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Modern Psychiatry Offers New Hope for Depression

• Dr. Michael Koren, Dr. Heather Luing • Episode 336

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Triple-board certified psychologist Dr. Heather Luing joins Dr. Erich Schramm to talk about depression. Major depressive disorder affects one in five Americans and ranks among the most disabling conditions worldwide. In spite of this, treatments for depression can be unsatisfying or ineffective for up to 1/3 of patients. The doctors discuss the symptoms, treatments, and biological underpinnings of depression. They move to advances in medications and devices and the possibilities that clinical trials hold for the not-too-distant future, including non-medical solutions like Transcranial Magnetic Stimulation and Vagus Nerve Stimulation for medication-resistant patients.

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Announcer:

Welcome to MedEvidence!, where we help you navigate the truth behind medical research with unbiased, evidence-proven facts Hosted by cardiologist and top medical researcher, Dr Michael Koren.

Dr. Erich Schramm:

Hello and welcome back to the MedEvidence podcast. I'm your host, Dr. Erich Schramm, sitting in for Dr. Michael Koren today. For those who don't know me, I'm a board-certified family physician and long-term clinical research investigator with the ENCORE Clinical Research Group and I'm very excited to be here with my guest, Dr. Heather Luing. Dr. Luing is an excellent clinical psychiatrist and I've had the pleasure to get to know Dr. Luing over the last two years. We share a clinical space and also an interest in clinical research, so welcome to the MedEvidence! podcast, Dr. Luing.

Dr. Heather Luing:

Thank you, Dr. Schramm. It's so exciting to be here today.

Dr. Erich Schramm:

Well, thank you, and we've got a very interesting topic to discuss major depressive disorder. But before we do the deep dive into that, perhaps you could tell us a little bit about your background, tell us, kind of where you grew up and how you ended up getting interested in psychiatry and specifically interventional psychiatry that you practice.

Dr. Heather Luing:

Okay, well, that's a big question. I'm a native Floridian, so I grew up in South Florida and studied microbiology as my undergraduate degree and then moved up to University of Florida and I did my medical training there so medical school residency and a fellowship in forensic psychiatry so I'm now triple board certified in general and forensic psychiatry as well as addiction medicine, and I've done a lot of different things in my career. So I started in community mental health and worked there for quite a while, did a little bit of time working as a medical director at a substance abuse treatment facility, and then I've done a lot of inpatient hospital work and in 2017, I started my private practice.

Dr. Erich Schramm:

Wow, that's very impressive. Going back to your training, tell me a little bit about you. Had a fellowship in forensic psychiatry. Okay, exactly what is that and what got you interested in that?

Dr. Heather Luing:

Forensic psychiatry is a subspecialty of psychiatry, so it really focuses on the areas where psychiatry and the law intersect, and there's quite a few of those when you think about it. There's criminal-type work, when people are being evaluated for sanity, and then there's a lot of questions that come up in civil cases that involve psychiatry. So a lot of it is acting as a consultant and really an educator to help people understand about psychiatry and mental wellness and health.

Dr. Erich Schramm:

Right, and that's still an important part of your practice today.

Dr. Heather Luing:

It's a percentage of the work that I do. I do enjoy speaking and consulting and educating, and I spend a lot of time still with patients as well. So I do a little bit of everything.

Dr. Erich Schramm:

Oh, that's terrific. And talking a little bit about your background, you actually were involved in teaching residents at one time in the course of your training and your work at University of Florida.

Dr. Heather Luing:

Yeah, teaching has always been important to me. Right now, I work with psychiatry residents from the HCA Orange Park program, so I always have a third-year resident who rotates through my clinic, which has been a lot of fun. It keeps you on your toes.

Dr. Erich Schramm:

Right and full disclosure. When I do have opportunities to be in the office with you, I'm never against coming to pick your brain on particular patients or a condition, so I think I often see you in that kind of teaching and support role, so that's really fantastic.

Dr. Heather Luing:

Well, I think medicine is a team sport, right? So it takes a lot of members of the team to make things work.

Dr. Erich Schramm:

Wow. Well, so today we have a really interesting discussion on major depressive disorder. My background in family medicine sees a lot of depression, so you know, we can talk a little bit, maybe a little about epidemiology, if you could work us through a little bit of major depressive disorder 101.

