A concise guide to monoamine oxidase inhibitors: How to avoid drug interactions

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Monoamine oxidase inhibitors (MAOIs) have well-established efficacy for treating depression, panic disorder, and social phobia. However, a lack of familiarity with these agents and misconceptions about the risks associated with their use have led to MAOIs being substantially underutilized. The goal of this 2-part guide to MAOIs is to educate clinicians about this often-overlooked class of medications. Part 1 (“A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A) described the pharmacology of MAOIs, the mechanism by which tyramine induces hypertension in patients taking MAOIs, and what to tell patients about dietary restrictions associated with these medications. Part 2 covers how to avoid potential drug interactions, including serotonin syndrome (SS) and pressor effects, that could affect patients receiving an MAOI; other factors to consider when starting a patient on an MAOI; and augmentation strategies for depressed patients who do not achieve remission from MAOI monotherapy.

MAOIs and potential drug interactions

One source of concern in patients receiving irreversible nonselective MAOIs is the development of excessive serotonergic neurotransmission resulting in SS. In the 1960s, researchers noted that administering large doses of tryptophan to MAOI-treated patients resulted in clonus and hyperactive reflexes without hypertensive events.¹ In 1991, Sternbach² provided an extensive case series and described the first set of criteria for SS. Features of SS include:

mild symptoms: tremor, akathisia, inducible clonus
moderate symptoms: spontaneous or sustained clonus, muscular hypertonicity
severe symptoms: hyperthermia, diaphoresis.²

Although SS can be induced by significant exposure to individual agents that promote excess synaptic serotonin (eg, overdose of selective serotonin reuptake inhibitors [SSRIs]), the majority of fatal cases have occurred among patients taking MAOIs who were coadministered an agent that inhibited serotonin reuptake (Table 1³). Animal studies have determined that excessive stimulation of the 5HT2A receptor is primarily responsible for SS,⁴ and that 5HT2A antagonists, such as mirtazapine, can block the development of SS in a mouse coadministered fluoxetine and tranylcypromine.⁵ In addition to a patient’s medication history, the clinical hallmark of SS that helps distinguish it from neuroleptic malignant syndrome, delirium, and other acute syndromes is clonus, which becomes spontaneous and sustained as the severity increases.

Risk for SS. Most medications that promote serotonergic activity are well known for their use as antidepressants, but other agents that have 5HT reuptake properties (eg, the antihistamine chlorpheniramine) must be avoided. Although older literature suggests that the use of lower doses of certain tricyclic antidepressants concurrently with MAOIs may not be as dangerous as once believed,⁶ there are sufficient reports of serious outcomes that tricyclics should be avoided in patients taking MAOIs because of the risk of SS, and also because, in general, tricyclics are poorly tolerated.⁷

Desipramine, a potent norepinephrine transporter (NET) inhibitor, blocks the entry of tyramine into cells by NET, thereby preventing hypertensive events in animal models of tyramine overexposure. However, in some assays, the affinity for the serotonin transporter is not insignificant, so at higher doses desipramine may pose the same theoretical risk for SS as seen with other tricyclics.³

Lastly, rasagiline is an MAO-B selective inhibitor that has been available in the United States since 2008 for the treatment of Parkinson’s disease (PD). Although this drug lacks MAO-A antagonism, its package insert carries SS warnings; however, analysis of outcomes from a large multicenter rasagiline trial (N = 1,504) found no SS events in the 471 patients receiving rasagiline plus antidepressants (74.5% on SSRIs).⁸ Because depression is a common comorbidity in PD, clinicians who encounter rasagiline-treated patients who need antidepressant therapy should consult with the patient’s neurologist regarding their experience and comfort level with combining rasagiline and SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs).

Astute clinicians will recognize that antidepressants that lack 5HT reuptake (eg, bupropion, mirtazapine) are not on this list of agents that may increase SS risk when taken with an MAOI. Older papers often list mirtazapine, but as a 5HT2A antagonist, it does not possess a plausible mechanism by which it can induce 5HT toxicity.^9,10 Most atypical antipsychotics have significant 5HT2A antagonism and can be combined with MAOIs, but ziprasidone is an exception: as a moderate SNRI, it has been associated with SS when administered with an MAOI.¹¹

Pressor reactions. The only theoretical sources of concern for pressor effects are medications that act as norepinephrine releasers through interactions at the trace amine-associated receptor 1 (TAAR1) (for more information on TAAR1, see “A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A). Amphetamines are one such class, but a 2004 review did not find cases of hypertensive crises when amphetamines were combined with MAOIs,¹² nor did a recent article that described the combined use of lisdexamfetamine and transdermal selegiline.¹³ Presumably, the low level of intracellular exposure mitigates the risk of excessive TAAR1 agonism, but amphetamine derivatives should be approached cautiously and with careful blood pressure monitoring. On the other hand, methylphenidate is an inhibitor of dopamine reuptake with no affinity for TAAR1¹⁴ or the serotonin transporter,¹⁵ and does not induce a pressor response nor increase risk for SS when combined with MAOIs.³ Concerns about the use of α1-adrenergic agonists in patients taking MAOIs are not universal, as the deleterious effects on blood pressure are seen only in certain vulnerable patients, typically those with preexisting hypertension. Nonetheless, all patients should be cautioned about the use of phenylephrine and pseudoephedrine.¹⁶

Starting a patient on an MAOI

Contraindicated medications need to be tapered before beginning MAOI treatment. The duration of the washout period depends on the half-life of the medication and any active metabolites. Antidepressants with half-lives of approximately ≤24 hours should be tapered over 7 to 14 days (depending on the dose) to minimize the risk of withdrawal syndromes, while those with long half-lives (eg, fluoxetine, vortioxetine) can be stopped abruptly. After stopping a medication for 5 half-lives, 96.875% of the medication is removed, so adequate time must elapse after the last dose before starting an MAOI. Table 2^17-22 lists the half-lives of commonly used newer antidepressants and any active metabolites or isomers. Clinicians should always err on the side of caution before starting an MAOI, and give their patients a brief overview of SS symptoms; however, be mindful of not extending time the patient is without effective antidepressant levels.

