Dosing MAO inhibitors

Dosing MAO Inhibitors

This article of discusses doses of MAO inhibitors and how to start, maintain, and stop treatment.

The following are general guidelines for initiating MAO inhibitor treatment. The steps involved with starting and maintaining MAO inhibitor treatment as well as determining dose and frequency of dosing for your care should be determined from a discussion with your provider and based on your unique situation and preferences, medical and psychiatric history, side effects that you may experience, and response to the medication.

Before Starting a MAO Inhibitor

You will need to obtain two sets of baseline vital signs (blood pressure and heart rate) prior to the starting a MAO inhibitor. These measurements should be taken correctly and spaced at least 15 minutes apart. Your vital signs should be recorded and shared with your prescribing provider. Extremes in blood pressure or heart rate may preclude you from starting a MAO inhibitor until the underlying issues responsible for aberrant vital signs are addressed.
If you are starting Nardil or Marplan, your provider may instruct you to start taking 100-200 mg of Vitamin B6 (Pyridoxine) daily as Nardil and Marplan can cause Vitamin B6 deficiency. Unless you have peripheral neuropathy or risk factors for Vitamin B6 deficiency including a history of alcoholism, it is generally not recommended that you take more than 200 mg of Vitamin B6 per day since Nardil binds with the vitamin to produce an inactive complex. As a result, taking too much Vitamin B6 can reduce the effectiveness of Nardil. [1-3]
While liver injury with MAO inhibitors is uncommon and thus it is uncommon to check liver function tests via a blood test to assess for liver damage prior to starting a MAO inhibitor, this blood test may be appropriate if there is concern for pre-existing liver damage. Reasons to suspect that you may have liver damage include a history of heavy alcohol use, hepatitis, behaviors that may increase risk of hepatitis B (e.g., unprotected sexual encounters, use of contaminated needles, working in a healthcare setting without appropriate vaccination against hepatitis B), or signs of end-stage liver disease or cirrhosis such as yellowing of the skin or eyes, swelling, and easy bleeding or bruising. Any time you display potential signs of liver damage or a few months after starting a MAO inhibitor, your provider may provide you with a lab order form for a blood test to check these liver function tests to assess if there is any liver damage.

Vital Sign Assessments

Orthostatic Hypotension (Low Blood Pressure)

Definition – Orthostatic hypotension is a transient drop in blood pressure that occurs when changing to a more upright postural positions (i.e., from laying down to sitting up or from sitting up to standing). This transient drop in blood pressure is often accompanied with a transient increase in heart rate although this finding may be absent in patients on a beta blocker drug.
Presentation – Orthostatic hypotension classically presents as dizziness or the feeling that you may lose consciousness when standing up suddenly. In severe cases of orthostatic hypotension, patients may lose consciousness while standing up suddenly. Orthostatic hypotension is common when starting and titrating up MAO inhibitors, particularly Nardil. [4, 5]
Assessment – If you are feeling dizzy, your provider may request you measure your blood pressure after you have been seated for at least 5 minutes. (Don’t worry, we will send you a free blood pressure monitor.) Subsequently, you should stand up and immediately measure your vital signs again after standing. However, you should only attempt to measure vital signs in this manner, if it can be done safely (e.g., no risk of falling while attempting to measure vital signs due to dizziness or lightheadedness). Significant orthostasis may be characterized by a significant increase in heart rate, a drop in systolic blood pressure (i.e., the top number on a blood pressure reading) of >19 mm Hg, or a drop in diastolic blood pressure (i.e., the bottom number on a blood pressure reading) >9 mm Hg.
Treatment – Visit our Common Side Effects page

Paradoxical Hypertension (Transient High Blood Pressure)

