MAOIs and Depression Treatment Guidelines

Michael E. Thase, MD

Departments of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia Veterans Affairs Medical Center, and the University of Pittsburgh Medical Center, Philadelphia and Pittsburgh

Although MAOIs were the first effective antidepressant medications to be developed and were once a cornerstone of depression treatment, they have not been viewed as first-line agents for the past 40 years, due in part to concerns about side effects and the potential for hypertensive crises associated with dietary tyramine ingestion and drug-drug interactions. However, to this day, the potential utility of this venerable class of medications is still recognized in practice guidelines, and the availability of a newer transdermal MAOI formulation may reduce some of the safety concerns.

Overview of MAOIs

Mechanism of action. MAOIs are thought to treat depression by inhibiting MAO, which is an enzyme that inactivates neuronal dopamine, serotonin, and norepinephrine. By inhibiting MAO in the brain, MAOIs increase the synaptic availability of these monoamines. There are 2 forms of this enzyme: MAO-A and MAO-B. Some evidence suggests that it is inhibition of MAO-A that is most relevant for an antidepressant effect1 and, as such, all MAOIs with antidepressant efficacy are either selective for inhibiting the A isomer or used in doses that are nonselective (inhibiting both isomers). Of the medications available in the United States, phenelzine, tranylcypromine, and isocarboxazid are nonselective, whereas selegiline, which is selective for MAO-B at low oral doses, is nonselective at the high CNS concentrations delivered by the transdermal patch. All of these MAOIs are irreversible, meaning that they permanently bind to MAO for the life of the enzyme. Moclobemide, which is a reversible inhibitor of MAO-A, is not available in the United States, although it is widely available throughout much of the rest of the world.

AV 1. Propensity of MAOIs to Cause Certain Adverse Events (00:29)

Based on Amsterdam3 and Bauer et al4
Circle size indicates propensity: red = moderate, blue = mild, gray = very low/none
Abbreviations are defined before the References

Adverse side effects. The most common side effects of older, oral MAOIs include insomnia, sedation, orthostatic hypotension, dizziness, nausea, weight gain, edema, muscle pain, myoclonus, paresthesia, and sexual dysfunction (AV 1).2–4 In the era in which antidepressant selection was largely limited to MAOIs and TCAs, the overall burden of this side effect profile was generally comparable, although some patients tolerated MAOIs better than TCAs and vice versa. A more important characteristic of the older, nonselective MAOIs was the inhibition of MAO-A in the gut and liver, which inhibited metabolism of dietary tyramine during digestion. When MAOIs inhibit this effect, high levels of tyramine enter the blood stream, which in turn can rapidly increase blood pressure and possibly lead to hypertensive crisis, stroke, or even death due to cerebral hemorrhage. Therefore, patients taking MAOIs must follow dietary restrictions limiting tyramine intake,5 which has been perceived by patients and clinicians as difficult to manage and has contributed to the limited use of MAOIs. Nevertheless, these dietary restrictions are not as onerous as they might appear at first glance and generally should not preclude use of MAOIs with properly informed and motivated patients.

One way to improve the safety of MAOI therapy is to deliver the medication in a way that minimizes inhibition of MAO-A in the gut, and the FDA has approved a transdermal formulation of selegiline that allows the drug to be absorbed directly into the blood stream, thereby minimizing the role of the drug in the digestive process.6 Dietary restrictions are not required at the minimum effective dose of the selegiline patch (6 mg/24 h), but are still required at higher doses due to insufficient safety data. The tolerability profile of transdermal selegiline is similar to that of placebo, except for application site reactions.3 The art of prescribing this transdermal medication thus partly centers on being able to provide useful information about the application of skin patches, such as the need to rotate patch sites daily, clean the patch sites with warm soapy water after each application, and avoid applying patches to areas of skin that are hairy, shaved, or subject to sweating or rubbing against garments.

