| | The selegiline transdermal system in major depressive disorder: A systematic review of safety and tolerability☆Received 19 December 2006; received in revised form 4 April 2007; accepted 24 April 2007. Abstract BackgroundMonoamine oxidase inhibitors (MAOIs) are highly efficacious antidepressants, but safety concerns have limited their broad use. ResultsExcept for the initial trial, subsequent trials, which involved STS doses ranging from 3 mg/24 h to 12 mg/24 h, lacked tyramine restrictions, and no acute hypertensive reactions occurred during study treatment. Safety experience with STS 6 mg/24 h supports this therapeutic dose without tyramine dietary modifications, but until more data are available for STS doses 9 mg/24 h and 12 mg/24 h, foods that are rich sources of tyramine should be avoided. The principal side effects of STS therapy were local dermal reactions and insomnia, both of which were dose-related. Side effects associated with MAOI treatment, such as sexual dysfunction and excessive weight gain, were uncommon. ConclusionsA comprehensive review of safety from the clinical development program suggests that the STS is safe and well tolerated, with an improved safety margin compared with orally administered MAOIs. 1. Introduction  Monoamine oxidase inhibitors (MAOIs), the first class of effective antidepressant drugs, have been extensively investigated since their introduction in the 1950s (Amsterdam and Chopra, 2001, Robinson, 2002). Although MAOIs enjoyed a reputation for robust efficacy in treating major depressive disorder (MDD), enthusiasm for their use has been tempered by the risk of tyramine-induced acute hypertensive reactions and the consequent need for tyramine dietary restrictions (Blackwell, 1963). Therefore, therapy with oral MAOIs is largely relegated to patients with MDD with atypical features or to patients with treatment-resistant depression. Despite the advent of the tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs), more than 30% of patients with MDD will not achieve full remission even after a series of antidepressant treatments. Because of this disappointing response rate, it is important to continue searching for novel, more effective antidepressants (Greden, 2002). Attempts to improve the safety of MAOIs have involved developing selective irreversible and reversible MAOIs that might obviate the need for tyramine dietary restrictions. While irreversible, selective monoamine oxidase type A (MAO-A) inhibitors, like clorgyline, have been shown to be effective antidepressants, they still require avoidance of tyramine-rich foods (Rudorfer, 1992). Reversible MAO-A inhibitors, like moclobemide and brofaromine, have improved safety profiles with modest increases in tyramine sensitivity but inferior efficacy compared with conventional MAOIs (Amsterdam and Chopra, 2001, Robinson, 2002). Selegiline, an irreversible inhibitor with selectivity for monoamine oxidase type B (MAO-B) at low oral doses, has an established safety and efficacy profile as adjunctive treatment of Parkinson's disease (PD). At therapeutic doses up to 10 mg/day orally for PD, selegiline can be safely administered without the need for a tyramine-restricted diet. Oral selegiline may be an effective antidepressant (McGrath et al., 1989, Mann et al., 1989) at doses in excess of 20 mg daily when enzyme selectivity is lost (MAO-A is inhibited in addition to MAO-B), thus necessitating tyramine dietary restrictions (Prasad et al., 1988, Sunderland et al., 1994). A transdermal formulation of selegiline recently approved for treatment of MDD provides greater systemic delivery of selegiline to the brain with relative sparing of gastrointestinal MAO-A enzyme (Mawhinney et al., 2003, Wecker et al., 2003). The selegiline transdermal system (STS) achieves antidepressant concentrations of selegiline in neuronal tissues with fewer effects on gastrointestinal MAO-A, the principal enzymatic barrier to ingested tyramine. A series of clinical pharmacology studies in healthy subjects delineated the limited effects on tyramine sensitivity of STS compared with oral MAOI antidepressants (Azzaro et al., 2006a). Therapeutic benefits of STS for treatment of MDD have been documented in both short-term (Bodkin and Amsterdam, 2002, Amsterdam, 2003, Feiger et al., 2006) and long-term, placebo-controlled trials (Amsterdam and Bodkin, 2006). In this review, we summarize available data on the safety profile of STS derived from over 2000 patients treated with STS for MDD in pre-approval clinical trials. 