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Transdermal selegiline

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 Review Article

Transdermal Selegiline:
The New Generation of Monoamine Oxidase Inhibitors
By Ashwin A. Patkar, MD, Chi-Un Pae, MD, and Prakash S. Masand, MD

ABSTRACT
Needs Assessment
T h e c l i n i c a l u s e o f m o n o a m i n e ox i d a s e Despite evidence of antidepressant efficacy, the use of monoamine oxidase inhibi-
tors has declined due to concerns about food and drug interactions. To overcome
inhibitors (MAOIs) has declined due to con- these problems, the selegiline transdermal system (STS) was developed with novel
pharmacokinetic and pharmacodynamic properties. STS represents an advance over
cerns about food and drug interactions and older monoamine oxidase inhibitors because it can be used as an antidepressant
with minimal dietary modifications. STS may have an important therapeutic role in
waning physician experience. Evidence indi- major depressive disorder.
cates that MAOIs are effective in depressive Learning Objectives
disorders, in particular depression with atypi- At the end of this activity, the participant should be able to:
• List drug interactions and dietary restrictions with monoamine oxidase inhibitors.
cal features. Effor ts to address safety issues • Understand the advantages of transdermal selegiline over older monoamine
have led to the development of more selective oxidase inhibitors.
• Understand how to use transdermal selegiline to treat depression.
and reversible MAOIs, such as moclobemide. Target Audience: Neurologists and psychiatrists
Selegiline, a selective monoamine oxidase B Accreditation Statement
inhibitor, has been approved for the adjunctive Mount Sinai School of Medicine is accredited by the Accreditation Council for
Continuing Medical Education to provide Continuing Medical Education for physicians.
treatment of Parkinson’s disease at low doses. The Mount Sinai School of Medicine designates this educational activity for a
maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit
At higher doses, oral selegiline is also effec- commensurate with the extent of their participation in the activity.
tive in major depressive disorder (MDD) but It is the policy of Mount Sinai School of Medicine to ensure fair balance, indepen-
dence, objectivity and scientific rigor in all its sponsored activities. All faculty partici-
loses its selectivity and has the potential for pating in sponsored activities are expected to disclose to the audience any real or
apparent discussion of unlabeled or investigational use of any commercial product
tyramine interactions. To overcome these prob- or device not yet approved in the United States.
This activity has been peer-reviewed and approved by Eric Hollander, MD, professor
lems, a transdermal formulation of selegiline, of psychiatry, Mount Sinai School of Medicine. Review Date: April 10, 2006.
the selegiline transdermal system (STS), was To Receive Credit for This Activity: Read this article, and the two
CME-designated accompanying articles, reflect on the information presented,
developed with novel pharmacok inetic and and then complete the CME quiz found on pages 397 and 398. To obtain credits,
you should score 70% or better. Termination date: May 31, 2008. The estimated
pharmacodynamic properties. Compared with time to complete this activity is 3 hours.
oral administration, transdermal selegiline

Dr. Patkar is an associate professor in the Department of Psychiatry and Behavioral Sciences at Duke University Medical Center in Durham,
North Carolina. Dr. Pae is visiting fellow in psychopharmacology in the Department of Psychiatry and Behavioral Sciences at Duke
University Medical Center and assistant professor in the Department of Psychiatry at The Catholic University of Korea in Seoul. Dr. Masand
is a consulting professor in the Department of Psychiatry and Behavioral Sciences at Duke University Medical Center.
Disclosure: Dr. Patkar is a consultant for and/or on the advisory boards of Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, and Reckitt
Benckiser; has received honoraria and is on the speaker’s bureaus of Bristol-Myers Squibb, GlaxoSmithKline, and Reckitt Benckiser;
and has received research support from AstraZeneca, Bristol-Myers Squibb, Forest, GlaxoSmithKline, Janssen, McNeil Consumer and
Specialty Inc, the National Institutes of Health, Organon, Jazz Pharmaceuticals, and Pfizer. Dr. Pae has received research support from
GlaxoSmithKline. Dr. Masand is a consultant for Bristol-Myers Squibb, Forest, GlaxoSmithKline, Health Care Technology, Janssen, Jazz
Pharmaceuticals, Organon, Pfizer, and Wyeth; has received honoraria from and is on the speaker’s bureaus of AstraZeneca, Bristol-Myers
Squibb, Forest, GlaxoSmithKline, Janssen, Pfizer, and Wyeth; has received research support from AstraZeneca, Bristol-Myers Squibb,
Forest, GlaxoSmithKline, Janssen, Ortho-McNeil, and Wyeth; and is a stockholder in psychCME.
Acknowledgements: The authors would like to thank K. Ranga Krishnan, MD, chair of psychiatry at Duke University Medical Center for
providing his poster presentation on monoamine oxidase inhibitors from the American Psychiatric Association, 2004.
Submitted for publication: March 6, 2006, and accepted on April 4, 2006.
Please direct all correspondence to: Ashwin A. Patkar, MD, Department of Psychiatry and Behavioral Sciences, Duke University Medical
Center, 4323 Ben Franklin Boulevard, Suite 700, Durham, NC 27704; Tel: 919-471-3826; Fax: 919-620-0346; E-mail: ashwin.
[email protected].
CNS Spectr 11:5 363 May 2006
 Review Article

