Symptoms of sexual dysfunction in patients treated for major depressive disorder: a meta-analysis comparing selegiline transdermal system and placebo using a patient-rated scale.

OBJECTIVE: Spontaneous reports of sexual side effects were infrequent during placebo-controlled clinical trials of selegiline transdermal system (STS). The objective of this study was to examine the impact of STS 6 mg/24 hours on various domains of sexual function in patients with major depressive disorder (MDD), using a patient-rated questionnaire. METHOD: Data from 4 short-term (6 to 8 weeks), randomized, double-blind, placebo-controlled trials of STS in patients with MDD (DSM-IV criteria) were included in the meta-analysis (STS, N = 389; placebo, N = 400). The Medex Sexual Dysfunction Subscale was used to assess sexual interest, arousal, maintenance of interest, orgasm, and satisfaction. Estimates of the average effect of study drug on each item of sexual function and 95% confidence intervals were calculated using a fixed-effects model due to homogeneity of study means. The direct effect of STS versus placebo was estimated using multivariate regression models, with baseline item score as a covariate and controlling for improvement in depression. Analyses were performed on the total population and by gender. Data were collected between January 1997 and April 2000. RESULTS: Estimates of difference between STS and placebo demonstrated a nonsignificant trend toward a positive treatment effect of STS on most sexual function items and significant improvement in sexual satisfaction. For women, there was a significant positive effect on interest, maintaining interest during sex, and satisfaction. The direct effect of STS on changes in individual item scores was minimal in men and showed a trend for improvement in women. CONCLUSION: This meta-analysis suggests that short-term therapy with STS 6 mg/24 hours does not impair any aspect of sexual function in MDD patients as measured using a patient-rated questionnaire.

Treatment effects of selegiline transdermal system on symptoms of major depressive disorder: a meta-analysis of short-term, placebo-controlled, efficacy trials.

OBJECTIVE: Selegiline transdermal system (STS) is efficacious for the treatment of major depressive disorder (MDD). This meta-analysis explores treatment effects of STS for individual symptoms of MDD derived from line-item analyses of the 28-item Hamilton Rating Scale for Depression (HAM-D28) and the Montgomery-Asberg Depression Rating Scale (MADRS). METHODS: Change in score from baseline to end of treatment for each item of the HAM-D28 and MADRS was assessed using a multilevel model for meta-analysis of continuous outcome data from all five short-term, randomized, placebo-controlled efficacy trials conducted during preapproval clinical development of STS for MDD. Utilizing a random-effects model with trial effects fixed and adjusting for baseline scores, confidence intervals (95%) were computed for treatment differences between STS and placebo. RESULTS: STS exhibited significant treatment effects on core depression symptoms (HAM-D Bech-6 items: depressed mood, guilt, work and activities, retardation, psychic anxiety, general somatic symptoms), reverse vegetative symptoms (oversleeping, overeating), motoric retardation, suicide, and genital symptoms (libido). Significant STS treatment effects were also noted for each MADRS item except for reduced sleep and appetite. The most prominent MADRS effects were improvement in sadness, lassitude, and poor concentration. CONCLUSIONS: STS, an monoamine oxidase inhibitor antidepressant that potentiates the three major monoamine neurotransmitters (serotonin, norepinephrine, and dopamine), has beneficial therapeutic effects for a spectrum of individual symptoms rated by the HAM-D28 and MADRS. Analyses of specific symptoms assessed by depression rating scales can offer guidance to clinicians in individualizing drug therapy based on presenting symptoms.

Pharmacokinetics and absolute bioavailability of selegiline following treatment of healthy subjects with the selegiline transdermal system (6 mg/24 h): a comparison with oral selegiline capsules.

The selegiline transdermal system is a monoamine oxidase inhibitor that was recently approved by the US Food and Drug Administration for the treatment of major depressive disorder. The current study was conducted during the selegiline transdermal system development program to characterize the single-dose pharmacokinetics and absolute bioavailability of selegiline administered by the 6-mg/24-h selegiline transdermal system in healthy volunteers. Selegiline transdermal system results were compared with those obtained after a single 10-mg oral dose of selegiline HCl. The selegiline pharmacokinetics differed greatly between the 2 routes of administration. Transdermal selegiline administration reduced metabolism and produced a high, sustained plasma selegiline concentration over the dosing period, with an absolute bioavailability of 73%. By contrast, oral dosing produced a sharp plasma selegiline peak that occurred within 1 hour and declined rapidly, with an absolute bioavailability of 4%. The data provide the basis for therapeutic advantages of the selegiline transdermal system in administering antidepressant doses of selegiline.

Evaluation of the potential for pharmacodynamic and pharmacokinetic drug interactions between selegiline transdermal system and two sympathomimetic agents (pseudoephedrine and phenylpropanolamine) in healthy volunteers.