Drug interactions. Serious drug interactions are possible with both oral and transdermal MAOIs. The risk of hypertensive crisis is increased when using MAOIs with adrenergic medications, including amphetamines, sympathomimetic vasoconstrictive agents, and over-the-counter decongestants. Additionally, serotonin syndrome may result from the interaction between MAOIs and drugs with strong serotonergic effects (eg, other antidepressants, synthetic opioids, and some migraine medications). To minimize the risk of drug interactions, prescribers should implement an appropriate wash-out period when switching to or from an MAOI (generally 2 weeks; 5–6 weeks if switching from fluoxetine).7,8 Patients also should be educated about the risk of drug-drug interactions and instructed to let their other doctors know that they are taking an MAOI.

Efficacy. The efficacy of oral MAOIs has been compared with that of placebo and TCAs for depression. For inpatients, MAOIs are more effective than placebo but not as effective as TCAs; for outpatients, MAOIs are more effective than TCAs in patients with atypical depression (ie, depression characterized by persistent vegetative symptoms coupled with sensitivity to rejection).9 MAOIs are also effective for depression that has not responded to TCAs, depression with comorbid panic attacks or phobias, and anergic bipolar depression.1,9 The efficacy of the transdermal formulation of selegiline has been established for treatment of depression by several placebo-controlled studies, but data are lacking for comparison with other classes of antidepressants.10


MAOIs and Treatment Guidelines

Due to the dietary restrictions and potential drug interactions associated with these medications, MAOIs are usually recommended as third-, fourth-, or fifth-line treatments in current depression treatment guidelines. Therefore, many practicing physicians have had little experience with these drugs.

American Psychiatric Association. The APA practice guideline8 notes that MAOIs have efficacy that is comparable to that of other antidepressants for patients with major depression. The older MAOIs are comparable to each other in efficacy, but marked individual differences in responses do exist, and these medications should not be viewed as interchangeable. MAOIs may be particularly appropriate for specific subsets of patients, such as those with atypical depression or treatment-resistant depression. However, it is unclear whether MAOIs are more effective than other strategies for patients with more advanced levels of treatment resistance.

AV 2. Factors to Consider When Choosing an Antidepressant (00:35)

Based on the American Psychiatric Association8
Abbreviations are defined before the References

According to the APA practice guideline,8 the selection of an initial antidepressant should be guided by clinical features that include both patient- and drug-related factors (AV 2). MAOI treatment is generally recommended only after a patient has not achieved an adequate response with several other treatment trials, preferably SSRIs or other newer antidepressants, but the guideline does advocate that psychiatrists consider MAOIs earlier in the treatment process for patients with atypical depression. Of course, these guidelines would not apply to a patient who, in the past, has had an excellent response to an MAOI and would like to resume therapy with this type of medication. If prescribing an MAOI is appropriate, the APA advises clinicians to start at a low dose and titrate up to the usual daily dosage (see the list of APA recommended dosages).

In addition to treating major depressive disorder, the APA practice guidelines also recognize that MAOIs are useful for selected patients with other psychiatric disorders, including bipolar depression,11 PTSD,12 borderline personality disorder,13 OCD,14 and panic disorder.15

British Association for Psychopharmacology. Like the APA guidelines, the BAP guidelines16 recommend SSRIs and other newer antidepressants as first-line treatment for depression due to their better safety and tolerability profiles. MAOIs are reserved for patients who have not responded to first-line medications, and the initiation of MAOIs is limited to physicians with expertise in treating mood disorders. The guidelines also note that evidence indicates that MAOIs are more effective than TCAs for atypical depression, but that not enough evidence exists to compare MAOIs with newer antidepressants. A family history of differential response to a TCA or an MAOI is a factor in choosing between the 2 classes.