leads to sustained plasma concentrations of the advent of selective serotonin reuptake inhibitors
parent compound, increasing the amount of drug (SSRIs), MAOIs were relegated to third- or even
fourth-line treatment.
delivered to the brain and decreasing metabo-
Nevertheless, the efficacy of MAOIs, in particu-
lite production. In addition, STS allows targeted lar for atypical and treatment-resistant depress-
inhibition of central nervous system monoamine sion (TRD) subtypes, has sustained interest in this
class of drugs. Recently, there have been renewed
A (MAO-A) and monoamine B isoenz ymes with
efforts to develop better-tolerated MAOIs lead-
minimal effects on MAO-A in the gastrointesti- ing to the introduction of reversible inhibitors
nal and hepatic systems, thereby reducing the of MAO isoenz yme A (RIMA), such as moclobe -
risk of interactions with tyramine-rich foods (the mide, and a transdermal formulation of selegiline
that targets brain MAO while initially bypassing
“cheese -reaction”). Clinical trials have found 6
gastrointestinal (GI) MAO. While moclobemide is
mg/24 hours of STS to be effective in MDD with- marketed in several countries, it will not become
out the need for dietary restrictions. The efficacy available in the United States in the foreseeable
and safety profile of STS supports its use in MDD. future. Therefore, this review will focus on criti-
cally evaluating the pharmacology, efficacy, and
It is possible that STS may demonstrate benefit in safety data for the selegiline transdermal system
MDD with atypical features or MDD resistant to (STS) that was introduced in the US in 2006. The
other antidepressants. However, more research is purpose of this review is to help clinicians make
informed decisions about the appropriate use of
needed. Clinicians should familiarize themselves
new MAOIs for the treatment of depression.
with the properties and indications for the new
generation of MAOIs.
PHARMACOLOGY
CNS Spectr. 2006;11(5)363-375
The Monoamine Oxidase Enzyme System
INTRODUCTION MAO is one of the most important enzymes in
M onoamine oxidase inhibitors (MAOIs) are neurotransmitter metabolism. The human MAO
an important class of antidepressants that have system consists of two isoforms designated MAO
been used for over 40 years. Iproniazid, an inhib- isoenz yme A (MAO-A) and isoenz yme B (MAO-
itor of the enz yme monoamine oxidase (MAO), B). 6 The ratio of MAO-A to MAO-B in the human
was originally synthesized as an antituberculosis brain is 25%:75%, in the liver is 50%:50%, in the
agent and ushered in the era of antidepressant intestine is 80%:20%, and in the peripheral adren-
development. 1 , 2 By the early 1960s, MAOIs were ergic neurons (adrenal glands, ar terial vessels,
s u cce s s f u l l y e s t a b l i s h e d a s a nt i d e p re s s a nt s. 3 and sympathetic ner ve) is 90%:10%. 7 , 8 MAO -A
These agents included the hydrazine derivatives preferentially metabolizes serotonin (5-HT ) and
phenelzine and isocarboxazid and the nonhydra- norepinephrine (NE) and is inhibited by clorgy-
zine drug tranylcypromine. However, in the early line. MAO-B preferentially metabolizes phenyl-
1960s, iproniazid was withdrawn from the mar- ethylamine and benzylamine and is inhibited by
ket due to reports of hepatotoxicity. selegiline. Dopamine and tyramine are metabo -
By the mid-1960s, there were over 40 reports of lized equally by both isoforms. 7 Within the human
hypertensive crisis associated with MAOIs, most brain, MAO-A is found in the locus ceruleus and
commonly with tranylcypromine. These episodes reticular formation, regions that contain a high
often followed ingestion of tyramine-rich cheese, density of catecholaminergic neurons. MAO-A is
hence the term “the cheese reaction.” 4,5 The Food also present in the presynaptic terminals of dopa-
and Drug Administration revised the labeling minergic neurons. In contrast, MAO-B is abun-
for MAOIs to include extensive dietar y restric- dant in the dorsal raphe nucleus, which is rich
tions. Although this dramatically reduced the in 5-HT neurons. MAO-B is also found in basal
incidence of hypertensive crises, most patients ganglia, primarily within glial cells, that contain
found the dietary restrictions inconvenient. When dopamine neurons. 9 MAO metabolizes exoge -
tric ylic antidepressants ( TCAs) rapidly gained nous amines, such as dietary tyramine, and regu-
acceptance, the use of MAOIs declined. With the lates neurotransmitter levels.10

CNS Spectr 11:5 364 May 2006

 Review Article

Irreversibility and Nonselectivity Reversible Monoamine Oxidase A

Irreversible and Nonselective Inhibitors: Moclobemide
Monoamine Oxidase Inhibitors: Moclobemide was the first RIMA to be approved
Phenelzine and Tranylcypromine as an antidepressant in Europe and is available in
Many of the problems associated with older over 50 countries, excluding the US. 14 Moclobemide
MAOIs, such as tranylcypromine and phenelzine, is better tolerated than the older MAOIs and is sel-
result from two pharmacologic characteristics: dom associated with hypertensive crisis because it
irreversibility and nonselectivity. Irreversibility is readily displaced from its binding site on MAO-A
refers to the tenacious binding of the drug to by tyramine. 15 However, questions remain regarding
the MAO enz yme essentially for the lifetime of efficacy of moclobemide compared with the older
the molecule (ie, 14–28 days). 1 1 Thus, even high MAOIs. 16 A meta-analysis 11 found that there was a
concentration of substrate cannot displace an clinically significant advantage for the older MAOIs
irreversible MAOI from the enz yme. Therefore, (13.3%) over moclobemide. It is hypothesized 1 that
normally insignificant concentrations of vaso- MAO inhibition by reversible MAOIs is less pro-
pressors, such as t yramine, can be dangerous found and sustained compared with the irreversible
when ingested with an irreversible MAOI. MAOIs, which may explain the possible efficacy dif-
Nonselectivity refers to the tendency of a drug ferences. Despite a more favorable tolerability pro-
to bind both the A and B isoenzymes. 1 2 Several file, RIMAs have not yet established a strong track
MAOIs with selectivity toward either MAO-A or record as a preferred treatment for depression.17
MAO-B have been developed. Table 1 lists the var-
ious MAOIs that have been clinically tested. One Selective Monoamine Oxidase B
of the earliest selective MAOIs to be identified Inhibitors: Selegiline
was the irreversible MAO-A inhibitor clorgyline. 1 3 The accessibility of the blood platelets that
However, clorgyline had the liabilit y to cause contain MAO-B for research facilitated the iden-
hypertensive crisis with high concentrations of tification of selective MAO-B inhibitors, such as
tyramine despite its selectivity. To address these selegiline. At low oral doses (5–10 mg/day), sele-
limitations, RIMAs were developed. giline inhibits >90% of brain MAO-B while avoid-

