Surprising Depression Treatments Show Promise

Guests

Jon Hamilton, science correspondent, NPR
Gerard Sanacora, professor of psychiatry, Yale University

Traditional antidepressants like Prozac are widely used to treat depression by boosting serotonin levels, which researchers have long believed are at the root of depression. Research shows that other drugs, including ketamine — also known by its street name, Special K — may be more effective.

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NEAL CONAN, HOST:

This is TALK OF THE NATION. I'm Neal Conan, in Washington. Like too many of the many millions with depression, Chris Stevens tried just about every drug out there. None worked very well. Many caused side effects. Then one day he tried ketamine.

CHRIS STEVENS: Monday afternoon, I felt like a completely different person. It was, you know, same-day, same-day effects. And, you know, I woke up Tuesday morning, and I said wow, there's stuff I want to do today. And I woke up Wednesday morning and Thursday morning, and for the first time in I don't even remember, I actually wanted to do things. I wanted to live life.

CONAN: Ketamine is approved by the FDA as an anesthetic and may be better known as a club drug, often called Special K. But new studies show it can give at least some patients almost immediate relief and, along with some other drugs, could point the way toward a new kind of anti-depressive.

Doctors, what questions do you hear from your patients about their options? Give us a call, 800-989-8255. Email us, talk@npr.org. You can also join the conversation on our website. That's at npr.org. Click on TALK OF THE NATION.

Later in the program, an argument to seek out opinions you disagree with, even that one. But first, you may have heard NPR science correspondent Jon Hamilton's reports on MORNING EDITION this week. He joins us here in Studio 3A. Jon, always nice to have you on the program.

JON HAMILTON, BYLINE: Great to be here.

CONAN: And it's interesting, we have to think of this drug not as an end to itself but maybe as a pointer towards a new direction.

HAMILTON: That's one of the points I was really trying to make in my piece, is that nobody is saying this drug ketamine is the perfect drug for - to fight depression. But the hope is that something that is chemically very similar to it, that maybe doesn't have some of the bad side effects, could be that drug, and that that might not be too far off.

CONAN: And this of course, what, 30, 40 years ago Prozac came along, and everyone said hip, hip, hooray. And, well, we've learned in the years since Prozac has some limitations.

HAMILTON: Yeah, indeed, in the '70s, Prozac was invented. It came along, I think it was actually approved in this country until the '80s sometime. But it really was, you know, hailed as something - if you were to read all the press about it, you would think wow, we have solved the depression problem.

And of course, that turned out not to be the case, and one of the big problems, of course, with Prozac and the drugs like it is that they typically take a long time to work. It can be a month or more. And so if you're talking about somebody who has, say, got suicidal depression right now, a month can be a very, very long time to wait.

CONAN: And as you pointed out in your piece, I think yesterday, people with severe depression, if they go to the hospital concerned about their safety, that they may kill themselves, there's very little option except to, well, put them in isolation.

HAMILTON: There is no drug that you can give. If somebody has severe pain or something, there are drugs you can give them that give them the relief almost immediately. But when you get people who they think are going to hurt themselves or somebody else because of their depression, they may put them on drugs, but then what they actually have to do is make sure - essentially monitor them until they're feeling better.

CONAN: And that can take minimum days, as long as a month or more.

HAMILTON: It can take a long time until the drugs kick in. Fortunately, most people who are in this type of extreme depression will feel better on their own after a few days or with some counseling and other things, but it's not the drugs that's curing them.

CONAN: And it turns out Prozac and its ilk, they don't work for maybe 40 percent of the patients.

HAMILTON: With patients with major depression, that is true. There is a large segment of the population for whom they will not get much, if any, relief from these drugs. And so that tells us that there is really room for a new type of drug that not only works faster but reaches some of the people who don't respond to the existing drugs.

CONAN: And so then essentially, anecdotally, we stumbled across ketamine.

HAMILTON: Yeah, I've heard different versions of this, but this is a drug that goes back to the '60s and, in fact, as I understand it, was used for battlefield surgery in Vietnam and other places. And one of the things that doctors, clinicians started to hear occasionally were these sort of reports.

