Module 1: Advances in the Biology and Treatment of Depression

MAO is an enzyme that is responsible for metabolizing catecholamines and serotonin in both the central nervous system and in the periphery. There are two different forms of MAO, type A and type B, which are distinguished on the basis of which substrate they preferentially metabolize. MAO type A preferentially metabolizes serotonin and norepinephrine, whereas type B preferentially metabolizes other catecholamines, such as phenylethylamine. Both dopamine and pyramine are equally metabolized by MAO-A or MAO-B.

There are some differences in the regional distribution of these two subtypes of MAO in the body. In the brain, MAO-A is found in areas that are rich in catecholaminergic neurons, whereas type B is found in areas that are rich in serotonergic neurons. Both type A and type B are found in the central nervous system in neurons that contain dopamine as the primary neurotransmitter. In the periphery, MAO-A and MAO-B are found widely dispersed in neurons and also in platelets throughout the body, and also in some tissues and organs, such as the liver, lungs, placenta, and other tissues.

Pharmacology of MAO-A:

It would be helpful for me to start here with this familiar scheme about how neurotransmission occurs so I can explain the role of MAO. In this familiar scheme of a neuron, in which there is a presynaptic neuron interfacing with a postsynaptic neuron and receptor, and the response to an action potential that is received in a neuron. On the left, for example, serotonin is released into the synaptic cleft. This gives the opportunity for serotonin to either interact with presynaptic receptors or postsynaptic serotonergic receptors. The termination of action of a neurotransmitter normally occurs by reuptake into the presynaptic terminal to specialized carriers or transporters. In the stylized neuron on your left, MAO, which is bound to mitochondrial membranes, is available to metabolize serotonin after it is taken back up into this presynaptic terminal. In the presence of an irreversible MAOI, though, the serotonin is taken back up and transported into the presynaptic neuron and isunavailable for metabolism.

There are some alternative routes of metabolism, such as catecholomethyl transferase, but again the end result is that there is an increase in availability of serotonin. In a similar fashion, in the neuron on your right, norepinephrine undergoes the same process, in which an irreversible MAOI may prevent its metabolism.

Pharmacology of MAO-B:

A similar situation occurs with dopamine-containing neurons, where dopamine is taken back up into the presynaptic terminal, normally to be metabolized by MAO, type B or type A. But in this particular picture in type B, the presence of a MAOI will prevent its metabolism.

Rationale for MAOIs in the Treatment of Depression:

What ultimately occurs, and this is the rationale for the use of MAOIs in the treatment of depression, is that they can potentiate the neurotransmission in the brain due to serotonin, norepinephrine, and dopamine. These increased levels of neurotransmitters in the brain then can result in changes in neuronal firing from serotonin, for example, and even the rate of firing.

Ultimately, there is a homeostatic mechanism that is introduced by the body, and some of these changes are reversed. But the bottom line is that increased levels of serotonin, norepinephrine, and dopamine caused by MAO inhibition are believed to play a prominent role in the treatment of depression in causing antidepressant effects.

MAOIs: History and Use:

The MAOIs have been around since the early 1950s. In fact, this is how they were discovered. Isoniazid was a drug that was being used to treat TB. Unfortunately, it was not a very good anti-tuberculosis drug. But what was discovered, and this is a testimony to clinical observation, is that many of the patients with TB who were also depressed had an elevation of their mood when taking isoniazid. Subsequently, isoniazid was determined to be a MAOI, which led to the development and subsequent marketing of several different MAOIs around the world and in the US. Isocarboxazid, phenelzine, and tranylcypromine, for example, are irreversible, nonselective MAOIs. By this I mean two different characteristics. They are irreversible in the sense that when they are given to a patient, they combine and bind with MAO in a permanent fashion, totally eliminating the activity of the enzyme. So this is the reason that we must wait at least 2 weeks after administration of one of these MAOIs in orderto give the body time to regenerate the MAO.