TABLE 1.
Classification of MAOIs 9
Therapeutic dose Available
Agent (mg/day) Selectivity Reversibility in the US
Tranylcypromine 20–90 Nonselective Irreversible Active
Phenelzine 15–90 Nonselective Irreversible Active
Isocarboxazid 10–30 Nonselective Irreversible Active
Selegiline transdermal system 6–12 mg/24 hours Nonselective *
Irreversible Active
Oral selegiline 10 MAO-B† Irreversible Active
Pargyline N/A MAO-B Irreversible Discontinued
Clorgyline N/A MAO-A Irreversible Unavailable
Nialamide N/A Nonselective Irreversible Unavailable
Befloxatone N/A MAO-A Reversible Unavailable
Moclobemide 300–600 MAO-A Reversible Unavailable
Brofaromine N/A MAO-A Reversible Unavailable
*
Transdermal selegiline is nonselective for brain MAO.
†
At antidepressant doses (>20 mg/day), oral selegiline loses its selectivity.

Riederer P, Konradi C, Schay V, et al. Localization of MAO-A and MAO-B in human brain: a step in understanding the therapeutic action of
L-deprenyl. Adv Neurol. 1987;45:111-118.
MAOIs=monoamine oxidase inhibitors; MAO-B=monoamine oxidase B inhibitor; N/A=not applicible; MAO-A=monoamine oxidase A inhibitor.
Patkar AA, Pae C-U, Masand PS. CNS Spectr. Vol 11, No 5. 2006.

CNS Spectr 11:5 365 May 2006

 Review Article

ing inhibition of GI MAO-A, eliminating the need consequences can be a severe hypertensive reac-
for dietary restrictions. 1 8 , 1 9 At doses >20 mg/day, tion that typically occurs within 10 minutes and
selegiline loses its selectivity. Oral selegiline in can last up to 2 hours after a meal.37
low doses (5–10 mg/day) has been approved for Therefore, dietary restrictions are required for
the adjunctive treatment of Parkinson’s disease patients receiving older MAOIs. Extensive dietary
without any dietary restrictions.20,21 restrictions were previously recommended, how-
To date, clinical trials 2 2 - 2 4 have not established ever, due to changes in food processing and more
oral selegiline as a potent antidepressant at doses reliable analytical methods, newer recommenda-
selec tive for MAO -B inhibition (5–10 mg/day). tions are less restrictive. 3 8 The tyramine content
The best evidence for antidepressant efficac y of foods varies due to the differences in process-
comes from trials 25-27 employing larger, nonselec- ing. Large quantities of tyramine are formed if
tive doses (20–60 mg/day) that required dietary products are aged, fermented, or spoiled. Because
restrictions. This suggests that inhibition of MAO- the cheese reaction is dose-related, it can be mini-
A alone or in combination with MAO-B is critical mized without the complete avoidance of tyra-
to the antidepressant response.28 mine-containing foods.
Oral selegiline undergoes extensive first-pass
metabolism by the hepatic cytochrome P450 sys-
DEVELOPMENT OF SELEGILINE
tem. Desmethylselegiline, l-methamphetamine,
TRANSDERMAL SYSTEM
and l-amphetamine are the main metabolites.
From an antidepressant efficac y and safet y
There is concern that the metabolites with the
standpoint, the ideal MAOI should inhibit brain
oral formulation may be associated with cardio-
MAO-A and MAO-B but not GI MAO-A. Oral
vascular side effects and neurotoxicity.29
selegiline suffers from the limitations of loss of
A freeze - dried, orally disintegrating form of
selectivity for MAO-B at antidepressant doses,
selegiline has been developed. I t is absorbed
thereby introducing the need for dietary restric-
through the buccal mucosa directly into the sys-
tions. Recent advances in drug-delivery systems
temic circulation 3 0 , 3 1 and seems to be better tol-
have permitted systemic deliver y of a drug via
erated than the conventional formulation and
transdermal route.
less sensitive to a tyramine challenge. 2 9 Orally
STS has been developed with novel pharma-
disintegrating selegiline 1.25–2.5 mg/day has
cokinetic and pharmacodynamic properties. It uti-
been demonstrated to have short-term efficacy
lizes selegiline as an amine base embedded in an
as adjunctive treatment for Parkinson’s disease.
However, its antidepressant efficacy remains to
be evaluated.
FIGURE 1.
Rasagiline is a selective, irreversible MAO-B
The mechanism of the cheese reac-
inhibitor that is 10–15 times more potent than
tion and NE release and metabolism
selegiline. Unlike selegiline, it does not give rise
to methamphetamine metabolites nor does it after MAO-A inhibition 15
have the sympathomimetic activity of selegiline. 32 Noradrenaline

While it is effective in the treatment of Parkinson’s

disease, 33 its antidepressant efficacy has not been Noradrenaline
Adrenergic Neuron
investigated in controlled trials. MAO-A
Irreversable MAO
Inhibition
Synthesis Noradrenaline
Vesicle Tyramine
THE CHEESE REACTION
The “cheese reaction” occurs when food and Noradrenaline Tyramine Uptake
Release
alcoholic beverages containing t yramine and MAO-A
Small Intestine Tyramine
other indirectly acting sympathomimetic amines Blood Stream
MAO-A 80%, MAO-B 20%
are consumed along with MAOIs. 34 Normally, tyra-
Youdim MB, Riederer PF. A review of the mechanisms and role of mono-
mine is metabolized into inactive substances by
amine oxidase inhibitors in Parkinson’s disease. Neurology. 2004;63(7
GI MAO (primarily MAO-A). 3 5 , 3 6 When peripheral suppl 2):S32-S35. Adapted with permission by Lippincott Williams &
MAO-A is inhibited by at least 80%, tyramine is Wilkins, Copyright (2004).