Initiation of an MAOI is always based on whether the patient can reliably follow the basic dietary advice (see “A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A), and they agree to check with their clinician before starting new medications. Titration of MAOIs should be based on tolerability; orthostasis is the primary dose-limiting adverse effect associated with rapid titration or higher dosages. This may be especially true in older patients with poor vasomotor tone, or those on α1-adrenergic antagonists or other agents that may induce orthostatic effects. The rapid titration schedules present in certain package inserts (eg, phenelzine²³) should not be followed.

The orthostasis management strategy is similar to that employed for clozapine: minimize the use of concurrent α1-adrenergic antagonists, lower the doses of antihypertensives as much as possible, and encourage adequate fluid intake. For patients with ongoing orthostasis and without a history of congestive heart failure, consider using the potent mineralocorticoid fludrocortisone starting at 0.1 mg/d, and titrating every 10 to 14 days if needed to a maximum of 0.3 mg/d.²⁴ Older literature noted weight gain, peripheral edema, and sexual dysfunction as common adverse effects. Research on the most recently studied MAOI, selegiline transdermal, reported rates of these adverse effects as follows: weight gain: 2.1% for selegiline transdermal vs 2.4% for placebo; all forms of sexual dysfunction: 0 to 1% for selegiline transdermal vs 0 to 0.4% for placebo.²⁵

Augmentation options for patients taking MAOIs

For depressed patients who do not achieve remission of symptoms from MAOI therapy, augmentation options should be sought, as patients who respond but fail to remit are at increased risk of relapse.²⁶ Lithium augmentation is one of the more common strategies, with abundant data supporting its use.^27,28 Case reports dating back >12 years describe the concurrent use of bupropion and MAOIs.^12,29 A recent review of augmentation of MAOIs with second-generation antipsychotics found multiple positive reports for most agents, including aripiprazole, with the sole exception of ziprasidone, a moderate SNRI for which cases of SS have been reported.¹¹ As of November 2017, there are no case reports for asenapine, lurasidone, brexpiprazole, or cariprazine. Triiodothyronine is often a neglected strategy, but older case reports of combined treatment with MAOIs found no obvious concerns beyond those related to the use of thyroid hormone.^30,31

Bottom Line

When prescribing a monoamine oxidase inhibitor (MAOI), ensure that your patient isn’t taking other medications that could cause an interaction that results in serotonin syndrome or pressor effects. When initiating MAOI therapy, titrate slowly to avoid orthostasis. Strategies for augmenting MAOIs include lithium, bupropion, and second-generation antipsychotics, except for ziprasidone.

Related Resource

Meyer JM. A concise guide to monoamine oxidase inhibitors. First of 2 parts. Current Psychiatry. 2017;16(12):14-16,18-23,47,A.

Drug Brand Names

Amitriptyline • Elavil
Aripiprazole • Abilify
Asenapine • Saphris, Sycrest
Brexpiprazole • Rexulti
Bupropion • Wellbutrin XL, Zyban
Cariprazine • Vraylar
Chlorpheniramine • Chlorphen, Chlor-Trimeton
Citalopram • Celexa
Clomipramine • Anafranil
Clozapine • Clozaril
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Dextromethorphan • Delsym, Robitussin
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fentanyl • Duragesic, Subsys
Fludrocortisone • Florinef
Fluoxetine • Prozac, Sarafem
Fluvoxamine • Luvox
Imipramine • Tofranil
Levomilnacipran • Fetzima
Linezolid • Zyvox
Lisdexamfetamine • Vyvanse

