Selegiline, a monoamine oxidase (MAO) inhibitor, is FDA-approved as an adjunct treatment in the management of patients with Parkinson disease and as a treatment for a major depressive disorder (MDD) in adults. Selegiline is also used off-label for early Parkinson disease and the treatment of attention-deficit/hyperactivity disorder (ADHD).[1][2]

Selegiline is an irreversible inhibitor of monoamine oxidase (MAO), an enzyme that catabolizes norepinephrine, serotonin, and dopamine. The blockage of this enzyme prevents the reuptake of these neurotransmitters in the CNS, conferring increased levels of the biologically active monoamines at the synaptic cleft. With lower doses, selegiline exhibits selective B-type monoamine oxidase (MAO-B) inhibition. Loss of dopamine-containing neurons in the substantia nigra of the midbrain and resultant depletion of dopamine in the striatum is the cause of Parkinson disease. Therefore, the selective inhibition of MAO-B is desired for the treatment of Parkinson disease because MAO-B primarily metabolizes dopamine.[3] In contrast, selective inhibition of MAO-B is not the desired outcome when using selegiline to treat MDD. Inhibition of both MAO-A and MAO-B is implicated as selegiline's effective mechanism of action when utilized as a treatment for MDD. The monoamine hypothesis of depression predicts the underlying pathophysiologic basis of depression as a depletion in the levels of serotonin, norepinephrine, and dopamine in the central nervous system.[4] Because increasing the levels of all three of these monoamines is often the targeted outcome for treating MDD, nonselective inhibition of both MAO subtypes is preferred.

As with most psychotropic medications, the mechanism of action of selegiline is not fully understood. Although the above-proposed mechanisms are widely accepted, other proposed mechanisms may contribute to selegiline's clinical efficacy. There is a hypothesis that selegiline's metabolites, which include amphetamine, may play a role in its mechanism of action by augmenting the release of monoamine neurotransmitters.[5] Additionally, selegiline may have neuroprotective effects that prevent progression in Parkinson disease through increases in production of neurotrophins such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF) that protect neurons from the inflammatory process. This induction and activation of multiple factors for anti-oxidative stress and anti-apoptosis may preserve healthy brain tissue.[6]

Selegiline is administered via two different routes and in three different forms. The oral route, in either capsule or oral disintegrating tablet (ODT) form, produces the low plasma concentration levels, which bestow the selective inhibition of MAO-B that is desirable for the treatment of Parkinson disease. The other route of administration of selegiline is transdermal, in which a patch is applied to the patient's skin to facilitate absorption of the medication directly into the blood, bypassing the first-pass metabolism. The transdermal route achieves greater plasma concentration levels than the oral route; the elevated levels of selegiline produce the anti-depressive effect, nonselective MAO inhibition, desired for treatment of MDD.

Selegiline may cause a hypertensive crisis, a severe elevation of blood pressure when the patient consumes the medication concurrently with food, drink, or supplements that are rich in tyramine. Other dangerous adverse effects include sudden sleep episodes, orthostatic hypotension, arrhythmias, mental status alteration, hallucinations, extrapyramidal symptoms, dyskinesia, and serotonin syndrome. Common adverse effects of selegiline are predominantly due to the drug's anticholinergic effects, xerostomia, and constipation. The most commonly reported are headache, dizziness, insomnia, and nausea. Abrupt cessation of selegiline is not advisable because of the risk of antidepressant and antiparkinsonian discontinuation syndromes.[7]

Adverse effects specific to the form of administration exist. For the transdermal route, a black box warning for the antidepressant use of selegiline cautions the use of antidepressants in pediatric and young adult populations due to an increase in the risk of suicidal thoughts and behaviors. Selegiline is not FDA-approved for bipolar depression as it may precipitate a manic episode. Transdermal use commonly causes skin irritation at the site of application. The ODT form can cause buccal mucosa irritation.[7]

Use of selegiline within ten days before elective surgery is contraindicated due to adverse effects on blood pressure. Transdermal selegiline is contraindicated for use in children younger than 12 years and in patients of any age who have pheochromocytoma. Patients should discontinue transdermal selegiline for at least two weeks before starting any of the following medications: carbamazepine, serotonin reuptake inhibitors, clomipramine, imipramine, tramadol, propoxyphene, methadone, pentazocine, and dextromethorphan. Conversely, transdermal selegiline therapy should not start within five half-lives of the previously listed medications. Oral selegiline should not be used concomitantly with cyclobenzaprine, dextromethorphan, St John's wort, methadone, propoxyphene, tramadol, and other MAO inhibitors. Selegiline, in any form, should not be used if there is a previously identified hypersensitivity to selegiline, and all forms are contraindicated with concomitant use of the medication meperidine.[8]

Selegiline metabolism involves many subunits of the cytochrome P450 system. The 2B6 subunit plays a significant role in metabolism, so interactions and impairments with this enzyme are clinically important. Patients with hepatic impairment may need adjustment of selegiline dosage, and selegiline ODT is not recommended for patients with severe hepatic impairment. Likewise, selegiline ODT should be avoided in patients with creatinine clearance less than 30 mL/min.