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Antidepressant may cut COVID-19–related hospitalization, mortality: TOGETHER
The antidepressant fluvoxamine (Luvox) may prevent hospitalization and death in outpatients with COVID-19, new research suggests.
Results from the placebo-controlled, multisite, phase 3 TOGETHER trial showed that in COVID-19 outpatients at high risk for complications, hospitalizations were cut by 66% and deaths were reduced by 91% in those who tolerated fluvoxamine.
“Our trial has found that fluvoxamine, an inexpensive existing drug, reduces the need for advanced disease care in this high-risk population,” wrote the investigators, led by Gilmar Reis, MD, PhD, research division, Cardresearch, Belo Horizonte, Brazil.
The findings were published online Oct. 27 in The Lancet Global Health.
Alternative mechanisms
Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), is an antidepressant commonly prescribed for obsessive-compulsive disorder.
Besides its known effects on serotonin, the drug acts in other molecular pathways to dampen the production of inflammatory cytokines. Those alternative mechanisms are the ones believed to help patients with COVID-19, said coinvestigator Angela Reiersen, MD, child psychiatrist at Washington University, St. Louis.
Based on cell culture and mouse studies showing effects of the molecule’s binding to the sigma-1 receptor in the endoplasmic reticulum, Dr. Reiersen came up with the idea of testing if fluvoxamine could keep COVID-19 from progressing in newly infected patients.
Dr. Reiersen and psychiatrist Eric Lenze, MD, also from Washington University, led the phase 2 trial that initially suggested fluvoxamine’s promise as an outpatient medication. They are coinvestigators on the new phase 3 adaptive platform trial called TOGETHER, which was conducted by an international team of investigators in Brazil, Canada, and the United States.
For this latest study, researchers at McMaster University, Hamilton, Ont., partnered with the research clinic Cardresearch in Brazil to recruit unvaccinated, high-risk adults within 7 days of developing flu-like symptoms from COVID-19. They analyzed 1,497 newly symptomatic COVID-19 patients at 11 clinical sites in Brazil.
Patients entered the trial between January and August 2021 and were assigned to receive 100 mg fluvoxamine or placebo pills twice a day for 10 days. Investigators monitored participants through 28 days post treatment, noting whether complications developed requiring hospitalization or more than 6 hours of emergency care.
In the placebo group, 119 of 756 patients (15.7%) worsened to this extent. In comparison, 79 of 741 (10.7%) fluvoxamine-treated patients met these primary criteria. This represented a 32% reduction in hospitalizations and emergency visits.
Additional analysis requested
As Lancet Global Health reviewed these findings from the submitted manuscript, journal reviewers requested an additional “pre-protocol analysis” that was not specified in the trial’s original protocol. The request was to examine the subgroup of patients with good adherence (74% of treated group, 82% of placebo group).
Among these three quarters of patients who took at least 80% of their doses, benefits were better.
Fluvoxamine cut serious complications in this group by 66% and reduced mortality by 91%. In the placebo group, 12 people died compared with one who received the study drug.
from complications of the infection.
However, clinicians should note that the drug can cause side effects such as nausea, dizziness, and insomnia, she added. In addition, because it prevents the body from metabolizing caffeine, patients should limit their daily intake to half of a small cup of coffee or one can of soda or one tea while taking the drug.
Previous research has shown that fluvoxamine affects the metabolism of some drugs, such as theophylline, clozapine, olanzapine, and tizanidine.
Despite huge challenges with studying generic drugs as early COVID-19 treatment, the TOGETHER trial shows it is possible to produce quality evidence during a pandemic on a shoestring budget, noted co-principal investigator Edward Mills, PhD, professor in the department of health research methods, evidence, and impact at McMaster University.
To screen more than 12,000 patients and enroll 4,000 to test nine interventions, “our total budget was less than $8 million,” Dr. Mills said. The trial was funded by Fast Grants and the Rainwater Charitable Foundation.
‘A $10 medicine’
Commenting on the findings, David Boulware, MD, MPH, an infectious disease physician-researcher at the University of Minnesota in Minneapolis, noted fluvoxamine is “a $10 medicine that’s available and has a very good safety record.”
By comparison, a 5-day course of Merck’s antiviral molnupiravir, another oral drug that the company says can cut hospitalizations in COVID-19 outpatients, costs $700. However, the data have not been peer reviewed – and molnupiravir is not currently available and has unknown long-term safety implications, Dr. Boulware said.