Selegiline transdermal system is a recently approved monoamine oxidase inhibitor antidepressant. Medications that inhibit monoamine oxidase type A can augment the pressor effects of sympathomimetic amines, increasing the potential for hypertensive crisis. This study examined the potential for drug-drug interactions during treatment with selegiline transdermal system and pseudoephedrine or phenylpropanolamine. Two studies were conducted with 25 healthy volunteers to assess changes in blood pressure and heart rate during administration of pseudoephedrine or phenylpropanolamine alone or together with selegiline transdermal system. No significant differences in mean maximum changes in vital signs occurred with pseudoephedrine. No significant differences were found in mean maximum changes in systolic heart rate with phenylpropanolamine; however, 4 of 12 subjects each experienced 1 isolated protocol-defined minimal pressor response without concurrent adverse effects (1 with phenylpropanolamine alone; 3 with phenylpropanolamine + selegiline transdermal system). Pharmacokinetic parameters obtained following selegiline transdermal system and pseudoephedrine or phenylpropanolamine were unremarkable. The results suggest that selegiline transdermal system 6 mg/24 h does not significantly alter the pharmacodynamics or pharmacokinetics of either pseudoephedrine or phenylpropanolamine when administered to healthy volunteers; however, it is prudent to avoid coadministration of selegiline transdermal system and sympathomimetics.

Selegiline transdermal system: an examination of the potential for CYP450-dependent pharmacokinetic interactions with 3 psychotropic medications.

Selegiline transdermal system (STS) is a recently approved monoamine oxidase inhibitor antidepressant. This article reports results from 3 studies examining the potential for cytochrome P450-dependent pharmacokinetic interactions between STS and 3 psychotropic medications that might be coadministered. Three open-label, randomized, Latin square, 3-sequence crossover design studies were conducted with healthy volunteers to determine the pharmacokinetic parameters of STS 6 mg/24 h and test drug (alprazolam, olanzapine, or risperidone) when administered alone and concomitantly. All pharmacokinetic parameters of interest were unaltered following selegiline or test drug monotherapy when compared to concomitant therapy. This was confirmed by least squares mean ratios and their 90% confidence intervals of log(e)-transformed C(max) and AUC(tau) values, using either standard bioequivalence criteria of 80% to 125% or study-defined 70% to 143% boundary criteria. These results demonstrate that STS 6 mg/24 h may provide an antidepressant option that is unlikely to result in CYP450-mediated pharmacokinetic drug-drug interactions.

Effects of a tyramine-enriched meal on blood pressure response in healthy male volunteers treated with selegiline transdermal system 6 mg/24 hour.

BACKGROUND: Monoamine oxidase inhibitors are well recognized as effective antidepressant agents but are rarely used due, in part, to the risk of hypertensive crisis following the ingestion of foods high in tyramine ("cheese reaction"). A selegiline transdermal system (STS) was developed to provide antidepressant concentrations of selegiline in the brain, while preserving the gastrointestinal monoamine oxidase A (MAO-A) barrier. The present study was conducted to determine the effect of the STS 6 mg/24 hour on cardiovascular safety following the ingestion of approximately 400 mg of tyramine consumed as a component of aged cheeses. METHODS: In this open-label, single-center phase I study, cardiovascular vital signs were recorded following tyramine challenges during placebo and STS 6 mg/24 hr treatment. Subjects were observed for clinical signs and symptoms of a pressor response and/or potential hypertensive crisis during and following the challenges. RESULTS: Ingestion of tyramine-enriched meals following 13 consecutive days of treatment with the STS 6 mg/24 hr (pharmacokinetic steady-state) produced no clinically significant changes in cardiovascular vital signs in 12 healthy adult male subjects. No evidence of a tyramine pressor effect on systolic blood pressure or evidence of hypertensive crisis occurred during the STS treatment. CONCLUSION: These results suggest that STS 6 mg/24 hr may be administered without concern for dietary tyramine consumption.

Tyramine pressor sensitivity during treatment with the selegiline transdermal system 6 mg/24 h in healthy subjects.

The oral tyramine pressor test was administered to healthy males during treatment with a selegiline transdermal system (STS; 6 mg/24 h). The tyramine sensitivity factor (TSF) was calculated from the ratio of baseline and on-treatment tyramine pressor doses. The tyramine sensitivity factor value following 9 days of treatment with the selegiline transdermal system was 1.85 +/- 0.10. Extended treatment, 33 days, produced a small, clinically non-meaningful increase in this value. The tyramine sensitivity factor for the selegiline transdermal system was similar to that following treatment with 10 mg/d of oral selegiline capsules but more than 20 times less than observed during tranylcypromine treatment. A larger increase in the tyramine sensitivity factor was observed following extended selegiline transdermal system treatment at a higher dose (12 mg/24 h), which was significantly decreased following coadministration of tyramine capsules with a meal. These results suggest a wide tyramine safety margin for the selegiline transdermal system and provide evidence that the 6-mg/24-h selegiline transdermal system can be administered safely without dietary tyramine restrictions.

Systemic absorption of topical lidocaine in normal volunteers, patients with post-herpetic neuralgia, and patients with acute herpes zoster.

Topical lidocaine has been recently marketed as a new treatment for post-herpetic neuralgia. The aim of our study was to characterize the absorption profile of and systemic exposure to lidocaine from patch and gel formulations in normal volunteers, patients with post-herpetic neuralgia, and patients with acute herpes zoster. The bioavailability of lidocaine from the patch formulation averaged 3%, and was similar after single and repeated doses. Systemic exposure to lidocaine and monoethylglycinexylidide (MEGX), the primary active metabolite of lidocaine, after application of lidocaine gel or patches was minimal in normal volunteers, patients with post-herpetic neuralgia, and patients with acute herpes zoster. Considering the benefit versus risk of topical lidocaine, systemic absorption and toxicity of lidocaine seems not to be a significant risk.