Canadian Network for Mood and Anxiety Treatments. The CANMAT guidelines17 support evidence of small differences in efficacy between newer antidepressants (ie, SSRIs and SNRIs), but find no substantive differences in efficacy between SSRIs and older antidepressants (ie, MAOIs, TCAs). Therefore, SSRIs, SNRIs, moclobemide, and other newer antidepressants are recommended as first-line treatment for depression; transdermal selegiline, a TCA, an atypical antipsychotic, and an SSRI as second-line treatment; and other MAOIs as third-line treatment.

National Institute for Health and Clinical Excellence. The NICE guidelines18 do not recommend using pharmacotherapy for patients with subthreshold depressive symptoms or for mild depression. However, if patients have persisting subthreshold symptoms, mild-to-moderate depression that has not improved with nonpharmacologic strategies, or moderate-to-severe depression, NICE advises prescribing a generic SSRI as first-line treatment (because of the favorable risk-benefit ratio and comparable efficacy to other antidepressants). Changing initial treatment strategies based on depressive subtype (eg, atypical or seasonal depression) is not endorsed, as evidence supporting this practice is not convincing. However, switching to an MAOI for patients who have not adequately responded to at least 2 sequential trials of SSRIs or newer antidepressants is authorized. Like the BAP guidelines, the NICE guidelines advise that MAOIs should be prescribed only by specialists in mental health rather than by other professionals.

Other treatment guidelines. MAOIs are likewise not considered first-line treatment in either the TMAP treatment algorithm19 or the WFSBP4 guidelines because of the safety and tolerability concerns. In the TMAP algorithm, MAOIs appear as a therapeutic option at stage 3 and are recommended before trying combination strategies. The WFSBP guidelines state that no evidence decisively supports one antidepressant class over another, but acknowledges that MAOIs are particularly effective for patients with atypical depression or depression with comorbid anxiety disorders.


Although MAOIs have demonstrated efficacy for treating depression, particularly atypical depression, treatment guidelines avoid recommending them as first-line pharmacotherapy due to safety and tolerability issues, such as the potential to cause hypertensive crises, serotonin syndrome, and other drug interactions. For these reasons, current guidelines typically recommend using MAOIs as third- or fourth-line treatments for depression, although psychiatrists can consider using MAOIs sooner for atypical depression. If an MAOI is prescribed, patients should be instructed on the dietary restrictions and advised of possible drug-drug interactions. Additionally, physicians should conduct the appropriate wash-out periods when switching to or from an MAOI.

For Clinical Use


  • Consider MAOIs for patients who have had several unsuccessful trials of first-line treatments for depression
  • Monitor for adverse effects and safeguard against hypertensive crisis and serotonin syndrome, which are associated with MAOIs co-administered with adrenergic and serotonergic medications, respectively
  • Educate patients taking MAOIs about necessary dietary restrictions to limit tyramine intake to prevent hypertensive crisis
  • Be aware that guidelines generally reserve MAOIs as third- and fourth-line treatments due to concerns over safety and tolerability; a transdermal MAOI can avoid some of the safety risks


Drug Names

fluoxetine (Prozac and others), isocarboxazid (Marplan), phenelzine (Nardil), selegiline transdermal system (EMSAM), tranylcypromine (Parnate and others)


APA = American Psychiatric Association, BAP = British Association for Psychopharmacology, CANMAT = Canadian Network for Mood and Anxiety Treatments, CNS = central nervous system, CYP = cytochrome P450, FDA = US Food and Drug Administration, MAO = monoamine oxidase, MAOI = MAO inhibitor, NICE = National Institute for Health and Clinical Excellence, SNRI = serotonin norepinephrine reuptake inhibitor, SSRI = selective serotonin reuptake inhibitor, TCA = tricyclic antidepressant, TMAP = Texas Medication Algorithm Project, WFSBP = World Federation of Societies of Biological Psychiatry

