MAOIs and Transdermal Delivery
Chad M. VanDenBerg, PharmD, BCPP
Department of Pharmacy Practice and the Center for Clinical Research, Mercer University College of Pharmacy and Health Sciences, Atlanta, Georgia
For several decades after their introduction in the 1950s, MAOIs were widely used as effective antidepressants, particularly in treating atypical depression1 and treatment-resistant depression.2 Today, MAOIs have been largely replaced by newer antidepressants because of concerns regarding potential side effects from drug and food interactions and the need for dietary restrictions. However, MAOIs are useful treatment options for patients who have not responded to first-line treatments, and understanding their mechanism of action can help clinicians to accurately and safely prescribe these medications. In addition, newer MAOI formulations are easier to use and have better safety profiles than older formulations.
MAOI Mechanism of Action
AV 1. The Mechanism of Action of MAOIs (00:37)
Serotonin, norepinephrine, and dopamine are thought to be involved in the neurobiology of depression, and all antidepressants work by increasing the synaptic action of one or more of these monoamines. The efficacy of MAOIs in treating depression is based on their inhibition of MAO, a mitochondrial enzyme that metabolizes neurotransmitter molecules, including these monoamines. Thus, inhibition of MAO in the brain allows serotonin, norepinephrine, and dopamine to accumulate, thereby increasing their availability and enhancing synaptic transmission ().3
The 2 isomers of MAO are MAO-A and MAO-B.3 MAO-A is found primarily in the intestine, where its primary substrate is tyramine, and in the brain, where its substrates include serotonin, norepinephrine, and dopamine; MAO-B is concentrated in platelets and in brain regions rich in serotonergic neurons. MAO-A preferentially metabolizes serotonin and norepinephrine, and MAO-B preferentially metabolizes trace amines (histamine and phenylethylamine); both MAO-A and MAO-B metabolize dopamine and tyramine.4 Therefore, MAO-A inhibition in the brain is necessary to have an antidepressant effect on the 3 monoamines involved in depression.5
MAOIs are either nonselective (inhibiting both MAO-A and MAO-B) or selective (preferentially inhibiting only one form of the enzyme). All MAOIs available in the United States are nonselective except for selegiline, an MAO-B inhibitor that is FDA-approved at low doses (10 mg/d) as an adjunct to carbidopa/levodopa for Parkinson’s disease. However, at doses high enough to induce an antidepressant effect (30 to 60 mg/d), oral selegiline loses its selectivity and inhibits both MAO-A and MAO-B.3
All MAOIs approved by the FDA to treat depression (ie, isocarboxazid, phenelzine, tranylcypromine, and transdermal selegiline) irreversibly bind to MAO for the life of the enzyme. Once the medication is stopped, a period of 7 to 14 days is required for new enzyme to be generated and enzymatic activity to resume.6
While MAO-A inhibition in the brain is necessary for an antidepressant effect,5 intestinal inhibition of MAO-A can lead to serious interactions with foods containing tyramine. In the GI system and liver, MAO-A metabolizes dietary tyramine, which restricts the uptake of tyramine into the circulatory system. When MAO-A is inhibited in the gut, an excessive amount of dietary tyramine can enter the bloodstream, causing an increase in the release of norepinephrine. Excess norepinephrine causes a rapid and sometimes severe increase in blood pressure that can lead to hypertensive crisis, possibly resulting in stroke or even death. Thus, patients taking nonselective, irreversible MAOIs must follow dietary restrictions that limit tyramine intake.7
Moclobemide is a reversible MAO-A inhibitor (RIMA), meaning that excess tyramine can displace the medication from its binding site on the MAO-A enzyme. This allows the tyramine to be metabolized normally, greatly reducing the risk for hypertensive crisis.8 Although moclobemide is widely available throughout the world, it has not received approval for use in the United States.
In addition to food interactions, serious, potentially fatal, drug interactions are also possible with MAOIs. Hypertensive crisis can occur when MAOIs are co-administered with any drugs that raise blood pressure by sympathomimetic or vasoconstrictive actions. Additionally, serotonin syndrome is a serious risk when MAOIs are used concurrently with other drugs that affect serotonergic activity.