They are also nonselective in the sense that they equally seem to inhibit MAO type A and MAO type B. Most physicians in the US are more familiar with phenelzine and tranylcypromine than they are with isocarboxazid. Moclobemide departs a little bit from the pharmacology of these first three MAOIs in that it is a selective and reversible inhibitor of MAO type A. I will explain in a few moments the significance and clinical benefit for such a characterization as moclobemide.

Selegiline has been around for a while. It is actually marketed in an old form for the treatment of Parkinson's disease. It is a relatively selective MAO type B inhibitor, but it also has an irreversible inhibition on MAO type D. In higher doses, those that are given for the treatment of Parkinson's disease, it can inhibit MAO type A, and this forms the basis for its use in the treatment of depression.

The selegiline transdermal system, marketed as Emsam^®, is a recent addition in the US to the MAOI armamentarium. By changing the simple route of administration of this drug, it produces several therapeutic benefits, which I will explain in just a few minutes. I would like to say that moclobemide, as a reversible selective MAO-A inhibitor, is marketed in many countries around the world, including Canada, but unfortunately has not been available in the US.

Infrequent MAOI Use:

The MAOIs are infrequently used in the US for the treatment of depression. In fact, one reliable survey has shown that less than 1% of all antidepressant prescriptions are for MAOIs. What is thought to be the major reason for this infrequent use of the drug, which has been shown to be therapeutically effective, and in many situations, safe and well tolerated, are the guidelines that have been promoted to make dietary modifications with the use of MAOIs.

Pharmacolgic Interaction of Oral MAOIs and Dietary Tyramine:

Let me explain the pharmacologic interaction between MAOIs that are taken orally, and dietary tyramine. The whole reason for the recommendations of dietary modification is that tyramine, when ingested in food and absorbed systemically, can increase the blood pressure by stimulation, and also by release of norepinephrine. The nonselective MAOIs, isocarboxazid, phenelzine, tranylcypromine, and oral selegiline when taken in doses greater than 20 milligrams a day, more or less block the protective effect of MAO A and B in intestine and liver, which normally would metabolize tyramine. You get much more absorption of tyramine into the systemic circulation and this has a risk of producing hypertension, which can even lead to hypertensive crisis in some patients.

Foods Containing Tyramine:

For a long time, there have been charts that have publicized the differences in various foods that contain tyramine. Especially reputed to have high amounts of tyramine are eggs and fermented foods such as aged cheese, fermented meats, soybean products, beer that is not pasteurized, and also red wine, white wine, and beer that may contain moderate amounts of tyramine.

The problem is that this is not very specific. In fact, what has happened in clinical practice is that these dietary modifications have resulted in very low utilization of MAOIs for fear that patients would be unable to follow these dietary restrictions.

Portions and Tyramine Content of a Sample High-Tyramine Meal:

In recent years, there has been more of a quantitative approach to determining how much tyramine is actually in different types of food. There is a widespread consensus that you need about 40 milligrams of tyramine in a meal to constitute a high-tyramine diet.

This is a hypothetical meal that contains some of the foods that are reputed to be very high in tyramine. You can see that in order to get nearly 40 milligrams of tyramine in such a meal, a patient could drink a couple of bottles of beer, almost an entire bottle of pinot noir, and ingest these other amounts of various foods that contain tyramine. It is not arbitrary that 454 grams has been calculated here for how much tyramine it contains: 454 grams equals 1 pound. For this meal to constitute a high-tyramine diet, someone would have to drink all of that alcohol, ingest a pound of sauerkraut, a pound of boiled potatoes, and a pound of roast pork, in addition to eating cheese. Thus, it may be somewhat of a myth that many of the foods that are reputed to have high amounts of tyramine and, therefore, increase the risk of a hypertensive crisis when ingested in combination with a MAOI, may in fact be over dramatized.

MAOI Drug-Drug Interactions:

However, the MAOI drug-drug interaction story is a little bit different from that of tyramine-high foods. Notice on this chart that, as we have discussed, a hypertensive response can result when a MAOI is taken along with foods high in tyramine. The reason, of course, is that the inhibitor has destroyed the protective effect of MAO-A in the intestine, which normally would metabolize tyramine. However, there is no such protective effect against other sympathomimetic drugs, or other drugs that, when combined with a MAOI that increases serotonin and that has serotonergic effects themselves, could lead to either a serotonergic syndrome or to a hypertensive crisis. There are a number of drug-drug interactions that apply to all of the MAOIs simply because of this pharmacodynamic possibility of a drug-drug interaction.