Dr. Heather Luing:

Yeah, yeah. I think it's so interesting in the US that really the majority of depression is treated by primary care, so definitely the important front lines and for a lot of patients, the only doctor or practitioner that they're going to see for their depression journey. So it's a kind of a rare patient that actually gets to us as psychiatrists. Depression in general is such an interesting condition, I think partly because it's so common. So one in five Americans are going to deal with a major depressive disorder at some point in their life, which, if you think about it, it's a huge amount.

Dr. Heather Luing:

Probably all of us either have gone through depression ourselves or know somebody in our circle who has struggled with it. So it's very common. However, you know, I've heard it referred to as the common cold of psychiatry, and certainly in its frequency it is, but it's a common cold that could kill you. It has a fatality rate right and so it's a very serious condition and besides the risk of suicide, it's a very disabling condition. So it's actually in the top one or two disabling conditions worldwide. That keeps people not only from working occupationally but functioning in their normal environment with relationships, with just day-to-day activities.

Dr. Erich Schramm:

Wow, and really that's a great reflection on the scope of the disease, the effect that it has on patients and, like you said, it's debilitating, and so maybe we could talk a little bit about you know what are the kind of typical symptoms that a lot of people might be experiencing with depression.

Dr. Heather Luing:

Yeah, I think depression is interesting, because when you ask an average layperson about what is depression, we all kind of have a little bit of an idea, right. We recognize depression in some degree when we see it, but I think we tend to under-recognize it. And so the DSM-5 is our Diagnostic and Statistical Manual. It has a very clear definition of what depression is. So in order to meet the criteria for a major depressive disorder, you have to have a low mood and or anhedonia for at least two weeks, and that has to happen for at least most of the days. Now anhedonia is that concept of lack of pleasure. So it's where you used to enjoy going to your son's baseball game and you're still going, but you're not getting pleasure out of it anymore. It's not enjoyable to you and it's one of really the key diagnostic criterias of depression.

Dr. Erich Schramm:

Wow.

Dr. Erich Schramm:

So you're there but you're not really there.

Dr. Heather Luing:

Yeah

Dr. Erich Schramm:

You just feel like you're kind of going through the moves and yeah, I've seen a lot of patients like that, so it's really such a challenge. So with that, do you see other things being affected? Sleep.

Dr. Heather Luing:

Yeah. So besides those two criteria, there's a list of other things that may be affected, and sleep is definitely one of those. Now, sleep and appetite are interesting is that for some people they have less of them, right, maybe they have a hard time sleeping, they're suffering from insomnia, or their appetite is just gone and they're losing a lot of weight. But for others, it really swings in the opposite direction. So we have people who have hypersomnia. They have a hard time getting out of bed, they spend many, many more hours sleeping than they should and kind of use it as an escape. And we also have a subset of patients who will overeat as something of their depression, so they may be gaining weight rather than losing weight.

Dr. Heather Luing:

Other things that we see commonly affected is energy. So a lot of times when you're depressed, you just don't have much energy or motivation. Concentration is one that I see a lot, and I have a lot of adult patients who contact me thinking maybe they have ADD or ADHD, they're having a hard time staying on task with their work, but the reality is a lot of times it's depression. So some of the symptoms of depression really can cross over to other psychiatric disorders, which can be confusing.

Dr. Erich Schramm:

Boy. That really resonates to me as a family practice physician because again, I'm kind of checking off the boxes for the patients that I see and you've really, really nailed down the symptoms really, really accurately. So when you're seeing these patients, what kind of therapies do you have to offer these patients?

Dr. Heather Luing:

Yeah, I always think in a really holistic way. So the first thing I want to think about when somebody is dealing with depression is lifestyle. Right, are you getting enough sleep? Is your diet sufficient? Are you getting enough of some of the essential nutrients that we know the brain really needs to function at its best? What about exercise?

Dr. Heather Luing:

So many people, right, neglect exercise, but it's one of our best antidepressants and the really exciting things that the studies show is that it doesn't take really extreme exercise to get the mental health benefits. Even something very low, very moderate, can be helpful. So I encourage patients try walking around the block. You know, take your dog out for a walk, take a bike ride. You know, things like that can have a profound effect on mental health. So we always start with the basics. After we make those lifestyle adjustments, then the next thing I always think about is psychotherapy. Therapy is very safe. You're not going to hurt anyone with therapy and for a lot of people it can be beneficial. So that's the foundation we build on. For some people that'll be enough and then others are going to need a more biological way of treating depression. So traditionally that's been our antidepressant medications.

