Mixing Up Meds to Treat Depression Results of the nation's largest depression study are out this week in the New England Journal of Medicine, and the message largely backs up what psychiatrists and patients have known for a long time: You may have to try many different drugs before you find the one -- or ones -- that work.
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Mixing Up Meds to Treat Depression

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Mixing Up Meds to Treat Depression

Mixing Up Meds to Treat Depression

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You're listening to TALK OF THE NATION: SCIENCE FRIDAY. I'm Ira Flatow. For the rest of the hour, we're going to turn to new research on treating depression. Results of the nation's largest depression study are out this week in the New England Journal of Medicine and the message largely backs up what psychiatrists and patients have known for a long time. You may have try many different drugs before you find the one or the ones that work. And we'll talk with the study's principal investigator.

Plus, another study out in the Journal of the American Medical Association shows that when mothers are treated for their depression, and that treatment works, their children are less likely to suffer mental health problems. So, if you'd like to join our discussion, give us a call, our number 1-800-989-8255, 1-800-989-TALK. And keep in mind, remember, as a rule here, we cannot address your particular situation, so please try to keep your questions in general.

John Rush Jr. is a M.D. at the Rosewood Corporate -- at the, and Professor of Psychiatry and of Clinical Sciences at the University of Texas Southwestern Medical Center in Dallas. He joins us today by phone from his office there. Thank you, Dr. Rush, for being with us today.

Dr. JOHN RUSH JR. (Professor of Psychiatry and of Clinical Sciences, University of Texas Southwest and Medical Center in Dallas): You bet. My pleasure.

FLATOW: Give us an idea first of what the overall goal of that study was?

Dr. RUSH: Right, well, this study is called the Star D Study, Sequenced Treatment Alternatives to Relieve Depression. And it is a large national study conducted in both primary and psychiatric care practices, both in the private and public sector. And the main target of the study was to figure out what are the next best treatments if the first treatment or even a second or a third treatment doesn't work fully, or is not well tolerated. And secondly, we are going to take a look at the longer term outcomes for those individuals that did encounter a treatment that was good enough for them to stay on it and be followed in the long term. So those are forthcoming publications.

The two studies that came out in the New England Journal of Medicine yesterday actually are the level two or second step studies. But those studies were designed for patients who had already gone through the first step, a common selective serotonin reuptake inhibitor, in this case, Celexa or Citalopram, and they had not gotten rid of the depression fully. In this study, we set the bar quite high. We said we don't want to look at people who just got better. We want to look at people who really got rid of the depression. We call that a remission, a symptom remission. And about a third of the people got into remission with the first step, but that left us two thirds who had not achieved that, or couldn't tolerate the medicine, and they were offered some options at the second step or level two.

And in that step, we asked them, would you like to stay on the first medicine and have something else added? Or would you like to get rid of the first medicine and start something new? So, that gave us two groups. It turned out that patients really had strong opinions of whether they wanted to stay on or get off of the first medicine and so then we wound up with a switch group, and then we had an add-on group. And in each of those two groups, we randomized patients to one of three treatments for the medication switch. And one of two treatments for the medication add-on or augment.

The bottom line of the second level treatment is taken across both kinds of strategies, switching and/or adding. We found about 30 percent of the patients who entered that level actually got into remission themselves. So, that was a little bit surprising and quite encouraging. That we did that well with patients who had already not done well with the very first treatment.

FLATOW: Mm-hmm.

Dr. RUSH: And it further turned out that the medications which we chose for very particular pharmacologic and mechanistic reasons, they turned out to be not all that different in terms of overall benefit. It wasn't that we could recommended this is the best switch drug or this is the best add-on drug. But rather, it would appear that different patients may be responding to different medications. Though at the moment we can't make that match very well clinically.

FLATOW: So, is the take home message here is if the medication that you're on doesn't work, don't resist switching to another medication?

Dr. RUSH: That is correct, and also don't resist, if it's more preferable to the patient, to having a second medication added to the first. In other words, this is not poly-pharmacy of the "try anything" but rather a particular selection is made in order to add to the effect perhaps a partial effect already achieved with the first drug.

FLATOW: Mm-hmm. So overall in your studies, you had 30 percent of the first group that overcame with the, with the single drug recommendation.

Dr. RUSH: That's right.

FLATOW: And you had the 30 percent of the second group who switched? So that's...

Dr. RUSH: That's right, switched or had add-on, if we would just...