not metabolized, able to enter the circulatory sys- NE=norepinephrine; MAO-A=monoamine oxidase isoenzyme A;
MAO=monoamine oxidase; MAO-B=monoamine oxidase isoenzyme B.
tem, and cause a significant release of NE from Patkar AA, Pae C-U, Masand PS. CNS Spectr. Vol 11, No 5. 2006.
the peripheral adrenergic neurons (Figure 1). The

CNS Spectr 11:5 366 May 2006

 Review Article

acrylic polymer-adhesive matrix and is released at compared with 4.4% after oral administration due
a controlled rate by the components in the matrix to first-pass metabolism. Therefore, STS produces
so that a steady plasma-drug level is maintained. 39 higher and more sustained steady-state levels
STS has undergone extensive evaluation in compared with oral selegiline. Figure 2 4 3 shows
humans. These studies 4 0 , 4 1 have found that STS differences in plasma concentrations with oral
offers sustained plasma concentrations, minimal selegiline 10 mg/day versus STS 6 mg/24 hours.
peak-trough fluctuations, higher bioavailability, Protein binding is ~90% and it rapidly penetrates
and reduced concentration of metabolites. STS the central nervous sytem. Selegiline is metabo-
a l l ows i n h i b i t ion of brain MAO -A and MAO -B lized by multiple cytochrome P450 isoenzymes
e n z y m e s w i t h re d u c e d e f fe c t s o n G I MAO - A , 2C9, 2B6, 3A4/5 to form N-desmethylselegiline
thereby reducing the risk of possible interactions or R-methamphetamine. Both these metabolites
with tyramine -rich foods at therapeutic doses. can be further transformed into R-amphetamine.
The prolonged duration of action with STS per- The increase in selegiline concentration after STS
mits the lower frequency of administration and compared with oral administration occurs with a
possibly improved patient compliance.1 70% reduction in the formation of amphetamine-
like metabolites that may be associated with toxic
PHARMACOKINETICS OF SELEGILINE effects on brain neurochemistry and behavior. 44,45
TRANSDERMAL SYSTEM The pharmacokinetics of STS does not seem to
O ver 30 human pharmacok inetics studies 4 2 be significantly influenced by gender, renal func-
have examined dermally applied selegiline in tion, or mild to moderate hepatic impairment.
over 650 subjects. STS is extensively absorbed Table 2 describes the pharmacokinetics of STS.
through the skin with plasma levels maintained
over a 24-hour period permitting once-daily appli- PHARMACODYNAMICS OF
cation. About 25% to 30% of selegiline in STS is SELEGILINE TRANSDERMAL SYSTEM
delivered within 24 hours. Selegiline delivered Studies 46 have shown that selegiline doses that
by 20 mg/20 cm 2 , 30 mg/30 cm 2 , and 40 mg/40 produce at least 70% inhibition of brain MAO-A
cm 2 STS approximates 6 mg, 9 mg, and 12 mg and 90% inhibition of brain MAO-B predict antide-
over 24 hours, respectively. Steady-state levels pressant activity. STS also was 10–20 times more
are reached after 5 days of STS treatment. 2 3 The potent than oral selegiline in producing its antide-
bioavailability of selegiline is ~75% following STS pressant-like effect and inhibiting cortical MAO-A.10
Animal studies24 have demonstrated that
doses of STS that inhibit activities of both MAO-
FIGURE 2.
A and MAO-B in the brain by >90% only partially
Pharmacokinetics of STS compared i n h i b i t G I e n z y m e a c t i v i t i e s, w i t h a m a x i m a l
with oral selegiline 43 40% inhibition of MAO-A and 70% to 75% inhi-
STS 6 mg/24 hours
2,000
Selegiline PO 10 mg/day
TABLE 2.
1,500 Pharmacokinetics of STS 47
Pharmacokinetic Parameters STS
ng/mL

1,000
Half-life 20.1 hours
Steady-state 5 days
500
Bioavailability 75%

0 Hepatic metabolism CYP 2C9, 2B6, 3A4

2 4 8 12 16 24 28 36 72 100
Hours Metabolites l-methamphetamine,
N-desmethylselegiline
Adapted from Krishnan R. Advances in psychopharmacology: MAOIs.
Scientific report session. American Psychiatric Association, New Adapted from EMSAM [package insert]. Princeton, NJ: Bristol-Myers Squibb
York, NY, 2004. Company; 2006.
STS=selegiline transdermal system; PO=oral. STS=selegiline transdermal system; CYP=cytochrome P450.
Patkar AA, Pae C-U, Masand PS. CNS Spectr. Vol 11, No 5. 2006. Patkar AA, Pae C-U, Masand PS. CNS Spectr. Vol 11, No 5. 2006.