Pharmaceutical companies typically spend tens of thousands of dollars on a trial evaluating a single drug, he noted.
In addition, the National Institutes of Health’s ACTIV-6 study, a nationwide trial on the effect of fluvoxamine and other repurposed generic drugs on thousands of COVID-19 outpatients, is a $110 million effort, according to Dr. Boulware, who cochairs its steering committee.
ACTIV-6 is currently enrolling outpatients with COVID-19 to test a lower dose of fluvoxamine, at 50 mg twice daily instead of the 100-mg dose used in the TOGETHER trial, as well as ivermectin and inhaled fluticasone. The COVID-OUT trial is also recruiting newly diagnosed COVID-19 patients to test various combinations of fluvoxamine, ivermectin, and the diabetes drug metformin.
Unanswered safety, efficacy questions
In an accompanying editorial in The Lancet Global Health, Otavio Berwanger, MD, cardiologist and clinical trialist, Academic Research Organization, Hospital Israelita Albert Einstein, São Paulo, Brazil, commends the investigators for rapidly generating evidence during the COVID-19 pandemic.
However, despite the important findings, “some questions related to efficacy and safety of fluvoxamine for patients with COVID-19 remain open,” Dr. Berwanger wrote.
The effects of the drug on reducing both mortality and hospitalizations also “still need addressing,” he noted.
“In addition, it remains to be established whether fluvoxamine has an additive effect to other therapies such as monoclonal antibodies and budesonide, and what is the optimal fluvoxamine therapeutic scheme,” wrote Dr. Berwanger.
In an interview, he noted that 74% of the Brazil population have currently received at least one dose of a COVID-19 vaccine and 52% have received two doses. In addition, deaths have gone down from 4,000 per day during the March-April second wave to about 400 per day. “That is still unfortunate and far from ideal,” he said. In total, they have had about 600,000 deaths because of COVID-19.
Asked whether public health authorities are now recommending fluvoxamine as an early treatment for COVID-19 based on the TOGETHER trial data, Dr. Berwanger answered, “Not yet.
“I believe medical and scientific societies will need to critically appraise the manuscript in order to inform their decisions and recommendations. This interesting trial adds another important piece of information in this regard,” he said.
Dr. Reiersen and Dr. Lenze are inventors on a patent application related to methods for treating COVID-19, which was filed by Washington University. Dr. Mills reports no relevant financial relationships, as does Dr. Boulware – except that the TOGETHER trial funders are also funding the University of Minnesota COVID-OUT trial. Dr. Berwanger reports having received research grants outside of the submitted work that were paid to his institution by AstraZeneca, Bayer, Amgen, Servier, Novartis, Pfizer, and Boehringer Ingelheim.
A version of this article first appeared on Medscape.com.
The antidepressant fluvoxamine (Luvox) may prevent hospitalization and death in outpatients with COVID-19, new research suggests.
Results from the placebo-controlled, multisite, phase 3 TOGETHER trial showed that in COVID-19 outpatients at high risk for complications, hospitalizations were cut by 66% and deaths were reduced by 91% in those who tolerated fluvoxamine.
“Our trial has found that fluvoxamine, an inexpensive existing drug, reduces the need for advanced disease care in this high-risk population,” wrote the investigators, led by Gilmar Reis, MD, PhD, research division, Cardresearch, Belo Horizonte, Brazil.
The findings were published online Oct. 27 in The Lancet Global Health.
Alternative mechanisms
Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), is an antidepressant commonly prescribed for obsessive-compulsive disorder.
Besides its known effects on serotonin, the drug acts in other molecular pathways to dampen the production of inflammatory cytokines. Those alternative mechanisms are the ones believed to help patients with COVID-19, said coinvestigator Angela Reiersen, MD, child psychiatrist at Washington University, St. Louis.
Based on cell culture and mouse studies showing effects of the molecule’s binding to the sigma-1 receptor in the endoplasmic reticulum, Dr. Reiersen came up with the idea of testing if fluvoxamine could keep COVID-19 from progressing in newly infected patients.
Dr. Reiersen and psychiatrist Eric Lenze, MD, also from Washington University, led the phase 2 trial that initially suggested fluvoxamine’s promise as an outpatient medication. They are coinvestigators on the new phase 3 adaptive platform trial called TOGETHER, which was conducted by an international team of investigators in Brazil, Canada, and the United States.