Dr. Erich Schramm:

Okay and I guess you know and each patient is different, obviously to know. Okay when all those in a holistic approach totally agree with, because I'm a holistic physician. But of course, when somebody might come in and maybe there's some red flags or a higher level of concern for a patient, then you know, obviously you have priorities that allow those patients to seek, you know, maybe more intensive or more appropriate treatments.

Dr. Heather Luing:

Absolutely, absolutely. And the longer that I really specialize in depression treatment, the more I see depression as an emergency. So by taking a holistic approach we certainly don't want to slow down more aggressive treatment if patient's depression is severe and warrants that. The quicker we can get a depressive episode under control, the better prognostically a patient is going to do so. We don't want to waste a lot of time trying treatments that don't work or letting patients kind of get into this situation where they have a partially treated depression. And unfortunately that's what I see really commonly is patients who maybe have been started on an antidepressant, or maybe they've tried some therapy along with it, but the symptoms haven't resolved. They're not in remission of their depression, it's just improved a bit, but they still have a lot of lingering symptoms, and so that's really what I want to work with in trying to get patients into full remission.

Dr. Erich Schramm:

Wow, and thinking about your experiences, not just in the clinic, but you actually have a good bit of hospital-based experience where you would obviously be working with a more acute and more severe patient population in terms of people that are having suicidal ideation or suicidal attempts. Is that right?

Dr. Heather Luing:

Yeah, absolutely Suicidal ideations and attempts are one of the more severe and concerning symptoms of depression. We always want to be watching for those and sometimes those are what brings patients to the hospital and sometimes it's more a profound level of dysfunction. So patients with depression can even go into a catatonic state where they really just stop responding like we would kind of think of someone as responding and might just sit immobile for a period of time or have really profound symptoms.

Dr. Erich Schramm:

Right and is there a concerted effort to try to make that transition for those hospitalized patients? Do they typically come back into your practice or do they have to be referred out to other primary psychiatrists out there?

Dr. Heather Luing:

No, frequently we'll see this type of patient in our practice. My goal is to treat depression effectively from the beginning so patients ultimately don't have to have hospitalization. Hospitalization is kind of our last resort, right? Nobody likes to be in a psychiatric hospital. It's a challenging environment, and so we want to work to try to find an effective treatment as quickly as possible. So hopefully things don't get to that level, but if they do, absolutely they would return to our practice and we would do everything to keep them at their best state.

Dr. Erich Schramm:

Well, again, I really love the continuity of care. You offer holistic approach and I do actually get to see your patients and I think you're doing a fantastic job. Yeah, that's why I say. I feel like you're really outstanding in your field for what you're offering the patients a really very realistic approach. So thank you for being there for that

Dr. Heather Luing:

Yeah absolutely.

Dr. Erich Schramm:

So let's get back, If we can talk about. You're an interventional psychiatrist and you've already alluded to that. Obviously you're comfortable with pharmaceutical approaches to treating patients with depression, but you're offering something else as an interventional psychiatrist, and in our particular workspace you offer TMS and the esketamine, which is the Spravato, which I find interesting because, again, I see these therapies being applied just about every day and it's quite amazing. So can you tell us a little bit about some of those therapies?

Dr. Heather Luing:

Yeah, absolutely, and we can talk about antidepressants, which have been kind of the backbone of psychiatric treatment, but the reality is there's about a third of patients who those medications just haven't worked for, and traditionally our oral antidepressants have targeted primarily serotonin, to a lesser extent norepinephrine and dopamine, and for some people that can be a miracle, it can be really, really effective.

Dr. Heather Luing:

But about a third of patients it just doesn't work for them, and so we have, as as a field, labeled that as a treatment-resistant depression. Now I personally wonder if in the future, we don't consider that more of a monoaminergic, treatment-resistant depression, which is our serotonin system, but at this point we call it TRD, and so the treatments that you mentioned are treatments for TRD or treatment-resistant depression. So TMS is transcranial magnetic stimulation. It's an FDA-approved treatment that's been around for about 17 years at this point, so it's not new. But I think it's the best-kept secret in psychiatry. We just don't have enough people who are really aware of it as a treatment option, as well as the efficacy that it provides these patients. What TMS does is it uses a small high-powered magnet to provide a focal stimulation to a part of the brain that we know in depression tends to be hypoactive and it's called the left dorsolateral prefrontal cortex, so it's right about here.

