Neurostimulation, Genomics and the Future of Mental Health Care

David Condos: Hello, and welcome to this episode of Recovery Unscripted, a podcast powered by Foundations Recovery Network. I’m David Condos. For today’s show, I’m joined by Dr. Manish Sheth, expert in the practice of transcranial magnetic stimulation, which employs magnetic waves to non-invasively treat specific parts of the brain.
He sat down with me at the Innovations in Recovery conference in San Diego to discuss how they use emerging technology and Achieve TMS to help patients with mental health issues and even substance use disorders when other remedies have failed. He also explains why these electrical pulses tuned to very specific frequencies can have such a profound effect on the world’s leading cause of disability, depression. Now, here’s Dr. Sheth.

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David: All right, I’m here with Dr. Manish Sheth. Thank you so much for being with us today.

Dr. Manish Sheth: Thank you for having me.

David: Yes, of course. Let’s start off by having you tell us a little bit about your personal story and how you got started in the world of psychiatry and behavioral health.

Dr. Sheth: All right. I’m a board-certified psychiatrist and also boarded in addiction medicine, but the journey goes at least 25 years back. As a child, I wanted to be a doctor. That was one thing that I knew because I always like to be around people. The thing that still I remember vividly is that over the span of about a year and a half, two years, during the third, fourth year of my medical school, I lost three of my classmates, my friends because of suicide.

David: Oh wow, really?

Dr. Sheth: I realized that I need to in the mental health. I need to be in the heal health. That was just my decision was made. After finishing medical school, I went to graduate school to get a PhD, somewhat, unorthodox course. My residency and my PhD were in the Midwest, my medical school was in India. I grew up in India. I moved to this country after I finished my med school, did five years of research. PhD was more about learning genetics and I wanted to apply that to psychiatry and neurology. That was a four-year program were I learned some clinical skills.

I still remember my first day or seeing a physician, he comes and says, “Whatever you all do, just make sure none of your clients should leave your office without hope. You may give them medicine or not, you may give them therapy or not, but always give them hope.” I still believe in that. That what we work in our field is folks who have gone through several trauma, but also, several ways to accommodate for that, several treatment protocols and they just haven’t found the right one yet or they have found a very short-term relief and they are back to where they were a year ago, six months ago. One thing we make sure in our organization is that we give hope and we keep looking for new ways of giving hope.

I started my practice– My wife is also a psychiatrist, who is a child and adolescent psychiatrist. We started our practice here in southern California, in San Diego, about 10 years ago. We have three boys. I don’t want to become philosophical about it, but as parents, we want to leave the world nice and safe for our children.

David: Better place.

Dr. Sheth: Better place, yes.

David: Sure, yes. Then, how did that process work when you decided to start your own practice and then, move out here to California like you said?

Dr. Sheth: We talked to peers and they said that there is a need, so we came down here. First, I started working with the hospitals and nursing homes and within about two, three years, we realized that we should maybe look for something unique and that’s where we landed with TMS. At that time, TMS was very new.

David: Yes. Sorry, just to back up, that’s transcranial-

Dr. Sheth: Magnetic Stimulation. It has been studied for over 30 years, but the first machine that was FDA-cleared for use in depression was in 2008.

David: So, pretty recent?

Dr. Sheth: 10 years, yes.

David: When you moved out here, you said 10 years ago starting your practice, was that achieved at that time?

Dr. Sheth: That was achieved just from the medical center, not TMS. In about six and a half years ago, we got our first machine for TMS. Again, that was also stimulated by one of our patients who came out to us and said they used to go to Canada before the TMS was approved here. What we thought is, “Oh my, that must be pretty unique treatment.”

David: If somebody’s going to that extent to receive the treatment.

Dr. Sheth: Exactly, yes. Exactly.

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David: Can you introduce, overall, how do you explain how it works medically, scientifically?