References

1. Krishnamoorthy S, Ma Z, Zhang G, et al. Involvement of 5-HT2A receptors in the serotonin (5-HT) syndrome caused by excessive 5-HT efflux in rat brain. Basic Clin Pharmacol Toxicol. 2010;107(4):830-841.
2. Sternbach H. The serotonin syndrome. Am J Psychiatry 1991;148(6):705-713.
3. Gillman PK. Monoamine oxidase inhibitors: a review concerning dietary tyramine and drug interactions. PsychoTropical Commentaries. 2016;16(6):1-90.
4. Haberzettl R, Fink H, Bert B. Role of 5-HT(1A)- and 5-HT(2A) receptors for the murine model of the serotonin syndrome. J Pharmacol Toxicol Methods. 2014;70(2):129-133.
5. Shioda K, Nisijima K, Yoshino T, et al. Mirtazapine abolishes hyperthermia in an animal model of serotonin syndrome. Neurosci Lett. 2010;482(3):216-219.
6. White K, Simpson G. Combined MAOI-tricyclic antidepressant treatment: a reevaluation. J Clin Psychopharmacol. 1981;1(5):264-282.
7. Otte W, Birkenhager TK, van den Broek WW. Fatal interaction between tranylcypromine and imipramine. Eur Psychiatry. 2003;18(5):264-265.
8. Panisset M, Chen JJ, Rhyee SH, et al. Serotonin toxicity association with concomitant antidepressants and rasagiline treatment: retrospective study (STACCATO). Pharmacotherapy. 2014;34(12):1250-1258.
9. Gillman PK. Mirtazapine: unable to induce serotonin toxicity? Clin Neuropharmacol. 2003;26(6):288-289; author reply 289-290.
10. Gillman PK. A systematic review of the serotonergic effects of mirtazapine in humans: implications for its dual action status. Hum Psychopharmacol. 2006;21(2):117-125.
11. Meyer JM, Cummings MA, Proctor G. Augmentation of phenelzine with aripiprazole and quetiapine in a treatment resistant patient with psychotic unipolar depression: case report and literature review. CNS Spectr. 2017;22(5):391-396.
12. Feinberg SS. Combining stimulants with monoamine oxidase inhibitors: a review of uses and one possible additional indication. J Clin Psychiatry. 2004;65(11):1520-1524.
13. Israel JA. Combining stimulants and monoamine oxidase inhibitors: a reexamination of the literature and a report of a new treatment combination. Prim Care Companion CNS Disord. 2015;17(6). doi: 10.4088/PCC.15br01836.
14. Simmler LD, Buchy D, Chaboz S, et al. In vitro characterization of psychoactive substances at rat, mouse, and human trace amine-associated receptor 1. J Pharmacol Exp Ther. 2016;357(1):134-144.
15. Froimowitz M, Gu Y, Dakin LA, et al. Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter. J Med Chem. 2007;50(2):219-232.
16. Stahl SM, Felker A. Monoamine oxidase inhibitors: a modern guide to an unrequited class of antidepressants. CNS Spectr. 2008;13(10):855-780.
17. Hiemke C, Härtter S. Pharmacokinetics of selective serotonin reuptake inhibitors. Pharmacol Ther. 2000;85(1):11-28.
18. Pristiq [package insert]. New York, NY: Pfizer Inc; 2016.
19. Savella [package insert]. Irvine, CA: Allergan USA Inc; 2016.
20. Viibryd [package insert]. Irvine, CA: Allergan USA Inc; 2016.
21. Trintellix [package insert]. Deerfield, IL: Takeda Pharmaceuticals America Inc; 2016.
22. Fetzima [package insert]. Irvine, CA: Allergan USA Inc; 2017.
23. Nardil [package insert]. New York, NY: Pfizer Inc; 2009.
24. Testani M Jr. Clozapine-induced orthostatic hypotension treated with fludrocortisone. J Clin Psychiatry. 1994;55(11):497-498.
25. Emsam [package insert]. Morgantown, WV: Somerset Pharmaceuticals Inc; 2015.
26. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917.
27. Tariot PN, Murphy DL, Sunderland T, et al. Rapid antidepressant effect of addition of lithium to tranylcypromine. J Clin Psychopharmacol. 1986;6(3):165-167.
28. Kok RM, Vink D, Heeren TJ, et al. Lithium augmentation compared with phenelzine in treatment-resistant depression in the elderly: an open, randomized, controlled trial. J Clin Psychiatry. 2007;68(8):1177-1185.
29. Quante A, Zeugmann S. Tranylcypromine and bupropion combination therapy in treatment-resistant major depression: a report of 2 cases. J Clin Psychopharmacol. 2012;32(4):572-574.
30. Joffe RT. Triiodothyronine potentiation of the antidepressant effect of phenelzine. J Clin Psychiatry. 1988;49(10):409-410.
31. Hullett FJ, Bidder TG. Phenelzine plus triiodothyronine combination in a case of refractory depression. J Nerv Ment Dis. 1983;171(5):318-320.

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Author and Disclosure Information

Jonathan M. Meyer, MD
Psychopharmacology Consultant
California Department of State Hospitals
Sacramento, California
Clinical Professor of Psychiatry
University of California, San Diego
San Diego, California
Deputy Editor, Current Psychiatry

Disclosure
Dr. Meyer is a consultant to Acadia Pharmaceuticals, Neurocrine Biosciences, Inc., and Teva Pharmaceutical Industries; and is a speaker for Acadia Pharmaceuticals, Alkermes, Allergan, Merck, Otsuka America, Inc., and Sunovion Pharmaceuticals.

Issue

January 2018

Publications

MDedge Psychiatry

Current Psychiatry

Topics

Depression

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22-24,28,33

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Evidence-Based Reviews

Reviews

Author(s)

Jonathan M. Meyer, MD

Author(s)

Jonathan M. Meyer, MD

Author and Disclosure Information

Jonathan M. Meyer, MD
Psychopharmacology Consultant
California Department of State Hospitals
Sacramento, California
Clinical Professor of Psychiatry
University of California, San Diego
San Diego, California
Deputy Editor, Current Psychiatry

Disclosure
Dr. Meyer is a consultant to Acadia Pharmaceuticals, Neurocrine Biosciences, Inc., and Teva Pharmaceutical Industries; and is a speaker for Acadia Pharmaceuticals, Alkermes, Allergan, Merck, Otsuka America, Inc., and Sunovion Pharmaceuticals.

Author and Disclosure Information

Jonathan M. Meyer, MD
Psychopharmacology Consultant
California Department of State Hospitals
Sacramento, California
Clinical Professor of Psychiatry
University of California, San Diego
San Diego, California
Deputy Editor, Current Psychiatry

Disclosure
Dr. Meyer is a consultant to Acadia Pharmaceuticals, Neurocrine Biosciences, Inc., and Teva Pharmaceutical Industries; and is a speaker for Acadia Pharmaceuticals, Alkermes, Allergan, Merck, Otsuka America, Inc., and Sunovion Pharmaceuticals.

Article PDF

CP01701022.PDF

Article PDF

CP01701022.PDF

Monoamine oxidase inhibitors (MAOIs) have well-established efficacy for treating depression, panic disorder, and social phobia. However, a lack of familiarity with these agents and misconceptions about the risks associated with their use have led to MAOIs being substantially underutilized. The goal of this 2-part guide to MAOIs is to educate clinicians about this often-overlooked class of medications. Part 1 (“A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A) described the pharmacology of MAOIs, the mechanism by which tyramine induces hypertension in patients taking MAOIs, and what to tell patients about dietary restrictions associated with these medications. Part 2 covers how to avoid potential drug interactions, including serotonin syndrome (SS) and pressor effects, that could affect patients receiving an MAOI; other factors to consider when starting a patient on an MAOI; and augmentation strategies for depressed patients who do not achieve remission from MAOI monotherapy.

