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Transdermal Selegiline: The New Generation of Monoamine Oxidase Inhibitors

Published online by Cambridge University Press:  07 November 2014


The clinical use of monoamine oxidase inhibitors (MAOIs) has declined due to concerns about food and drug interactions and waning physician experience. Evidence indicates that MAOIs are effective in depressive disorders, in particular depression with atypical features. Efforts to address safety issues have led to the development of more selective and reversible MAOIs, such as moclobemide. Selegiline, a selective monoamine oxidase B inhibitor, has been approved for the adjunctive treatment of Parkinson's disease at low doses. At higher doses, oral selegiline is also effective in major depressive disorder (MDD) but loses its selectivity and has the potential for tyramine interactions.To overcome these problems, a transdermal formulation of selegiline, the selegiline transdermal system (STS), was developed with novel pharmacokinetic and pharmacodynamic properties. Compared with oral administration, transdermal selegiline leads to sustained plasma concentrations of the parent compound, increasing the amount of drug delivered to the brain and decreasing metabolite production. In addition, STS allows targeted inhibition of central nervous system monoamine A (MAO-A) and monoamine B isoenzymes with minimal effects on MAO-A in the gastrointestinal and hepatic systems, thereby reducing the risk of interactions with tyramine-rich foods (the “cheese-reaction”). Clinical trials have found 6 mg/24 hours of STS to be effective in MDD without the need for dietary restrictions. The efficacy and safety profile of STS supports its use in MDD. It is possible that STS may demonstrate benefit in MDD with atypical features or MDD resistant to other antidepressants. However, more research is needed. Clinicians should familiarize themselves with the properties and indications for the new generation of MAOIs.

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1.Robinson, DS. Monoamine oxidase inhibitors: a new generation. Psychopharmacol Bull. 2002;36:124138.Google ScholarPubMed
2.Ban, TA. Pharmcotherapy of depression: a historical analysis. J Neural Transm. 2001;108:707716.CrossRefGoogle Scholar
3.Amsterdam, JD, Chopra, M. Monoamine oxidase inhibitors revisited. Psychiatr Ann. 2001;31:361370.CrossRefGoogle Scholar
4.Asatoor, AM, Levi, AJ, Milne, MD. Tranylcypromine and cheese. Lancet. 1963;54:733734.CrossRefGoogle Scholar
5.Horwitz, D, Lovenberg, W, Engelman, K, Sjoerdsma, A. Monoamine oxidase inhibitors, tyramine, and cheese. JAMA. 1964;188:11081110.CrossRefGoogle Scholar
6.Johnson, AG. Monoamine oxidase inhibitors. Br Med J. 1968;2:433.CrossRefGoogle ScholarPubMed
7.Billett, EE. Monoamine oxidase (MAO) in human peripheral tissues. Neurotoxicology. 2004;25:139148.CrossRefGoogle Scholar
8.Yamada, M, Yasuhara, H. Clinical pharmacology of MAO inhibitors: safety and future. Neurotoxicology. 2004;25:215221.CrossRefGoogle Scholar
9.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;45:111118.Google ScholarPubMed
10.Mawhinney, M, Cole, D, Azzaro, AJ. Daily transdermal administration of selegiline to guinea-pigs preferentially inhibits monoamine oxidase activity in brain when compared with intestinal and hepatic tissues. J Pharm Pharmacol. 2003;55:2734.CrossRefGoogle ScholarPubMed
11.Lotufo-Neto, F, Trivedi, M, Thase, ME. Meta-analysis of the reversible inhibitors of monoamine oxidase type A moclobemide and brofaromine for the treatment of depression. Neuropsychopharmacology. 1999;20:226247.CrossRefGoogle ScholarPubMed
12.Johnston, JP. Some observations upon a new inhibitor or monoamine oxidase in brain tissue. Biochem Pharmacol. 1968;17:12851297.CrossRefGoogle ScholarPubMed