For this latest study, researchers at McMaster University, Hamilton, Ont., partnered with the research clinic Cardresearch in Brazil to recruit unvaccinated, high-risk adults within 7 days of developing flu-like symptoms from COVID-19. They analyzed 1,497 newly symptomatic COVID-19 patients at 11 clinical sites in Brazil.
Patients entered the trial between January and August 2021 and were assigned to receive 100 mg fluvoxamine or placebo pills twice a day for 10 days. Investigators monitored participants through 28 days post treatment, noting whether complications developed requiring hospitalization or more than 6 hours of emergency care.
In the placebo group, 119 of 756 patients (15.7%) worsened to this extent. In comparison, 79 of 741 (10.7%) fluvoxamine-treated patients met these primary criteria. This represented a 32% reduction in hospitalizations and emergency visits.
Additional analysis requested
As Lancet Global Health reviewed these findings from the submitted manuscript, journal reviewers requested an additional “pre-protocol analysis” that was not specified in the trial’s original protocol. The request was to examine the subgroup of patients with good adherence (74% of treated group, 82% of placebo group).
Among these three quarters of patients who took at least 80% of their doses, benefits were better.
Fluvoxamine cut serious complications in this group by 66% and reduced mortality by 91%. In the placebo group, 12 people died compared with one who received the study drug.
from complications of the infection.
However, clinicians should note that the drug can cause side effects such as nausea, dizziness, and insomnia, she added. In addition, because it prevents the body from metabolizing caffeine, patients should limit their daily intake to half of a small cup of coffee or one can of soda or one tea while taking the drug.
Previous research has shown that fluvoxamine affects the metabolism of some drugs, such as theophylline, clozapine, olanzapine, and tizanidine.
Despite huge challenges with studying generic drugs as early COVID-19 treatment, the TOGETHER trial shows it is possible to produce quality evidence during a pandemic on a shoestring budget, noted co-principal investigator Edward Mills, PhD, professor in the department of health research methods, evidence, and impact at McMaster University.
To screen more than 12,000 patients and enroll 4,000 to test nine interventions, “our total budget was less than $8 million,” Dr. Mills said. The trial was funded by Fast Grants and the Rainwater Charitable Foundation.
‘A $10 medicine’
Commenting on the findings, David Boulware, MD, MPH, an infectious disease physician-researcher at the University of Minnesota in Minneapolis, noted fluvoxamine is “a $10 medicine that’s available and has a very good safety record.”
By comparison, a 5-day course of Merck’s antiviral molnupiravir, another oral drug that the company says can cut hospitalizations in COVID-19 outpatients, costs $700. However, the data have not been peer reviewed – and molnupiravir is not currently available and has unknown long-term safety implications, Dr. Boulware said.
Pharmaceutical companies typically spend tens of thousands of dollars on a trial evaluating a single drug, he noted.
In addition, the National Institutes of Health’s ACTIV-6 study, a nationwide trial on the effect of fluvoxamine and other repurposed generic drugs on thousands of COVID-19 outpatients, is a $110 million effort, according to Dr. Boulware, who cochairs its steering committee.
ACTIV-6 is currently enrolling outpatients with COVID-19 to test a lower dose of fluvoxamine, at 50 mg twice daily instead of the 100-mg dose used in the TOGETHER trial, as well as ivermectin and inhaled fluticasone. The COVID-OUT trial is also recruiting newly diagnosed COVID-19 patients to test various combinations of fluvoxamine, ivermectin, and the diabetes drug metformin.
Unanswered safety, efficacy questions
In an accompanying editorial in The Lancet Global Health, Otavio Berwanger, MD, cardiologist and clinical trialist, Academic Research Organization, Hospital Israelita Albert Einstein, São Paulo, Brazil, commends the investigators for rapidly generating evidence during the COVID-19 pandemic.
However, despite the important findings, “some questions related to efficacy and safety of fluvoxamine for patients with COVID-19 remain open,” Dr. Berwanger wrote.
The effects of the drug on reducing both mortality and hospitalizations also “still need addressing,” he noted.
“In addition, it remains to be established whether fluvoxamine has an additive effect to other therapies such as monoclonal antibodies and budesonide, and what is the optimal fluvoxamine therapeutic scheme,” wrote Dr. Berwanger.
