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Published: May 17, 2016, 5:07 p.m.

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Host \u2013 Dan Keller

Hello, and welcome to Episode Eight-two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I\u2019m 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 \u2013 Dan Keller

Let\u2019s 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 \u2013 Adam Kaplin

It\u2019s a great question, and what I will tell you is one of my patients says to me that you\u2019re either stressed, or you\u2019re dead. We all have stress going on, and it\u2019s always possible to look at something in our life and say, ah, that\u2019s 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\u2019s not a character flaw. It\u2019s 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\u2019t correlate with their level of disabilities. So if it was you know, gee, it\u2019s 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\u2019t. 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\u2019t 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\u2019s 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\u2019s in any clinic you go into \u2013 neurology clinic \u2013 that\u2019s 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\u2019s 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 \u2013 the suicide rate in MS \u2013 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 \u2013 fully 10% will attempt suicide. And that lethality is profound.

But if it doesn\u2019t 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\u2014more important than their pain, or more important than their cognitive impairment, or weakness, or other symptoms\u2014the number one correlate of the quality of life of the patient is their depression or whether they are depressed or not. And it\u2019s similarly the number one quality of life of the care givers\u2014not 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\u2019t 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\u2019s get up and go has gotten up and gone. Feelings of guilt or worthlessness \u2013 and that\u2019s a big problem, because patients who are depressed as a result of that often won\u2019t seek help. You have to ask about it. They won\u2019t volunteer it. And loss of energy or fatigue; low mood \u2013 that\u2019s the sadness part; concentration problem; appetite changes, either increased or decreased weight; and psychomotor retardation, they\u2019re 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 \u2013 or two pearls \u2013 if you\u2019re 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\u2019s 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\u2019s a good indication that it\u2019s not demoralization; it\u2019s 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\u2019re pretty much on the right track if you\u2019re 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\u2019s 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\u2019t tell you whether your cognitive impairment is due to the depression or due to the MS, or maybe it\u2019s 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\u2019t have good treatments for cognitive impairment in MS to reverse the cognitive impairment, but boy, we can reverse it if it\u2019s a symptom of depression. What\u2019s 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\u2019t 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\u2019t 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 \u2026 we could spend an hour and just sort of get only the highlights done there. But generally there\u2019re sort of two strategies. One is to use a medication that has the fewest side effects, so that you won\u2019t have drug-drug interactions with the patient if they\u2019re on a numerous medicines for other concerns\u2014their other symptoms and syndromes\u2014that the antidepressant won\u2019t interfere with it. And so along those lines, escitalopram and sertraline have the fewest drug-drug interactions. You essentially don\u2019t need to look up drug-drug interactions if your patient is on one of those two medicines.

The other approach is to say let\u2019s 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\u2019re 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\u2014which are often a comorbidity\u2014that 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\u2019ve 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\u2019t, 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\u2014inflammation, 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\u2014the depression in MS\u2014and 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\u2019s just one cytokine, and in MS, all of the cytokines get activated. And similarly, interferon-beta that\u2019s used, or Copaxone, you know, the ABCR drugs that we\u2019ve used to try to\u2014you know, with great effect since 1993\u2014to slow the exacerbations down in MS; they don\u2019t 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\u2014we have data for it\u2014because that really does shut the inflammation down in the brain, and since that\u2019s causing the depression in MS, that\u2019s what benefits them.

MSDF

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

Dr. Kaplin

Exactly right. That\u2019s exactly right. Although, you know, it\u2019s good that you clarified that. What\u2019s 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\u2019ve seen some studies on anti-inflammatories\u2014traditional ones, NSAIDS sort of things\u2014presented a German study at a neurology conference. Didn\u2019t 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\u2014I can\u2019t remember what other; it might have been sertraline\u2014it 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\u2019s depressed, isn\u2019t it hard to get them up and do physical activity?

Dr. Kaplin

Well, I\u2019m so glad brought that up, because I\u2019d 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\u2019s a crucial issue. And to make sense of what has happened\u2014and often when people are depressed, they\u2019ve been depressed, and that\u2019s caused damage to their professional life and personal life, and having someone help them sort of, depending how long the depression\u2019s 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\u2019t really pick a topic related to MS where the answer isn\u2019t 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\u2019re not going just go back out and start running. So you\u2019ve got to begin to have a plan where you say, look, we\u2019re 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\u2019s very beneficial.

MSDF

Are there barriers to recognizing and/or treating depression both on the patient\u2019s side and on the physician\u2019s side?

Dr. Kaplin

The big barrier on the physician\u2019s side is, you know, don\u2019t ask, don\u2019t tell. So if you don\u2019t think of depression, or worse, if the neurologist says, well, I went into neurology not psychiatry, you know, this whole depression thing, that\u2019s not my bailiwick, that\u2019s not my responsibility, you\u2019re missing the fact that this is \u2014first of all, this is very rewarding. There\u2019s 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\u2019s compliance with all your other medicines. It affects their ability to exercise, etc., etc. So, you know, you\u2019ve 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\u2019t 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\u2019re still in that sort of steep portion of the curve where something comes along\u2014an MS attack or you even a viral infection\u2014and they will slip right down that curve. Whereas, if you can push them way out into the hundred percent well, that\u2019s great. Now you can\u2019t always do it with one medicine. You take the dose as high as the patient can tolerate, where the side effects don\u2019t become worse than the depression you\u2019re trying to treat. But then you might need to add another medicine, an augmenting agent or something, so you\u2019ve got to make sure you recognize it and treat it.

And then, what I always tell my colleagues\u2014and my colleagues at Hopkins are wonderful; they do appreciate you know you\u2019re treating the whole patient, not just you know their reflex arcs and that kind of stuff\u2014and 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\u2019ll work together. So if you\u2019ve got someone who\u2019s 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\u2019s 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.