13.Lipper, S, Murphy, DL, Slater, S, Buchsbaum, MS. Comparative behavioral effects of clorgyline and pargyline in man: a preliminary evaluation. Psychopharmacology (Berl). 1979;62:123128.CrossRefGoogle ScholarPubMed
14.Chen, DT, Ruch, R. Safety of moclobemide in clinical use. Clin Neuropharmacol. 1993;16(suppl 2):S63S68.Google ScholarPubMed
15.Youdim, MB. The advent of selective monoamine oxidase A inhibitor antidepressants devoid of the cheese reaction. Acta Psychiatr Scand Suppl. 1995;386:57.CrossRefGoogle ScholarPubMed
16.Thase, ME, Frank, E, Mallinger, AG, Hamer, T, Kupfer, DJ. Treatment of imipramine-resistant recurrent depression, III: Efficacy of monoamine oxidase inhibitors. J Clin Psychiatry. 1992;53:511.Google ScholarPubMed
17.Lonnqvist, J, Sintonen, H, Syvalahti, E, et al.Antidepressant efficacy and quality of life in depression: a double-blind study with moclobemide and fluoxetine. Acta Psychiatr Scand. 1994;89:363369.CrossRefGoogle ScholarPubMed
18.Riederer, P, Youdim, MB. Monoamine oxidase activity and monoamine metabolism in braines of parkinsonian patients treated with I-deprenyl. J Neurochem. 1986;46:13591365.CrossRefGoogle Scholar
19.Glover, V, Elsworth, JD, Sandler, M. Dopamine oxidation and its inhibition by I-deprenyl in man. J Neural Transm Suppl. 1980;16:163172.Google Scholar
20.Birkmayer, W. Deprenyl (selegiline) in the treatment of Parkinson's disease. Acta Neurol Scand Suppl. 1983;95:103105.CrossRefGoogle ScholarPubMed
21.Tetrud, JW, Langston, JW. The effect of deprenyl (selegiline) on the natural history of Parkinson's disease. Science. 1989;245:519522.CrossRefGoogle ScholarPubMed
22.Barrett, JS, Hochadel, TJ, Morales, RJ, et al.Pharmacokinetics and safety of a selegiline transdermal system relative to single-dose oral administration in the elderly. Am J Ther. 1996;3:688698.CrossRefGoogle ScholarPubMed
23.Rohatagi, S, Barrett, JS, DeWitt, KE, Morales, RJ. Integrated pharmacokinetic and metabolic modeling of selegiline and metabolites after transdermal administration. Biopharm Drug Dispos. 1997;18:567584.3.0.CO;2-7>CrossRefGoogle ScholarPubMed
24.Wecker, L, James, S, Copeland, N, Pacheco, MA. Transdermal selegiline: targeted effects on monoamine oxidases in the brain. Biol Psychiatry. 2003;54:10991104.CrossRefGoogle Scholar
25.Mann, JJ, Aarons, SF, Wilner, PJ, et al.A controlled study of the antidepressant efficacy and side effects of L-deprenyl. Arch Gen Psychiatry. 1989;46:4550.CrossRefGoogle Scholar
26.McGrath, PJ, Stewart, JW, Harrison, W, Wager, S, Nunes, EW, Quitkin, FM. A placebo-controlled trial of L-deprenyl in atypical depression. Psychopharmacol Bull. 1989;25:6367.Google ScholarPubMed
27.Sunderland, T, Cohen, RM, Molchan, S, et al.High-dose selegiline in treatment-resistant older depressive patients. Arch Gen Psychiatry. 1994;51:607615.CrossRefGoogle ScholarPubMed
28.Trivedi, MH, Rush, AJ, Wisniewski, SR, et al.Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163:2840.CrossRefGoogle ScholarPubMed
29.Clarke, A, Brewer, F, Johnson, ES, et al.A new formulation of selegiline: improved bioavailability and selectivity for MAO-B inhibition. J Neural Transm. 2003;110:12411255.CrossRefGoogle ScholarPubMed
30.Seager, H. Drug-delivery products and the Zydis fast-dissolving dosage form. J Pharm Pharmacol. 1998;50:375382.CrossRefGoogle ScholarPubMed
31.Tetrud, JW, Koller, WC. A novel formulation of selegiline for the treatment of Parkinson's disease. Neurology. 2004;63(7 suppl 2):S2S6.CrossRefGoogle ScholarPubMed
32.Finberg, JP, Lamensdorf, I, Weinstock, M, Schwartz, M, Youdim, MB. Pharmacology of rasagiline (N-propargyl-1R-aminoindan). Adv Neurol. 1999;80:495499.Google Scholar
33.Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study. Arch Neurol. 2002;59:19371943.CrossRefGoogle Scholar
34.Anderson, MC, Hasan, F, McCrodden, JM, Tipton, KF. Monoamine oxidase inhibitors and the cheese effect. Neurochem Res. 1993;18:1145–9.CrossRefGoogle ScholarPubMed