Transdermal Delivery System
Although simplified over the years, the dietary restrictions for MAOI use have been perceived by patients and clinicians as difficult to manage. One effort to improve the safety of MAOIs and limit or avoid the need for dietary restrictions was the development of the transdermal delivery system for selegiline.
AV 2. Transdermal Delivery of MAOIs (00:42)
By bypassing the GI tract, the transdermal delivery system accomplishes 2 goals: (1) at lower dosages, it avoids completely inhibiting MAO-A within the GI tract, which in turn avoids excessive amounts of tyramine entering the bloodstream; (2) it delivers a higher plasma concentration of selegiline over a longer period of time and with a lower dose compared with oral administration ().9,10
The physiochemical properties of selegiline (eg, low molecular weight, high lipid solubility) make it well-suited for transdermal delivery. When delivered transdermally, selegiline directly enters into the circulatory system, is rapidly absorbed, and quickly reaches its target sites. This direct absorption lowers the dosage needed for an antidepressant effect. The greater bioavailability of 6 mg of transdermal selegiline (73%) versus 10 mg of oral selegiline (4%) is due to the avoidance of the extremely high first-pass metabolism of the oral medication in the GI system and liver before entering the circulatory system.10 Transdermal selegiline also maintains a sustained plasma concentration during the 24-hour application period of the patch, whereas the oral medication plasma concentration peaks within 1 hour and then declines rapidly.10 Since transdermal delivery limits initial, direct exposure to the GI system, MAO-A is largely unaffected in the gut; thus, patient sensitivity to dietary tyramine is more than 20 times less with the selegiline transdermal patch than with oral tranylcypromine.11
The selegiline transdermal patch is FDA-approved to treat major depressive disorder, and dietary restrictions are not necessary at the recommended starting dose of 6 mg/24 h. However, at higher dosages, dietary restrictions are still recommended because of the lack of safety data. The side effect profile for transdermal selegiline is similar to that of placebo except for the occurrence of application site reactions, which are generally mild or moderate.12 Transdermal selegiline is classified as a nonallergen; application site reactions are similar to those of other transdermally delivered medications and probably due to the adhesive used in the patch.13
MAOIs are effective antidepressants, particularly for certain subtypes of depression, although safety and tolerability concerns exist. FDA-approved oral MAOIs inhibit both MAO-A and MAO-B; inhibition of MAO-A in the brain is required for an antidepressant effect, but inhibition of the enzyme in the intestinal tract can allow excessive absorption of dietary tyramine. To prevent potential hypertensive crisis, patients taking oral MAOIs are required to follow dietary restrictions. The transdermal formulation of selegiline delivers the medication directly into the circulatory system, bypassing the first-pass metabolism that normally occurs during digestion of oral medications. The skin patch allows for a lower dose of the drug to achieve an antidepressant effect, maintains a sustained dose over a longer period of time, and avoids the need for dietary restrictions at the minimum effective dose. Drug interaction precautions needed with other MAOIs should also be used with transdermal selegiline.
For Clinical Use
- Consider MAOIs for patients with atypical or treatment-resistant depression
- Understand that MAOIs increase the synaptic activity of serotonin, norepinephrine, and dopamine by inhibiting the MAO enzyme
- Educate patients regarding the importance of dietary restrictions with oral MAOIs and higher doses of transdermal MAOI as well as drug interactions with any MAOI
carbidopa/levodopa (Parcopa, Sinemet, and others), isocarboxazid (Marplan), phenelzine (Nardil and others), selegiline oral formulation (Eldepryl, Zelapar, and others), selegiline transdermal system (EMSAM), tranylcypromine (Parnate and others)
FDA = US Food and Drug Administration
GI = gastrointestinal tract
MAO = monoamine oxidase
MAOI = MAO inhibitor
RIMA = reversible inhibitor of MAO-A
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