Multiple Sclerosis Discovery -- Episode 82 with Dr. Adam Kaplin

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Host – Dan Keller

Hello, and welcome to Episode Eight-two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

Depression affects as many as 50 percent of people with MS during their lifetimes. But according to Dr. Adam Kaplin, a psychiatrist in the Johns Hopkins MS Center in Baltimore, it is treatable to a large extent, and with good results. Dr. Kaplin studies the immune basis of depression and cognitive impairment, specifically in MS and central nervous system-related autoimmune diseases. We met in Baltimore.

Interviewer – Dan Keller

Let’s talk about depression in multiple sclerosis. Is it a reaction to someone having a chronic disease, or is there something more going on because of the disease?

Interviewee – Adam Kaplin

It’s a great question, and what I will tell you is one of my patients says to me that you’re either stressed, or you’re dead. We all have stress going on, and it’s always possible to look at something in our life and say, ah, that’s what caused the trouble. But we know now, in multiple sclerosis, the depression is due primarily and dramatically significantly to the inflammation going on in the brain that causes all of the symptoms that you see in MS, such as cognitive impairment, or weakness/numbness/tingling, autonomic nervous system dysfunction; all of those are effects of the MS on the CNS.

And in the case of depression, it is similar. It’s not a character flaw. It’s not a personal weakness. And just to, you know, clarify, one of the best pieces of evidence we have for that is, number 1, that people who are depressed with MS, it does not correlate with their EDSS scores. It doesn’t correlate with their level of disabilities. So if it was you know, gee, it’s just a matter of stress, then those people who are in wheel chairs or on ventilators should be depressed, and those people who are upright and walking around shouldn’t. But in fact, I think the key element is that this is one of the, as they often say, silent symptoms of MS. It occurs to 50% of patients across their lifetime. And it is important you know for people to understand that this is not something that people aren’t rising to the occasion, or those kinds of things.

MSDF

Is depression accompanying MS more prevalent than in the general population, and how serious is it?

Dr. Kaplin

You know people often ask why, as a neuropsychiatrist, why study MS? And I say, you know, why did Willie Sutton rob banks? That’s where the money is. MS has the highest rate of clinical depression of any medical neurological or surgical disease. Again, 50% of people, following the diagnosis of MS, will have a clinical depression. We can talk about what that is. And it turns out that that’s in any clinic you go into – neurology clinic – that’s one in four patients. If you go out to the waiting room, one in four patients will be suffering from a clinical depression.

MSDF

How serious a problem is it? What aspects of life does it affect? Does it affect everything, and how serious is it?

Dr. Kaplin

I think what is often misunderstood about the depression in MS is, I would argue, that it has the highest morbidity and mortality of any of the symptoms of MS, in the sense that it is the third leading cause of death in the largest study that looked at, across the lifespan, what causes death in people with MS, [found] a study out of Canada, where it’s more prevalent because of the higher elevation and the lower vitamin D levels, probably. And it is absolutely the case that seven-and-a-half times the rate – the suicide rate in MS – to the general population. And in fact, in the studies that were done, 30% of people with multiple sclerosis will have thoughts of suicide at some point during their life. Ten percent – fully 10% will attempt suicide. And that lethality is profound.

But if it doesn’t kill you, it is important to understand that it has significant, significant morbidity associated with it. Just to begin with, the number one correlate of quality of life of patients—more important than their pain, or more important than their cognitive impairment, or weakness, or other symptoms—the number one correlate of the quality of life of the patient is their depression or whether they are depressed or not. And it’s similarly the number one quality of life of the care givers—not whether they have to push them around in a wheelchair, it is whether their loved one is suffering from a clinical depression. So it has significant morbidity and mortality associated with it.

MSDF

Are there aspects of serious depression in MS that are very characteristic? Any different from other severe depression? Or can it be recognized in the same way with the same diagnostic criteria?

Dr. Kaplin

There actually are some specifics to MS, although that hasn’t been well-published. I can be clear about things that are well-supported by the literature, and then those that are my clinical experiences. What I can tell you is that the way we diagnose depression in MS is the same way we diagnose depression in people without MS, which is you have to have 5 of 9 symptoms greater than two weeks, one of which must be either decreased mood or decreased interest. And we remember it by SIG-EM-CAPS, the nine symptoms. Trouble with sleep, where people are often having early morning awakenings or hypersomnia where they just sleep all day. Loss of interest, people’s get up and go has gotten up and gone. Feelings of guilt or worthlessness – and that’s a big problem, because patients who are depressed as a result of that often won’t seek help. You have to ask about it. They won’t volunteer it. And loss of energy or fatigue; low mood – that’s the sadness part; concentration problem; appetite changes, either increased or decreased weight; and psychomotor retardation, they’re not their normal bubbly self; and thoughts of death or suicide.

