Selegiline is a selective monoamine oxidase-B (MAO-B) inhibitor. In contrast, classic monoamine oxidase inhibitors (MAOIs) block both the A and B enzymes. MAO-A metabolizes serotonin and norepinephrine; MAO-B metabolizes dopamine. By blocking the B enzyme, selegiline is a purely dopaminergic drug. In contrast, classic MAOIs (like phenelzine or tranylcypromine) are also noradrenergic and serotonergic. These differences in neurotransmitter effects may help explain why selegiline should not be seen as a simple MAOI, similar in effect to other agents in this classic, and also why selegiline should not be assumed to be as effective as other MAOIs.
MAO-A blockade is associated with greater clinical benefit, but, since norepinephrine activity is robustly increased, it is associated with a risk of hypertensive crisis if a person eats food rich in tyramine. Tyramine is converted to tyrosine and then norepinephrine; in the setting of irreversible MAO-A inhibition, the massive presence of norepinephrine leads to very high blood pressure, which can produce a stroke and be fatal.
Hence the dilemma of MAOIs: If they work robustly, they’re dangerous. If they’re not dangerous, they don’t work robustly.
As is well known, an extensive literature shows that classic MAOIs, like phenelzine and tranylcypromine, are more effective than other antidepressants, like tricyclic antidepressants or serotonin reuptake inhibitors (SRIs). Many clinicians assume this greater efficacy extends to selegiline. This is not the case. No clinical trials ever have proven that selegiline is more effective than other antidepressants. Since selegiline does not increase norepinephrine or serotonin activity, unlike other MAOIs, it makes sense that it may not have similar clinical effects.
Atomoxetine blocks reuptake of norepinephrine at the synapse. Unlike other “stimulants” it does not have direct or indirect agonism of dopamine activity.
The diminished efficacy of selegiline, relative to other MAOIs, is more relevant to the patch form of this medication, as opposed to the oral pill. FDA indication for major depressive disorder (MDD) exists fro the patch, but not the pill, mainly because the pill is generic and thus the pharmaceutical industry was able to obtain profits by producing and studying a patch formulation. Biologically, the patch is a selective MAO-B inhibitor at 6-12 mg/d, but at higher doses it blocks MAO-A. This is good if you want more antidepressant effect, but it is bad if you want to avoid the restrictive diet needed with classic MAOIs to prevent hypertensive crisis.
The MAO-A inhibition begins at 9 mg/d but increases markedly above 12 mg/d, hence the pharmaceutical company’s decision to cut off dosing at 12 mg/d. FDA recommendations are that MAOI dietary restrictions begin at 9 mg/d in any case based on the theoretical concern of MAO-A inhibition, although clinical harm through tyramine dietary exposure has not been reported extensively at that dose.
If the oral pill is used, the FDA-approved dose for Parkinson’s disease is 5-10 mg/d. At that dose the drug is a selective MAO-B inhibitor, and no dietary restrictions are needed. At 15 mg/d, dietary restrictions often are recommended, and at 20-30 mg/d, some clinical studies find efficacy for acute depressive episodes, although such use of the oral pill would be off-label. At such doses, MAO-A inhibition occurs, and dietary restrictions should be instituted. Some experts thinks that selegiline may have less risk of hypertensive crisis, even at higher doses that inhibit MAO-A, than other MAOIs, but this clinical hypothesis has neither been proven nor disproven.