Definition – Paradoxical hypertension is a phenomenon that has reported in a small subset of patients taking MAO inhibitors. [6] However, from our experience, paradoxical hypertension is most common with Parnate and can occur in as much as 30-40% of patients.
Presentation – In almost all cases, there are no symptoms associated with paradoxical hypertension and thus patients only discover if they are experiencing the phenomenon or not by checking their blood pressures. Some patients have noted a headache and/or palpitations, however, with paradoxical hypertension. Elevations in blood pressure with paradoxical hypertension typically present 1-2 hours after consumption of a MAO inhibitor and are likely most commonly associated with Parnate. [7] In most cases, paradoxical hypertension resolves on its own over a few weeks. [6]
Assessment – To check for paradoxical hypertension, you should be fasting for at least 60 minutes before taking a dose of MAO inhibitor. Prior to taking your next dose of MAO inhibitor, you should measure and record your vital signs. After taking the MAO inhibitor, you should then continue to fast for at least another 90 minutes. Ninety minutes after you have taken the MAO inhibitor and after at least 2.5 hours of fasting, you should measure and record your vital signs. If your systolic blood pressure (i.e., the top number on a blood pressure reading) is >30 mm Hg greater than the measurement obtained prior to taking a dose of MAO inhibitor or if it is >20 mm Hg for more than 3 hours, you should notify your provider immediately as treatment may be required.
Treatment – For most patients, simply monitoring one’s blood pressure is enough as paradoxical hypertension typically resolves on its own within a few weeks to months at a given dose. Patients can divide up their doses rather than taking their medication all at once to reduce spikes in blood pressure or can more slowly go titrate up on their dose when starting the MAOI. In patients who do not have a slow heart rate (> 65 bpm), Propranolol 20-40 mg may be appropriate to take with the MAOI. In patients with a slow heart rate (< 65 bpm), Amlodipine 2.5-10 mg may be appropriate to take with a MAOI.

When To Take It? Should I Divide The Dose?

In general, from our experience, most patients benefit from taking their entire day’s medication all at once. This is because of the inconvenience of having to take some of their medication later in the day and because of the risk of worsening insomnia or difficulty falling and/or staying asleep when MAOIs are taken later in the day. However, particularly when first starting the medication, patients may benefit from splitting up the dose because they may notice a greater therapeutic benefit from dividing the dose or dividing the dose may help treat side effects including too high or too low blood pressure or heart rate, fatigue, and dizziness. A small subset of patients may have improved sleep when taking the MAOI in the evening or right before bed.

Parnate (Tranylcypromine)

Day 1-2: Then take 10 mg (1 x 10 mg tablet) in the morning.
Day 4+: Take 20 mg (2 x 10 mg tablets) in the morning.
Increase the daily dose by 10 mg (1 tablet) no sooner than every week.

Nardil (Phenelzine)

Day 1-3: Take 30 mg (2 x 15 mg tablets) in the morning.
Day 4-10: Take 45 mg (3 x 15 mg tablets) in the morning.
Day 11+: Take 60 mg (4 x 15 mg tablets) in the morning.
Increase the daily dose by 15 mg (1 tablet) no sooner than every 10 days and, preferentially, no sooner than every 30 days.

Maintenance Dose: Some dosing guidelines suggest attempting to reduce the daily dose of MAO inhibitors, particularly Nardil, to a lower maintenance dose after an effective therapeutic dose has been achieved and maintained for several weeks. However, in our experience, this may not always be possible without a loss of effectiveness of treatment. Although conventional dosing guidelines frequently recommend a maintenance dose of below 45 mg per day, several studies have found this to be inadequate and have suggested that maintenance doses of 45-60 mg are more commonly appropriate. [9, 10]

Marplan (Isocarboxazid)

Day 1-2: Then take 10 mg (1 x 10 mg tablet) in the morning.
Day 4+: Take 20 mg (2 x 10 mg tablets) in the morning.
Increase the daily dose by 10 mg (1 tablet) no sooner than every week.

Selegiline (oral)

Day 1-5: Then take 5 mg (1 x 5 mg tablet) in the morning.
Day 6+: Take 10 mg (2 x 5 mg tablets) in the morning.
Increase the daily dose by 5 mg (1 tablet) no sooner than every 5 days.

