patient who is hurting and panicky to an ER, and call to suggest what the attending might do (i.e., IV phentolamine or oral nifedipine or chlorpromazine, or the emergency physician’s preference for hypertensive crisis).

Avoiding other MAOI-related side effects

Orthostatic hypotension is the most common early side effect of phenelzine and isocarboxazid. Clinically significant hypotension is best managed via dosage adjustment. If that fails, add Na Cl, 1 to 2 grams bid with increased fluids. If that doesn’t work, administer fludrocortisone, 0.1 to 0.4 mg/d. If that fails, administer d-amphetamine, starting with 2.5 to 5 mg/d, and observe carefully for hypertension.

An altered diurnal sleep cycle is another MAOI-related side effect. Some patients get extremely drowsy in the late afternoon but then may have insomnia at night.²⁶ Attempts to alter this odd cycle by changing the timing of administration have generally not helped. We add a stimulant—pemoline (18.75 to 35.5 mg), d-amphetamine (2.5 to 5 mg), methylphenidate (5 to 10 mg), or modafinil (50 to 100 mg)—either in the morning or during afternoon sleepiness, with good effect and no hypertensive crises. We supervise the effect on blood pressure of the first few doses. Another helpful alternative has been to administer trazodone at night to initiate sleep.

Box 2

MAOIs are adrenergic agonists, and dry mouth and constipation can occur as side effects; these can be treated with bethanechol. Edema also occurs, mainly with isocarboxazid and phenelzine, and responds in most cases to modest diuretic doses, such as hydrochlorothiazide, 50 mg/d.

The now-recognized trouble reaching orgasm on SSRIs was first reported to us by women on phenelzine, and this side effect is as difficult to treat with MAOIs as it is with other antidepressants. We have found that sexual dysfunction is less likely to occur with tranylcypromine and selegiline than other MAOIs.

Toward safer MAOIs

Newer reversible MAOIs are in development, and two agents are available (although not in the United States). Delivery systems that reduce the risk of hypertensive crisis also may soon be available (Box 2).^27,28

Related resources

• Amsterdam JD, Chopra M. Monoamine oxidase inhibitors revisited. Psychiatric Ann2001;31(6):361-70.
• Treatment with antidepressants. In: Janicak PG, Davis JM, Preskorn SH, Ayd FJ, eds. Principles and practice of psychopharmacotherapy. 3rd ed. Philadelphia: Lippincott, Williams & Wilkins, 2001:215-326.
• Kennedy SH, ed. Clinical Advances in Monoamine Oxidase Inhibitor Therapies. Progress in Psychiatry Series. Washington, DC: American Psychiatric Press, 1994.

Drug brand names

• Isocarboxazide • Marplan
• Moclobemide • Aurorix, Manerix
• Phenelzine • Nardil
• Selegiline • Eldepryl
• Tranylcypromine • Parnate

Disclosure

Dr. Cole reports that he has served as a consultant to SmithKline Beecham Pharmaceuticals, manufacturer of tranylcypromine, and to Somerset Pharmaceuticals, manufacturer of selegiline in the United States. He also has participated in clinical studies of selegiline.

Dr. Bodkin reports that he has served as a consultant to Somerset Pharmaceuticals and has been principal investigator in several multicenter trials of selegiline.