Dr. Sheth: TMS, as I said, stands for transcranial magnetic stimulation. It uses an electrical coil that is placed on top of the head, generally, focusing on the prefrontal area in the frontal part of the brain and with appropriate setting, once the machine is turned on, it emits magnetic pulses. Now, what happens after that is a very old principle, it’s called Faraday’s law or Faraday’s principle about magnetic pulses. If there is a change in the magnetic field that is induced by these changes in the magnetic pulses, that initiates electric current. Now, on the practical basis though we use-

David: Here’s a quick primer on what Dr. Sheth is talking about. Faraday’s law of induction is a basic law of electromagnetism that predicts how a magnetic field will interact within the electric circuit to produce a phenomenon called electromotive force. In other words, as you change your magnetic field, you also change the amount of electric current or voltage that’s produced. Discovered by British scientist Michael Faraday in 1831, it’s become the foundational principle for a number of building blocks of the modern world, from electric motors and transformers to batteries. As you’ll hear, scientists are still finding new ways to use these principles today. Here’s Dr. Sheth with more.

Dr. Sheth: – a full trial of one medication. Now, that electric current, in this case, is induced in the brain. Very small pressure, not very strong, but it is strong enough that it stimulates the nerve cells and then, in turn, those nerve cells are now action potential and they start new networking.

David: It’s activating them, getting them to start working new again?

Dr. Sheth: Yes. What we know in certain parts of- certain types of neuropsychiatric condition with depression or substance use, like cocaine use, our frontal areas- frontal part of the brain is inactive or hypoactive, less active than it should be. When you do TMS, it stimulates that part of the brain and brings them back to their baseline. I mean, brain basically works like a lithium-ion battery. It has a chemical part and it has electric power. The chemistry we have known for 50 years about serotonin and norepinephrine and dopamine. There are about one-third of the patients who have depression who don’t respond to any medication. What do we do from them? We can’t just leave them alone.

David: That’s significant.

Dr. Sheth: A lot of people, yes. It came out in Time Magazine last year, that there are 300 million people worldwide who have depression and they are not responding to standard treatments. This is where this neuromodulation or the TMS comes in for those patients. As I said, it stimulates the frontal area. They are looking at other parts of the brain, if it will work in other parts of the brain, but the dorsolateral left-sided prefrontal cortex. Again, dorsolateral prefrontal cortex on the left side, that is the area that has been found to be the most significant in [unintelligible 00:08:05] depression.

David: That’s what I was going to ask. I know depression is a big part of what you treat, could you say a little bit about how TMS works with depression and then, maybe some other mental health conditions that you it treat with?

Dr. Sheth: If you look at conditions like OCD, PTSD, close to 50% of those patients have both depression and OCD or depression and PTSD. If we only treat PTSD or you only treat OCD, that’s not going to get better until we treat depression. When you look at substance use disorders, more than 50% of those patients also have depression. They have done studies to look at substance use independently and depression independently and they found that if we treat both with TMS, it improves the outcome as well.

David: How does that work to treat the substance use disorder with TMS? Is it the same thing, it’s still igniting those areas of the brain, the same areas?

Dr. Sheth: Yes, there are several areas, but there are also different protocols and different frequency if you think of it as a different dose of the medicines. It’s the same medicine. For example, if you are using Prozac for depression, you can probably respond to 20 milligram. If you are using Prozac for OCD, obsessive-compulsive disorder, you may need 60 or 80 milligram. For depression, you may use focusing on the dorsolateral prefrontal cortex, but for OCD, you may need to focus on orbitofrontal cortex, which is more medial.

One of the areas that we know is very important for substance use disorder is anterior cingulate areas, then, ventral tegmental area, and nucleus accumbens. There is no easy way to reach out to them because they are deep inside and that’s where the value of the Deep TMS comes in. There are two types of TMS, surface TMS, which is most superficial. Deep TMS is about three times as deep. The idea is that we can activate those networks, which are working on the reward pathways in the addiction pathways.

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David: As you’re having patients come in for TMS treatment, could you describe a little bit about what a typical session looks like or what a typical treatment plan looks like that incorporates TMS?