35.Finberg, JP, Tenne, M, Youdim, MB. Tyramine antagonistic properties of AGN 1135, an irreversible inhibitor of monoamine oxidase type B. Br J Pharmacol. 1981;73:6574.CrossRefGoogle ScholarPubMed
36.Youdim, MB, Riederer, PF. A review of the mechanisms and role of monoamine oxidase inhibitors in Parkinson's disease. Neurology. 2004;63(7 suppl 2):S3235.CrossRefGoogle ScholarPubMed
37.Da Prada, M, Zurcher, G, Wuthrich, I, Haefely, WE. On tyramine, food, beverages and the reversible MAO inhibitor moclobemide. J Neural Transm Suppl. 1988;26:3156.Google ScholarPubMed
38.McCabe, BJ. Dietary tyramine and other pressor amines in MAOI regimens: a review. J Am Diet Assoc. 1986;86:10591064.Google ScholarPubMed
39.Wilkosz, MF. Transdermal Drug Delivery. Part 1: Current Status. US Pharmacist [serial online/. 2003;28. Available at: Accessed November 30, 2005.Google Scholar
40.Oh, C, Murray, B, Bhattacharya, N, Holland, D, Tatton, WG. L-deprenyl alters the survival of adult murine facial motoneurons after axotomy: increases in vulnerable C57BL strain but decreases in motor neuron degeneration mutants. J Neurosci Res. 1994;38:6474.CrossRefGoogle ScholarPubMed
41.Rohatagi, S, Barrett, JS, McDonald, LJ, Morris, EM, Darnow, J, DiSanto, AR. Selegiline percutaneous absorption in various species and metabolism by human skin. Pharm Res. 1997;14:5055.CrossRefGoogle ScholarPubMed
42. EMSAM® selegiline transdermal system new drug application 21,336/21,708. Food and Drug Administriation Web site. Available at: Accessed October 26, 2005.Google Scholar
43.Krishnan, R. Advances in psychopharmacology: MAOIs. Scientific report session. Abstract presented at: the 157th Annual Meeting of the American Psychiatric Association: May 1-6, 2004: New York, NY.Google Scholar
44.Wagner, GC, Walsh, SL. Evaluation of the effects of inhibition of monoamine oxidase and senescence on methamphetamine-induced neuronal damage. Int J Dev Neurosci. 1991;9:171174.CrossRefGoogle ScholarPubMed
45.Cadet, JL, Sheng, P, Ali, S, Rothman, R, Carlson, E, Epstein, C. Attenuation of methamphetamine-induced neurotoxicity in copper/zinc superoxide dismutase transgenic mice. J Neurochem. 1994;62:380383.CrossRefGoogle ScholarPubMed
46.Gordon, MN, Muller, CD, Sherman, KA, Morgan, DG, Azzaro, AJ, Wecker, L. Oral versus transdermal selegiline: antidepressant-like activity in rats. Pharmacol Biochem Behav. 1999;63:501506.CrossRefGoogle ScholarPubMed
47.EMSAM [package insert]. Princeton, NJ: Bristol-Myers Squibb Company: 2006.Google Scholar
48.Barrett, JS, Hochadel, TJ, Morales, RJ, et al.Pressor response to tyramine after single 24-hour application of a selegiline transdermal system in healthy males. J Clin Pharmacol. 1997;37:238247.CrossRefGoogle ScholarPubMed
49.Berlin, I, Zimmer, R, Cournot, A, Payan, C, Pedarriosse, AM, Puech, AJ. Determination and comparison of the pressor effect of tyramine during long-term moclobemide and tranylcypromine treatment in healthy volunteers. Clin Pharmacol Ther. 1989;46:344351.CrossRefGoogle ScholarPubMed
50.Simpson, GM, Gratz, SS. Comparison of the pressor effect of tyramine after treatment with phenelzine and moclobemide in healthy male volunteers. Clin Pharmacol Ther. 1992;52:286291.CrossRefGoogle ScholarPubMed
51.VanDenBerg, CM, Blob, LF, Gerrick, G, et al. Blood pressure response produced by a tyramine-enriched meal following multiple does administration of 20cm2/20mg selegiline transdermal system (STS) in health male volunteers. Abstract presented at: Annual Meeting of the New Clinical Drug Evaluation Unit. May 30-June 2, 2000: Boca Raton, FL.Google Scholar
52.Mccabe, BJ, Gurley, BJ. Transdermal selegiline and dietary tyramine: is there a concern? J Am Diet Assoc. 2003:103(9 suppl 1):A25.CrossRefGoogle Scholar
53.Shulman, KI, Walker, SE. A Reevaluation of Dietary Restrictions for Irreversible Monoamine Oxidase Inhibitors. Psychiatr Ann. 2001;31:378384.CrossRefGoogle Scholar