With that explanation of the tyramine food effect, let me shift our attention to how pharmacologic advances over the traditional MAOIs can actually reduce the potential for tyramine interaction.

Reversible Inhibitor of Monoamine Oxidase-A (RIMA):

The first advance I would like to talk about is moclobemide. Most of the previous drugs have been irreversible inhibitors of MAO. That is, they bind to MAO and permanently disable it from having any further metabolic activity. However, moclobemide is a reversible inhibitor. That means that when it is bound to MAO-A in the gut, for example, the tyramine ingested in the diet can displace moclobemide from MAO-A, and that allows the MAO type A to actually metabolize tyramine. Therefore, this undermines the possibility that dietary tyramine will cause a rise in blood pressure and lead to a hypertensive crisis. In fact, it takes eight times more tyramine to cause a 30-millimeter rise in blood pressure in a patient who is taking moclobemide than it does in someone who is taking an irreversible MAO, such as tranylcypromine. This definitely increases the safety of moclobemide in terms of increasing blood pressure. In fact, moclobemide is marketed in many countries around the world withoutany requirement for dietary modifications or dietary restrictions.

Moclobemide:

Moclobemide is a selective reversible MAOI. And like the MAOIs, it also inhibits the metabolism of norepinephrine, serotonin, dopamine, and tyramine. It causes many of the same effects that you would expect from any MAOI in the central nervous system. It changes the metabolic pattern of neurotransmitters. It reverses some of the pathophysiology that Dr. Nemiroff mentioned earlier, such as down-regulating beta adrenergic receptors in the cerebral cortex. However, the good thing about moclobemide being a selective MAO-A type antidepressant and being reversible is that it does not significantly lead to any increases in blood pressure from tyramine, because as a reversible inhibitor, tyramine can displace the drug and be metabolized. It is unfortunate that this drug is not available in the US.

Moclobemide: Clinical Trials:

Let me review for you some of the abundant clinical trial data that support the marketing of moclobemide and its efficacy and safety in the treatment of depression. In almost all of the meta-analyses that have been published, moclobemide was more efficacious than placebo and was equal to tricyclic antidepressants and SSRIs for the treatment of acute depression. There is some evidence of long-term efficacy as well.

Clearly, there are no data that show that the drug is inferior to other antidepressants. And while the drug has not been evaluated as extensively as the SSRIs or tricyclics for treatment of a major anxiety disorder, there are some data that support its similarity to fluoxetine and clomipramine for the treatment of panic disorder.

Moclobemide Efficacy:

Here are the results of two studies, one comparing moclobemide to another MAOI and one to TCAs. In the top figure, in patients who had major depression consistent with DSM-IV criteria, results at 4 weeks showed that the moclobemide group was just as efficacious as those treated with the traditional irreversible, nonselective MAOI tranylcypromine. In the bottom figure, moclobemide was compared with imipramine in doses that were allowed to go up to 250 milligrams a day, if tolerated, and results showed that moclobemide was at least as efficacious as the tricyclic and that both drugs were better than placebo.

Let me move on and now talk about the selegiline transdermal system, which also represents an advance in MAOI therapy to treat depression, and also is an advance because it reduces the possibility of tyramine interaction.

Selegiline Transdermal Pharmacology:

The second advance in MAOI therapy that I would like to talk about is the selegiline transdermal system. By taking selegiline, which is marketed in oral form for the treatment of Parkinson's disease, and changing its route of delivery by putting it into a patch for transdermal administration, the drug bypasses metabolization by the gut and liver. This has a primary benefit of reducing the inhibition of gut and liver MAO type A. This means that tyramine ingested in food can still be normally metabolized in the gut.