CNS Spectr 11:5 367 May 2006

 Review Article

bition of MAO -B. I n addition, doses of STS that with that seen with oral selegiline 10 mg/day.51
inhibit brain MAO-A and MAO-B by 60% and 90%, The results of tyramine challenge studies 4 8 - 5 0
respectively, do not alter GI MAO-A activity. This suggest that STS 6 mg/24 hours is equivalent to
s u p p o r t s a t a rg e te d e f fe c t o f S TS o n t h e b ra i n oral selegiline 10 mg/day in pressor responses at
versus the periphery (Figure 3). 1 0 , 2 4 Because >80% 10 days and is ~20 times less sensitive than tran-
inhibition of GI MAO-A is necessar y to affect the ylcypromine. Doses of STS 12 mg/24 hours are ~4
ability of the enzyme to catabolize tyramine, STS times less sensitive than tranylc ypromine. With
6 mg/24 hours does not seem to significantly STS 6 mg/24 hours, it seems vir tually impossible
impair tyramine metabolism in the gut. that an individual can consume sufficient amounts
of tyramine -rich food to produce a hyper tensive
crisis. Even at 12 mg/24 hours, the mean pressor
TYRAMINE CHALLENGE TESTS
dose (172±92 mg/24 hours) in the fed state repre-
Tyramine is a vasopressor and can produce clin-
sents >4 times the amount in a tyramine-rich meal.
ically significant increases in blood pressure (>30
However, the most sensitive subject had a pres-
mmHg) in healthy volunteers at extremely high
sor dose of tyramine 75 mg. Given individual vari-
doses (~1 gram/meal). 48,49 About 2–3 times more
abilities in tyramine sensitivity and unusual dietary
t yramine is required with food compared with
habits, dietary modifications are required with STS
fasting condition to induce a pressor response.
9 mg/24 hours and 12 mg/24 hours. McCabe and
Tyramine pressor sensitivity to STS 6 mg/24 hours
Gurley 5 2 reviewed tyramine content of over 360
and 12 mg/24 hours has been investigated under
samples in >17 food categories and could identify
both fasting and fed conditions. Studies 48,49 have
only seven items (mostly aged or fermented cheese,
found that, on average, at least 200 mg of tyra-
meat, or fish products) that, when consumed in
mine in fasting state (well above the content of a
large amounts (>5 servings at a time), could reach
tyramine -rich meal, which is 40 mg) was neces-
the mean tyramine threshold in the fed state that
sary to produce a 30 mm increase in blood pres-
may produce a pressor effect with 12 mg/24 hours.
sure. In contrast, as little as 10–25 mg of tyramine
The lists of food to avoid are available in local phar-
can produce a 30 mm increase in blood pressure
macies and are shown in Table 3.53
with tranylc ypromine. 49,50 Even with long-ter m
Consistent with these findings, phase III trials 4 2
STS 6 mg/24 hours treatment, there is only a
of >2,500 patients exposed to STS 6 mg, 9 mg, and
slight increase in tyramine sensitivity compared
12 mg over 24 hours without dietary modifications
revealed no episodes of hypertensive crises. Oral
FIGURE 3. selegiline has been used to treat Parkinson’s dis-
Effect of STS at steady-state on MAO- ease without dietary restrictions since 1989 with
A inhibition* 42 >1.5 million patient exposures. Pharmacovigilance
data from 1997 4 2 found that the rate of hyperten-
100 sive crisis per 100,000 exposure years was 1.56 for
90 Cortex
Percentage Inhibition (%)

oral selegiline compared with 43.36 for tranylcy-

80 Duodenum
promine. Of the four reported events, three were
70 Striatum not tyramine related and possibly due to interac-
60
Liver tions with multiple dopaminergic drugs.
50
40
30 DRUG INTERACTIONS
20 O l d e r MAO I s we re l i a b l e to p ro d u ce hy p e r-
10
tensive episodes when taken concomitantly
0 2
Patch Area (cm )/24 hours 0.4 0.71 1.0 1.5 2.0 2.5 3.75 5 10 with indirectly acting sympathomimetics, such
–
mg kg 1/24 hours 0.68 1.24 1.76 2.66 3.6 4.55 7.37 9.9 21.29
as pseudoephedrine. Therefore, several cough
* Even at the highest observed STS-induced brain MAO-A inhibition, hepatic MAO- and cold medications carr y a specific warning
A function (and presumed tyramine-metabolizing capacity) remained robust.
a g a i n s t u s i n g s u c h p re p a r a t i o n s w i t h MAO I s.
Adapted from EMSAM® selegiline transdermal system new drug appli-
cation 21,336/21,708. Food and Drug Administriation Web site. Available Pharmacologic studies 54,55 have shown that the
at: http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4186B2_01_01_ oral decongestants pseudoephedrine or phen-
Somerset-EMSAM.pdf. Accessed October 26, 2005.
y l p ro p a n o l a m i n e d i d n o t p ro d u c e s i g n i f i c a n t
STS=selegiline transdermal system; MAO-A=monoamine oxidase isoenzyeme A.
blood pressure increases when given to individ-
Patkar AA, Pae C-U, Masand PS. CNS Spectr. Vol 11, No 5. 2006.
uals administered STS 6 mg/24 hours. However,

CNS Spectr 11:5 368 May 2006

 Review Article

due to the limited number of subjects exposed possibly consistent with serotonin syndrome.
in these two studies, sympathomimetic drugs Only two (0.04%) had serious symptoms. There
are contraindicated with STS. were no fatalities. 5 8 Currently, there is insuffi-
Another potentially life -threatening compli- cient evidence to determine whether STS has a
cation of MAOI therapy is the development of decreased risk to induce the serotonin syndrome
s e ro to n i n s y n d ro m e c h a ra c te r i ze d by co n f u- in depressed patients. Therefore, it is prudent to
sion, fever, diaphoresis, ataxia, or diarrhea. The obser ve a minimum washout period equal to 5
most common drug combinations that cause half-lives (~1 week with all antidepressants, 5
serotonin syndrome are MAOIs with SSRIs, weeks with fluoxetine) when switching from an
t r y p to p h a n , TC As, o r m e p e r i d i n e ( o p i o i d s ) . 5 6 antidepressant to an MAOI and to allow at least
This syndrome is rare. Since 1950, ~225 cases 2 we e k s o f w a s h o u t w h e n s w i tc h i n g f ro m a n
of serotonin syndrome have been reported and MAOI to an SSRI.
h a v e i n c l u d e d c a s e s d u e t o n o n - M AO I d r u g Comprehensive data are not available for drug
combinations. 57 The syndrome is usually mild interactions with STS. Therefore, STS should not
and, if managed with drug withdrawal and sup- be used in combination with several drugs that
por tive therapy, generally improves within 24 affect monoamine activity for at least 2 weeks
hours. 57 As in the case of older MAOIs, these after discontinuation of STS. Table 4 provides a
agents are contraindicated dur ing STS treat-
list of contraindicated medications with STS.
ment.
A sur vey of 47 investigators involved in the
Pa r k i n s o n s S t u d y G r o u p 5 8 f o u n d t h a t o f t h e ANTIDEPRESSANT EFFICACY OF
4,568 patients treated with a combination of oral SELEGILINE TRANSDERMAL SYSTEM
s e l e g i l i n e a n d a n a n t i d e p re s s a n t ( c o m m o n l y Th e e f f i c a c y o f S TS i n M D D h a s b e e n e va l-
an SSRI), 11 (0.24%) experienced symptoms uated in five short-term, randomized, dou-

