Monoamine oxidase inhibitors (MAOIs)?the first drug treatment for depression that has been largely abandoned because of serious side effects such as a hypertensive crisis?have reemerged in a new formulation. Approved in March 2006 by the FDA, transdermal selegiline (EMSAM; Bristol-Myers Squibb/Somerset Pharmaceuticals) is the first transdermal delivery system available for the treatment of major depressive disorder in adults. This system circumvents the direct effect on intestinal monoamine oxidase that was responsible for the prohibitive side-effect profile of the oral MAOIs.
"Transdermal selegiline is to MAOIs what the SSRIs were to TCAs. This is a user-friendly MAOI, just like SSRIs are basically userfriendly TCAs."
?J. Alexander Bodkin, MD
"We haven't had a new MAOI in the United States since about 1958, and we have a lot of patients who need them," said J. Alexander Bodkin, MD, chief, Clinical Psychopharmacology Research Program, Harvard Medical School's McLean Hospital, Boston. "This gives physicians an alternative to treat patients who don't respond to SSRIs [selective serotonin reuptake inhibitors]. In its own way, it is completely revolutionary. It is something that has been utterly neglected for 40 years."
The new patch may also help overcome one of the most troublesome and frustrating bugaboos of depression treatment: noncompliance. "This really is the ideal remedy for the elderly," Dr Bodkin says. "Compliance is enhanced when you?or the nurse can see that the patch is on your skin. Another thing is that its side-effect profile, aside from drug interactions, is more innocuous than almost anything else that an elderly person is taking."
Transdermal administration may have the further advantage of a faster onset of action. "When you take an oral drug, it takes 5 half-lives, or a couple of days, to build up to its desired goal steady state," he explains. "But with infusions, which is in effect what transdermal administration is, it just takes a couple of hours."
Monoamine Oxidase Inhibition
The monoamine oxidase enzyme is found in the brain and in the digestive tract. Blocking this enzyme in the brain is thought to enhance the activity of the neurotransmitters that help battle depression. But as Dr Bodkin says, "the liver and the gut are also full of monoamine oxidase, which detoxifies certain compounds that you don't want to get into your bloodstream, chief among them being tyramine."
This nonessential amino acid is a constituent of many foods that are aged with bacteria, such as cheese. "That's the problem with oral MAOIs; when you swallow them, they zap all your gastrointestinal protections against tyramine long before they get to your brain to do what you want them to do." The patch bypasses the gut, while allowing the brain to get adequate inhibition of monoamine oxidase, he notes.
Clinical Trials Outcomes
The first study to evaluate transdermal selegiline (Am J Psychiatry. 2002;159: 1869-1875) included 177 adult outpatients with major depressive disorder who were randomized to the selegiline patch or placebo. All patients followed a tyramine-restricted diet.
Symptoms were measured using the 17- and 28-item Hamilton Depression Rating Scales, the Montgomery-?sberg Depression Rating Scale, and the Clinical Global Impression measure of severity of illness. The selegiline patch outperformed placebo on all 3 tools, with improvements in the Hamilton and Montgomery-"*"sberg depression scales becoming evident as early as the first week and continuing throughout the entire 6-week treatment period.
The patch was well tolerated; only application-site reactions (eg, rash, itching, redness) were reported more often by selegiline-treated than by placebo-treated patients (36% vs 17%, respectively). Although the treatment group had a slightly greater orthostatic change in blood pressure (BP) at the end of the trial, this was not considered clinically significant. None of the participants had a hypertensive episode.
A second placebo-controlled study (J Clin Psychiatry. 2003;64: 208-214) evaluated the safety of up to 8 weeks of transdermal selegiline therapy without tyramine dietary restrictions in 365 adult outpatients with major depressive disorder. Again, side effects, including BP measures, were similar in the treatment and placebo groups, with the exception of application-site reactions (32% vs 15%, respectively).
Dr Bodkin credits "our extremely cautious FDA" for maintaining for the selegiline patch all the restrictions and contraindications that applied to oral MAOIs.
He concedes that "drug?drug interactions are an issue even with the patch. But there are a lot of drugs that elderly persons take that do not have anything to do with MAOIs. The things you have to worry about are adrenergic drugs, serotonergic drugs, and also meperidine [Demerol] and similar drugs such as dextromethorphan, which is found in over-the-counter cold remedies. Most of the things that elderly people take will be fine, but not everything."
In the Real World
There has been scant research on identifying optimal candidates for transdermal selegiline. Dr Bodkin, who was involved in many clinical trials of the patch in which he treated about 150 patients, explains, "In my experience, patients with lassitude or impairment in everyday functioning?difficulty in getting things done, difficulty getting started?lethargy-type problems" are more likely to respond to transdermal selegiline. He cites "a low-energy state" as the best predictor of response, noting that this is consistent with the anti-Parkinsonian properties of selegiline, for which it is also approved.
"In the real world, SSRIs are always the first treatment used by primary care physicians. If an SSRI is tried at an adequate dose and for an adequate time, and it doesn't work, then rather than switching to another SSRI, which is conventional, or switching to a slightly enhanced SSRI like a serotonin-norepinephrine reuptake inhibitor, it would be reasonable to try an MAOI."
He cautions, however, that if the ineffective SSRI was fluoxetine (Prozac), the physician must wait for it to wash out completely, because, "SSRIs and MAOIs do not mix. For "ordinary, relatively short half-life drugs that take 4 or 5 days to wash out of the system, an appropriate next step would be to try an MAOI. These used to be off-limits, but that is no longer the case. As long as you have a reasonably reliable patient who is not going to mix it with medicines that are not allowed?who is not, for example, going to take an over-the-counter cold medicine without checking with you?it's no big deal."
The new patch is available in 3 strengths: 6, 9, and 12 mg; the recommended starting dose is 6 mg/day. A new patch is applied daily. Dr Bodkin wants physicians to appreciate that "it is only at the lowest strength that you don't have to worry about diet" (Table). The 2 higher dosage strengths were introduced just before the patch was approved, and thus there was insufficient evidence for the FDA to approve a nonrestricted diet.
"Most of the experience with this drug has been at 6 mg a day," Dr Bodkin notes, adding that only a relatively small proportion of patients is likely to require the 12-mg dosage.
"The important thing for primary care physicians to understand," he says, "is that transdermal selegiline is to MAOIs what the SSRIs were to TCAs [tricyclic antidepressants]. This is a user-friendly MAOI, just like SSRIs are basically user-friendly TCAs."