FLATOW: Right.

Dr. RUSH: ...the switched group actually had about a 25% remission rate, and the add-on group had about a 33% remission rate. But they're two different groups of people, basically.

FLATOW: Would that be, so then, would it be fair to say that you had a success rate of about 50 to 60 percent?

Dr. RUSH: That's correct. If you take the two steps together, and you make an important assumption, which is, nobody drops out of treatment...

FLATOW: Right...

Dr. RUSH: ...we would expect about a 53%, slightly over 50%, actual remission rate, the depression is gone and the patient is back to their old normal selves.

FLATOW: Is that a good number of, you know, lay people don't know, is 50% remission good? Is that a good number in the world of psychiatry?

Dr. RUSH: That is a very good number in the world of chronic diseases overall, because...


Dr. RUSH: ...remember that when you're dealing with things like diabetes, hypertension, congestive heart failure and the like, we often have to go through multiple steps. Sometimes the first works terrifically, if you are treated early and the doctor is guessing right, if you will. But sometimes we have to go to several treatments to actually get the full benefit that we want. And these patients who were representative of the kinds of people being seen in practice all the time really had quite an illness burden. That is, their overall depression was over 16 years in length, the current episode was, on average, over two years. And two-thirds of these patients had another either psychiatric problem and/or a general medical problem. This additional disease burden and the length of the illness are argue towards not having a really good outcome, but yet, in spite of that, with two steps, over 50% getting rid of their depression is quite good.

FLATOW: What about other therapies added to it, like talk therapies? Do you think you could even raise the success rate?

Dr. RUSH: We actually will have a little bit of an answer to that, because at our second step, not in these articles, but it'll be coming out shortly, at the second step the patient could have entered a switch to a talk therapy or an add-on, that is, the talk therapy is added on to the first drug, Celexa, Citalopram. So we'll actually have some real evidence to comment on that shortly.

FLATOW: How did you choose which drug to use?

Dr. RUSH: You know, we set about trying to identify drugs with different enough mechanisms that clinicians and theoreticians and researchers would say, this drug is really going to have a different kind of therapeutic effect than that drug. So we picked, for example, in the second step switch, we took a drug called bupropion, or Wellbutrin; that's a drug that affects dopamine and norepinephrine. Quite different than serotonin. And we compared that with another drug called sertraline, the brand name is Zoloft. That's another serotonin reuptake inhibitor just like Celexa or Citalopram. And then the third drug was a drug that seems to, at least in higher doses, affect both norepinephrine and serotonin. That's called venlafaxine or Effexor Extended Release. And therefore, they represent different classes or approaches, and in spite of their apparent pharmacologic differences, they were more alike than different in terms of getting people into remission. Similarly, for the add-on drugs, one was augmenting the serotonin effect. That was buspirone or Buspar. The other add-on was, again Wellbutrin or bupropion, a dopamine norepinephrine drug. We really thought they would have quite different outcomes, but in fact they were very, very close to each other. That's not to say the same people are responding, but the overall benefit of those different options looks quite good.

FLATOW: Could you tell a difference of why some people dropped out? Or saying it another way, you mentioned before how difficult it is for people to stay, to take their medications?

Dr. RUSH: Yes.

FLATOW: Did you learn anything about how to overcome that, or to convince people to stay on their medications?

Dr. RUSH: Well, we did provide a whole patient education platform or interaction. And I think, importantly, we added on a couple of things that are maybe sometimes used in practice, but not as commonly as perhaps they should be. So we asked the patients to actually fill out a self-report of their depressive symptoms and their side-effect burden at every visit. And we added some additional assistance through a clinical research coordinator to the doctor who would interact with the patient, remind them of their appointments and track them down if they didn't come in. So this extra delivery system, we attempted to improve the quality of care beyond what might be common in practice, but not to the degree that it could not be done in practice. And we do think that additional care was important in retaining patients, and in fact, obtaining the kinds of results that we got.

FLATOW: And I would think that you'd need to specify that to patients and doctors that you did this extra thing to make it work. Would you not?

Dr. RUSH: Oh, absolutely. And we in fact have those tools on the Star-D Website available to everybody. They're in the public domain, and the website is www.star-d, as in depression.org.

FLATOW: Is there a fundamental difference between those depressed people who respond to the drug therapy who don't, do you suspect?