Dr. Sheth: The first appointment is the most robust and most critical appointment. That’s the appointment where we- again, the doctor goes through it, all the pros and cons and we create, what we call, cortical mapping, where we actually map the different parts of the brain to see where the motor cortex is and from there, we measure where the prefrontal cortex should be where we are going to do treatment.

David: That’s different for every patient?

Dr. Sheth: That is different for every patient, yes. It’s a very individualized process. There are two things which could be different, location of the motor cortex and second, the threshold, meaning, the dose of the treatment. I always tell my clients that if you had a twin, same size, same shape, same age, of course, same gender, you might still have different thresholds.

David: How do you tell what the threshold is at the front end of that?

Dr. Sheth: Yes, great question. What we do is, these devices for TMS, they are equipped to give magnetic pulses of different power. We start low and we gradually go up by maybe 1% or 2% to see what is the minimum power to get a response, a motor response.

David: You’re looking for their response?

Dr. Sheth: Yes, that’s the motor response. We find the motor cortex part of the brain that controls my right hand, for example, and then, I’ll place the coil on my left side of the brain, on the motor cortex, give one pulse at a time and look at the movement of my right hand.

David: Really? Wow. Okay.

Dr. Sheth: If I need a higher range of power, that means my threshold is higher. If I need lower range, then, that means I have a lower threshold. Now, threshold can also be determined by different things. If I had too much caffeine, my threshold will be low because I’m more excited, my brain is more excited. If I had too much medications like benzodiazepines or Valium or chloroprene, then, I will need more power TMS to respond because I’m more sedated. We work very closely to say which medicine to take before TMS, which not to take. Once we have that threshold, once we have that location, then, we place the helmet such that the magnetic coil faces the left prefrontal cortex area. Now, helmet is somewhat bilateral, it has coil on both sides.

David: That’s across the forehead?

Dr. Sheth: Yes. Then, we start the treatment. Treatment protocol is generally 20 to 30 minutes. There are several different frequencies that we can use. The most commonly used frequency all around the studies and all around- all over the country, all over the world is what they call high-frequency protocol, where one gets more than 15 pulses per second. With BrainsWay, the protocol is you get 36 pulses rapidly within two seconds and then, there is a 20-second break, then, there is 2 seconds of pulses, then, again, there is 20-second break. These cycles, they repeat itself 55 times. That’s the standard protocol and what we try to do is we try to keep-

David: I’m going to jump in here real quick to recap some of what Dr. Sheth is describing. This particular TMS protocol was developed by an Israel-based company called BrainsWay. They’ve been a major pioneer in the research and development of TMS, especially the Deep TMS treatment that Dr. Sheth referred to earlier, which BrainsWay has been approved to market in the US and Canada since 2013, but the technology that’s the foundation of their work goes back a bit further than that.

As you’ve heard already, the main component of a TMS device is a magnetic oil. Now, standard TMS treatment employs what’s called a figure eight coil, which as you can probably guess, looks more or less like a two-dimensional pair of circles placed above a patient’s head. Deep TMS, however, uses an H-coil, which was actually developed by the US National Institutes of Health back in the late 1990s.

With this design, the coil elements are interwoven into a lattice pattern, both horizontally and vertically, all wrapped up in a helmet that surrounds a patient’s head. The H-coils three-dimensional orientation is what allows it to reach deeper into the brain. As you’re about to hear, both types of coil can allow for a multitude of possibilities. Since the variables can be fine-tuned in many ways. Here’s Dr. Sheth.

Dr. Sheth: – if you can see are somewhat limited. Now, there are other protocols. There are some protocol where we recommend the right-sided prefrontal cortex at a low frequency, meaning, 1-Hz. You get one per second.

David: This is the standard for depression?

Dr. Sheth: For depression and also anxiety. The right-sided one, as I said, that it actually inhibits activity and that helps with anxiety. The left-sided, the rapid protocol, it stimulates the activity and it helps with depression.