54.Azzaro, AJ, Blob, LF, Kemper, EM, Sharoky, M, VanDenBerg, CM. Pressor effects of oral tyramine and over-the-counter (OTC) sympathomimetic amines following steady-state transdermal administration of selegiline to healthy volunteers. In: Scientific Abstracts of the 2000 Annual Meeting of the American College of Neuropsychopharmacology. Nashville, Tenn: Abstract 268.Google Scholar
55.Blob, LF, VanDenBerg, CM, Kemper, EM, et al. Safety of selegiline transdermal system: concomitant administration of pseudoephedrine, a sympathomimetic amine. Abstract presented at: Annual Meeting of the New Clinical Drug Evaluation Unit. May 28-31, 2001: Phoenix, Ariz.Google Scholar
56.Sternbach, H. The serotonin syndrome. Am J Psychiatry. 1991;148:705–13.Google ScholarPubMed
57.Hilton, SE, Maradit, H, Moller, HJ. Serotonin syndrome and drug combinations: focus on MAOI and RIMA. Eur Arch Psychiatry Clin Neurosci. 1997;247:113119.CrossRefGoogle ScholarPubMed
58.Richard, IH, Kurlan, R, Tanner, C, et al.Serotonin syndrome and the combined use of deprenyl and an antidepressant in Parkinson's disease. Parkinson Study Group. Neurology. 1997;48:10701077.CrossRefGoogle ScholarPubMed
59.Bodkin, JA, Amsterdam, JD. Transdermal selegiline in major depression: a double-blind, placebo-controlled, parallel-group study in outpatients. Am J Psychiatry. 2002;159:18691875.CrossRefGoogle ScholarPubMed
60.Amsterdam, JD. A double-blind, placebo-controlled trial of the safety and efficacy of selegiline transdermal system without dietary restrictions in patients with major depressive disorder. J Clin Psychiatry. 2003;64:208214.CrossRefGoogle ScholarPubMed
61.Guelfi, JD, Strub, N, Loft, H. Efficacy of intravenous citalopram compared with oral citalopram for severe depression. Safety and efficacy data from a double-blind, double-dummy trial. J Affect Disord. 2000;58:201209.CrossRefGoogle ScholarPubMed
62.Moonsammy, G, Blob, LF, Sharoky, M, VanDenBerg, CM, Azzaro, AJ. Safety of selegiline transdermal system in long-term prevention of relapse of depression. Abstract presented at: the Annual Meeting of the New Clinical Drug Evaluation Unit: May 27-30, 2003: Boca Raton, FL.Google Scholar
63.Pauporte, M, Azzaro, AJ, Moonsammy, G, Maibach, H. Selegiline Transdermal System (STS): Assessment of dermal safety in human. J Toxicol. 2004;23:179187.Google Scholar
64.Robinson, DS, Campbell, IC, Walker, M, Statham, NJ, Lovenberg, W, Murphy, DL. Effects of chronic monoamine oxidase inhibitor treatment on biogenic amine metabolism in rat brain. Neuropharmacology. 1979;18:771776.CrossRefGoogle ScholarPubMed
65.Campbell, IC, Shiling, DJ, Lipper, S, Slater, S, Murphy, DL. A biochemical measure of mono-amine oxidase type A and B inhibitor effects in man. J Psychiatr Res. 1979;15:7784.CrossRefGoogle Scholar
66.Blier, P, De Montigny, C, Azzaro, AJ. Modification of serotonergic and noradrenergic neurotransmissions by repeated administration of monoamine oxidase inhibitors: electrophysiological studies in the rat central nervous system. J Pharmacol Exp Ther. 1986;237:987994.Google ScholarPubMed
67.Stamford, JA, Davidson, C, McLaughlin, DP, Hopwood, SE. Control of dorsal raphe 5-HT function by multiple 5-HT(1) autoreceptors: parallel purposes or pointless plurality? Trends Neurosci. 2000;23:459465.CrossRefGoogle ScholarPubMed
68.Cesura, AM, Pletscher, A. The new generation of monoamine oxidase inhibitors. Prog Drug Res. 1992;38:171297.Google ScholarPubMed
69.Magyar, K, Palfi, M, Tabi, T, Kalasz, H, Szende, B, Szoko, E. Pharmacological aspects of L-deprenyl. Curr Med Chem. 2004;11:20172031.CrossRefGoogle Scholar
70.Khanzode, SD, Dakhale, GN, Khanzode, SS, Saoji, A, Palasodkar, R. Oxidative damage and major depression: the potential antioxidant action of selective serotonin re-uptake inhibitors. Redox Rep. 2003;8:365370.CrossRefGoogle ScholarPubMed
71.Nierenberg, AA, Alpert, JE, Pava, J, Rosenbaum, JF, Fava, M. Course and treatment of atypical depression. J Clin Psychiatry. 1998;59(suppl 18):59.Google ScholarPubMed