With MS, what I will tell you, I find that patients with MS often, rather than sadness, have very frequently irritability. That tends to be more common. And sleep is usually decreased, not increased, so I see very frequently increased early morning awakening and those kinds of things. One pearl, though, to keep in mind is – or two pearls – if you’re trying to make the diagnosis of depression in somebody with MS, the first thing to do, because there are overlapped symptoms like fatigue, like concentration problems between depression and MS, so there is frequently, in up to 80% of people, will have diurnal variations in their moods; so usually worst in the morning and better at night. Sometimes it’s reversed, but you know that person has the same life circumstance, the same disease circumstance in the evening that they did in the morning, but their mood has changed dramatically, often, with MS with these cyclical changes. And that’s a good indication that it’s not demoralization; it’s depression.

The other thing is ask the loved one. Get an outside informant, because nobody gets the brunt of it quite like the family. And they know that person, and if the family member says the one thing I hear so often, this is not the person I married, then you’re pretty much on the right track if you’re thinking about depression.

MSDF

How amenable to treatment is depression in MS?

Dr. Kaplin

I think that that is probably one of the key aspects is to understand that it is very treatable. So my expectation when patients come to me and I diagnose them with depression is that I will get them a hundred percent well with respect to those SIG-EM-CAPS symptoms, back to their baseline. And it’s very hard to get patients a hundred percent well from their gait problems; a hundred percent well from their cognitive problems. And, again, what I tell people is, look, I can’t tell you whether your cognitive impairment is due to the depression or due to the MS, or maybe it’s 10% depression/90% MS or 90% depression/10% MS. But I can promise you this: treating the depression, the depression is much more amenable to treatment. We don’t have good treatments for cognitive impairment in MS to reverse the cognitive impairment, but boy, we can reverse it if it’s a symptom of depression. What’s really exciting now is that we are now understanding more and more that many of the treatments you use for depression end up being good nerve tonics.

So, there was a double-blind placebo-controlled study of fluoxetine demonstrating that, in patients who weren’t depressed with MS, they had fewer gadolinium-enhancing lesions over 24 weeks. And then there was the FLAME study in a related kind of way looking at fluoxetine as a way of significantly enhancing the recovery of hemiplegic stroke patients. So it turns out that I wasn’t so misguided in thinking that studying the immune basis of depression would be important, because as it turns out, our treatments actually do have an effect on the nervous system and the immune system for general types of depression as well.

MSDF

That sort of covers the SSRI class. What about tricyclic antidepressants? What about SNRIs? Do those fit in?

Dr. Kaplin

Yes, so absolutely. So the topic of how to choose and select the right treatment for patients with MS is … we could spend an hour and just sort of get only the highlights done there. But generally there’re sort of two strategies. One is to use a medication that has the fewest side effects, so that you won’t have drug-drug interactions with the patient if they’re on a numerous medicines for other concerns—their other symptoms and syndromes—that the antidepressant won’t interfere with it. And so along those lines, escitalopram and sertraline have the fewest drug-drug interactions. You essentially don’t need to look up drug-drug interactions if your patient is on one of those two medicines.

The other approach is to say let’s choose a medicine that will have favorability with respect to the side effects, will be beneficial for the problems that the patient has. So a classic example is duloxetine is FDA-approved, not just for depression, not just for anxiety, but also for neuropathic and musculoskeletal pain. So here you’re talking about one treatment that will help you with the fact that your patient, their depression will get better; their neuropathic pain will get better if they have migraines—which are often a comorbidity—that will also benefit the neuropathic pain from that as well. And you know you will get two birds with one stone, as it were.

And then the tricyclics, as you had asked about, we’ve had a lot of experience with them. They also will benefit in terms of the urinary incontinence problem. They are strongly anticholinergic, and so you can also benefit in terms of preventing the urinary/bowel problems. So really Cymbalta as just sort of son-of-tricyclics, has some fewer side effects, but doesn’t, therefore, cover some of the things that the tricyclics will.

MSDF

As you alluded to earlier, the depression in MS may largely be a result of immune processes going on—inflammation, cytokines, things like that. So how well do the disease-modifying therapies of MS attack the depression?

Dr. Kaplin

You know you mentioned cytokines. So that is another way that we know that this is due to the inflammation—the depression in MS—and not just other things, because for instance, interferon-alpha used to treat patients with hepatitis C will cause depression in upwards of 20 to 25% of people who take it, not when they first start it, but within you know a week to two weeks after starting it, you know, then up to eight weeks. So that’s just one cytokine, and in MS, all of the cytokines get activated. And similarly, interferon-beta that’s used, or Copaxone, you know, the ABCR drugs that we’ve used to try to—you know, with great effect since 1993—to slow the exacerbations down in MS; they don’t stop the inflammation, they just alter it. And so not surprisingly, they do not have antidepressant properties.

But when you look at something like Tysabri, we actually have not published this yet. We did present it at a MS conference but working in collaboration with Biogen. We are going to publish shortly data that shows that, in a double-blind placebo-controlled study of adding natalizumab to Avonex, or adding placebo to Avonex, those patients who were depressed to begin with show a dramatic and statistically significantly decrease in their depression as a result of the natalizumab. So natalizumab is actually quite a good antidepressant—we have data for it—because that really does shut the inflammation down in the brain, and since that’s causing the depression in MS, that’s what benefits them.

MSDF

Just to clarify, natalizumab is a good antidepressant in MS.