David: This is all non-invasive. These pulses, are they feeling them? How was the experience?

Dr. Sheth: The pulses feel like something tapping, like pecking on the forehead. They shouldn’t have any movement in the hands or feet or anything like that because, number one, this focuses on the prefrontal cortex, not on the motor cortex and the feelings are more from the superficial nerve activation. We have nerves in our skin and muscles through which these magnetic pulses go through before they reach brains.

David: You’re feeling it more in your in your skin?

Dr. Sheth: Yes.

David: The follow-up question to that is, how long, generally, are patients doing this? How does that work as far as- you say, the first week is this and then, how long might that play out?

Dr. Sheth: The traditional protocol is 30 sessions of 5 days a week, followed by twice a week for 3 weeks and complete the protocol, so about 36 sessions. Again, there are several variations to that. Studies have been published with different protocols. That’s one. There’s a study where they had four weeks of five days a week. Then, they had 8 weeks of twice a week and they had 10 weeks of once a week. They had remission rates of 71%. 71% of folks, by the end of the protocol, they were completely symptom-free, which is unheard.

I’ll give you a reference point to make it even more important is- they have done studies for this treatment-resistant depressed clients, where they have failed 2, 3, 4 medications. After second or third medicine, their remission rates are 13% or less. Here we are looking at remission rates of 50% or more. This is mind-boggling.

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David: Coming up, Dr. Sheth, illustrates the factors that determine whether someone’s a good candidate for TMS, share some of the outcomes data he’s seen so far, and explains how tailoring treatment plans to each patient’s unique genome map could drastically alter the future of medicine, but first, I get to introduce another installment of our trivia segment, this week in recovery history. Today’s question looks at the Americans with Disabilities Act, the first comprehensive federal civil rights legislation to protect those with mental health conditions and it was signed into law on this very week, in which of the following years? 1990, 1993 or 1996? Find out after the interview.
Now, back to my conversation with Dr. Sheth. You were talking earlier about when you’re meeting with patients in the early stages of introducing them to this, part of what you’re doing is determining if this is a good candidate for this. Could you describe what makes someone a good candidate? When is a good time to introduce this as part of a larger treatment plan?

Dr. Sheth: One of the things we’ll say is that most of the psychiatrists in this day and age, we get our clients who have already been on one, two or three medications because primary care providers are more comfortable and confident prescribing antidepressants, but many times, it is prescribed by cardiologists for their patient or OB-GYN for their postpartum patient or family doctor. By the time a patient or client comes to psychiatrists, it’s generally after the third or fourth time or at that point, if they are not working. Right off, they are a good client.

David: Sure. That’s one sign?

Dr. Sheth: Yes. You have to have, at least, maybe two or three medication attempts. Either you couldn’t take it because of side effects or they were not effective even though they took it right. It has also been used with pregnant women because some pregnancies are little complicated pregnancies, they cannot take medication.

David: It has been effective for pregnant women because they can’t take medication?

Dr. Sheth: Yes. Some fears come across some pilots who don’t want to take medication, which can affect their functioning. The great thing about this is it doesn’t have the side effects of medicine. That’s one thing most people say when they under anti-depressant, “My depression is down, but I feel blah.” There is no clinical term for that except to say it that way. Those things aren’t there for TMS. Second thing, they don’t have any other very clear medical reason or other non-psychotic reason why they would be depressed, having thyroid problems or they are having some chronic pain, which has not been addressed because all those things can also cause depression.
Certainly, if someone is actively using any substance, that can also cause depression. Once they are clean and sober for a few weeks and if their depression persists, they are a good candidate. The reason I say that is if we don’t treat their depression, they are likely to relapse again.

David: Right.

Dr. Sheth: That is the population that I’m really focusing on doing this meeting and say, “Look, you get people better, you can put them in sobriety, you keep them sober a month or two month, three months, whatever, however long the program is, but if you don’t do something before we let them out in the community, we are doing a disservice to them.