MAOIs and potential drug interactions

One source of concern in patients receiving irreversible nonselective MAOIs is the development of excessive serotonergic neurotransmission resulting in SS. In the 1960s, researchers noted that administering large doses of tryptophan to MAOI-treated patients resulted in clonus and hyperactive reflexes without hypertensive events.¹ In 1991, Sternbach² provided an extensive case series and described the first set of criteria for SS. Features of SS include:

mild symptoms: tremor, akathisia, inducible clonus
moderate symptoms: spontaneous or sustained clonus, muscular hypertonicity
severe symptoms: hyperthermia, diaphoresis.²

Although SS can be induced by significant exposure to individual agents that promote excess synaptic serotonin (eg, overdose of selective serotonin reuptake inhibitors [SSRIs]), the majority of fatal cases have occurred among patients taking MAOIs who were coadministered an agent that inhibited serotonin reuptake (Table 1³). Animal studies have determined that excessive stimulation of the 5HT2A receptor is primarily responsible for SS,⁴ and that 5HT2A antagonists, such as mirtazapine, can block the development of SS in a mouse coadministered fluoxetine and tranylcypromine.⁵ In addition to a patient’s medication history, the clinical hallmark of SS that helps distinguish it from neuroleptic malignant syndrome, delirium, and other acute syndromes is clonus, which becomes spontaneous and sustained as the severity increases.

Risk for SS. Most medications that promote serotonergic activity are well known for their use as antidepressants, but other agents that have 5HT reuptake properties (eg, the antihistamine chlorpheniramine) must be avoided. Although older literature suggests that the use of lower doses of certain tricyclic antidepressants concurrently with MAOIs may not be as dangerous as once believed,⁶ there are sufficient reports of serious outcomes that tricyclics should be avoided in patients taking MAOIs because of the risk of SS, and also because, in general, tricyclics are poorly tolerated.⁷

Desipramine, a potent norepinephrine transporter (NET) inhibitor, blocks the entry of tyramine into cells by NET, thereby preventing hypertensive events in animal models of tyramine overexposure. However, in some assays, the affinity for the serotonin transporter is not insignificant, so at higher doses desipramine may pose the same theoretical risk for SS as seen with other tricyclics.³

Lastly, rasagiline is an MAO-B selective inhibitor that has been available in the United States since 2008 for the treatment of Parkinson’s disease (PD). Although this drug lacks MAO-A antagonism, its package insert carries SS warnings; however, analysis of outcomes from a large multicenter rasagiline trial (N = 1,504) found no SS events in the 471 patients receiving rasagiline plus antidepressants (74.5% on SSRIs).⁸ Because depression is a common comorbidity in PD, clinicians who encounter rasagiline-treated patients who need antidepressant therapy should consult with the patient’s neurologist regarding their experience and comfort level with combining rasagiline and SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs).

Astute clinicians will recognize that antidepressants that lack 5HT reuptake (eg, bupropion, mirtazapine) are not on this list of agents that may increase SS risk when taken with an MAOI. Older papers often list mirtazapine, but as a 5HT2A antagonist, it does not possess a plausible mechanism by which it can induce 5HT toxicity.^9,10 Most atypical antipsychotics have significant 5HT2A antagonism and can be combined with MAOIs, but ziprasidone is an exception: as a moderate SNRI, it has been associated with SS when administered with an MAOI.¹¹

Pressor reactions. The only theoretical sources of concern for pressor effects are medications that act as norepinephrine releasers through interactions at the trace amine-associated receptor 1 (TAAR1) (for more information on TAAR1, see “A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A). Amphetamines are one such class, but a 2004 review did not find cases of hypertensive crises when amphetamines were combined with MAOIs,¹² nor did a recent article that described the combined use of lisdexamfetamine and transdermal selegiline.¹³ Presumably, the low level of intracellular exposure mitigates the risk of excessive TAAR1 agonism, but amphetamine derivatives should be approached cautiously and with careful blood pressure monitoring. On the other hand, methylphenidate is an inhibitor of dopamine reuptake with no affinity for TAAR1¹⁴ or the serotonin transporter,¹⁵ and does not induce a pressor response nor increase risk for SS when combined with MAOIs.³ Concerns about the use of α1-adrenergic agonists in patients taking MAOIs are not universal, as the deleterious effects on blood pressure are seen only in certain vulnerable patients, typically those with preexisting hypertension. Nonetheless, all patients should be cautioned about the use of phenylephrine and pseudoephedrine.¹⁶

Starting a patient on an MAOI

Contraindicated medications need to be tapered before beginning MAOI treatment. The duration of the washout period depends on the half-life of the medication and any active metabolites. Antidepressants with half-lives of approximately ≤24 hours should be tapered over 7 to 14 days (depending on the dose) to minimize the risk of withdrawal syndromes, while those with long half-lives (eg, fluoxetine, vortioxetine) can be stopped abruptly. After stopping a medication for 5 half-lives, 96.875% of the medication is removed, so adequate time must elapse after the last dose before starting an MAOI. Table 2^17-22 lists the half-lives of commonly used newer antidepressants and any active metabolites or isomers. Clinicians should always err on the side of caution before starting an MAOI, and give their patients a brief overview of SS symptoms; however, be mindful of not extending time the patient is without effective antidepressant levels.