Dr. Kaplin

Exactly right. That’s exactly right. Although, you know, it’s good that you clarified that. What’s interesting is that now that people are beginning to appreciate the role of the immune system in idiopathic depression, people are beginning to say, hmm, maybe we should be looking at these anti-inflammatories and seeing if the anti-inflammatories benefit patients with depression. Now, nobody has tried natalizumab, but TNF-alpha inhibitors have actually been tried. There was a study out of Emory looking at using TNF-alpha inhibitors for refractory depression. And I think coming down the road there will be more and more studies that begin to show the role of anti-inflammatories for not all, but some people with refractory depression.

MSDF

Yes, I’ve seen some studies on anti-inflammatories—traditional ones, NSAIDS sort of things—presented a German study at a neurology conference. Didn’t do too much.

Dr. Kaplin

Yes. What I can tell you is that not all NSAIDs are created equal. Celecoxib actually now has five studies that are placebo-controlled that have shown its benefit for depression or bipolar disorder. And so when added to antidepressant by itself: No. But when added to fluoxetine or—I can’t remember what other; it might have been sertraline—it clearly had a statistically significant improvement in the depression response, celecoxib. But not all NSAIDs are created the same.

MSDF

What about non-drug therapies, cognitive behavioral therapy, even just physical activity? And, if someone’s depressed, isn’t it hard to get them up and do physical activity?

Dr. Kaplin

Well, I’m so glad brought that up, because I’d be remiss to forget that. So all of the data says, look, therapies like cognitive behavioral therapy are effective for mild and moderate depression. Antidepressants are effective as well. The data shows that the antidepressants work quicker, but that the combination of antidepressants and psychotherapy is much better than either one alone. So that’s a crucial issue. And to make sense of what has happened—and often when people are depressed, they’ve been depressed, and that’s caused damage to their professional life and personal life, and having someone help them sort of, depending how long the depression’s been going on, sort of talk them through, coach them through, how to get back up and going.

However, in severe depression, you can talk till the cows come home. If your patient is so depressed that basically they have this tunnel vision, and all of the options that are in front of them, the kind of mental flexibility that you need for CBT to work, for instance, it will not work if you patient is really severely depressed. You have to get them started with the antidepressant, which really then serves as a catalyst for the psychotherapy to kick in. And then the aspect of exercise, you can’t really pick a topic related to MS where the answer isn’t exercise. Cognitive impairment, absolutely exercise is beneficial.

Depression, exercise is beneficial. It stimulates growth hormones that have positive neurological effects on the CNS, as well as on the peripheral nervous system and body.

What I tell people, again, is that if your patient is severely depressed, they’re not going just go back out and start running. So you’ve got to begin to have a plan where you say, look, we’re going to begin this medicine. As you start to be able to have the ability to you know maybe push yourself more than you might usually and just sort of walk down the block, and then you know walk for a mile and then start jogging for a mile and sort of build up to it, that’s very beneficial.

MSDF

Are there barriers to recognizing and/or treating depression both on the patient’s side and on the physician’s side?

Dr. Kaplin

The big barrier on the physician’s side is, you know, don’t ask, don’t tell. So if you don’t think of depression, or worse, if the neurologist says, well, I went into neurology not psychiatry, you know, this whole depression thing, that’s not my bailiwick, that’s not my responsibility, you’re missing the fact that this is —first of all, this is very rewarding. There’s nothing else that you could treat that gets a patient from being non-functional, sitting at home, not taking care of the family, not working, in a bed to fully functional, taking care of the family, back at work, like treating the depression can. But also it is. It affects all aspects. It affects the patient’s compliance with all your other medicines. It affects their ability to exercise, etc., etc. So, you know, you’ve got to think of it.

And then you have to know something about treating it. One of the big problems with neurologists when they treat depression is that they don’t appreciate the fact that the goal is to get that patient a hundred percent well, because you sort of have this sigma curve where, if you get them 50% well, they’re still in that sort of steep portion of the curve where something comes along—an MS attack or you even a viral infection—and they will slip right down that curve. Whereas, if you can push them way out into the hundred percent well, that’s great. Now you can’t always do it with one medicine. You take the dose as high as the patient can tolerate, where the side effects don’t become worse than the depression you’re trying to treat. But then you might need to add another medicine, an augmenting agent or something, so you’ve got to make sure you recognize it and treat it.

And then, what I always tell my colleagues—and my colleagues at Hopkins are wonderful; they do appreciate you know you’re treating the whole patient, not just you know their reflex arcs and that kind of stuff—and what they are very good at is, if the patient is depressed and suicidal, that is the psychiatric equivalent of a heart attack. So then they will get in touch with me and we’ll work together. So if you’ve got someone who’s suicidal, you really want to get in touch. Unless you have the utmost experience and confidence in treating the worst cases of depression, you probably want to get a psychiatrist involved, or mental health professional involved, to help coordinate the care for someone like them.

MSDF

Very good! I appreciate it.

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MSDF

Thank you for listening to Episode Eighty-two of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

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For Multiple Sclerosis Discovery, I'm Dan Keller.