David: You alluded earlier to some of the results that you’re saying, what can you say about the success or the effectiveness that TMS is having for some of these conditions?

Dr. Sheth: Depression data, what we know from studies, which were double-blinded, where half the people got real treatment, the other half got what they call sham treatment, so they still wore the helmets and everything and they felt like they were getting some vibration, but they were not getting real treatment. In those studies, they found that about half the patients, 60% of them, get what we call response. They get 50% better for depression, but our goal is to go beyond that. We don’t want to be 50% better. We want to be 90% or more better, which is what we call remission. Meaning, their symptoms have declined so well that they are functional back to normal.

Remission rates are around 40%. 40% of patients who have failed all other medications, they are getting remission and about 60% getting what we call response. That is our internal data as well. We have about 45% for remission. When you look at the addiction, I was just quoting a study in my talk where they looked at someone who was using cocaine and they divided that group into two and the treatment group got TMS, the control group got the standard treatment, the therapy, all that, the other group got therapy and TMS.
After 21 days, 80% of patients who were in the treatment group, they were relapse-free. Their urine screen was negative for any cocaine, but this is the kicker– You will love to hear this. Those who are not getting TMS, 80% of them had relapsed, so it is a completely opposite result. 80% got better here and 80% relapsed on the other group.

David: The rest of the therapy they were getting was the same?

Dr. Sheth: Everything else was same. The only thing different was getting TMS. It’s very profound. I mean, the responses are very profound.

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David: I read that you also have some history working with genomes and genetic technology, could you describe some of the work you’ve had in that world?

Dr. Sheth: Yes. My reason for going into PhD is I wanted to– At that time, genetic research was becoming really new and upcoming and I wanted to learn more about it. I’m just a Curious George, and at the bottom of my heart, I like to learn new things and bring it to other people and train other people, so they can carry it on. About 20 years ago, that was when I got into some genetic studies and research. I wanted to learn how we can make some profile or individualized treatment for an individual based on their clinical symptoms, but also add on their genetic profile.

There are two things we look into genetics, pharmacodynamic and pharmacokinetic. Pharmacodynamic means, it tells us which genes are expressed in my body that determines how a medication will work in my body. That’s pharmacodynamic. Then, anything I take, most of it is metabolized in the liver. Our liver has lots of this metabolism genes and they are called cytochromes. Depending on what kind of cytochromes I have in the liver, that determines am I fast metabolizer, slow metabolizer, intermediate metabolizer. That helps determine what should be the dose of the medicine or is that medicine even safe for me or not.

Again, an example, if I’m a poor metabolizer of 2D6 gene, cytochrome 2D6, that means medications like Prozac, Paxil, Wellbutrin, I should take very low doses of those because my enzyme system, my metabolism system is not robust enough to chew it up.

David: You’re just staying a step ahead, so you don’t have to wait and see what the results are. You can say, “Well, based on this gene that we see or this genetic component, we can say, well, let’s go ahead and start at a lower dose because you’re at risk for that.”

Dr. Sheth: Or even to the extent to which medication not to start. Like the Pharmacodynamic genes that I was telling you earlier, that is a serotonin transporter gene, and if I have a certain expression of that gene, I’m not going to respond to SSRIs. SSRIs are the primary medications like Prozac, Paxil, Zoloft. If I know that upfront, there is no point in trying three of those and putting a person through all the side effects and not getting any relief from their depression. Those testing, they help us determine which medication to use, which medications not to use and what are the appropriate doses.

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David: Are there other applications for that besides just the medicine? Like looking at TMS or other types of therapy that genetics can tell us?

Dr. Sheth: Yes, some preliminary studies have shown that if you look at– There is another gene for folic acid. It converts folic acid into methylfolate. If I have low expression of that gene, that means I can take as much folic acid I want, but it won’t be converted to methylfolate. Methylfolate is necessary for the synthesis of serotonin, norepinephrine, and dopamine in the brain. I may be taking the right antidepressant, but if I don’t have enough methylfolate, that antidepressant would be ineffective.