Initiation of an MAOI is always based on whether the patient can reliably follow the basic dietary advice (see “A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A), and they agree to check with their clinician before starting new medications. Titration of MAOIs should be based on tolerability; orthostasis is the primary dose-limiting adverse effect associated with rapid titration or higher dosages. This may be especially true in older patients with poor vasomotor tone, or those on α1-adrenergic antagonists or other agents that may induce orthostatic effects. The rapid titration schedules present in certain package inserts (eg, phenelzine²³) should not be followed.

The orthostasis management strategy is similar to that employed for clozapine: minimize the use of concurrent α1-adrenergic antagonists, lower the doses of antihypertensives as much as possible, and encourage adequate fluid intake. For patients with ongoing orthostasis and without a history of congestive heart failure, consider using the potent mineralocorticoid fludrocortisone starting at 0.1 mg/d, and titrating every 10 to 14 days if needed to a maximum of 0.3 mg/d.²⁴ Older literature noted weight gain, peripheral edema, and sexual dysfunction as common adverse effects. Research on the most recently studied MAOI, selegiline transdermal, reported rates of these adverse effects as follows: weight gain: 2.1% for selegiline transdermal vs 2.4% for placebo; all forms of sexual dysfunction: 0 to 1% for selegiline transdermal vs 0 to 0.4% for placebo.²⁵

Augmentation options for patients taking MAOIs

For depressed patients who do not achieve remission of symptoms from MAOI therapy, augmentation options should be sought, as patients who respond but fail to remit are at increased risk of relapse.²⁶ Lithium augmentation is one of the more common strategies, with abundant data supporting its use.^27,28 Case reports dating back >12 years describe the concurrent use of bupropion and MAOIs.^12,29 A recent review of augmentation of MAOIs with second-generation antipsychotics found multiple positive reports for most agents, including aripiprazole, with the sole exception of ziprasidone, a moderate SNRI for which cases of SS have been reported.¹¹ As of November 2017, there are no case reports for asenapine, lurasidone, brexpiprazole, or cariprazine. Triiodothyronine is often a neglected strategy, but older case reports of combined treatment with MAOIs found no obvious concerns beyond those related to the use of thyroid hormone.^30,31

Bottom Line

When prescribing a monoamine oxidase inhibitor (MAOI), ensure that your patient isn’t taking other medications that could cause an interaction that results in serotonin syndrome or pressor effects. When initiating MAOI therapy, titrate slowly to avoid orthostasis. Strategies for augmenting MAOIs include lithium, bupropion, and second-generation antipsychotics, except for ziprasidone.

Related Resource

Meyer JM. A concise guide to monoamine oxidase inhibitors. First of 2 parts. Current Psychiatry. 2017;16(12):14-16,18-23,47,A.

Drug Brand Names

Amitriptyline • Elavil
Aripiprazole • Abilify
Asenapine • Saphris, Sycrest
Brexpiprazole • Rexulti
Bupropion • Wellbutrin XL, Zyban
Cariprazine • Vraylar
Chlorpheniramine • Chlorphen, Chlor-Trimeton
Citalopram • Celexa
Clomipramine • Anafranil
Clozapine • Clozaril
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Dextromethorphan • Delsym, Robitussin
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fentanyl • Duragesic, Subsys
Fludrocortisone • Florinef
Fluoxetine • Prozac, Sarafem
Fluvoxamine • Luvox
Imipramine • Tofranil
Levomilnacipran • Fetzima
Linezolid • Zyvox
Lisdexamfetamine • Vyvanse

Monoamine oxidase inhibitors (MAOIs) have well-established efficacy for treating depression, panic disorder, and social phobia. However, a lack of familiarity with these agents and misconceptions about the risks associated with their use have led to MAOIs being substantially underutilized. The goal of this 2-part guide to MAOIs is to educate clinicians about this often-overlooked class of medications. Part 1 (“A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A) described the pharmacology of MAOIs, the mechanism by which tyramine induces hypertension in patients taking MAOIs, and what to tell patients about dietary restrictions associated with these medications. Part 2 covers how to avoid potential drug interactions, including serotonin syndrome (SS) and pressor effects, that could affect patients receiving an MAOI; other factors to consider when starting a patient on an MAOI; and augmentation strategies for depressed patients who do not achieve remission from MAOI monotherapy.

MAOIs and potential drug interactions

One source of concern in patients receiving irreversible nonselective MAOIs is the development of excessive serotonergic neurotransmission resulting in SS. In the 1960s, researchers noted that administering large doses of tryptophan to MAOI-treated patients resulted in clonus and hyperactive reflexes without hypertensive events.¹ In 1991, Sternbach² provided an extensive case series and described the first set of criteria for SS. Features of SS include:

mild symptoms: tremor, akathisia, inducible clonus
moderate symptoms: spontaneous or sustained clonus, muscular hypertonicity
severe symptoms: hyperthermia, diaphoresis.²

Although SS can be induced by significant exposure to individual agents that promote excess synaptic serotonin (eg, overdose of selective serotonin reuptake inhibitors [SSRIs]), the majority of fatal cases have occurred among patients taking MAOIs who were coadministered an agent that inhibited serotonin reuptake (Table 1³). Animal studies have determined that excessive stimulation of the 5HT2A receptor is primarily responsible for SS,⁴ and that 5HT2A antagonists, such as mirtazapine, can block the development of SS in a mouse coadministered fluoxetine and tranylcypromine.⁵ In addition to a patient’s medication history, the clinical hallmark of SS that helps distinguish it from neuroleptic malignant syndrome, delirium, and other acute syndromes is clonus, which becomes spontaneous and sustained as the severity increases.