And the patient, they say, you know, yeah, it helped with my pain, but, you know, my depression seemed better. And so this was sort of a curiosity for a long time until a few years ago, when some folks at the National Institutes of Health decided that they really wanted to check this out.

And they did a study and found that of 17 people with depression who'd been on an average of I think six other drugs before this one, they gave them ketamine, and 12 of the 17 got much better...

CONAN: Much faster.

HAMILTON: Yeah, and it happened within hours, which is quite remarkable.

CONAN: So then you have to go and say well, clearly it's not the same mechanism as Prozac, it's nothing like that chemically. What is the mechanism that's working here?

HAMILTON: Well, if we go back to Prozac, and we go back to an era when the people used to talk about depression in terms of this chemical in the brain called serotonin, right. Everybody, oh, your serotonin is low, that's why you're depressed. And that turned out not to be the case, or it was not nearly that simple, that depression was simply a lack of serotonin.

And there are depression drugs that work on some other brain chemicals, dopamine for instance, and a chemical called norepinephrine. But the thing about ketamine that seems to be the key, is that it works in a totally different set of chemicals in the brain. It's something they call the glutamate system.

And glutamate is all over the brain and does lots of things, but ketamine seems to affect it in a way that has this remarkable effect on depression in a way that the other drugs just don't.

CONAN: We're told, in other words, and I'm quoting from your piece here, that anxiety and stress and depression rewrite your wiring in your brain. Somehow, ketamine seems to rewire it or allow the rewiring.

HAMILTON: Something like that, yeah. There's been a theory about depression for some years now that is I believe called the neurogenesis theory, neurogenesis meaning essentially the creation of new brain cells, and that what it - there was this thinking that what it took was you actually had to stimulate the production of new brain cells, and it may be that's even why drugs like Prozac, when they eventually did work, maybe that's what they were doing.

More recently, people have talked about not just the creation of new brain cells but the wiring between brain cells, the synapses, and the thinking now is that ketamine may work because it encourages brain cells to form new connections, connections that probably were lost when somebody was depressed or under stress.

And that's why you can get this really quick effect because the brain can form new connections very quickly.

CONAN: And not just ketamine as it turns out but maybe scopolamine, which people may have used for anti-nausea, for seasickness.

HAMILTON: Exactly - you never know where these things are going to come from. And in fact the scientist I was talking with at the NIH said she - and I have this in my story - she said a woman called her up and said, you know, I was out on a - sailing, or out on a boat, and they gave me this scopolamine stuff, and suddenly I noticed that my depression was getting better.

And again, you started to hear these anecdotal reports, and when they did a study it turned out to be true that scopolamine, which also by the way seems to affect the glutamate system in the brain, it seems to be also able to relieve depression.

CONAN: Well, we want to hear from doctors in our audience. What are your patients asking you about their options? 800-989-8255. Email us, talk@npr.org. We'll start with Scott(ph), and Scott's on the line with us from Kalamazoo.

SCOTT: Hi, how are you today?

CONAN: Good, thanks.

SCOTT: This is a really interesting conversation. I work at Parke-Davis, Pfizer, and I did research on mechanism of action of ketamine, PCP-related compound. My concern is - so you made several points. My concern is how, in the clinic, you deal with the psychotomimetic effect. How does it relate to ECT? And then how do you argue that by blocking glutamaturgic action, glutamate in the brain at those receptors, how does that then lead to neurogenesis and antidepressant effect?

CONAN: Well, Jon, I'm not going to put you on the spot. Gerard Sanacora is on the line with us, a professor of psychiatry at Yale University School of Medicine. He also directs the Yale Depression Research Program and joins us now from his office in New Haven. Nice to have you with us.

GERARD SANACORA: Nice to join you, Neal.

CONAN: And can you help us with Scott's question?

SANACORA: Yes, yes, I think I can. So it is one of the concerns, or one of the things that we have to deal with, is the fact that ketamine has what's called psychotomimetic effects, which are really effects where there's some changes in perception, seeing flashing lights, bright colors seem...