Another gene is COMT, catechol-O-methyltransferase. That gene produces the enzyme that metabolizes dopamine. If I have too much of that, then, I wouldn’t have enough dopamine in my frontal lobe.

David: It goes through it too fast?

Dr. Sheth: Too fast. What that means is most of the medications are not going to be very effective for me. Thus, TMS or neuromodulation is the way to go for me.It’s an additional tool that we can use and we should be using it. The good, cool thing about genetic testing is, it doesn’t change. My genes don’t change in my lifetime. Now, they may add more genes that we learn about and say, “Okay, well, instead of these 5 genes, now we are looking at 10 genes to make a decision,” but those five genes that they looked at for me, they’re not going to change the rest of my life. It’s good data to have.

David: All right. Well, I’m going to wrap up with this last question. You’ve devoted a lot of your time in your life to this mission, this cause over the last 20, 25 years, right?

Dr. Sheth: Yes.

David: Could you wrap us up by summing up why helping people heal from depression and other psychiatric issues and find recovery- why is that so important to you?

Dr. Sheth: Yes. Again, as I mentioned earlier, it all started when I was pretty young and still in medical school. The events that I experienced that almost directed me towards going into mental health and psychiatry. What we have found is that depression is something that, in itself, causes the most significant functional deficit for our people.

David: They see the biggest practical effects in their life?

Dr. Sheth: Yes. I was recording a study in my talk where neuropsychiatric conditions, as an entity, is the number one reason for disability right now, worldwide. You want to [unintelligible 00:26:33] any cardiovascular conditions or cancer or things like that. It is affecting our society. I mean, of course, trillions of dollars of lost productivity, I mean, if you look at the financial side of it, but just the day to day life.

If the parents are depressed or if one of the parent is depressed, we know that the outcome for the children is not good. If a pregnant woman is depressed, we know that the pregnancy outcomes are not good because the babies are either born very small, they have neurological issues, they take longer to catch up with other babies whose mom we’re not depressed. Depression is affecting every aspect of our life and the best part about it is, it is not too hard to treat it. We have so many avenues treat it.

David: We have options.

Dr. Sheth: We have options. Yes, that drives me. That gets me going every morning when I wake up.

David: All right. Well, Dr. Sheth, thank you so much for your time and for being with us today.

Dr. Sheth: Thank you.

David: Thanks again to Dr. Sheth for sharing that with us and thank you for sticking around to the end of this episode for another installment of our trivia segment, this week in recovery history. Today’s question highlights the Americans with Disabilities Act or ADA, which was signed into law by President George H. W. Bush on July 26th, 1990. The first draft of the bill was written by Robert L. Burgdorf Jr. of the National Council on Disability in response to what he described as widespread systemic inhumane discrimination against people with disabilities in schools, healthcare, public services, and employment.

While the ADA also led to many tangible reforms related to physical disabilities, it’s very deliberate in its protection of those with mental health issues as well. For example, it grants two main workplace rights to those who have, what the policy language refers to as, psychiatric disabilities. First, is the right to privacy. Meaning, that it’s the individual’s own choice whether or not to disclose a disability to an employer, both during the job interview and during employment.

The second is the right to accommodation, which means that employees have the right to request changes to the work environment or process that allow them an equal opportunity to do their jobs. Some examples of this could be doing some work remotely to help with anxiety, taking more frequent breaks for medication or just implementing a quieter workplace setting to help with concentration. That’s the Americans with Disabilities Act, which became law on this week in the year 1990. Stay tuned for more trivia from recovery history in future episodes.

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David: This has been the Recovery Unscripted podcast. Today, we’ve heard from Dr. Manish Sheth from Achieve TMS. To learn more about their work, visit achievetms.com. Thank you for listening today. If you’ve enjoyed this episode, please pass it along to someone else who might enjoy it as well. We’d love to have your help spreading the word. See you next time.