Sublingual Dosing: Some evidence suggests that the absorption rate or bioavailability of sublingual Selegiline is several fold greater than the oral Selegiline. [5] However, it should be noted that given the sublingual formulation of Selegiline is only indicated for Parkinson’s and is often too low of a dose to be effective for mood disorders, one option is to place the oral formulation of Selegiline under one’s tongue. Given that this is off-label administration of the oral Selegiline and that the tablet may not full be absorbed through the blood vessels under the tongue before some of it is swallowed, it is often difficult to ensure a consistent day-to-day dose when taken sublingually.

Selegiline (transdermal)

Day 1-30: Apply a 6 mg patch in the morning. Apply the patch to the upper chest or upper back (below the neck and above the waist), upper thigh, or outer side of the upper arm. Patches should be replaced every 24 hours.
Days 31-60: Apply a 9 mg patch in the morning. Patches should be replaced every 24 hours.
Day 61-90: Apply a 12 mg patch in the morning.

Note: The full effects of transdermal selegiline are often not felt for 4 weeks and thus require a slow up titration schedule. [12]

Discontinuing a MAO Inhibitor

You should never stop taking a MAO inhibitor on your own. Stopping a MAO inhibitor should only b done under the guidance of a qualified medical provider. In general, MAOIs should be tapered off slowly, rather than stopped suddenly. However, depending on the circumstances of an individual patient, a provider may recommend a more quick or slow approached to weeing off a MAO inhibitor may be titrated down or stopped more quickly.

Withdrawal symptoms vary significantly among patients and among medications. In addition to depressed mood, withdrawal may cause nausea, GI upset, insomnia, fatigue, agitation, and mild confusion. In some cases, patients may experience muscle contractions and pressured speech. In severe cases, withdrawal may cause significant behavior changes, psychosis, aggression, severe confusion, and hallucinations. These can typically be managed with a slower taper and supportive medications.

Once a MAO inhibitor has been tapered down, as a general rule, one should wait 14 days before starting a serotonergic drug to allow sufficient levels of MAO to build up in the body and reduce the chances of serotonin syndrome.

Of note, patients may observe a transient rise in their blood pressure while tapering off a MAOI secondary to MAOI withdrawal.

Swapping MAO Inhibitors

The best way to swap MAO inhibitors has not been clearly established. A concern with rapid switching is the potential for serotonin syndrome due to excessive MAO inhibition. Providers generally take one of three approaches:

Stopping one MAO inhibitor suddenly, and then waiting 2 weeks before starting another MAO inhibitor. [13]
Cross-tapering MAO inhibitors (i.e., slowly reducing the dose of one MAO inhibitor while slowly increasing the dose of another). [14]
Stopping one MAO inhibitor suddenly, and then start another the following day or shortly thereafter. [14-16]

The case studies above have shown that all three methods can be done safely. However, there have been cases of severe adverse effects and even fatality coinciding with rapid MAO inhibitor swapping, although it is unclear if the severe effects were directly related to the switch in MAOIs [17-19]. Therefore, in many cases, the best approach may be to discontinue a MAO inhibitor, wait a minimum of 2 weeks, then start another MAO inhibitor.

From our experience, among the four FDA-approved MAOIs, Nardil is most likely to have the most significant withdrawal symptoms and thus often requires the slowest taper. In an extreme cases, abrupt cessation of Nardil may precipitate delirium and tremors. Withdrawal symptoms with each MAOI vary significantly among different patients and may include, but are not limited to, fatigue, muscle aches, difficulty thinking, anxiety, depressed mood, and heachaches.

Citations

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2. Demers RG, McDonagh PH, Moore RJ. Pyridoxine deficiency with phenelzine. South Med J. 1984 May;77(5):641-2. doi: 10.1097/00007611-198405000-00026. PMID: 6719168.