In an interview, he noted that 74% of the Brazil population have currently received at least one dose of a COVID-19 vaccine and 52% have received two doses. In addition, deaths have gone down from 4,000 per day during the March-April second wave to about 400 per day. “That is still unfortunate and far from ideal,” he said. In total, they have had about 600,000 deaths because of COVID-19.
Asked whether public health authorities are now recommending fluvoxamine as an early treatment for COVID-19 based on the TOGETHER trial data, Dr. Berwanger answered, “Not yet.
“I believe medical and scientific societies will need to critically appraise the manuscript in order to inform their decisions and recommendations. This interesting trial adds another important piece of information in this regard,” he said.
Dr. Reiersen and Dr. Lenze are inventors on a patent application related to methods for treating COVID-19, which was filed by Washington University. Dr. Mills reports no relevant financial relationships, as does Dr. Boulware – except that the TOGETHER trial funders are also funding the University of Minnesota COVID-OUT trial. Dr. Berwanger reports having received research grants outside of the submitted work that were paid to his institution by AstraZeneca, Bayer, Amgen, Servier, Novartis, Pfizer, and Boehringer Ingelheim.
A version of this article first appeared on Medscape.com.
The antidepressant fluvoxamine (Luvox) may prevent hospitalization and death in outpatients with COVID-19, new research suggests.
Results from the placebo-controlled, multisite, phase 3 TOGETHER trial showed that in COVID-19 outpatients at high risk for complications, hospitalizations were cut by 66% and deaths were reduced by 91% in those who tolerated fluvoxamine.
“Our trial has found that fluvoxamine, an inexpensive existing drug, reduces the need for advanced disease care in this high-risk population,” wrote the investigators, led by Gilmar Reis, MD, PhD, research division, Cardresearch, Belo Horizonte, Brazil.
The findings were published online Oct. 27 in The Lancet Global Health.
Alternative mechanisms
Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), is an antidepressant commonly prescribed for obsessive-compulsive disorder.
Besides its known effects on serotonin, the drug acts in other molecular pathways to dampen the production of inflammatory cytokines. Those alternative mechanisms are the ones believed to help patients with COVID-19, said coinvestigator Angela Reiersen, MD, child psychiatrist at Washington University, St. Louis.
Based on cell culture and mouse studies showing effects of the molecule’s binding to the sigma-1 receptor in the endoplasmic reticulum, Dr. Reiersen came up with the idea of testing if fluvoxamine could keep COVID-19 from progressing in newly infected patients.
Dr. Reiersen and psychiatrist Eric Lenze, MD, also from Washington University, led the phase 2 trial that initially suggested fluvoxamine’s promise as an outpatient medication. They are coinvestigators on the new phase 3 adaptive platform trial called TOGETHER, which was conducted by an international team of investigators in Brazil, Canada, and the United States.
For this latest study, researchers at McMaster University, Hamilton, Ont., partnered with the research clinic Cardresearch in Brazil to recruit unvaccinated, high-risk adults within 7 days of developing flu-like symptoms from COVID-19. They analyzed 1,497 newly symptomatic COVID-19 patients at 11 clinical sites in Brazil.
Patients entered the trial between January and August 2021 and were assigned to receive 100 mg fluvoxamine or placebo pills twice a day for 10 days. Investigators monitored participants through 28 days post treatment, noting whether complications developed requiring hospitalization or more than 6 hours of emergency care.
In the placebo group, 119 of 756 patients (15.7%) worsened to this extent. In comparison, 79 of 741 (10.7%) fluvoxamine-treated patients met these primary criteria. This represented a 32% reduction in hospitalizations and emergency visits.
Additional analysis requested
As Lancet Global Health reviewed these findings from the submitted manuscript, journal reviewers requested an additional “pre-protocol analysis” that was not specified in the trial’s original protocol. The request was to examine the subgroup of patients with good adherence (74% of treated group, 82% of placebo group).
Among these three quarters of patients who took at least 80% of their doses, benefits were better.
Fluvoxamine cut serious complications in this group by 66% and reduced mortality by 91%. In the placebo group, 12 people died compared with one who received the study drug.
from complications of the infection.