2. Methods We reviewed key safety and tolerability data from all trials in MDD accrued during clinical development of STS, as reported to the Food and Drug Administration. In these studies, patients applied STS as dermal patches delivering 3 mg/24 h (10 cm2), 6 mg/24 h (20 cm2), 9 mg/24 h (30 cm2), or 12 mg/24 h (40 cm2). In the 5 placebo-controlled clinical trials, patients applied dermal patches containing either drug or an identical-appearing placebo patch. Three placebo-controlled efficacy trials compared fixed-dose STS 6 mg/24 h versus placebo, one efficacy trial compared 2 fixed doses (STS 3 mg/24 h and 6 mg/24 h) versus placebo, and one efficacy trial employed flexible-dose titration comparing STS administered within a dose range of 6 mg/24 h to 12 mg/24 h versus placebo. Long-term treatment studies included open-label STS treatment following completion of short-term double-blind therapy, a double-blind relapse prevention trial (6 mg/24 h), and an uncontrolled trial involving open-label treatment of depressed patients with STS 6 mg/24 h to 12 mg/24 h. This last trial enrolled depressed patients without an upper age limit and included many elderly patients. This review summarizes safety data derived from pre-approval trials as of April 30, 2003, on file with Somerset Pharmaceuticals, Inc. Data from all MDD patients receiving STS (n =2036) have been pooled for meta-analysis of safety measures for the entire safety population as well as for subgroups based on STS dose and type of study (controlled and uncontrolled). The short-term placebo-controlled trials enrolled 1485 patients with major depression (STS 817, placebo 668). To facilitate comparisons of STS and placebo treatments, pooled data from the 5 placebo-controlled efficacy trials were analyzed. In these analyses, 4 treatment groups were assessed: patients who received double-blind STS 3 mg/24 h only (n=151), STS 6 mg/24 h only (n=550), STS 9 or 12 mg/24 h as maximum dose (n=116), or placebo (n=668). Assessments included incidence and type of adverse event (AE), routine clinical laboratory tests, electrocardiograms (ECGs), and vital signs, including postural blood pressure (BP) changes in most trials. In addition to analyzing overall AE incidences, the safety database was searched by computer algorithm using specified AE preferred terms that might be indicative of untoward events that have been associated with MAOI treatment, e.g., acute hypertension, orthostatic hypotension, and serotonin syndrome. Clinical records of patients identified by algorithm underwent comprehensive independent review by 2 medical reviewers blinded to study treatment, which included examination of AEs, vital signs, and clinical course in order to ascertain whether an unrecognized event of interest might have occurred. Also, all patients receiving concomitant medications, particularly psychotropic, antitussive, or decongestant agents, were identified and underwent a similar comprehensive record review. 3. Results 3.2. Adverse events Table 2 lists reported or observed AEs with ≥5% incidence in placebo-controlled efficacy trials. In these studies, 72% of placebo-treated patients and 76% of STS-treated patients experienced at least 1 AE. Within the STS maximum dose groups (i.e., STS 9 mg/24 h or STS 12 mg/24 h), 83% of patients experienced at least 1 AE. The only AE in the STS 6 mg/24 h placebo-controlled trials with an incidence of approximately twice that of placebo was ‘application site reaction’ (ASR). In the high-dose STS group (STS 9 mg/24 h or STS 12 mg/24 h), however, several other AEs had an incidence at least twice that of placebo treatment, including insomnia (32% versus 7%), dry mouth (13% versus 6%), dizziness (14% versus 5%), nervousness (10% versus 4%), and abnormal dreams (5% versus 2%). Most AEs were rated as ‘mild’ or ‘moderate’ in intensity. In the placebo-controlled trials, only 0.6% (5/817) and 0.1% (1/668) of ASRs were rated as ‘severe’ in patients receiving STS or placebo, respectively. Most ‘severe’ ASRs (4) occurred with the 9 mg/24 h and 12 mg/24 h dose formulations. Severe insomnia was rated as an AE in 2.2% (18/817) of STS-treated patients compared with 0.7% (5/668) of placebo-treated patients, and the majority (13/18) occurred in the highest STS dose group. The effect of AEs on treatment discontinuation was also assessed. The overall incidence of discontinuations due to an AE was modestly higher for STS (7.3%) versus placebo (4.0%). ASR was the only AE associated with a dropout rate greater than 1% of STS patients (STS 2%, placebo 0%). 