72.Asnis, GM, McGinn, LK, Sanderson, WC. Atypical depression: clinical aspects and noradrenergic function. Am J Psychiatry. 1995;152:3136.Google ScholarPubMed
73.Angst, J, Gamma, A, Sellaro, R, Zhang, H, Merikangas, K. Toward validation of atypical depression in the community: results of the Zurich cohort study. J Affect Disord. 2002;72:125138.CrossRefGoogle ScholarPubMed
74.Henkel, V, Mergl, R, Allgaier, AK, Kohnen, R, Moller, HJ, Hegerl, U. Treatment of depression with atypical features: a meta-analytic approach. Psychiatry Res. 2006;141:89101.CrossRefGoogle ScholarPubMed
75.McGrath, PJ, Stewart, JW, Janal, MN, Petkova, E, Quitkin, FM, Klein, DF. A placebo-controlled study of fluoxetine versus imipramine in the acute treatment of atypical depression. Am J Psychiatry. 2000;157:344350.CrossRefGoogle ScholarPubMed
76.Nolen, WA, van de Putte, JJ, Dijken, WA, et al.Treatment strategy in depression. II. MAO inhibitors in depression resistant to cyclic antidepressants: two controlled crossover studies with tranylcypromine versus L-5-hydroxytryptophan and nomifensine. Acta Psychiatr Scand. 1983;78:676683.CrossRefGoogle Scholar
77.Anderson, IM, Nutt, DJ, Deakin, JF. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 1993 British Association for Psychopharmacology guidelines. British Association for Psychopharmacology. J Psychopharmacol. 2000;14:320.CrossRefGoogle ScholarPubMed
78.Amsterdam, JD, Shults, J. MAOI efficacy and safety in advanced stage treatment-resistant depression–a retrospective study. J Affect Disord. 2005;89:183188.CrossRefGoogle ScholarPubMed
79.McGrath, PJ, Stewart, JW, Nunes, EV, et al.A double-blind crossover trial of imipramine and phenelzine for outpatients with treatment-refractory depression. Am J Psychiatry 1993;150:118123.Google ScholarPubMed
80.Mohammadi, MR, Ghanizadeh, A, Alaghband-Rad, J, Tehranidoost, M, Mesgarpour, B, Soori, H. Selegiline in comparison with methylphenidate in attention deficit hyperactivity disorder children and adolescents in a double-blind, randomized dinicaf trial. J Child Adoles Psychopharmacol. 2004;14:418425.CrossRefGoogle Scholar
81.Mechcatie, E. Transdermal MAO inhibitor patch effective for ADHD. Clinical Psychiatry News. June 2003:18.Google Scholar
82.Houtsmuller, EJ, Notes, LD, Newton, T, et al.Transdermal selegiline and intravenous cocaine: safety and interactions. Psychopharmacology (Berl). 2004;172:3140.CrossRefGoogle ScholarPubMed
83.Bartzokis, G, Beckson, M, Newton, T, et al.Selegiline effects on cocaine-induced changes in medial temporal lobe metabolism and subjective ratings of euphoria. Neuropsychopharmacology 1999;20:582590.CrossRefGoogle ScholarPubMed
84.Biberman, R, Neumann, R, Katzir, I, Gerber, Y. A randomized controlled trial of oral selegiline plus nicotine skin patch compared with placebo plus nicotine skin patch for smoking cessation. Addiction. 2003;98:14031407.CrossRefGoogle ScholarPubMed
85.George, TP, Vessicchio, JC, Termine, A, Jatlow, PI, Kosten, TR, O'Malley, SS. A preliminary placebo-controlled trial of selegiline hydrochloride for smoking cessation. Biol Psychiatry. 2003;53:136143.CrossRefGoogle ScholarPubMed
86.Bodkin, JA, Cohen, BM, Salomon, MS, Cannon, SE, Zornberg, GL, Cole, JO. Treatment of negative symptoms in schizophrenia and schizoaffective disorder by selegiline augmentation of antipsychotic medication. A pilot study examining the role of dopamine. J Nerv Ment Dis. 1996;184:295301.CrossRefGoogle ScholarPubMed
87.Gupta, S, Droney, T, Kyser, A, Keller, P. Selegiline augmentation of antipsychotics for the treatment of negative symptoms in schizophrenia. Compr Psychiatry. 1999;40:148150.CrossRefGoogle Scholar
88.Fiedorowicz, JG, Swartz, KL. The role of monoamine oxidase inhibitors in current pychiatric practice. J Psychiatr Pract. 2004;10:239248.CrossRefGoogle Scholar
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