Risk for SS. Most medications that promote serotonergic activity are well known for their use as antidepressants, but other agents that have 5HT reuptake properties (eg, the antihistamine chlorpheniramine) must be avoided. Although older literature suggests that the use of lower doses of certain tricyclic antidepressants concurrently with MAOIs may not be as dangerous as once believed,⁶ there are sufficient reports of serious outcomes that tricyclics should be avoided in patients taking MAOIs because of the risk of SS, and also because, in general, tricyclics are poorly tolerated.⁷

Desipramine, a potent norepinephrine transporter (NET) inhibitor, blocks the entry of tyramine into cells by NET, thereby preventing hypertensive events in animal models of tyramine overexposure. However, in some assays, the affinity for the serotonin transporter is not insignificant, so at higher doses desipramine may pose the same theoretical risk for SS as seen with other tricyclics.³

Lastly, rasagiline is an MAO-B selective inhibitor that has been available in the United States since 2008 for the treatment of Parkinson’s disease (PD). Although this drug lacks MAO-A antagonism, its package insert carries SS warnings; however, analysis of outcomes from a large multicenter rasagiline trial (N = 1,504) found no SS events in the 471 patients receiving rasagiline plus antidepressants (74.5% on SSRIs).⁸ Because depression is a common comorbidity in PD, clinicians who encounter rasagiline-treated patients who need antidepressant therapy should consult with the patient’s neurologist regarding their experience and comfort level with combining rasagiline and SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs).

Astute clinicians will recognize that antidepressants that lack 5HT reuptake (eg, bupropion, mirtazapine) are not on this list of agents that may increase SS risk when taken with an MAOI. Older papers often list mirtazapine, but as a 5HT2A antagonist, it does not possess a plausible mechanism by which it can induce 5HT toxicity.^9,10 Most atypical antipsychotics have significant 5HT2A antagonism and can be combined with MAOIs, but ziprasidone is an exception: as a moderate SNRI, it has been associated with SS when administered with an MAOI.¹¹

Pressor reactions. The only theoretical sources of concern for pressor effects are medications that act as norepinephrine releasers through interactions at the trace amine-associated receptor 1 (TAAR1) (for more information on TAAR1, see “A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A). Amphetamines are one such class, but a 2004 review did not find cases of hypertensive crises when amphetamines were combined with MAOIs,¹² nor did a recent article that described the combined use of lisdexamfetamine and transdermal selegiline.¹³ Presumably, the low level of intracellular exposure mitigates the risk of excessive TAAR1 agonism, but amphetamine derivatives should be approached cautiously and with careful blood pressure monitoring. On the other hand, methylphenidate is an inhibitor of dopamine reuptake with no affinity for TAAR1¹⁴ or the serotonin transporter,¹⁵ and does not induce a pressor response nor increase risk for SS when combined with MAOIs.³ Concerns about the use of α1-adrenergic agonists in patients taking MAOIs are not universal, as the deleterious effects on blood pressure are seen only in certain vulnerable patients, typically those with preexisting hypertension. Nonetheless, all patients should be cautioned about the use of phenylephrine and pseudoephedrine.¹⁶

Starting a patient on an MAOI

Contraindicated medications need to be tapered before beginning MAOI treatment. The duration of the washout period depends on the half-life of the medication and any active metabolites. Antidepressants with half-lives of approximately ≤24 hours should be tapered over 7 to 14 days (depending on the dose) to minimize the risk of withdrawal syndromes, while those with long half-lives (eg, fluoxetine, vortioxetine) can be stopped abruptly. After stopping a medication for 5 half-lives, 96.875% of the medication is removed, so adequate time must elapse after the last dose before starting an MAOI. Table 2^17-22 lists the half-lives of commonly used newer antidepressants and any active metabolites or isomers. Clinicians should always err on the side of caution before starting an MAOI, and give their patients a brief overview of SS symptoms; however, be mindful of not extending time the patient is without effective antidepressant levels.

Initiation of an MAOI is always based on whether the patient can reliably follow the basic dietary advice (see “A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A), and they agree to check with their clinician before starting new medications. Titration of MAOIs should be based on tolerability; orthostasis is the primary dose-limiting adverse effect associated with rapid titration or higher dosages. This may be especially true in older patients with poor vasomotor tone, or those on α1-adrenergic antagonists or other agents that may induce orthostatic effects. The rapid titration schedules present in certain package inserts (eg, phenelzine²³) should not be followed.

The orthostasis management strategy is similar to that employed for clozapine: minimize the use of concurrent α1-adrenergic antagonists, lower the doses of antihypertensives as much as possible, and encourage adequate fluid intake. For patients with ongoing orthostasis and without a history of congestive heart failure, consider using the potent mineralocorticoid fludrocortisone starting at 0.1 mg/d, and titrating every 10 to 14 days if needed to a maximum of 0.3 mg/d.²⁴ Older literature noted weight gain, peripheral edema, and sexual dysfunction as common adverse effects. Research on the most recently studied MAOI, selegiline transdermal, reported rates of these adverse effects as follows: weight gain: 2.1% for selegiline transdermal vs 2.4% for placebo; all forms of sexual dysfunction: 0 to 1% for selegiline transdermal vs 0 to 0.4% for placebo.²⁵

Augmentation options for patients taking MAOIs

For depressed patients who do not achieve remission of symptoms from MAOI therapy, augmentation options should be sought, as patients who respond but fail to remit are at increased risk of relapse.²⁶ Lithium augmentation is one of the more common strategies, with abundant data supporting its use.^27,28 Case reports dating back >12 years describe the concurrent use of bupropion and MAOIs.^12,29 A recent review of augmentation of MAOIs with second-generation antipsychotics found multiple positive reports for most agents, including aripiprazole, with the sole exception of ziprasidone, a moderate SNRI for which cases of SS have been reported.¹¹ As of November 2017, there are no case reports for asenapine, lurasidone, brexpiprazole, or cariprazine. Triiodothyronine is often a neglected strategy, but older case reports of combined treatment with MAOIs found no obvious concerns beyond those related to the use of thyroid hormone.^30,31

Bottom Line

When prescribing a monoamine oxidase inhibitor (MAOI), ensure that your patient isn’t taking other medications that could cause an interaction that results in serotonin syndrome or pressor effects. When initiating MAOI therapy, titrate slowly to avoid orthostasis. Strategies for augmenting MAOIs include lithium, bupropion, and second-generation antipsychotics, except for ziprasidone.