3.3. Serious adverse events Serious adverse events (SAEs) include (by definition) any fatal or life-threatening experiences, hospitalizations, or neoplasms. In placebo-controlled efficacy trials, 13 patients (0.9%) experienced an SAE (STS n=6; placebo n=7). Most of these SAEs involved an intercurrent medical illness and were judged unrelated to study treatment. SAEs such as suicide attempts or worsening of depressive symptoms requiring hospitalization were considered to be treatment-related and occurred with similar incidences in STS (n=2) and placebo (n=1) treatment groups. There were no fatalities or completed suicides, and none of the SAEs was considered to be potentially life-threatening, except for one in which a patient with multiple drug–drug interactions required urgent treatment for serotonin syndrome (see below). Across all STS treatment (controlled and uncontrolled), the incidence of SAEs was 1.8% (37/2036) of STS-treated patients, and 31 of these resulted in treatment discontinuation. The SAEs that led to discontinuation in more than a single patient were worsening depression (n=3), accidental injuries unrelated to study treatment (n=3), drug overdose and/or drug–drug interaction (n=3), and 2 patients each for chest pain, hypertension, and bone fracture. 3.4. Safety review of selected adverse events Patient records were selected for comprehensive review to search for a possible clinical event linked to MAOI use. The safety database was searched by computer algorithm to identify patients with preferred terms or vital sign values potentially indicative of one of the following clinical events: acute hypertensive reaction, orthostatic hypotension, serotonin syndrome, excessive weight gain, or sexual dysfunction. 3.5. Acute hypertensive reaction With the exception of the initial trial (Bodkin et al., 2002), patients in all subsequent studies were not required to follow a tyramine-restricted diet. No hypertensive crises occurred during study treatment. Preferred terms that were used in a search to identify patients for possible acute hypertensive reactions included the following AEs: hypertension, tachycardia, arrhythmia, migraine, severe headache, chest pain, myocardial infarction, visual symptoms, neck rigidity, stupor, and coma, as well as any abnormal BP values during treatment. Detailed review of case records of identified patients revealed no events suggestive of acute hypertensive episodes linked to tyramine ingestion. While receiving selegiline, 63 of 2867 (2.2%) patients had elevated BP values recorded (there were 64 hypertension AE reports). Most of these AEs occurred in patients with pre-existing hypertension, and blood pressure elevations were judged as being unrelated to STS. Presence of medically controlled hypertension was not an exclusion from participation in an STS trial. Of those patients being treated for hypertension prior to the study, most had no changes in their antihypertensive medications during the study. Not all patients with pre-existing hypertension reported this fact at the time of entry to a trial. Some patients with undiagnosed essential hypertension were discovered on the basis of abnormal BP values recorded during study treatment, and they received concomitant antihypertensive treatment without changes in study medication. In a few isolated instances, it was judged clinically prudent to discontinue patients from the study in order to facilitate diagnostic workup of hypertension prior to initiation of antihypertensive therapy. 