Oral Versus Transdermal Selegiline: Modes of Absorption:

I want to make certain that these points about oral versus transdermal selegiline are clear. The panel on the left shows that when a drug is taken orally, it can go through the gut wall and the liver and be metabolized. For a drug like selegiline, which has a very high hepatic extraction and extensive first pass effect, that means that not much drug enters the systemic circulation for distribution to the brain, where it can result in an antidepressant effect.

In contrast to this situation, whenever selegiline is administered transdermally via a patch on the torso or on the thigh, it bypasses the liver and the gut completely on the first pass, so there is a greater amount of drug that is available to the brain to exert antidepressant effects.

Selegiline Pharmacology:

Oral selegiline is highly metabolized upon administration, and the low concentrations inhibit MAO type B, because selegiline is relatively specific for MAO type B. So there is sufficient amount of drug to enter the central nervous system and produce beneficial effects from dopaminergic neurons, so it can be useful in the treatment of Parkinson's disease.

However, in order to get high enough concentrations in the brain to treat depression, the dose of oral selegiline has to be increased sufficiently. When this occurs, while you can get MAO type A inhibited in the brain and have therapeutic effects in the treatment of depression, you also, unfortunately, inhibit tyramine metabolism in the gut, increasing the possibility of a tyramine food interaction. In contrast, transdermal selegiline results in a much higher systemic availability of the drug, which distributes to the brain and inhibits both MAO-A and MAO-B, increasing the concentrations and the availability of catecholamines and serotonin, which is useful in the treatment of depression.

Rationale for Transdermal Delivery of STS:

To further illustrate this, in the panel on the left, consider the situation where a selegiline transdermal system has been given to a patient not taking tyramine or not having any dietary problems. The drug bypasses the liver and you still have intact MAO-A in the gut to metabolize tyramine, should it be ingested in sufficient amounts to cause a pressor effect in the diet. In addition, you have inhibition of both MAO-A and MAO-B in the brain to exert an antidepressant effect.

Whenever tyramine is given with the selegiline transdermal system, the availability of free MAO-A in the gut still provides a protective effect for tyramine in reducing its availability to the systemic circulation.

Selegiline and Metabolite Pharmacokinetics Following Transdermal vs Oral Delivery:

Let me emphasize the differences in the pharmacokinetics of selegiline according to route of administration. What you see in this table is selegiline and its free metabolites, N-desmethylselegiline, L-amphetamine, and L-methamphetamine, which are not the dextro forms, but the inactive forms. And you see various pharmacokinetic parameters depicted. What I would like to draw your attention to in the results of this study is the middle column, for example, and the area under the curve, which is a general measure of the total systemic availability of the drug. Here you see a value of about 0.5 ng·h/mL. When selegiline is given orally, you start with a value of about 0.5, but the concentrations and the exposure to the metabolites have much higher values—42, 95, and 264 as we go down the column. That is because selegiline is very avidly bound to liver enzymes, and it is extracted upon its first pass through the liver highly metabolized, resulting in low parent drugconcentrations and very high metabolite concentrations.

The column on the right shows values for roughly the same dose of selegiline given in a transdermal system. You can see that there is about a 50- to 60-fold difference in the increase in the selegiline exposure in the systemic circulation, at 31 ng·h/mL. But now we have much lower exposure to metabolites, N-desmethylselegiline, L-amphetamine, and L-methamphetamine.

Selegiline Plasma Concentration Versus Time by Mode of Delivery:

To further illustrate this, look at a single dose where the oral selegiline was given in a 10-mg dose to volunteers, depicted in the concentrations-versus-time profile shown in yellow. You can see that the concentration of selegiline drops dramatically over the first 12 hours. Now, for reference, an intravenous infusion of the same amount of selegiline was given in this study, and the results are shown in red. When you have a profile like this, where an intravenous route of administration results in much higher plasma concentrations compared with the oral route, there are two primary possibilities for the differences in the concentration profiles. One is that the oral drug has very low absorption and bioavailability; two, the oral drug is dramatically metabolized on its first pass through the liver.