TABLE 3.
Dietary Modifications with MAOIs* 53
Type of Food Acceptable Foods
and drink Tyramine-Rich Foods and Drinks to Avoid containing little or no tyramine
Vegetables Broad bean pods (fava bean pods) All other vegetables
Meat, Air dried, aged and fermented meats, sausages and salamis, Fresh meat, poultry and fish, including
Poultry, including cacciatore, hard salami, and mortadella fresh processed meats (eg, lunch meats,
and Fish Pickled herring hot dogs, breakfast sausage, and cooked
sliced ham)
Any spoiled or improperly stored meat, poultry and fish. These
are foods that have a change in color, odor, or become moldy.
Spoiled or improperly stored animal livers
Dairy (milk Aged cheeses Processed cheeses, mozzarella, ricotta
products) cheese, cottage cheese, and yogurt
Drinks All tap beers and other beers that have not been pasteurized As with other antidepressants, concomi-
tant use of alcohol with STS is not rec-
ommended (bottled and canned beers
and wines contain little or no tyramine)
Other Concentrated yeast extract, such as Marmite Brewer’s yeast, baker’s yeast, soy milk,
Sauerkraut commercial chain restaurant pizzas pre-
pared with cheeses low in tyramine
Most soybean products, including soy sauce and tofu
OTC supplements containing tyramine
* All foods you eat must be fresh or properly frozen. Avoid foods when you do not know their storage conditions.
Shulman KI, Walker SE. A reevaluation of dietary restrictions for irreversible monoamine oxidase inhibitors. Psychiatr Ann. 2001; 31: 378-384.
MAOIs=monoamine oxidase inhibitors; STS=selegiline transdermal system; OTC=over the counter.

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CNS Spectr 11:5 369 May 2006

 Review Article

ble -blind, placebo-controlled trials and one D 17 score <8) compared with 23% response and
maintenance trial. 4 7 , 5 9 - 6 1 Four trials compared a 11% remission rate in the placebo group. The
f i xe d - d o s e o f S TS ( 6 m g / 2 4 h o u r s ) w h i l e o n e compliance with the patch was high, with nearly
study 6 2 had a flexible-dosing strategy (STS 6–12 90% of STS subjects completing the trial.
mg/24 hours). In the pivotal trials, STS produced The second trial 6 0 was an 8-week, dose titra-
significantly greater improvement on primar y tion (STS 6–12 mg/24 hours) trial of 289 sub -
and secondary outcome measures, which jects without dietar y restrictions. Primar y and
included the 28-item Hamilton Rating Scale for secondar y efficac y endpoints included scores
Depression (HAM-D 28 ) and Montgomery-Åsberg on the HAM-D 17 , HAM-D 28 , and the MADRS. STS
D e p re s s i o n R at i n g S c a l e ( MA D R S ) s co re s a n d was significantly superior to placebo according
Clinical Global Impression (CGI) ratings. to HAM-D28 and MADRS scores and showed
To date, results from t wo randomized con- a n o n s i gn i f i c a n t s u p e r i o r i t y o n t h e H A M - D 1 7
trolled trials (RC Ts) 5 9 , 6 0 have been repor ted. In (P=.07) and Clinical Global Impression rat-
a 6-week, fixed- dose, RC T of 176 subjects, STS ings (P=.055). Responders ( > 50% reduc tion in
6 mg/24 hours was significantly more effective MADRS scores) were significantly higher in
compared with placebo on the primary (17-item t h e S TS gro u p ( 3 3 % ) t h a n t h e p l a ce b o gro u p
HAM -D and secondar y endpoints. 5 9 Tyramine - (21%). Responder differences were not striking
restricted diet was recommended in this study. when defined by HAM-D 1 7 or HAM-D 2 8 scores.
STS was separated from placebo by week 1, Overall, there was a modest but statistically sig-
raising the possibility of accelerated response nificant improvement with STS compared with
due to a systemic drug-deliver y route. 6 1 About placebo. Data from this trial were supportive of
38% of subjects on STS responded (>50% STS but the drug did not significantly separate
reduction in HAM-D 17 ) and 23% remitted (HAM- from placebo on the primary endpoint.
In a long-term trial, 6 2 322 subjects with MDD
who had responded during an initial, open-label,
TABLE 4. 10-week trial of fixed- dose STS, were random-
Contraindicated Drugs with STS* 47 ized to STS 6 mg/24 hours or placebo for up to
12 months. Relapse rates at 6 and 12 months
Drug Classes Examples
favored STS (17% at 12 months) over placebo
Antidepressants (31% at 12 months). Substantially greater num-
TCAs Amitriptyline, imipramine bers of placebo patients (61%) received rescue
SSRIs Fluoxetine, paroxetine, sertraline, medication during the first 26 weeks of treatment
than STS patients (29%). 62 It seems that improve-
Newer Bupropion, venlafaxine, mirtazapine, ment seen in short-term trials is maintained for
antidepressants duloxetine
at least 1 year with continued STS treatment. The
MAOIs Oral selegiline, isocarboxazid, phenelzine, data from the three trials as well as an unpub-
tranylcypromine lished trial (data submitted to the FDA) are sum-
Antitussive agents Dextromethorphan, phenylpropanolamine, marized in Table 5.
and cold products pseudoephedrine, ephedrine, phenylephrine
Sympathomimetic Amphetamine SAFETY OF SELEGILINE
amines
TRANSDERMAL SYSTEM
Narcotics Meperidine Data from clinical trials 60 indicate that STS
Muscle relaxants Cyclobenzaprine has a favorable side-effect profile. No drug-pla-
cebo differences in cardiovascular side effects
Analgesics Tramadol, methadone, propoxyphene
were observed in the trial that did not restrict
Others St. John’s wort, carbamazepine, oxcarbazepine tyramine. Although or thostatic changes in
* STS should be discontinued at least 10 days before surgery requiring blood pressure (ie, a decrease of > 10 mmHg in
general anesthesia.
mean blood pressure when changing position
Adapted from EMSAM [package insert]. Princeton, NJ: Bristol-Myers
Squibb Company; 2006. from supine or sitting to standing) were slightly
STS=selegiline transdermal system; TCAs=tricyclic antidepressants; higher with STS (–2.3 mmHg) than placebo (–
SSRIs=selective serotonin reuptake inhibitors; MAOIs=monoamine oxi- 0.8 mmHg) at week 6 in one trial, 59 these were
dase inhibitors.
not judged to be clinically meaningful. In short-
Patkar AA, Pae C-U, Masand PS. CNS Spectr. Vol 11, No 5. 2006.
term STS trials, 59,60 the incidence of orthostatic