3. Larsen, JK, Bendsen, BB, and Bech, P, Vitamin B6 treatment of oedema induced by mirtazapine and isocarboxazid. Acta Psychiatr. Scand., 2011. 124(1): p. 76-7; discussion 77.

4. Sidhu G, Marwaha R. Phenelzine. [Updated 2021 Feb 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554508/

5. Nanda RN, Johnson RH, Keogh HJ. Treatment of neurogenic orthostatic hypotension with a monoamine oxidase inhibitor and tyramine. Lancet. 1976 Nov 27;2(7996):1164-7. doi: 10.1016/s0140-6736(76)91681-0. PMID: 62995.

6. Fallon B, Foote B, Walsh BT, Roose SP. ‘Spontaneous’ hypertensive episodes with monoamine oxidase inhibitors. J Clin Psychiatry. 1988 Apr;49(4):163-5. PMID: 3281932.

7. Zajecka, J., & Fawcett, J. (1991). Susceptibility to spontaneous MAOI hypertensive episodes. The Journal of Clinical Psychiatry, 52(12), 513–514.

8. Amsterdam JD, Berwish NJ. High dose tranylcypromine therapy for refractory depression. Pharmacopsychiatry. 1989 Jan;22(1):21-5. doi: 10.1055/s-2007-1014572. PMID: 2710808.

9. Ravaris CL, Nies A, Robinson DS, Ives JO, Lamborn KR, Korson L. A Multiple-Dose, Controlled Study of Phenelzine in Depression-Anxiety States. Arch Gen Psychiatry. 1976;33(3):347–350. doi:10.1001/archpsyc.1976.01770030057008

10. Tyrer P, Gardner M, Lambourn J, Whitford M. Clinical and pharmacokinetic factors affecting response to phenelzine. Br J Psychiatry. 1980 Apr;136:359-65. doi: 10.1192/bjp.136.4.359. PMID: 6992903.

11. Sunderland T, Cohen RM, Molchan S, Lawlor BA, Mellow AM, Newhouse PA, Tariot PN, Mueller EA, Murphy DL. High-dose selegiline in treatment-resistant older depressive patients. Arch Gen Psychiatry. 1994 Aug;51(8):607-15. doi: 10.1001/archpsyc.1994.03950080019003. PMID: 7519005.

12. Bodkin JA, Amsterdam JD. Transdermal selegiline in major depression: a double-blind, placebo-controlled, parallel-group study in outpatients. Am J Psychiatry. 2002 Nov;159(11):1869-75. doi: 10.1176/appi.ajp.159.11.1869. PMID: 12411221.

13. Gitlin MJ. Venlafaxine, monoamine oxidase inhibitors, and the serotonin syndrome. J Clin Psychopharmacol. 1997;17:66–67.

14. Polnak JF, Finegan A, Ji H, Crouse EL, Rosenblatt A, Weitzner M, Gardner KN. Monoamine Oxidase Inhibitor Switching Strategies: No Adverse Events Associated With Outpatient Cross-taper or Inpatient Rapid Switch. J Clin Psychopharmacol. 2018 Feb;38(1):92-94. doi: 10.1097/JCP.0000000000000809. PMID: 29189408.

15. Marangell LB. Switching antidepressants for treatment-resistant disorder. J Clin Psychiatry. 2001;62:12–17.

16. Szuba MP, Hornig-Rohan M, Amsterdam JD. Rapid conversion from one monoamine oxidase inhibitor to another. J Clin Psychiatry. 1997;58:307–310.

17. Bazire, S.R., Sudden death associated with switching monoamine oxidase inhibitors. Drug Intell Clin Pharm, 1986. 20(12): p. 954-6.

18. Safferman, A.Z. and S.J. Masiar, Central nervous system toxicity after abrupt Monoamine inhibitor switch: a case report. Pharmacotherapy, 1992. 26: p. 337-338.

19. Mattes, J.A., Stroke resulting from a rapid switch from phenelzine to tranylcypromine. J Clin Psychiatry, 1998. 59(7): p. 382.