We know that the bioavailability of selegiline, that is, its absorption at least to the liver, is not an important factor in producing this profile. Conversely, so much of the selegiline gets metabolized on the first pass when it is taken orally, that it results in high metabolite concentrations. A third study in this same group illustrates what happens when a similar dose of selegiline is given transdermally. These results are shown in green. The transdermal system is formulated to release a constant amount of drug over a 24-hour period. What you see is something in between the oral and the intravenous profile, and you see relatively sustained concentrations during this period of time.

N-Desmethylselegiline Plasma Concentration Versus Time by Mode of Delivery:

This is also illustrated here by a profile showing that when selegiline is given orally, you have very high concentrations of the primary metabolite, desmethylselegiline, shown in green. In fact, it is so high that it can not be shown on this graph. Conversely, the concentrations of metabolite when selegiline is given transdermally, via a patch, are low, as shown in red.

Selegiline Transdermal System (STS) Pharmacokinetic Parameters:

This offers more information about the pharmacokinetic parameters of the selegiline transdermal system (STS). There may be some discrepancy that will appear to you in the doses, where 20-, 30-, and 40-milligram patches are available, but in fact, this formulation only delivers about 25% or 30% of the selegiline contained in the patch over a 24-hour period. This equates to either a 6-, 9-, or 12-milligram per 24-hour dose of selegiline. As I have already said, the transdermal exposure to selegiline results in substantially higher parent drug concentrations, and much lower drug metabolite concentrations.

In a study that was conducted over about a 10-day period, it was found that with the transdermal administration system at steady state, concentrations of selegiline occurred in about 5 days of daily dosing. Fortunately, the transdermal system can be applied to different parts of the body, and the concentration time profiles from either upper torso, or upper thigh, administration, are almost identical. Fortunately, selegiline is not very highly bound to plasma proteins—only about 80% to 90%—as are many other antidepressants. This minimizes the possibility of displacement drug-drug interactions from protein binding sites, resulting in increased pharmacologic effects. This is not known to be an issue with selegiline.

Selegiline STS Metabolism and Drug-Drug Interactions:

Selegiline is metabolized by multiple cytochrome P450 enzymes, including 2C9, 2B6, 3A4, and to a minor degree by 2A6. Whenever a drug is metabolized by multiple, simultaneous pathways, this minimizes the possibility of the drug interacting with other drugs and causing drug-drug interactions. Nevertheless, a number of studies have been carried out to determine whether selegiline participated in pharmacokinetic drug interactions. Many of the drugs with characteristics similar to those enzymes that metabolize selegiline, such as alprazolam and ketoconazole, have been shown to lack substantial drug-drug interactions with selegiline when it is administered as a patch.

Two of the drugs shown, pseudoephedrine and phenylpropanolamine, were at one time available as over-the-counter decongestants. In fact, the study that was carried out did not show an interaction with pseudoephedrine, but did show a slight increase in blood pressure with phenylpropanolamine. There are a couple of other drug-drug interactions with selegiline. Carbamazepine appears to increase plasma selegiline through a mechanism that, at this point, is not completely understood. But overall, the same warnings that apply to other MAOIs and drug-drug interactions apply to selegiline administered as a transdermal system as well. These are all detailed in the package labeling.

Tryamine and STS: Tyramine Challenge Studies:

Because the dietary modifications and restrictions with MAOIs are based on the amount of tyramine in the diet that can cause an increase in blood pressure leading to a hypertensive crisis, I would like to review some tyramine challenge studies that have been conducted with the selegiline transdermal system. There have been 14 different studies that have enrolled more than 214 volunteers, and they unequivocally demonstrate the safety of selegiline, probably without any dietary restrictions at this low dose.

These 14 different studies have included doses of STS of 6-, 9-, and 12-mg/24 hours. They have been conducted using both fasting and fed conditions, because tyramine is obviously introduced in a fed condition. Several comparator drugs to the transdermal system have been tested, including an SSRI, fluoxetine, oral selegiline, and another traditional MAOI, phenylcypromine.

The objective of these studies was to determine the sensitivity to diet when someone takes tyramine without a MAOI and then when someone takes tyramine with the selegiline transdermal system. In a moment, I will show you the results of several of these studies. First, I would like to mention that there have been over 2,500 patients with major depressive disorder studied in the trials that led to marketing of Emsam^®, the transdermal selegiline system, and there was not a single hypertensive crisis in any of these patients—and all of these studies were conducted without dietary restrictions.