CNS Spectr 11:5 370 May 2006

 Review Article

hypotension was 9.8% in STS-treated patients jects required symptomatic treatment for the
and 6.7% in placebo-treated patients. However, ASRs in the trials and <10% discontinued treat-
or thostatic hypotension and falls are more of ment due to ASRs.
a concern in the elderly. Such patients should The potential for ASR can be minimized by
b e m o n i to re d fo r p o s t u ra l c h a n g e s i n b l o o d proper precautions while applying the patches.
pressure throughout treatment. Dose increases Th e s e i n c l u d e a p p l y i n g t h e p atc h o n i nt a c t ,
should be made cautiously in patients with pre - dr y sk in on the upper torso, upper thigh, or
existing orthostasis. Postural hypotension may upper arm; rotating the patch site daily; wash-
be relieved by having the patient recline until ing the site with soap and water and dr ying
the symptoms have abated or ask ing patients it before application; ensuring that the patch
t o c h a n g e p o s i t i o n s g r a d u a l l y. Pa t i e n t s d i s- a d h e re s p ro p e r l y by p re s s i n g i t f l a t a g a i n s t
playing or thostatic symptoms may need their the sk in; removing the patch ever y 24 hours;
dose adjusted. and gently rinsing the skin site with warm
Rates of sexual, digestive, and central water af ter removal. M ost reac tions subside
ner vous system side effects with STS were without treatment. If reac tions persist or are
comparable with those with placebo. In severe, local cor ticosteroids and/or oral anti-
6 – 8 -we e k s t u d i e s, 5 9 , 6 0 t h e re we re n o s i gn i f i - histaminic agents, such as diphenhydramine,
c a nt c h a n g e s i n we i g ht b e t we e n S TS ( m e a n should be used.
change: –1.2 pounds) compared with placebo I n s o m n i a h a s b e e n re p o r t e d, p a r t i c u l a r l y
(mean change: 0.3 pounds). The incidence with higher doses of STS (eg, 12 mg/24 hours).
of >5% weight gain or loss was no differ- To m i n i m i ze p o te nt i a l i n s o m n i a , S TS s h o u l d
ent between drug and placebo. In long-term b e i n i t i ate d at 6 m g / 2 4 h o u r s, p re fe ra b l y i n
studies (3–12 months), 42 the average weight t h e m o r n i n g. B e n zo d i a ze p i n e o r n o n b e n zo -
change with STS was –1.6 pounds. diazepine hypnotics can be used if insomnia
is troublesome.
Skin Reactions
Application site reactions (ASRs), such Teratogenic Effects
a s r a s h , i t c h i n g, re d n e s s, o r i r r i t a t i o n , we re STS is a Categor y C drug lik e most antide -
more common in STS -treated patients (36%) pressants and there are no data on secretion
t h a n i n p l a c e b o p a t i e n t s ( 1 7 % ) ( P = . 0 0 6 ) . 59 in human milk.
P a u p o r t e a n d c o l l e a g u e s 63 f o u n d t h a t t h e In clinical studies of STS, 4 2 there have been
rate of skin reactions was significantly higher no differences in efficac y between elderly and
with STS (22%) compared with placebo young patients, though the elderly appear at
(12%) in 1,326 subjects with a mean duration higher risk for sk in rash. There are no data on
of exposure of 75 days. I n general, few sub - pediatric population.

TABLE 5.
STS: Randomized, Placebo-Controlled, Double-Blind Trials in MDD 42
Bodkin and Amsterdam (2002) Amsterdam (2003)* P9303-P0052* S9303-P9806 (unpublished)*
Duration 6 weeks 8 weeks 8 weeks 52 weeks
N 176 289 265 322
Dose 6 mg/24-hour patch 6–12 mg/24-hour patch 6–12 mg/24-hour patch 6 mg/24-hour patch
Primary HAM-D17 HAM-D17 HAM-D28 K-M relapse
Endpoint P=.018 P=.069 P=.033 P=.006
* Patients were not required to follow a tyramine modified diet.
Adapted from EMSAM® selegiline transdermal system new drug application 21,336/21,708. Food and Drug Administriation Web site. Available at: http://www.fda.
gov/ohrms/dockets/ac/05/briefing/2005-4186B2_01_01_Somerset-EMSAM.pdf. Accessed October 26, 2005.
STS=selegline transdermal system; MDD=major depressive disorder; HAM-D17=17-item Hamilton Rating Scale for Depression; HAM-D28=28-item Hamilton Rating
Scale for Depression; K-M relapse=Kaplan-Meier time to relapse analysis.
Patkar AA, Pae C-U, Masand PS. CNS Spectr. Vol 11, No 5. 2006.

CNS Spectr 11:5 371 May 2006

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MECHANISM OF ANTIDEPRESSANT There are no data on discontinuation of STS.