However, clinicians should note that the drug can cause side effects such as nausea, dizziness, and insomnia, she added. In addition, because it prevents the body from metabolizing caffeine, patients should limit their daily intake to half of a small cup of coffee or one can of soda or one tea while taking the drug.
Previous research has shown that fluvoxamine affects the metabolism of some drugs, such as theophylline, clozapine, olanzapine, and tizanidine.
Despite huge challenges with studying generic drugs as early COVID-19 treatment, the TOGETHER trial shows it is possible to produce quality evidence during a pandemic on a shoestring budget, noted co-principal investigator Edward Mills, PhD, professor in the department of health research methods, evidence, and impact at McMaster University.
To screen more than 12,000 patients and enroll 4,000 to test nine interventions, “our total budget was less than $8 million,” Dr. Mills said. The trial was funded by Fast Grants and the Rainwater Charitable Foundation.
‘A $10 medicine’
Commenting on the findings, David Boulware, MD, MPH, an infectious disease physician-researcher at the University of Minnesota in Minneapolis, noted fluvoxamine is “a $10 medicine that’s available and has a very good safety record.”
By comparison, a 5-day course of Merck’s antiviral molnupiravir, another oral drug that the company says can cut hospitalizations in COVID-19 outpatients, costs $700. However, the data have not been peer reviewed – and molnupiravir is not currently available and has unknown long-term safety implications, Dr. Boulware said.
Pharmaceutical companies typically spend tens of thousands of dollars on a trial evaluating a single drug, he noted.
In addition, the National Institutes of Health’s ACTIV-6 study, a nationwide trial on the effect of fluvoxamine and other repurposed generic drugs on thousands of COVID-19 outpatients, is a $110 million effort, according to Dr. Boulware, who cochairs its steering committee.
ACTIV-6 is currently enrolling outpatients with COVID-19 to test a lower dose of fluvoxamine, at 50 mg twice daily instead of the 100-mg dose used in the TOGETHER trial, as well as ivermectin and inhaled fluticasone. The COVID-OUT trial is also recruiting newly diagnosed COVID-19 patients to test various combinations of fluvoxamine, ivermectin, and the diabetes drug metformin.
Unanswered safety, efficacy questions
In an accompanying editorial in The Lancet Global Health, Otavio Berwanger, MD, cardiologist and clinical trialist, Academic Research Organization, Hospital Israelita Albert Einstein, São Paulo, Brazil, commends the investigators for rapidly generating evidence during the COVID-19 pandemic.
However, despite the important findings, “some questions related to efficacy and safety of fluvoxamine for patients with COVID-19 remain open,” Dr. Berwanger wrote.
The effects of the drug on reducing both mortality and hospitalizations also “still need addressing,” he noted.
“In addition, it remains to be established whether fluvoxamine has an additive effect to other therapies such as monoclonal antibodies and budesonide, and what is the optimal fluvoxamine therapeutic scheme,” wrote Dr. Berwanger.
In an interview, he noted that 74% of the Brazil population have currently received at least one dose of a COVID-19 vaccine and 52% have received two doses. In addition, deaths have gone down from 4,000 per day during the March-April second wave to about 400 per day. “That is still unfortunate and far from ideal,” he said. In total, they have had about 600,000 deaths because of COVID-19.
Asked whether public health authorities are now recommending fluvoxamine as an early treatment for COVID-19 based on the TOGETHER trial data, Dr. Berwanger answered, “Not yet.
“I believe medical and scientific societies will need to critically appraise the manuscript in order to inform their decisions and recommendations. This interesting trial adds another important piece of information in this regard,” he said.
Dr. Reiersen and Dr. Lenze are inventors on a patent application related to methods for treating COVID-19, which was filed by Washington University. Dr. Mills reports no relevant financial relationships, as does Dr. Boulware – except that the TOGETHER trial funders are also funding the University of Minnesota COVID-OUT trial. Dr. Berwanger reports having received research grants outside of the submitted work that were paid to his institution by AstraZeneca, Bayer, Amgen, Servier, Novartis, Pfizer, and Boehringer Ingelheim.
A version of this article first appeared on Medscape.com.