3.6. Orthostatic hypotension The search algorithm used to identify hypotension included: measures of postural change, low BP, and the preferred AE terms of hypotension, orthostatic hypotension, bone fracture, accidental injury, dizziness, syncope, vertigo, and amblyopia. The last 4 AEs had to be rated at least moderate in intensity to qualify for further record review. Patients with a sitting or standing systolic BP <90 mm Hg, or the presence of a ≥10 mm Hg decrease in mean arterial BP were also identified to document significant postural hypotension. In the controlled trials with postural vital sign monitoring, 49 of 502 STS-treated patients (9.8%) and 24 of 357 placebo-treated patients (6.7%) had 1 or more occurrences of postural decline ≥10 mm Hg in mean arterial pressure during treatment. Across all STS trials with postural BP monitoring, 14.1% (231/1644) of STS-treated patients had an occurrence of orthostatic BP decline. Most of these patients with significant postural BP changes were asymptomatic and had unchanged heart rate. The incidence of the AE postural hypotension was 0.9% (7/817) in STS patients and 0.4% (3/668) in placebo patients. Subjects taking STS 9 mg/24 h and STS 12 mg/24 h accounted for 5 of these 7 reported cases of postural hypotension. The AEs hypotension and syncope each occurred in 1 patient in the STS treatment group and none in the placebo group. Among all STS-treated patients, the incidence of the AE of postural hypotension was 1.7% (35/2036). Other AEs possibly indicative of orthostasis had a higher incidence during STS versus placebo treatment. The incidence of dizziness (or vertigo) was 4.9% versus 3.1%, respectively, for STS and placebo treatment, and syncope was 0.5% versus 0.0%, respectively. Approximately 50% of these patients with 1 or more orthostatic-related AEs had at least 1 abnormal systolic BP value (<90 mm Hg) recorded at some point during treatment. 3.7. Serotonin syndrome Two cases of serotonin syndrome, both reported as SAEs, occurred during STS treatment. One patient experienced 2 acute episodes of severe akathisia 1 month apart, the first episode occurring 1 week after discontinuing study treatment. Both events required medical intervention to treat symptoms. The first episode 1 week after discontinuation of STS immediately followed ingestion of a single dose of venlafaxine. A similar event occurred 1 month later within 1 h of rechallenge with venlafaxine. The final assessment of this SAE was ‘akathisia secondary to venlafaxine treatment’ (Effexor® Package Insert, 2006) and not serotonin syndrome. A second patient was hospitalized 3 times for manifestations of drug overdose, a fact that was undiscovered until after the third episode while receiving STS extension treatment following double-blind therapy. At that time, it was determined that he had surreptitiously been taking several contraindicated medications, including nortriptyline, bupropion, and a sympathomimetic agent for weight loss, in addition to wearing 2 STS patches simultaneously (12 mg/24 h each). The patient required intensive care treatment including tracheal intubation for serotonin syndrome secondary to multiple drug–drug interactions. The patient responded to therapy and recovered uneventfully. 3.8. Sexual dysfunction Across all trials, the incidence of sexual dysfunction-related AEs was 2.7% (55/2036) in STS patients and 0.8% (7/831) in placebo-treated patients. The incidence of sexual dysfunction-related AEs in the 5 placebo-controlled trials was low in both men and women (Table 3). In 4 of the placebo-controlled, fixed-dose (STS 6 mg/24 h) trials, sexual dysfunction was also specifically evaluated with a 5-item self-rating questionnaire (1 = not at all; 5 = severe; or not applicable) to assess sexual function and satisfaction before and during study treatment Bodkin and Amsterdam, 2002; Amsterdam, 2003). The 5 items rated were: 1) decreased interest, 2) problems with arousal, 3) difficulty maintaining interest during sexual activity, 4) difficulty achieving climax, and 5) impaired sexual satisfaction. The mean self-rating scores of sexual dysfunction improved to the same extent during both STS and placebo treatment, a finding consistent with minimal adverse effects of STS treatment on sexual dysfunction. 