ACTION OF SELEGILINE TRANSDERMAL In the absence of data on downtitration of STS,
SYSTEM it is difficult to make specific recommendations
Selegiline has been found to potentiate dopa- about abrupt versus gradual discontinuation. In
mine transmission in the brain primarily due to clinical trials, subjects were abruptly discontin-
MAO -B inhibition. 7 Additionally, STS would be ued at the end of the trials; however most of the
expected to elevate brain 5-HT and NE levels due studies were shor t-term. From a clinical stand-
to inhibition of brain MAO-A. 64,65 Interestingly, the point, abrupt discontinuation of the 6 mg/24
acute increases in brain 5-HT and NE with MAOIs hours patch may be reasonable. Whether the
subside with continued treatment and the levels 12 mg- or 9 mg/24 hours patches should be dis-
gradually return to the pre-treatment state due to continued abruptly or tapered to the 6 mg/24-
end-product inhibition of biosynthesis and adaptive hour patch prior to discontinuation will depend
changes in the neurotransmitter receptor sensitiv- upon the clinical histor y as well as patient and
ity. 1 Chronic MAOI administration has been shown clinician preferences. A better understanding of
to enhance 5-HT neurotransmission by altering the taper strategies may occur with wider clinical
rate of 5-HT neuron firing and the release of 5-HT use of the drug. At least 2 weeks should elapse
from nerve endings. 6 6 , 6 7 It is likely that elevated af ter stopping STS before commencing treat-
levels of 5-HT, NE, and dopamine resulting from ment with another antidepressant or a drug that
MAO inhibition play some role in the antidepres- is contraindicated with STS.
sant effects of STS. 6 8 Selegiline also has several
pharmacologic effects in the brain other than its
THERAPEUTIC IMPLICATIONS
MAO inhibition. For example, selegiline has been
found to have antioxidant and neuroprotective
Major Depressive Disorder with Atypical
properties. 69 In this context, defects in antioxidative
Features
systems have been found in depression.70
MDD with atypical features characterized by
re ve r s e ve g e t at i ve s y m p to m s ( e g, hy p e r s o m -
DOSAGE AND INDICATION nia, hyperphagia, retardation) and mood reac-
S T S h a s b e e n F DA a p p ro ve d fo r t h e t re a t- tivity is viewed as distinct from other forms of
ment of MDD. STS comes in three strengths: a 6 depressive disorders. Prevalence rates of 30%
mg/24-hour patch (20 mg/20 cm 2 ), a 9 mg/24-hour in depressive outpatients and 5% in the commu-
patch (30 mg/30 cm 2 ), and a 12 mg/24-hour patch nity have been reported. 69-73 A recent large meta-
(40 mg/40 cm 2 ) in separate boxes of 30 patches. analysis 7 4 showed that MAOIs are super ior to
Dietary modifications are not necessary with the TCAs (effect size=0.27; 95% CI: 0.16-0.42) in MDD
6 mg/24-hour patch but are required with the 9 with atypical features, replicating results from an
mg/24-hour and 12 mg/24-hour patches. The start- earlier meta-analysis. 2 8 Only three RC Ts 2 8 have
ing and target dose should be 6 mg/24 hours. directly compared SSRIs with MAOIs in atypical
D o s e i n c re a s e s, if requ ired sh ou ld occ ur in 3 depression. Both drugs were found to have com-
mg/24 hours increments at > 2-week intervals until parable efficacy in atypical depression. However,
the maximum recommended dose of 12 mg/24 t h e re s u l t s s h o u l d b e i n t e r p re t e d c a u t i o u s l y
hours is reached. No data are available to sup - because two included the RIMA moclobemide
port a greater efficacy at higher doses. Generally, that may be less efficacious than the irreversible
the STS should be applied at the same time of MAOI. 7 5 While MDD without at ypic al features
the day, preferably in the morning. A minimum re s p o n d s e q u a l l y we l l t o MAO I s a n d TC A s o r
washout period equal to 5 half-lives from existing S S R I s, i t s e e m s t h a t a t y p i c a l d e p re s s i o n m ay
antidepressants (~1 week for most antidepres- preferentially respond to MAOIs.28
sants, 5 weeks for fluoxetine) is recommended
before initiating STS treatment. Patients should Treatment-Resistant Depression
be informed that tyramine-rich foods should be Results from Sequenced Treatment Alternatives
avoided from the first day of using the 9 mg/24 to Relieve Depression 2 8 trial showed that ~30%
hours or 12 mg/24 hours patch. The dietary modi- of patients with MDD achieve remission of their
fications should continue for at least 2 weeks after symptoms with SSRI monotherapy. Evidence sug-
dose reduction to 6 mg/24 hours or discontinua- gests MAOIs may benefit up to 50% of patients
tion of the 9 mg or 12 mg 24-hour patch. who have failed other antidepressants 2 8 , 7 6 and

CNS Spectr 11:5 372 May 2006

 Review Article

practice guidelines have recommended MAOIs in tions. STS represents a new generation of MAOI
TRD. 77 A recent retrospective study 78 of 59 patients that seems to have safety advantages over the
with TRD found that 56% of MAOI trials in patients older MAOIs. Available evidence shows that 6
with early TRD (defined as those who had failed mg/24 hours of STS is effective in MDD and can
to respond to < 3 previous antidepressant trials) be safely taken without dietar y modifications.
resulted in a CGI-Improvement score of 1 (ver y Although higher doses of STS (9 mg and 12
much better) or 2 (much better). However, only mg/24 hours) also demonstrate a superior safety
12% of MAOI trials in patients with advanced TRD profile than older MAOIs, the limited c linic a l
(failed >3 antidepressant trials) resulted in remis- and experimental evidence suggest that dietary
sion. 7 8 The MAOIs studied included older MAOIs modifications should be instituted at these doses.
and oral selegiline. Similar results supporting effi- Due to paucity of data, it is premature to infer
cacy of MAOIs in TRD have been reported previ- whether STS will offer any incremental value in
ously. 16,76,79 STS may benefit patients with TRD and efficacy over currently available antidepressants
clearly prospective, controlled studies to examine or whether its side-effect profile may differ with
this issue should be conducted. long-term use. Nevertheless, introduction of STS
expands the range of therapeutic options for clini-
Therapeutic Areas Needing Further Study cians to treat MDD. Further studies are necessary
Oral selegiline and STS has been shown to to compare STS with conventional antidepres -
hold promise in the treatment of attention-defi- sants and to suggest evidence-based guidelines
cit/hyperactivity disorder (ADHD). 8 0 , 8 1 STS was for the use of STS in clinical practice. CNS
also shown to block cocaine -induced euphoria
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