Dr. Erich Schramm:

Okay.

Dr. Heather Luing:

And that's a part of the brain that if you image, you do PET studies or functional MRIs in patients with depression, you'll see that part of the brain has kind of gone to sleep. It's just not doing its normal connections with other parts of the brain. By stimulating it with magnetic pulses we can generate neuroplasticity, so we help make some new connections that ultimately help restore the brain to its natural functioning, rather than artificially adding a chemical or something different to the brain. So that's a great treatment. The other kind of big advance we've had in the last oh, six or seven years in psychiatry is bringing in glutamate as a new neurotransmitter that we're modulating, and so Spravato, or Esketamine, was our first FDA-approved way of getting that glutamatergic action for patients' depression, and that's been really a fantastic treatment for patients as well. We now also have an oral antidepressant that has glutamatergic activity that's available, called Auvelity. So we're getting more and more advances and more options for patients, which is fantastic.

Dr. Erich Schramm:

So, in terms of the glutamate, are we looking at the possibility for neuroplasticity on that end, or is that just a different mechanism?

Dr. Heather Luing:

No, it's very similar actually. So neuroplasticity is thought to be the endpoint that we're looking at. We kind of get there a little bit of a different way, but we're getting ultimately the same results in the brain.

Dr. Erich Schramm:

Wow. So very, very interesting. And getting back to what you're saying, that we have had TMS for 17 years but it really hasn't moved into the forefront and as a you know, as a practicing family physician for 20 years, you know I'd have to consider that I really wasn't fully aware of the capabilities until again I'd had an opportunity to work with you and see what a profound difference it is for these patients.

Dr. Erich Schramm:

And it isn't just oh, you know, this is a feel good. This is actually kind of a rewiring of the brain, which is quite a bit different and more sophisticated than what we've been using with our SSRIs that have been around for I don't know.

Dr. Heather Luing:

Yeah, since the late 1980s, I think.

Dr. Erich Schramm:

Yeah, yeah, I'd be like, wow, so it looks like there is this kind of ready to move into this kind of whole new technology. Hopefully these therapies will be coming more accessible to patients and especially in the primary care field and the family medicine field. I think you know. Again, I feel that it's good to be educating and say, look, you know what are the options for patients once they've kind of they're reading their endpoint with their SSRI or similar. So that's terrific. I'd like to talk a little bit about your fellow clinical researcher and look forward to working with you as part of the ENCORE Clinical Research Group. But maybe you could tell us a little bit about your research background. What got you interested in doing clinical research?

Dr. Heather Luing:

Yeah, what got me interested in it is I'm always looking for cutting edge treatments and I want my patients to really be able to assess those as early as possible, because for some patients it is a life or death situation. It is something where they need access to that. So I got really interested in vagus nerve stimulation, which is another type of brain stimulation. We have ECT, which we haven't really talked about, but it's kind of our older way of treating depression with a procedure. We have TMS and now VNS as well.

Dr. Heather Luing:

And the interesting thing is vagus nerve stimulation was actually approved at the end of my residency training, so we're talking almost 20 years ago at this point. So we've known it worked, but we didn't have a way of accessing it through insurance so that patients could actually afford it. So this trial came about, called the RECOVER trial, that Liva Nova sponsored. That was really to show Medicare and CMS that that VNS was something worth paying for and that it was something that could save lives and really help patients with severe depression. So we had an opportunity to start getting involved in that trial and that's how I got my introduction to clinical research.

Dr. Erich Schramm:

Very interesting. But you, I recall in your background you had been involved doing, even in your undergrad you'd been doing, you'd been involved in research. So it's.

Dr. Heather Luing:

I did some bench research. Yeah, absolutely Back getting my chemistry degree. It was pretty fun actually ended up after. When I was in medical school, one of the compounds that I developed actually found promise and ended up in a publication. So that was kind of fun, but very different from what I do now with phase three and phase four trials, working with patients.