Spiders, dogs, and PTSD: A virtual treatment for phobias and fear
At Wayne State University’s Stress, Trauma, and Anxiety Research Clinic (STARC) in Michigan, researchers are developing novel interventions for treating some very ancient phobias hardwired into the human brain. By using augmented reality as means of conducting exposure therapy, STARC researchers – including Shantanu Madaboosi, Rakesh Ramaswamy, and Lana Grasser – and STARC director Arash Javanbakht, MD, have produced compelling evidence that they can free patients of their often debilitating fears of spiders, dogs, and snakes. Yet their work doesn’t stop there, and research into treating anxiety and posttraumatic stress disorder among first responders and others with high-stress occupations is ongoing.
This news organization spoke with Dr. Javanbakht, a psychiatrist, about the technological advances that have made this work possible; the future of remote-based psychiatry; and his tarantula colleague, Tony.
Augmenting exposure therapy
How did you begin using artificial intelligence as a way of delivering exposure therapy?
Exposure therapy is a very effective treatment for phobias, obsessive-compulsive disorder, and PTSD. But the problem we had is that, if someone comes to me and says they’re afraid of dogs, snakes, or spiders, I don’t have those in my office. Or, if its social phobia, I can’t create those scenarios. So, despite being such an effective treatment, it’s not utilized as much as it should be.
Several years ago, I saw a TED talk by the CEO of an augmented reality company who happened to be a neuroscientist. I thought the concept was amazing, because it offered a way to overcome those limitations.
Mixed augmented reality allows us to bring all those feared objects to the clinic. I can bring my Labrador to the office for someone who’s afraid of dogs, and they can get the exposure to that one dog. But we know good exposure therapy needs to be generalizable, with as many different breeds of dogs as possible, and is context dependent. If the patient sees a dog in their neighborhood, their fear response may come back. Doing it in a real-life context, and offering as many contexts as possible, makes it more effective.
Augmented reality allows all of these options because you can have as many different types of virtual objects as you want, and the difference between augmented reality and virtual reality is that augmented reality happens in a real-life context. You wear the goggles and you can walk around the environment and track the object, so the context is more realistic.
When did you begin researching augmented reality as a clinical tool?
I became a faculty member here in 2015, right out of my residency training, and I think it was around 2016 or 2017 that we began this work.
I’m very much involved in exposure therapy, utilize it myself, train others, and research how it works and changes the brain. I knew the ins and outs and what would make a better exposure therapy, based on my knowledge of neuroscience.
We spend time thinking about how we can apply these neuroscientific principles in software that can also be easily used by a not very technologically savvy therapist. Because that has been a big barrier when it comes to technology and human use in medicine.
Initially, we had a company create the software for us, but we’ve since brought all the programming inside.
The cool thing about these augmented reality devices is that they have excellent surface mapping. As soon as the person wears the goggles, it automatically maps the surfaces and provides a 3D view of the patient’s environment on the therapist’s computer. Say you’re treating a patient with a fear of spiders. Through drop-down menus, the therapist can choose what type of spider, its color and size, where it should be placed, and the motion. I can choose to move the spider from 6 feet away on the floor to the walls to the ceiling.
Virtual phobias, real fear
A big question for a lot of people was if the spiders are virtual, will they be scary, because it has to be realistic enough to create a fear response for the therapy to work. We use a couple of wires that you can put on a person’s finger and hook them up to a tablet or a cell phone. This provides an online measure of a person’s autonomic sympathetic response.
Like a lie detector test?
Exactly. We put that on their fingers and exposed them to a real-life tarantula and to our virtual tarantulas, and the fear response was no different. That means these do create an objective fear reaction in the body.
We also had people who said, “I know this is not real. I won’t be scared.” And when we started the therapy, it was with a tiny spider 5 meters away from them, and they’d lift their legs off the floor.
With the treatment, we’d come to one room and start with a very little spider, far from them. Then gradually we move them up to bigger, more diverse types of spiders, which are moving around. The patient comes near and tries to touch them.
Then at some point, I’d put a spiderweb on the door, put a few spiders on that, open the door, and have the patient walk through it. They kept walking through this spiderweb.
When they were desensitized to these spiders in this context – and as I said, context is important – we’d go to another room. This was darker, more like a basement, and we’d continue the same thing. That would actually take much less time because they already had desensitized a lot.
In our field, sense of control is very important, especially for when a patient goes home. So at the end, I’d leave the room and talk to the patient via a baby monitor. The patient was surrounded by 20 tarantulas, without the prompt moving around the environment.