Tyramine Challenge Studies: Measurement Variables:

It takes a bit of explanation about the methodology of the tyramine challenge studies to fully understand the results. First of all, there is the issue of the pressor dose. This is an estimate of how much tyramine, at a minimum, is necessary to produce a change in blood pressure. The change in blood pressure that is considered to be clinically relevant is a 30-millimeter increase in mercury in systolic blood pressure.

There is another parameter, called the baseline pressor dose. This is the dose of tyramine that causes the increase in blood pressure, a TYR-30 at baseline without taking any other drug. The problem is that there is considerable variability in the baseline pressor dose across individuals, so a way to more or less provide a common method of comparison across individuals or across drugs is to calculate a tyramine sensitivity factor. This consists of comparing the ratio of the amount of tyramine that causes the required increase in blood pressure (30 mm Hg at baseline) to the endpoint after drug is taken.

Thus, we have two different parameters. We have the baseline pressor dose, that is the total amount of tyramine needed to increase blood pressure to a clinically significant degree. We have the tyramine sensitivity factor, showing what is the relative change in the pressor dose between the no-drug and the drug condition. The lower the tyramine dose at baseline or at endpoint, the more sensitive the individual is, perhaps because of the comparator drug or the MAOI itself, to pressor effect, or the higher the TSF. That implies that there is a greater degree of MAO A inhibition, allowing a greater sensitivity. The blood pressure changes from ingested tyramine. I mentioned earlier than a diet that is considered high in tyramine would contain about 40 milligrams of tyramine.

Tyramine Sensitivity Factors (TSF) in Crossover Studies of STS (6 mg/24 h):

This slide shows the results of three different studies of tyramine challenges. The results are displayed as the tyramine sensitivity factor in crossover studies of the selegiline transdermal system, either compared with a difference in time or a difference in route of administration, or to another standardized MAOI.

In the panel on the left, the results show that the selegiline transdermal system at 6 mg/day (low dose) produces some change in tyramine sensitivity because the ratio has gone from 1, representing no change in sensitivity, up to 1.86. That was calculated after 9 days of administering the patch on a daily basis. After patients had continued on the selegiline patch for 33 days, there was hardly a substantial change in TSF, reaching only 2.85. Nevertheless, there is some increase in sensitivity, though not dramatic.

It is also interesting to compare the pressor effects induced by the selegiline transdermal system versus oral selegiline taken daily. You will recall that oral selegiline at the low doses, which are used to treat Parkinson's disease, do not require dietary modifications. The middle panel shows that the pressor ratio does not change much, from 1.75 to 1.67.

However, there is a dramatic difference in tyramine sensitivity factor, or TSF, between the selegiline transdermal system at the low dose, 6 milligrams/day, taken for 10 days, and tranylcypromine at a usual dose of 30 milligrams/day. With tranylcypromine, there is a 40-fold difference from transdermal selegiline in TSF, a dramatic increase in risk for producing pressor effects potentially leading to a hypertensive crisis. There is no increase in TSF with the selegiline transdermal system.

Tyramine Pressor Response in Healthy Male Volunteers on STS:

Let me show you some results of our tyramine challenge studies, in which the outcome variable is the tyramine pressor dose in milligrams. In this situation, the lower the dose required to produce a pressor effect, the more inhibition of monoamine oxidase A and the more risk of increase in blood pressure while taking a MAOI. Two different studies are depicted here. On the left is shown the baseline for 6 mg/24 hours and 12 mg/24 hours of transdermal selegilene required to produce a 30-millimeter increase in blood pressure at baseline, where there is no MAOI treatment. The right panel shows extended treatment for 33 days on the selegilene transdermal system at 6-mg or 12-mg/24 hours. You can see how the dose of tyramine used to produce the increase in blood pressure has changed.