Dr. Erich Schramm:

Right, but certainly equally, if not more, important, because you're the kind of where the rubber hits the road right Every stage of research is so important, Otherwise we wouldn't have any options for treating any disease. So you have treated the VNS patients with the vagal nerve stimulator. You've treated TMS patients. Do you see any similarities? How would you compare and contrast what you're seeing for patients with those therapies?

Dr. Heather Luing:

TMS is a non-invasive treatment so it's simply a matter of kind of sitting in a recliner chair and having a magnet placed against your head, so very easy for patients. Vns is a little bit more of a commitment in that you have to have a procedure to implant a device under your collarbone. It's a minor procedure certainly not a big surgery, but it is a bit more of a commitment, I think from that standpoint. Now the interesting thing about this VNS trial is a lot of patients had already failed other treatments, including TMS and esketamine, so a really severe group of patients as far as resistance, and we've seen really good effects. So I think VNS we know it works from those original trials where it was FDA approved. We just haven't had a chance to really utilize it. So I think you know all of these treatments for the right individual have a lot of promise and it's really a matter of kind of navigating those risks and benefits and determining what's the right fit for you as a patient.

Dr. Erich Schramm:

That's a great point to make. And ultimately as researchers we start thinking to ourselves "gee that'd be nice if we could find a way yo compare, head to head, TMS vagal nerve stimulation." it would take a lot of work, you know, to try to see how we could figure out how to make a placebo arm in that. But getting back to your interest in clinical research and cutting edge technology, it really resonates so that's really cool. So let's maybe talk a little bit about kind of the newer pharmaceutical options out there now, and I think we're looking at a study that's going to come up, looking at a particular compound, so maybe you could tell us a little bit about that.

Dr. Heather Luing:

Yeah. So you know we first discovered the first antidepressants by accident. It was serendipitous, right. These were patients who were being treated for tuberculosis and what they found is that when they were given a certain medication they had improvement in their mood symptoms. And so that's kind of where we got this idea that serotonin was the answer to treating depression. And we have run with that as a field for 40 years.

Dr. Heather Luing:

The reality is now we have learned that that may be kind of a backdoor way of treating depression, because the reality is I can deplete someone completely of serotonin by removing an essential amino acid from their diet and they don't get depressed. So we know it's not just a serotonin deficiency that causes depression. We also know if we treat somebody with a serotonergic agent, it takes six to eight weeks for most patients to have a clinical response. That's very slow and what we see is those serotonin levels actually correct much before we see the clinical improvement. So that's led us as a field to think well, what other things could we modulate to help get a quicker and more effective improvement of depression symptoms? So glutamate has kind of been the first that's come to market, come to fruition, and we're still trying to figure out other ways to affect the glutamatergic system. And you know, glutamate and GABA are kind of they go hand in hand, right. It's the brakes and the gas pedal, kind of, if you think about it.

Dr. Heather Luing:

So there's certainly yeah there's certainly GABA agents that are being investigated right now. One area that I'm particularly interested in is the kappa opioid system. So when we think of opiates, the first thing people think is like bad right, you think opiates are something you're artificially taking into your system and causing our opiate crisis. But the reality is we have an endogenous opioid system, so opioid system within us is natural, right. We have to figure out how can we influence that system because it seems to have a lot of effect on mood. So the particular study that I think you're referring to is the KOASTAL study looking at navacaprant, and that's a new novel agent that we think has antidepressant effects and it is a kappa opioid antagonist. So that's a study that I've been taking part in recently as a PI and we're hoping that we'll find new ways to positively affect depressive symptoms.

Dr. Erich Schramm:

That's wonderful. And getting back to understanding from a primary care standpoint and talking about some of the problems associated with serotonin-based medications. We talked a little bit about that, but we talked about anhedonia as a not uncommon circumstance where patients on antidepressants but also the potential for sexual side effects, you know, possibly weight gain. So there are certainly barriers that can come up with compliance for those, and you mentioned that there's a high rate for recurrence and so this sounds like this is a very promising potential avenue for treatment.

Dr. Heather Luing:

Yeah, you've highlighted a lot of reasons. People don't like their traditional antidepressants right, if you're depressed, getting fat and having problems with your sexual life does nothing to improve your depressive symptoms, so those are never popular. The other challenge with anhedonia and SSRIs is a lot of patients just don't get an improvement in that anhedonic tone or features that they have. So what that means I kind of describe it to patients is you go through life looking at things in black and white.