CONAN: Some of the things that make it popular as a club drug.

SANACORA: Some of the things that might make it popular as a drug of abuse. So that is some of the hurdles to developing it. Now, it's a relatively small price to pay if you do have these big effects, because remember, the main effect of ketamine - which is so important, I think, to get across is - the actual psychotomimetic-like effects are very short-lived when we give the drug. But the actual antidepressant effect lasts for days or possibly even weeks after a single dose.

So this is a short time period of having these adverse events or these adverse effects for the benefit of the depression that follows. Now that being said, I think there's a real strong impetus from the pharmaceutical industry and from academia, to try to figure out what's giving the benefit of ketamine and to minimize these psychotomimetic effects.

CONAN: It could also be addictive.

SANACORA: Exactly. I mean, it's a drug that - it's one of the major drugs of abuse. Even in Asia, it's a major drug of abuse. So there are real concerns about ketamine itself. That being said, ketamine is - besides being known as Special K and a street drug - is also a drug commonly used for pediatric anesthesia.

So, it's actually been given to thousands and thousands of people. So we know the safety profile overall with this, is not terrible for ketamine. In fact, it's a pretty safe drug. But it does have some baggage that we would clearly like to minimize to bring it to the clinic.

I think the second part - I don't know how much you want to get into the actual mechanism, because it gets quite complicated - but there are some really interesting studies coming out in the past year or two that really suggest that what the drug is doing - very much like Jon said - is actually increasing the neuroplasticity in the brain, increasing the number of new connections and synapses being formed in the brain.

CONAN: Scott, without getting too deep into the weeds, does that help you out?

SCOTT: That's really fascinating, especially since there's the opposite argument, that stimulating those neurons, those brain cells, increases synaptic activity.

SANACORA: So Scott, without getting too complicated, it actually looks like that probably is more what ketamine is doing. It looks like through ketamine's activity, blocking a specific glutamate receptor, VNMDA receptor, it's actually causing a release of glutamate and activation of other glutamate receptors like the AMPA receptor. So you're correct, it actually does look like it's through an increased stimulation, overall.

CONAN: Scott, thanks very much for the call, appreciate it.

SCOTT: Thank you, bye.

CONAN: Gerard Sanacora, stay with us, also Jon Hamilton. We're hoping to hear from more doctors today. What questions are patients asking you about their options for depression? Give us a call, 800-989-8255. Email us, talk@npr.org. More with Gerard Sanacora and NPR's Jon Hamilton in just a minute. Stay with us. I'm Neal Conan. It's the TALK OF THE NATION from NPR News.

(SOUNDBITE OF MUSIC)

CONAN: This is TALK OF THE NATION from NPR News. I'm Neal Conan. Recent research on ketamine, also known as Special K on the street, has encourage scientists to look for new ways to treat depression, and that's not the only non-traditional pharmaceutical under study these days.

At Imperial College London, scientists are looking at psilocybin, the active ingredient in magic mushrooms. Though it's long been assumed that a brain tripping on magic mushrooms is in overdrive, MRIs show they actually seem to calm brain activity. Some test subjects report long-lasting improvements in mood, in attitude, though some do experience bad trips on the drug. Scientists hope to study it further.

With ketamine and seasickness drugs also in the news, we want to hear from doctors today: What questions are patients asking you about their options? 800-989-8255. Email us, talk@npr.org. You can also join the conversation on our website. That's at npr.org. Click on TALK OF THE NATION.

Our guests are NPR's Jon Hamilton and Gerard Sanacora, director of the Yale Depression Research Program. And getting back to you, Gerard Sanacora, with any of these, it's important to point out that these are just being tested. Nobody should take these on their own.

SANACORA: Oh clearly these are in what we would consider very early phases of development. Like I said, ketamine is a drug that has been used clinically for many years. So in the right setting, usually in an anesthesia setting or in an emergency room setting, ketamine is quite safe to be used but clearly not what should be used by people out in the street in any way for a treatment.

CONAN: Jon, go ahead.