Related Resource

Meyer JM. A concise guide to monoamine oxidase inhibitors. First of 2 parts. Current Psychiatry. 2017;16(12):14-16,18-23,47,A.

Drug Brand Names

Amitriptyline • Elavil
Aripiprazole • Abilify
Asenapine • Saphris, Sycrest
Brexpiprazole • Rexulti
Bupropion • Wellbutrin XL, Zyban
Cariprazine • Vraylar
Chlorpheniramine • Chlorphen, Chlor-Trimeton
Citalopram • Celexa
Clomipramine • Anafranil
Clozapine • Clozaril
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Dextromethorphan • Delsym, Robitussin
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fentanyl • Duragesic, Subsys
Fludrocortisone • Florinef
Fluoxetine • Prozac, Sarafem
Fluvoxamine • Luvox
Imipramine • Tofranil
Levomilnacipran • Fetzima
Linezolid • Zyvox
Lisdexamfetamine • Vyvanse

References

1. Krishnamoorthy S, Ma Z, Zhang G, et al. Involvement of 5-HT2A receptors in the serotonin (5-HT) syndrome caused by excessive 5-HT efflux in rat brain. Basic Clin Pharmacol Toxicol. 2010;107(4):830-841.
2. Sternbach H. The serotonin syndrome. Am J Psychiatry 1991;148(6):705-713.
3. Gillman PK. Monoamine oxidase inhibitors: a review concerning dietary tyramine and drug interactions. PsychoTropical Commentaries. 2016;16(6):1-90.
4. Haberzettl R, Fink H, Bert B. Role of 5-HT(1A)- and 5-HT(2A) receptors for the murine model of the serotonin syndrome. J Pharmacol Toxicol Methods. 2014;70(2):129-133.
5. Shioda K, Nisijima K, Yoshino T, et al. Mirtazapine abolishes hyperthermia in an animal model of serotonin syndrome. Neurosci Lett. 2010;482(3):216-219.
6. White K, Simpson G. Combined MAOI-tricyclic antidepressant treatment: a reevaluation. J Clin Psychopharmacol. 1981;1(5):264-282.
7. Otte W, Birkenhager TK, van den Broek WW. Fatal interaction between tranylcypromine and imipramine. Eur Psychiatry. 2003;18(5):264-265.
8. Panisset M, Chen JJ, Rhyee SH, et al. Serotonin toxicity association with concomitant antidepressants and rasagiline treatment: retrospective study (STACCATO). Pharmacotherapy. 2014;34(12):1250-1258.
9. Gillman PK. Mirtazapine: unable to induce serotonin toxicity? Clin Neuropharmacol. 2003;26(6):288-289; author reply 289-290.
10. Gillman PK. A systematic review of the serotonergic effects of mirtazapine in humans: implications for its dual action status. Hum Psychopharmacol. 2006;21(2):117-125.
11. Meyer JM, Cummings MA, Proctor G. Augmentation of phenelzine with aripiprazole and quetiapine in a treatment resistant patient with psychotic unipolar depression: case report and literature review. CNS Spectr. 2017;22(5):391-396.
12. Feinberg SS. Combining stimulants with monoamine oxidase inhibitors: a review of uses and one possible additional indication. J Clin Psychiatry. 2004;65(11):1520-1524.
13. Israel JA. Combining stimulants and monoamine oxidase inhibitors: a reexamination of the literature and a report of a new treatment combination. Prim Care Companion CNS Disord. 2015;17(6). doi: 10.4088/PCC.15br01836.
14. Simmler LD, Buchy D, Chaboz S, et al. In vitro characterization of psychoactive substances at rat, mouse, and human trace amine-associated receptor 1. J Pharmacol Exp Ther. 2016;357(1):134-144.
15. Froimowitz M, Gu Y, Dakin LA, et al. Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter. J Med Chem. 2007;50(2):219-232.
16. Stahl SM, Felker A. Monoamine oxidase inhibitors: a modern guide to an unrequited class of antidepressants. CNS Spectr. 2008;13(10):855-780.
17. Hiemke C, Härtter S. Pharmacokinetics of selective serotonin reuptake inhibitors. Pharmacol Ther. 2000;85(1):11-28.
18. Pristiq [package insert]. New York, NY: Pfizer Inc; 2016.
19. Savella [package insert]. Irvine, CA: Allergan USA Inc; 2016.
20. Viibryd [package insert]. Irvine, CA: Allergan USA Inc; 2016.
21. Trintellix [package insert]. Deerfield, IL: Takeda Pharmaceuticals America Inc; 2016.
22. Fetzima [package insert]. Irvine, CA: Allergan USA Inc; 2017.
23. Nardil [package insert]. New York, NY: Pfizer Inc; 2009.
24. Testani M Jr. Clozapine-induced orthostatic hypotension treated with fludrocortisone. J Clin Psychiatry. 1994;55(11):497-498.
25. Emsam [package insert]. Morgantown, WV: Somerset Pharmaceuticals Inc; 2015.
26. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917.
27. Tariot PN, Murphy DL, Sunderland T, et al. Rapid antidepressant effect of addition of lithium to tranylcypromine. J Clin Psychopharmacol. 1986;6(3):165-167.
28. Kok RM, Vink D, Heeren TJ, et al. Lithium augmentation compared with phenelzine in treatment-resistant depression in the elderly: an open, randomized, controlled trial. J Clin Psychiatry. 2007;68(8):1177-1185.
29. Quante A, Zeugmann S. Tranylcypromine and bupropion combination therapy in treatment-resistant major depression: a report of 2 cases. J Clin Psychopharmacol. 2012;32(4):572-574.
30. Joffe RT. Triiodothyronine potentiation of the antidepressant effect of phenelzine. J Clin Psychiatry. 1988;49(10):409-410.
31. Hullett FJ, Bidder TG. Phenelzine plus triiodothyronine combination in a case of refractory depression. J Nerv Ment Dis. 1983;171(5):318-320.