Dr. Heather Luing:

You don't really just see life in technicolor that the rest of us do, and so we want to try to find medicines that are better, better at targeting that anhedonia, because it really is a disabling and disruptive symptom in patients' lives.

Dr. Erich Schramm:

So this is a receptor antagonist, so you are affecting neurotransmitters in that sense, but this wouldn't necessarily be considered something that would have neuroplasticity, or does that?

Dr. Heather Luing:

It potentially could. I think you know that's the exciting thing about clinical research is we're learning, right, we're learning how are things going to ultimately react in the brain. But I would highlight one of the nice things about being an antagonist is you know you're not influencing the opioid system in a negative way like we've been used to with opioid medications, so we're not causing any kind of reward and because of that they're not controlled medications.

Dr. Erich Schramm:

And I think that's a really good and important point to make because it is, you know I think a lot of peope would think ok well, again, I'm familiar with what opioids do for the opioid receptors in patients to have those to get that, but you know, gosh, here's this thing that is regulating a lot of our mood and our pleasure centers and reward centers. So you know, and here we are back to research and that cutting edge, looking at that. So this is, I think, a terrific opportunity and you know, if you think about now, compared to, you know, 20, 30 years ago, now we're really being able to offer patients a wide variety of options to consider, whether it's TMS or what's going to be esketamine. And now we look at glutamate and the KORA opioid receptor antagonist. So and we were talking earlier before because you know, we've both been in research for a long time and there was a period where it seemed like there wasn't a lot of new things coming down the pipe. And you know we're like gosh, now we can see that there's actually quite a bit opening up here.

Dr. Heather Luing:

Yeah, it was so depressing as a new graduate coming out of residency to see companies closing their CNS divisions and knowing that, knowing that I was going to face a career treating patients without getting new advances in the ways that I would do that. And it becomes very discouraging when you have a patient in front of you, and you know that after the second antidepressant failure that patient has about a 14% chance of having a response from one of our traditional antidepressants being used. Third line and we learned that from the STAR-D trial and we've known that for a long time, but we haven't had a whole lot of alternatives. So now we're at a point in time where it's so exciting that we have many alternatives and I think what we have now is just the tip of the iceberg. I think there's a lot of exciting things to come.

Dr. Erich Schramm:

Wow, you're saying everything I want to hear right now so well, terrific Heather. Thank you so much for giving us your time. Is there anything else you'd like to add or any question? I should have asked that. I didn't ask you.

Dr. Heather Luing:

You know, I think the biggest thing is just reminding everyone that depression is a treatable disease and that people don't have to live with these disabling symptoms, that there are effective and safe treatments out there that are FDA approved. Right, they have that clinical research behind which gives us information on efficacy and safety, and most of the time they're covered by insurance, so they're affordable and accessible. So there's no reason to accept depression as a reality that you have to endure.

Dr. Erich Schramm:

I love that. And also I'll add that you know, we're kind of the one of our themes here in clinical, this clinical research office, to let patients know that research is a very reasonable, you know, care option. You know we can't guarantee whether you're going to get on the study medication or placebo, but we know that patients just coming into the office, you know, get a level of care that will have a positive impact on their health. So we, you know again, I think that's a point we like to make here.

Dr. Heather Luing:

Absolutely. We were kind of talking before the show too about some of the challenge of depression. Trials is a placebo response, and you know the reality as a psychiatrist taking off my clinical research hat. Placebos are fine, right, we just want patients to feel better. So if somebody comes into a clinical trial and feels better, no matter how, that's a win for them as an individual. I think that you know something to think about with research is you're contributing to the future of science as well. you may have family members that may have depression in the future. And helping find better tre ments

Dr. Erich Schramm:

Wow. Great closing point, and thank you so much, and maybe we'll do another episode and we'll pick a topic and maybe we can talk again on maybe anxiety or sleep. So maybe we can do that in the future.

Dr. Heather Luing:

Absolutely, it's my pleasure being here today

Dr. Erich Schramm:

My pleasure seeing you again. Heather, take care,

Dr. Heather Luing:

Bye-bye,

Dr. Erich Schramm:

Bye.

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