HAMILTON: I had a question for Dr. Sanacora. I know that you've done some work with a drug we haven't mentioned yet. We've mentioned scopolamine and ketamine, but I believe you've also done some work with Riluzole. And could you talk a little bit about what you know about it?

SANACORA: Sure, that's correct. So Riluzole or Rilutek is a drug that's currently approved by the U.S. Food and Drug Administration for the treatment of amyotrophic lateral sclerosis, or Lou Gehrig's syndrome, and it's another drug that acts primarily on the glutamaturgic system.

So it works a little bit different than ketamine, which is thought to block a specific type of glutamate receptor, but Riluzole seems to modulate the amount of glutamate that's released and also how rapidly it's cleared from the synapse and how long that message is delivered from glutamate.

So it's a drug that's extremely interesting, since it's been shown to be neuroprotective, actually to be able to protect neurons and brain cells against all different types of traumatic events and stressors. And it's thought to believe that - it's believed that that's part of the mechanism, how it works in Lou Gehrig's syndrome.

We became very interested in it because it had a lot of the - what we thought was the positive signs, what we'd be looking for in changing neuroplasticity in the brain and having some neuroprotective properties. So it's been used in many what we call open-label studies, meaning that there isn't a placebo comparator, and in these studies, it has looked very promising, but right now we're just doing the real sort of gold-standard, double-blind, placebo-control study to see if it is, in fact, effective.

In rodent models, it looks very effective.

CONAN: And Jon, we have to point out that the studies that you've been reporting on involved severe depression, people going to the hospital and needing hopefully immediate relief. And there are different kinds of depression.

HAMILTON: There are, yes, and obviously Dr. Sanacora could talk about this with more authority than I. But just to state it simply, there is major depression, severe, major depression, and we're talking, you know, the kind of people who have been in these studies are people at one end of the spectrum who have depression so severe that either they're suicidal, or they've tried all these different drugs and haven't been able to get relief.

We're not talking about somebody who just has been feeling down for the past couple of months.

SANACORA: That's correct, Neal. These - all of the studies that I'm aware of with ketamine or even some of these other glutamaturgic drugs have been performed in populations of patients that are not only severely suffering from depression but also what we call treatment resistant, where they've tried at least two or three different types of the standard antidepressants without having much benefit. And that's when they've progressed on to these studies.

CONAN: Let's get another caller in. This is David, David with us from Lawrence, Kansas.

DAVID: Yeah, no, I was really intrigued by the discussion. I'd been traveling through Asia with some friends, and we had come across ketamine, and some people were using it, and this was completely recreational. And I had been put on Zoloft and Effexor and a few different types of antidepressants growing up, but nothing ever really took.

And we were trying the ketamine, and it was maybe four or five days later, I was eating lunch with one of my friends, and I said: I've never felt happier than I do right now. And I don't know why. And I just, I couldn't - I said, you know, in my whole life, I've never been happier than I have at this moment.

And I started thinking, well, what have I done different in the last few days? And I Wikipedia-ed ketamine, and it said many people report being happier in the days and weeks after they try this drug. And I thought this is absolutely the reason why I feel so happy right now.

CONAN: And this was when you tried it recreationally. Have you sought to get it from a doctor since you returned to the States?

DAVID: I was so happy to find out people are finally testing this because it - having tried other antidepressants in the past, you know, the reason I didn't enjoy - I just wasn't happy using them were all the side effects, and they almost capped my ability to be really happy in certain situations. Kind of, there were no high highs and no low lows. But with the ketamine, it was just, there was no anxiety. You know, you were just in a positive mood. It was really remarkable.

CONAN: Jon?

HAMILTON: And David, I should mention that in my reporting, I did talk to people who, as you did, took ketamine without a doctor's supervision or prescription and for a variety of different reasons. In fact, there are some people who have read about the effects of ketamine and have found ways to get it, including getting chemical cousins of it that may be - that are sort of on the verge of being legal, things you can order on the Internet.

I am not recommending that anybody do that, but it is interesting that that is already happening.