References

1. Krishnamoorthy S, Ma Z, Zhang G, et al. Involvement of 5-HT2A receptors in the serotonin (5-HT) syndrome caused by excessive 5-HT efflux in rat brain. Basic Clin Pharmacol Toxicol. 2010;107(4):830-841.
2. Sternbach H. The serotonin syndrome. Am J Psychiatry 1991;148(6):705-713.
3. Gillman PK. Monoamine oxidase inhibitors: a review concerning dietary tyramine and drug interactions. PsychoTropical Commentaries. 2016;16(6):1-90.
4. Haberzettl R, Fink H, Bert B. Role of 5-HT(1A)- and 5-HT(2A) receptors for the murine model of the serotonin syndrome. J Pharmacol Toxicol Methods. 2014;70(2):129-133.
5. Shioda K, Nisijima K, Yoshino T, et al. Mirtazapine abolishes hyperthermia in an animal model of serotonin syndrome. Neurosci Lett. 2010;482(3):216-219.
6. White K, Simpson G. Combined MAOI-tricyclic antidepressant treatment: a reevaluation. J Clin Psychopharmacol. 1981;1(5):264-282.
7. Otte W, Birkenhager TK, van den Broek WW. Fatal interaction between tranylcypromine and imipramine. Eur Psychiatry. 2003;18(5):264-265.
8. Panisset M, Chen JJ, Rhyee SH, et al. Serotonin toxicity association with concomitant antidepressants and rasagiline treatment: retrospective study (STACCATO). Pharmacotherapy. 2014;34(12):1250-1258.
9. Gillman PK. Mirtazapine: unable to induce serotonin toxicity? Clin Neuropharmacol. 2003;26(6):288-289; author reply 289-290.
10. Gillman PK. A systematic review of the serotonergic effects of mirtazapine in humans: implications for its dual action status. Hum Psychopharmacol. 2006;21(2):117-125.
11. Meyer JM, Cummings MA, Proctor G. Augmentation of phenelzine with aripiprazole and quetiapine in a treatment resistant patient with psychotic unipolar depression: case report and literature review. CNS Spectr. 2017;22(5):391-396.
12. Feinberg SS. Combining stimulants with monoamine oxidase inhibitors: a review of uses and one possible additional indication. J Clin Psychiatry. 2004;65(11):1520-1524.
13. Israel JA. Combining stimulants and monoamine oxidase inhibitors: a reexamination of the literature and a report of a new treatment combination. Prim Care Companion CNS Disord. 2015;17(6). doi: 10.4088/PCC.15br01836.
14. Simmler LD, Buchy D, Chaboz S, et al. In vitro characterization of psychoactive substances at rat, mouse, and human trace amine-associated receptor 1. J Pharmacol Exp Ther. 2016;357(1):134-144.
15. Froimowitz M, Gu Y, Dakin LA, et al. Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter. J Med Chem. 2007;50(2):219-232.
16. Stahl SM, Felker A. Monoamine oxidase inhibitors: a modern guide to an unrequited class of antidepressants. CNS Spectr. 2008;13(10):855-780.
17. Hiemke C, Härtter S. Pharmacokinetics of selective serotonin reuptake inhibitors. Pharmacol Ther. 2000;85(1):11-28.
18. Pristiq [package insert]. New York, NY: Pfizer Inc; 2016.
19. Savella [package insert]. Irvine, CA: Allergan USA Inc; 2016.
20. Viibryd [package insert]. Irvine, CA: Allergan USA Inc; 2016.
21. Trintellix [package insert]. Deerfield, IL: Takeda Pharmaceuticals America Inc; 2016.
22. Fetzima [package insert]. Irvine, CA: Allergan USA Inc; 2017.
23. Nardil [package insert]. New York, NY: Pfizer Inc; 2009.
24. Testani M Jr. Clozapine-induced orthostatic hypotension treated with fludrocortisone. J Clin Psychiatry. 1994;55(11):497-498.
25. Emsam [package insert]. Morgantown, WV: Somerset Pharmaceuticals Inc; 2015.
26. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917.
27. Tariot PN, Murphy DL, Sunderland T, et al. Rapid antidepressant effect of addition of lithium to tranylcypromine. J Clin Psychopharmacol. 1986;6(3):165-167.
28. Kok RM, Vink D, Heeren TJ, et al. Lithium augmentation compared with phenelzine in treatment-resistant depression in the elderly: an open, randomized, controlled trial. J Clin Psychiatry. 2007;68(8):1177-1185.
29. Quante A, Zeugmann S. Tranylcypromine and bupropion combination therapy in treatment-resistant major depression: a report of 2 cases. J Clin Psychopharmacol. 2012;32(4):572-574.
30. Joffe RT. Triiodothyronine potentiation of the antidepressant effect of phenelzine. J Clin Psychiatry. 1988;49(10):409-410.
31. Hullett FJ, Bidder TG. Phenelzine plus triiodothyronine combination in a case of refractory depression. J Nerv Ment Dis. 1983;171(5):318-320.