3.10. Drug–drug interactions In the phase I clinical pharmacology program, several drug interaction studies were carried out in healthy, nondepressed subjects for commonly prescribed drugs such as alprazolam, antipsychotic agents (risperidone and olanzapine), carbamazepine, ibuprofen, warfarin, and the oral decongestants pseudoephedrine and phenylpropanolamine (EMSAM® Package Insert, 2006; Data on File, Somerset Pharmaceuticals, Inc). There were no clinically meaningful pharmacokinetic or pharmacodynamic interactions of any of the tested drugs with STS, with the exception of a 2-fold increase in plasma selegiline during carbamazepine administration, which is thought to be of doubtful clinical importance given the fact that selegiline binds irreversibly to tissue MAO and plasma levels fail to correlate with degree of tissue enzyme inhibition. Nevertheless, it is recommended that concurrent use of carbamazepine and STS be avoided. The drug interaction studies between alprazolam, risperidone, or olanzapine and STS 6 mg/24 h have been previously reported (Azzaro et al., 2007). Prescribing information specifies that various psychoactive and sympathomimetic drugs are contraindicated during STS treatment because of risk of either hypertensive crisis or serotonin syndrome (EMSAM® Package Insert, 2006). Although specifically proscribed by study protocols, a number of patients in STS clinical trials (over 100 subjects) took a contraindicated medication, most frequently oral decongestants, antitussives, or opioid medications. Case records of these patients were carefully scrutinized for untoward events. There were no SAEs or AEs due to concomitant use of these drugs, except for a 19-year-old female patient who developed frequent ventricular premature contractions after self-medicating with pseudoephedrine; this event was resolved uneventfully. 4. Discussion This safety review pertaining to pre-approval safety experience with STS provides evidence of its safety and tolerability over a recommended therapeutic dose range of 6 mg/24 h to 12 mg/24 h (Bodkin and Amsterdam, 2002, Amsterdam, 2003, Feiger et al., 2006, Amsterdam and Bodkin, 2006). The demographic characteristics of the sample involving more than 2000 STS-treated and 800 placebo-treated individuals appear representative of patients with moderate or severe MDD. This sample included nearly 200 patients who were ≥65 years of age, many receiving STS 9 mg/24 h and 12 mg/24 h as the maximum dose, without untoward effects. No fatalities, suicides, or clinically important abnormalities of laboratory or ECG tests occurred in these depression studies. ASRs and insomnia were the 2 most commonly reported AEs during STS therapy (see Table 2). Both AEs were dose-related. In the STS 9 mg/24 h and 12 mg/24 h groups, the incidences of ASR and insomnia were the highest, 44% and 32% respectively, while the corresponding incidences for ASR and insomnia were 22% and 10% at the 6 mg/24 h STS dose. The majority of these AE occurrences were mild or moderate in intensity and did not affect treatment or lead to premature discontinuation. ASR was rated as severe in 5 of 817 (0.6%) STS-treated patients (4 at 9 mg/24 h and 12 mg/24 h doses) compared with 1 of 668 (0.1%) placebo-treated patients. Severe insomnia occurred in 18 of 817 (2.2%) STS-treated patients (13 at 9 mg/24 h or 12 mg/24 h) compared with 5 of 668 (0.7%) placebo-treated patients. Across all trials, the incidence of premature discontinuations due to an AE was 7.3% in STS-treated patients and 4.0% in placebo-treated patients. Premature discontinuations for ASR were not dose-related. In controlled trials, 2% (16/817) of STS-treated patients discontinued because of a dermal reaction, compared with none in the placebo group. Only 3 patients in the STS and 1 patient in the placebo group prematurely discontinued treatment as a result of insomnia. Overall, discontinuation rates for ASR or insomnia were 3.1% and 1.5%, respectively, among all STS-treated patients (n=2036). Local skin reactions usually responded well to topical corticosteroids. Dermal sensitivity studies in healthy, nondepressed subjects and rodents indicate that STS carries low propensity for causing allergic contact dermatitis (Pauporte et al., 2004a, Pauporte et al., 2004b). Nervous system side effects (other than insomnia) also showed modest dose-related rises in incidence. Dry mouth and dizziness were more frequent with STS than with placebo treatment, and these AEs were dose-related. The incidences in the higher STS dose groups were more than twice that for placebo (Table 2). The