To start with, normal, healthy volunteers who were not taking a MAOI have to take multiple times the amount of tyramine in a normal high-tyramine diet to produce a pressor effect, somewhere between 400 and 600 milligrams a day. The 6-milligram results show that it took about 500 milligrams to produce an increase in blood pressure at baseline (no treatment). After the subjects had been taking the selegiline transdermal system daily for a month, actually for 33 days, the dose to produce an increase in blood pressure had decreased down to something over 200 milligrams a day. But the 200 milligrams a day is still substantially above the amount of tyramine that would normally be contained in a high-tyramine meal.

If we look at the 12-milligram results, we see a decrease from somewhere around 550 milligrams down to an average of about 63 milligrams to produce a pressor effect. If these results are generalizable, this means that in order to produce a pressor effect, if you were taking selegilene at the higher dose, you would still need to take more tyramine at 1 meal than is normally found in a high-tyramine diet. I should point out that these results were obtained in fasting subjects.

However, if the subjects were also given tyramine with a meal, which would more closely replicate the normal situation, the pressor dose on 12 milligrams per day increased from 64 milligrams to 172 milligrams, but these results are not shown. Nevertheless, they support the safety, especially at 6 mg/24 hours, of not requiring dietary modifications for the selegiline transdermal system.

Positive Placebo-Controlled Efficacy Trials With STS:

Let me briefly review for you some of the efficacy and safety data that were generated in support of the marketing of the selegiline transdermal system as Emsam^®. There were two placebo-controlled studies, a 6-week trial, and an 8-week trial that were conducted in 176 and 265 patients, respectively, using the dose of 6 milligrams/24 hours for the 6-week trial, and either 6, 9 or 12 milligrams/24 hours for the 8-week trial. There was also a relapse-prevention study that lasted 52 weeks, also versus the comparator or placebo.

For all three of these studies, the primary endpoint—the Hamilton rating scale for depression in the 6- and 8-week study and the Kaplan-Meier time to relapse in the relapse-prevention study—the results with selegiline were significantly different from those with placebo.

STS in Major Depression 8-Week Trial: MADRS Change:

Looking closer at the 8-week trial, note that using a MADRS (Montgomery Asberg Depression Rating Scale, the selegiline transdermal system and placebo show statistical separation at the 4-week, 6-week, and 8-week endpoint intervals.

STS in Major Depression 8-Week Trial: Statistically Significant AEs vs Placebo:

Let me draw your attention to the recording of adverse events in the 8-week trial of selegiline transdermal system versus placebo. The only statistically significant adverse event difference between the patch and the placebo occurred in application-site reactions. There were very few withdrawals from this study due to any adverse event, and the ones that withdrew that were statistically significant were due to application site-reactions. In all the clinical trials, the application-site reactions were approximately equivalent to those that occur with adhesive bandages.

Treatment-Emergent AEs Occurring in ≥2% of Patients With STS vs Placebo:

If we look at all the treatment-emergent adverse events that occurred in greater than 2% of the patients with the selegiline transdermal system versus placebo, you can see that there are hardly any differences, with the exception of application-site reaction. I might point out that headaches occurring in 17% and 18% of patients in this clinical trial probably represent less than most often occur in trials with SSRIs, for example. Other complaints, including gastrointestinal, that occurred in greater than 2% of patients are also relatively few in number.

Sexual Side Effects Associated With Selected Antidepressants:

One of the possible adverse events that can occur with many antidepressants is the precipitation of sexual side effects. This slide shows the results of a meta-analysis, conducted by Michael Thase and published in 2005, that compares various approaches to quantifying sexual dysfunction with bupropion and that compared with placebo. As you can see, for example, in orgasmic dysfunction, bupropion results in no greater dysfunction than placebo, whereas the SSRIs can cause a substantial amount of sexual dysfunction in a variety of different parameters of this measurement. The first point here is that even placebo causes some sexual dysfunction, and there are antidepressants on the market that cause no greater dysfunction than placebo.

STS in Major Depression 6-Week Trial: Sexual Side Effects:

Although the selegiline transdermal system has not been compared with other active drugs, especially in this discussion, in relation to adverse events of sexual dysfunction, there are quantifiable results from this 6-week trial that show that treatment with selegiline 6 mg/24 hours reported no sexual dysfunction compared with placebo. In fact, results could be interpreted as a slight improvement with selegiline transdermal system over placebo.

