Posted by djmmm on February 12, 2003, at 17:10:02
Transdermal Selegiline Avoids Adverse Effects of Oral Form
from The Brown University Psychopharmacology Update
Posted 02/03/2003A new transdermal formulation of the monoamine oxidase inhibitor (MAOI) selegiline (Eldepryl) has proven effective in controlling depression without generating the serious side effects of oral MAOIs. The first placebo-controlled trial of transdermal selegiline reported a significantly greater improvement in symptoms of depression in patients taking transdermal selegiline as compared to patients taking placebo, with none of the dietary interactions associated with the oral formulation.
According to lead investigator J. Alexander Bodkin, M.D., many psychiatrists do not prescribe MAOIs any more due to fear of their side effects.
"The reason MAOIs aren't being used anymore is not because they aren't effective," Bodkin, Assistant Professor of Psychiatry, Harvard Medical School, and Associate Psychiatrist, McLean Hospital, Belmont, MA, told The Brown University Psychopharmacology Update. "They are supremely effective. But people who are on them can get killed as a result of eating the wrong food."
According to Bodkin, oral MAOIs currently available in the U.S., such as oral selegiline, inhibit the MAO-A enzymes in the gut, which detoxify dietary tyramine in fermented products such as cheese, red wine, soy sauce, beer on tap and air-cured sausage. Ingesting these fermented products while taking MAOIs can cause acute hypertension. Oral selegiline can also interact with medications such as over-the-counter cold remedies, as well as serotonergic antidepressants, causing hyperthermia.
Bodkin noted that although it is used off-label, oral selegiline is currently indicated for Parkinson's disease, not depression. At the lower doses used to treat Parkinson's disease, selegiline is selective for MAOB enzymes, which are not found in the gut. As a result, toxic interactions with dietary substances or other drugs are unlikely at such doses. At the higher doses needed to treat depression, MAO-B selectivity is lost.
Due to these interactions, MAOIs are used in treatment-resistant depression only, said Jonathan Cole, M.D., a senior consultant in psychopharmacology at McLean Hospital and a Professor of Psychiatry at Harvard Medical School. He added that, currently, few psychiatrists are even trained in how to use MAOIs.
Groundbreaking Study
This study, which was supported in part by the manufacturer of selegiline, randomly assigned 177 adult outpatients with major depressive disorder to six weeks of treatment with either 20 mg daily of transdermal selegiline applied by means of a patch (N=89), or placebo (N=88). Response to medication or placebo was measured by both the 17- and the 28-item versions of the Hamilton Depression Rating Scale, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI) severity and improvement measures.Patients taking transdermal selegiline improved more on all measures of depression than did patients taking placebo. Scores on the 17-item Hamilton Depression Rating Scale decreased by 8.73 from baseline to week six in the selegiline group, as compared to 6.10 over the same time period in the placebo group (p=0.01). The 28-item Hamilton Depression Rating Scale showed a decrease of 11.23 from baseline in the selegiline group, as compared to a 7.59 decrease from baseline in the placebo group over the six weeks of treatment (p=0.004). The MADRS, which according to Dr. Bodkin is a little bit more sensitive to changes due to medication, demonstrated a 9.77 point decrease from baseline in selegilinetreated patients and a 5.69 decrease from baseline in placebo-treated patients (p=0.005).
There was a statistically significant difference between the two groups on the 17-item Hamilton Depression Rating Scale (p=0.05), the 28-item Hamilton Depression Rating Scale (p=0.02) and the MADRS (p=0.01) as early as week one of treatment.
"It is quite unusual to find something that moves everything [all measures of depression] that rapidly," said Bodkin. Bodkin also noted that, although the first observation according to the study protocol was made at one week, several patients got well within a day of treatment.
The only statistically significant side effect of transdermal selegiline, according to Bodkin, was a skin rash, which occurred in 17 percent of the placebo group and 36 percent of the selegiline group (p=0.006). There were no significant differences between the two groups in side effects related to the body as a whole, or in the cardiovascular, nervous, digestive, respiratory, urogenital or musculoskeletal systems. There was no difference between the two groups in the rate of acute hypertension.
The selegiline-treated patients also reported significantly improved sexual function compared with placebo-treated patients (p=0.03). This improvement in sexual functioning compares favourably with currently popular antidepressants as well as with oral MAOIs, both of which often cause sexual side effects, said Bodkin.
The rate of compliance in this particular study was virtually one hundred percent, quite unusual when compared with compliance rates of 65 percent in clinical trials and of 50 percent in the community, stated Bodkin.
Transdermal Delivery
In speaking about the benefits of the transdermal formulation Bodkin said it "gets into the blood stream immediately, you get much higher concentrations in a much more sustained way, you see the [parent] drug rather than the metabolites, and you avoid the effect on the gut."Oral medications are metabolized almost immediately by the liver, explained Bodkin; therefore much of the drug is metabolized before it reaches the brain. Since transdermal delivery bypasses initial metabolism in the liver, more of the drug is available to enter the bloodstream.
It is believed that transdermal administration also results in slower metabolism of the drug, according to Cole, with more sustained concentrations. However, no studies have been done to test this hypothesis, he added.
Cole sees a role for transdermal selegiline in a significant subgroup of anxious depressed patients. Studies show MAOIs are better than placebo for a significant subgroup of anxious patients such as those with agoraphobia and social phobia, he said. With the transdermal delivery system addressing concerns about dietary interactions seen with the oral formulation, "maybe Eldepryl will help people who are now getting SSRIs" said Cole.
Bodkin added that transdermal selegiline might be a promising treatment for use in emergency situations, such as with depressed patients who are suicidal. Since it acts quickly, it might relieve depression more quickly than oral antidepressants, which take four to six days to take effect. Additionally, because the transdermal delivery system is always on the patient's body, it encourages compliance, especially in depressed individuals who can be unmotivated to take their medication, or the elderly, who forget to take oral medications. "It's really quite a compliance boon," he commented.
"The concern [with transdermal selegiline] is pretty much limited to the skin reaction," concluded Bodkin. "In people who had a bad skin reaction, it leaves a mark that lasts for two weeks. It's not the most discreet thing in the world."
"It will re-introduce American psychiatry to MAOIs," concluded Cole, commenting on the clinical implications of transdermal selegiline.
poster:djmmm
thread:140745
URL: http://www.dr-bob.org/babble/20030208/msgs/140745.html