overall incidence of the AE of nervousness did not differ between STS and placebo, but in the higher dose STS groups, the incidence was more than twice that of placebo (10% versus 4%). Somnolence, anxiety, and abnormal dreams were slightly more frequent in the high STS dose group compared with placebo (Table 2). Careful database searches to identify possible hypertensive reactions linked to tyramine ingestion did not detect any untoward events. The low incidence of cardiovascular events in this review comports with the favorable safety findings in tyramine challenge tests (Azzaro et al., 2006a). Studies have shown that sensitivity to ingested tyramine (administered as capsules to maximize bioavailability) is increased less than 2-fold over that at baseline at the STS 6 mg/24 h dose. Even at the highest dose, STS 12 mg/24 h administered for 3 months, sensitivity to tyramine was only 4-fold greater than that at baseline when taken with a meal, and no subject reached endpoint (30 mm Hg increase in systolic BP) at a tyramine dose less than 75 mg. This amount of tyramine exceeds that found in meals comprised largely of tyramine-rich food substances (Shulman et al., 1989, DaPrada et al., 1988). By contrast, oral tranylcypromine 30 mg administered for 10 days resulted in marked tyramine sensitivity (over 40-fold increase). Given the modest increases in tyramine sensitivity at the STS 6 mg/24 h dose and the apparent safety of unrestricted diets in these trials, the Food and Drug Administration approved use without need for dietary restrictions at this dose (EMSAM® Package Insert, 2006). In these pre-approval phase III studies, approximately 1600 patients received STS at a dose of 6 mg/24 h in the absence of tyramine dietary restrictions without untoward effects. Although no hypertensive reactions occurred in clinical trials even at higher STS doses, because the safety experience is more limited, it is recommended that patients avoid very high tyramine content food substances at the 9 mg/24 h and 12 mg/24 h doses. Therefore, certain specialty food products should be avoided, such as unpasteurized and tap beers, marmite (a concentrated yeast extract), aged cheeses and meats, a few vegetables (fava beans, sauerkraut), soy products (soy sauce, tofu), and nutritional supplements containing tyramine (EMSAM® Package Insert, 2006). Symptomatic postural hypotension, a well-known side effect of oral MAOIs, was an uncommon occurrence in STS-treated individuals, even in elderly patients. Overall, during study treatment, the AEs hypotension or postural hypotension had a low incidence in both STS- and placebo-treated patients, 2.2% versus 0.5%, respectively. In controlled trials, significant orthostatic BP pressure changes (≥10 mm Hg decrease) occurred slightly more frequently during STS treatment compared with placebo (9.8% versus 6.7%). The frequency of systolic hypotension (defined as BP<90 mm Hg and ≥20 mm Hg decrease from baseline value) was 3.0% (24/791) in STS-treated patients and 1.5% (10/648) in placebo-treated patients. While orthostatic hypotension was not found to be a prominent side effect in these trials, including in elderly patients, routine BP monitoring with postural BP change is recommended. The incidence of treatment-emergent sexual dysfunction in the STS trials was low (Table 3). Overall, the AE incidence of impotence, decreased libido, or anorgasmia with STS treatment was 0.8%, 0.7%, and 0.3%, respectively. These findings suggest that treatment-emergent sexual dysfunction is infrequent during STS therapy in contrast to several antidepressants, especially SSRIs (Kennedy et al., 2000). While hyperphagia and weight gain (≥5%) are quite common with long-term oral MAOI therapy (Amsterdam and Chopra, 2001, Robinson, 2002), it is noteworthy that more than twice as many STS-treated patients sustained a ≥5% loss of body weight as those who had ≥5% gain in body weight (5.0% versus 2.1%, respectively). In the placebo-controlled efficacy trials, mean weight change was −1.2 lb with STS compared with +0.3 lb for placebo treatment. Patients treated 3 months or longer with STS in uncontrolled continuation and maintenance treatment trials had an average weight loss of −1.6 lb, suggesting that long-term treatment carries low propensity for excessive