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  1. Krishnan KR. Revisiting monoamine oxidase inhibitors. J Clin Psychiatry. 2007;68(suppl 8):35–41. Abstract
  2. Fiedorowicz JG, Swartz KL. The role of monoamine oxidase inhibitors in current psychiatric practice. J Psychiatr Pract. 2004;10(4):239–248. PubMed
  3. Amsterdam JD. A double-blind, placebo-controlled trial of the safety and efficacy of selegiline transdermal system without dietary restrictions in patients with major depressive disorder. J Clin Psychiatry. 2003;64(2):208–214. Full Text
  4. Bauer M, Whybrow PC, Angst J, et al. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders, part 1: acute and continuation treatment of major depressive disorder. World J Biol Psychiatry. 2002;3(1):5–43. http://www.wfsbp.org/fileadmin/pdf/guides/827MDDTreatmentBauer.pdf. Accessed February 9, 2012.
  5. Gardner DM, Shulman KI, Walker SE, et al. The making of a user friendly MAOI diet. J Clin Psychiatry. 1996;57(3):99-104. PubMed
  6. Wecker L, James S, Copeland N, et al. Transdermal selegiline: targeted effects on monoamine oxidases in the brain. Biol Psychiatry. 2003;54(10):1099–1104. PubMed
  7. Sternbach H. The serotonin syndrome. Am J Psychiatry. 1991;148(6):705–713. PubMed
  8. American Psychiatric Association. Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition. Washington, DC: American Psychiatric Association; 2010. http://psychiatryonline.org/content.aspx?bookid=28&sectionid=1667485. Accessed February 9, 2012.
  9. Thase ME, Trivedi MH, Rush AJ. MAOIs in the contemporary treatment of depression. Neuropsychopharmacology. 1995;12(3):185–219. PubMed
  10. Wimbiscus M, Kostenko O, Malone D. MAO inhibitors: risks, benefits, and lore. Cleve Clin J Med. 2010;77(12):859–882. PubMed
  11. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Bipolar Disorder, Second Edition. Washington, DC: American Psychiatric Association; 2002. http://psychiatryonline.org/content.aspx?bookid=28&sectionid=1669577#50051. Accessed February 9, 2012.
  12. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Acute Stress Disorder and Posttraumatic Stress Disorder. Washington, DC: American Psychiatric Association; 2004. http://psychiatryonline.org/content.aspx?bookid=28&sectionid=1670530#52257. Accessed February 9, 2012.
  13. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Borderline Personality Disorder. Washington, DC: American Psychiatric Association; 2001. http://psychiatryonline.org/content.aspx?bookid=28&sectionid=1672600#54853. Accessed February 9, 2012.
  14. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Obsessive-Compulsive Disorder. Washington, DC: American Psychiatric Association; 2007. http://psychiatryonline.org/content.aspx?bookid=28&sectionid=1678180#149114. Accessed February 9, 2012.
  15. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Panic Disorder, Second Edition. Washington, DC: American Psychiatric Association; 2009. http://psychiatryonline.org/content.aspx?bookid=28&sectionid=1680635#154688. Accessed February 9, 2012.
  16. Anderson IM, Ferrier IN, Baldwin RC, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines. J Psychopharmacol. 2008;22(4):343–396. http://www.bap.org.uk/pdfs/antidepressants.pdf. Accessed January 25, 2012.
  17. Lam RW, Kennedy SH, Grigoriadis S, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults, pt 3: pharmacotherapy. J Affect Disord. 2009;117(suppl 1):S26–S43. PubMed
  18. National Institute for Health and Clinical Excellence. Depression: the Treatment and Management of Depression in Adults. London, United Kingdom: National Institute for Health and Clinical Excellence; 2009. http://www.nice.org.uk/nicemedia/live/12329/45888/45888.pdf. Accessed February 9, 2012.
  19. Suehs BT, Argo TR, Bendele SD, et al. Texas Medication Algorithm Project Procedural Manual: Major Depressive Disorder Algorithms. Austin, TX: Texas Department of State Health Services; 2008. http://www.pbhcare.org/pubdocs/upload/documents/TMAP%20Depression%202010.pdf. Accessed February 9, 2012.