DAVID: Yeah, no, I could completely see it because my depression is probably mild most of the time and then severe some of the time, but it just was remarkable how I just - and it wasn't like there was a placebo effect because I didn't feel like I was doing anything differently during my days. But I really had to sit down and think about what I had done differently that week and why I was so happy. Because I hadn't - you know, I'd just quit my job. I had a million reasons not to be really happy, and I was, and it was unbelievable.

CONAN: David, thanks very much.

DAVID: Thank you.

CONAN: And Gerard Sanacora, that - his experience, again, this is not something anybody should recommend to do.

SANACORA: Well, that's what I would really like to emphasize. I mean, this is actually - I mean, this is an anesthetic drug. I mean, this is what's used for anesthesia in operating rooms around the country, and there's a long history of evidence that ketamine at higher doses and for prolonged periods of time actually can cause significant brain damage or injury.

So this is - you know, this is really not something that should be tried outside of a study. Now, the good news is there are studies around the country that are currently running clinical trials both with ketamine and even newer versions of this drug that are being developed. So there are - there is the availability of getting into these studies to get it for treatment of depression.

But I would really caution not to use this drug outside of, you know, a supervised treatment.

CONAN: Let's go next to Shakar(ph), Shakar with us from Monroe in North Carolina.

SHAKAR: Yes, I was calling - I'm a family physician here in North Carolina, and of course, like most family doctors, we end up seeing and treating a lot of mental health problems in the absence of, you know, adequate psychiatric care in most communities.

But I do often see questions not specifically regarding ketamine as of yet, but I do see questions about the potential use of stimulants, those that would normally be used for conditions like ADHD, as an adjunct to a person's antidepressant regimen. And I think a lot of that comes from just people's experience when they're on multiple medicines and seeing the changes in mood that they either perceive to be positive or negative, you know, associated with the stimulants.

And I think one of the concerns I have is of course these are a majority of the time off-label uses of stimulants, and although a drug may have some mood-altering benefits or mood-elevating benefits, and so there's a perceived effect that this is improving the depression, it's not actually causing the same type of neurochemical changes that a true antidepressant would, or that other forms of nonpharmacologic therapy can offer, such as cognitive behavioral psychotherapy, which interestingly, now we have, you know, actual evidence such as functional MRI and PET scanning that even those forms of nonpharmacologic therapy actually produce some of the same neurochemical changes in brain metabolism and function that we see in people who are on FDA-approved drugs for depression.

CONAN: And, Shakar, are you talking about people asking about Adderall and that sort of thing?

SHAKAR: Yes.

CONAN: Yeah. I was going to ask, Gerard Sanacora, does not that speak to the actual - to real need for this - for something new, something that can, well, A, act more quickly, and B, address a lot of those people who aren't really helped by the Prozac and its type?

SANACORA: Yes. I think, you know, one of the large National Institutes of Health-funded studies, the STAR D study, was really meant to look at the real-world usefulness of these medications. And I think one of - the real take-home message from that study and other recent ones is that our drugs are actually fairly effective for a significant amount of people. About, you know, one-third to 40 percent of the people gain, you know, a significant benefit, almost a complete remission. And then there's another group of people that have a large benefit, probably about a 50-percent reduction in their symptoms.

So the medicines that are available are good, but it leaves a lot to be desired in terms of the fact that there's probably about a third of the people to a quarter of the people that really gain little benefit. And then there's probably another, you know, large percent of the patients that don't achieve a full remission. And as you said, the other major problem is the time of onset. Most of these drugs, the larger effects are seen after a month of continuously taking the medicine, where, you know, for that month is actually quite a difficult period where - in fact, some of the medicines might even make the people a little bit more restless and anxious during that time.

CONAN: Gerard Sanacora is professor of psychiatry at Yale University, director of the Yale Depression Research Program. He joined us from his office in New Haven. Also with us is Jon Hamilton, NPR correspondent who's been reporting this week on MORNING EDITION about new research on new kinds of drugs to treat severe depression. You're listening to TALK OF THE NATION, from NPR News. And this email from Robert: It's amazing that you would have a show about treating depression and not take even a minute to emphasize exercise and proper diet plus skilled therapy - well, we just mentioned that - as the most effective treatment for many sufferers.