weight gain, unlike other MAOIs. Drug–drug interactions with MAOIs are a potential concern. In the STS clinical trials, significant numbers of patients took a prescribed medication, such as an oral decongestant, antitussive, or opioid analgesic, without untoward sequelae. One patient experienced tachycardia with concomitant use of pseudoephedrine, and coadministration of over the counter (OTC) medications with sympathomimetics should be avoided. Serotonin syndrome is a serious, potentially lethal, central nervous system toxicity resulting from coadministration of various psychoactive drugs, especially agents that inhibit the reuptake of serotonin, such as SSRIs and tricyclic antidepressants, dextromethorphan, and certain opioids such as meperidine. Two cases of serotonin syndrome reported as SAEs occurred during STS treatment. Ultimately, one was attributed to venlafaxine-induced akathisia and not serotonin syndrome. The second case involved self-medicating with ephedrine and 2 other antidepressants, bupropion and nortriptyline, as well as overmedicating by simultaneous application of 2 STS 12 mg/24 h dermal patches. To avoid the occurrence of drug interactions, it is important to allow 4 to 5 elimination half-lives to wash out contraindicated drugs before initiating STS treatment. One week is generally sufficient, except for fluoxetine, which requires a 5-week washout period due to the long elimination half-life of the parent drug and metabolite. In addition, when switching from STS to another antidepressant or to a contraindicated drug, a 2-week washout period is recommended to allow sufficient time for regeneration of tissue MAO. 5. Limitations Interpretation of the present findings should take into consideration the limited numbers of patients exposed during clinical development of a new drug and the fact that the study sample is restricted to patients with depression. 6. Summary Pre-approval clinical studies indicate that STS is a safe, well-tolerated MAOI for treatment of MDD as evidenced by the safety experience in more than 2000 STS-treated patients with MDD, including nearly 200 patients who were ≥65 years of age. STS has a more favorable safety profile than conventional, irreversible oral MAOIs because of its low liability for tyramine reactions at all therapeutic doses and the resultant absence of need to observe a tyramine-restricted diet at the 6 mg/24 h dose. The absence of weight gain or sexual dysfunction associated with STS treatment also appears to differentiate this antidepressant agent from other MAOI antidepressants. Acknowledgments The authors thank Bryan Campbell, PharmD, Albert J. Azarro, PhD, and Chad VanDenBerg, PharmD, for valuable assistance in preparation and proofreading of the manuscript. References Amsterdam and Chopra, 2001. 1.Amsterdam JD, Chopra M. Monoamine oxidase inhibitors revisited. Psychiatr. Ann. 2001;31:361–370. 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a Worldwide Drug Development, 102 East Avenue, Burlington, VT 05401, United States b Depression Research Unit, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA, United States  Corresponding author. Tel.: +1 802 658 2961.
☆ Role of funding source: Data in this report were derived from research studies sponsored and funded by Somerset Pharmaceuticals, Inc. (Tampa, FL). Preparation of the report was partially funded by Bristol-Myers Squibb (Princeton, NJ) and The Jack Warsaw Endowment for Research in Biological Psychiatry of the University of Pennsylvania Medical Center (Dr. Amsterdam). Conflict of interest: Dr. Robinson has served as consultant to Bristol-Myers Squibb, Somerset Pharmaceuticals, Epix, Genaissance, Medicinova, and Ono Pharmaceuticals. Dr. Amsterdam has served as scientific consultant to Bristol-Myers Squibb and Somerset Pharmaceuticals. Contributors: Dr. Robinson analyzed and reviewed safety data in the selegiline transdermal system NDA submitted to the Food and Drug Administration by Somerset Pharmaceuticals, Inc. Dr. Robinson wrote the first draft of the manuscript. Both authors were involved with literature review, preparation, and final approval of the report. PII: S0165-0327(07)00148-6 doi:10.1016/j.jad.2007.04.024 © 2007 Elsevier B.V. All rights reserved. | |
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