Dr. RUSH: Fundamental, I'm not sure. But obviously we're looking and we're hoping down the road to have some answers in terms of genetic markers that we're analyzing now. So, we would like to know, and we suspect it may be the case, that there's some genetic differences between people that remit with one drug versus another, or even between people that don't do well after three or four steps as compared to those who do well after just one step.

FLATOW: Mm-hmm.

Dr. RUSH: And if we can get that kind of a signal, and it's clinically useful, we're going to be in a great position to actually do some laboratory tests a regular practice and make, recommend a particular drug or pathway, or a sequence of care for particular individuals that share certain genetic characteristics.

FLATOW: Mm-hmm. Dr. Rush, you're part of another study out this week in JAMA that found that treating depressed mothers helps keep their children healthier. Can you tell us about that, and why you suspect that is?

Dr. RUSH: This is actually a very important study. It has been known for a long time that depressed mothers, as compared to non-depressed mothers, different women, actually differ in the problems and difficulties that their children have. And, one possibility is that there's a genetic vulnerability that's passed on, and their children have received some of that vulnerability that they share with the mom. And the other possibility is the mom is having difficulty getting through day-to-day functions as a parent and supportive assistant to the child. It's never been shown one way or the other whether if you take the depressed mom and are able to make her well, or at least reduce the depression a lot, whether that really helps the child or not. And this study showed that in fact that was the case.

For the depressed mothers who were treated in the Star-D project, Dr. Weisman and her colleagues looked at the children and what they found was, if the mom got well, the children got better. They didn't necessarily get well, some still had problems, of course. But if the mom didn't get well, actually there was a small increase in the number of problems that the children presented. So this shows the importance of depression impacting other people. It also suggests that if a practitioner is seeing a child who's depressed or anxious or, you know, has a mental condition of some type, it could be profoundly important to evaluate the mom and encourage her to get into treatment, if she does have some sort of problems that the treatment's going to be able to address. So it really brings the focus back on the family and the family environment that we somehow have lost over the last ten years. It's a very important study.

FLATOW: Talking about depression this hour on TALK OF THE NATION Science Friday from NPR News, with Dr. John Rush. Let me see if I can get a quick phone call in before we have to say goodbye. Christina in Boise. Hi, Christina.

CHRISTINA (Caller): Hi.

FLATOW: Hi there.

Dr. RUSH: Hi.

CHRISTINA: Hi. I'm a counseling student right now, working on my master's degree. And I'm just wondering what is the average age group that you studied? I'm particularly interested in how it affects a younger population.

Dr. RUSH: And the question was average age?



Dr. RUSH: Yeah, the age range in the study was 18 to 75. The average age was 40. So we did not have children and adolescents in this study.

CHRISTINA: Okay. And how, was there a difference between a younger population and an older population how they responded to the medication?

Dr. RUSH: Well some of those analyses we don't have completed yet, so I really can't address it. We're certainly going to look at it, because the population is quite large. We can try to get the answer. What I can tell you is that about, oh, over a third of the patients actually had their first depressive episode before age 18. And, this is a group that, of course, often has longer and more profoundly disabling disorders in the long run. So, early onset, as is true with other medical disorders, is not a good sign in terms of long-term prognosis. So, quite important to get in early, and of course to get these patients into remission.

FLATOW: Thank you, Christina. And of course, we don't know very much about teenagers and how they respond to drugs. They haven't been studied that well.

Dr. RUSH: Well there have been some randomized controlled trials that are positive and have shown the drugs to be relatively safe. There's been, of course, recent concern about a small percentage, but a very important percentage, who might become more agitated or have increased suicidal thinking. But I point out that the suicide attempt rate has not been shown to go up when they're treated with antidepressants. It does mean we've got to be cautious, and of course not just with the younger people, but with all adults. You know, carefully monitor as we go along. It's not as simple as taking a pill or take an aspirin if you have a headache. These drugs go to different places, they do have important effects, but they also have side effects, and we've got to watch that and not just deal with depression as if it's some sort of nuisance factor. It's a serious illness that deserves its own particular care.

FLATOW: Mm-hmm. I want to thank you very much for taking time to be with us Today, Dr. Ruston.

Dr. RUSH: Thank you very much for having me. Appreciate it.

FLATOW: You're welcome. Dr. John Rush is the Betty Jo Hay distinguished chair in mental health, the Rosewood Corporation chair in biomedical science, and professor of psychiatry and of clinical sciences at the University of Texas, Southwestern Medical Center in Dallas.

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