The drugs get so much attention, despite all their side effects and failure for so many, because of the power of the drug companies' public relations. Would you please at least briefly give these points attention on the air? And again, Jon, we were talking about severe depression, but, Gerard Sanacora, yes, exercise, diet, all that's important.

SANACORA: Oh. I'm glad that we have a chance to talk about it. I mean, most studies would suggest that treatments such as cognitive behavioral therapy are equally effective to medications, especially for the mild-to-moderate depression; in fact, might even have a better long-term outcome. Unfortunately, it's not so easy always to get people to commit the time effort to do that. But clearly, for mild-to-moderate depression, treatments like cognitive behavioral therapy, even exercise alone - and I think as your previous speaker mentioned - actually does seem to have many of the same effects on brain plasticity and brain chemistry as we do see with the medications itself.

CONAN: Let's go next to Matt, and Matt's on the line from Columbus.

MATT: Hi. I'm a medical student and a future emergency physician. And with my somewhat limited experience, but - with patients with depression, I see patients with very acute depression that have thoughts of suicide or harming themselves. And the basic standard for what these patients get, they get admitted to the hospital. But sometimes, if the psychiatry floors are full, it could take days for them to be admitted. And if ketamine is a viable option to treat these patients quickly and effectively, I think it would open up psychiatry beds for people with other afflictions that need help.

It would free up emergency room beds for other patients that, you know, with heart disease or who have, you know, infections, things like that. And that's just one example. What other implications would this have in medicine if we could just - if we could treat depression quickly and effectively like this?

CONAN: Jon?

HAMILTON: Well, I can tell you what the physicians I spoke to and psychiatrists I spoke to in Houston - the first story I did was based at Ben Taub Hospital, which has a 24-hour psychiatric emergency center, which faces exactly the kind of problem you're talking about all the time. They don't have a lot of space. They're often full up. Sometimes, the patients spend probably longer than they wish they would in settings that are not ideal. And certainly, they say it would transform the field of - certainly of this type of emergency care, where if there was something you could give - it's not going to solve everybody's problem. But if there was something you could give to break people out of that severe, severe depressive state, they think it would change everything. And a lot of people would not have to be in, you know, essentially locked up during the period where they think they are a danger to themselves or others.

CONAN: And let me follow up with this email from Gail(ph).

SANACORA: Well, can I actually add - so there has been one study, actually, already published that was performed here at Yale University, looking at the ability to use ketamine in the emergency room for these acutely depressed patients - again, a very preliminary study. But it did appear that ketamine had a very rapid and large effect on these patients' suicidal thinking. So I think there is a real potential for use of this type of treatment, whether it's ketamine or some other agent, in that setting.

CONAN: And we just have a few seconds left, if I could sum up Gail's question: How soon?

SANACORA: Well, there are clinical trials under way with novel agents. There's a drug called AZD6765. There's another drug, CP-101606, that are - have been in clinical trials or are in clinical trials. And I encourage people, if they're looking to get this type of treatment, you can actually - there's a site run by the National Institutes of Health called ClinicalTrials.gov, www.clinicaltrials.gov, that you can actually look and see what studies are going on in hospitals or university settings near you and get into these treatments.

CONAN: Gerard Sanacora, thank you very much for your time today. Appreciate it.

SANACORA: You're welcome. Thank you, Neal.

CONAN: Matt, we'll let you go. Thanks very much for your call. And also our thanks to Jon Hamilton, NPR correspondent. You can go to npr.org and listen to the reports he filed earlier this week, yesterday and today, on MORNING EDITION. Jon, thanks very much.

HAMILTON: My pleasure.

CONAN: Coming up, we're going to be talking about - well, it's the last day of January. Danny Heitman's got a last-minute New Year's resolution for those of you who should probably be working on procrastination. He joins us after a quick break. Stay with us. I'm Neal Conan. It's the TALK OF THE NATION, from NPR News.

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