Advantages and Disadvantages of Transcutaneous Drug Delivery:

Let me summarize the advantages and disadvantages of the selegiline transdermal drug delivery system. There are clear advantages by avoiding the systemic exposure with oral administration of selegiline, by delivering it via a transdermal system. This allows a greater amount of drug to exist in the systemic circulation, thereby being available for distribution to the brain, where it can inhibit both MAO-A and MAO-B to produce antidepressant effects. This occurs because the transdermal system avoids the hepatic first-pass effect that metabolizes a great deal of selegiline when it is given orally. The transdermal patch also produces a relatively smooth plasma concentration during 24 hours. In clinical trials with this drug delivery system, there is clear efficacy against placebo in 6- and 8-week studies, and in a relapse-prevention study. Overall, the adverse-event profile of the selegiline transdermal system shows that it is generally well tolerated as well.

Fortunately, at the low dose of 6 mg/24 hours, at least, there does not appear to be a need to impose dietary modifications or restrictions on patients. As doses increase to 9 or 12 milligrams/24 hours, there are less data to justify that dietary modifications are not required. One disadvantage is the side effect of patch-site irritation, but it appears to be well tolerated despite the possibility of localized irritation and cutaneous reactions to the patch.

Developmental Timeline of Depression Treatment Options:

Since the early 1950s, we have had drugs available to treat depression. The earliest class was the MAOIs. Unfortunately, this class of drugs has been under-utilized for fear that the absence of dietary restrictions might result in dietary interactions, increasing blood pressure and increasing the risk of hypertensive crisis. Fortunately, in the last few years, we have had two advances in this category of drugs. With moclobemide, we now have a reversible, specific inhibitor of MAO-A, which is clearly an advance and does not require dietary restrictions. Unfortunately, the drug is currently not available in the US.

More recently, selegiline, a nonselective—or at least relatively selective for MAO-B, in the periphery, inhibiting both MAO types A and B in the brain—has become available in a transdermal system, and clearly has advantages in treatment of depression. A principal advantage is that it is effective, well tolerated, and does not require dietary modifications at the low dose of 6 mg/24 hours.

Having said this about the development of the antidepressants, and the MAOIs specifically, I would like to turn the presentation back to Dr. Nemiroff, who probably has some closing comments and conclusions of his own.

I would like to wrap up with a series of conclusions from our program. As you undoubtedly learned today, we have made remarkable advances in understanding the pathophysiology and treatment of depression. To be more specific, serotonin, norepinephrine, dopamine, the CRF system, GABA, substance P, and other endogenous neurotransmitters are the targets in the pharmacologic management of depression.

MDD is a chronic heterogeneous disorder that is very unlikely to remit spontaneously. Left untreated, it becomes chronic. It is associated with very severe morbidity and mortality. Continuation treatment is key to preventing relapse.

We do have many pharmacologic and nonpharmacologic advances that we have witnessed over the last decade for the treatment of depression. This includes, of course, advances in psychotherapy. Perhaps more important, there are additional treatment prospects on the horizon. Individual patients with MDD, and particularly those with specific subtypes of major depression, may have different responses to various treatment options. Combination and/or augmentation therapy is often necessary to convert partial or non-responders to responders.

Progress in depression pharmacotherapy has resulted in the development of effective agents that clearly have a reduced side-effect profile, and less of a propensity for drug-drug interactions. It is my belief that MAOIs have been terribly under-utilized, owing to the concerns about tyramine-induced hypertensive crises and interactions, untoward interactions with other medications.

The RIMA, moclobemide, that is the reversible MAOI, has been one advancement that has been made that minimizes risk for tyramine interactions, but it is not available in the US. I think it very unlikely that it ever will be. Another advancement, the selegiline transdermal system, affords higher plasma and CNS concentrations of selegiline compared with oral delivery of that drug. By bypassing the gut, it minimizes tyramine interaction, and it does not require, at least at the low dose, that we employ any kind of tyramine-restricted diet.