Now that they’re desensitized to my virtual spiders, the question is, how would that apply to a real spider? So, we had a real live tarantula, whose name was Tony Stark, because we’re the STARC lab. We’d put Tony at the end of a long hallway before the treatment and see how close the patients could get to him.
It was only one treatment session; nobody’s was longer than 1 hour, and the average treatment time was 38 minutes.
That’s pretty effective.
It’s pretty good, compared with other studies. And I believe this is because of all the components I mentioned: being able to use your real environment; combining it with the real tarantula; the variety of the types of the feared objects; and, of course, giving the patient a sense of autonomy at the end.
Then we had to see how prolonged the effects are. We had them come in 1 week and 1 month after the treatment. I’d remind them of the principles of good exposure therapy and ask them to keep practicing at home between the sessions, looking at pictures and videos. But we never tested who did or did not do it.
After 1 week and 1 month, the effects were either the same or better. A larger number of people at 1 month were able to touch the tarantula than right after treatment.
Treating PTSD in first responders
Did you start with spiders and dogs because those are common fears?
We started with spiders because that worked with the initial goal of creating a prototype. Spiders’ behavior is simple enough for the programming, which takes a lot of time. Another reason for choosing spiders was that we had a lot of other studies of real and virtual reality exposure therapy to compare against.
I think another reason for our success is that, when you do real exposure therapy, you have just one scared tarantula in the corner of their tank, and they don’t listen to you. But my spiders listen to me and do exactly what I tell them.
After our initial success, we obtained more funds to expand it to other phobias. The cool thing is that we don’t need separate software for different phobias. You can choose dogs or snakes, add it to the person’s environment, and decide their behaviors.
We just started a clinical trial using dogs, and another group in Turkey is running a clinical trial with dogs. Eastern Michigan University is working with spiders. And a clinic at the University of Nebraska Medical Center is going to start using them in real-world clinics, not for research.
We have another project whose goal is helping reduce the impact of trauma and also treating PTSD in first responders, who are exposed to a lot of horrible things. Rates of PTSD are around 20%-30% among cops, firefighters, and EMS personnel.
They commonly find it very painful being in crowds because the fight-or-flight instinct in the brain is constantly screening for any sign of threat in their environment. We’re working on them walking into an empty room wearing the goggles, and then their therapist can scale the stimulus up and down.
There’ll be two people in front of you talking to each other, and then another group comes in, and people get louder. People can look at you and talk to you. There’s kids running, Fourth of July fireworks, and other things that might bother someone who’s been involved in gun- or explosion-related traumas. You gradually scale up when the person is next to their therapist.
Another thing we’re doing is related to cardiopulmonary resuscitation. If a young person dies in a CPR situation, that is really painful and traumatic. So, for exposure therapy to that, we’re creating a difficult CPR scenario when that person may die. The responder wears the goggles and basically watches a group of people doing CPR while standing next to a therapist who can help them navigate it and then scale it off.
Another goal is combining this with telemedicine, where the person can do it in their real-life environment. Imagine a person with military trauma. You can put them back in the barracks, connected with their psychiatrists via telemedicine. Then we would put humans in military fatigues near them and have them interact with them to feel comfortable with that situation.
What else is next for you and your group?
The next biggest challenge that we’re tackling is PTSD, because of course creating human-encounter scenarios is much more complicated than spiders and dogs. We’re in the midst of developing this so we can basically bring it to people’s homes.
We’ve been working with some military personnel to see if we can basically give a device to a veteran with PTSD, so they can go home and practice on their own.
There’s another possibility for training. Let’s take the example of a police force, which can have a lot of difficulties and mistakes because of lack of exposure and training. They can wear these goggles, get fully geared up, and be placed in encounters with people of different backgrounds, of different severity, with people who could be severely mentally ill or present different challenges for the officers.
Those situations can teach them a lot. I’m the creator of this thing, but even I’m often surprised by how realistic this technology can be. I find myself interacting with avatars the same way I would if they were real humans. I actually had one of my colleagues, when we started launching the programming with the dogs, immediately jump back. It’s just like the animal brain reacts to them.
Last question: Do you actually interact with Tony, the tarantula?
Oh, Tony is my friend. Unfortunately, he’s not with our lab at this moment. He’s on a sabbatical at Eastern Michigan University for their clinical trials. But yes, I’ve held him. He’s very friendly.
A version of this article first appeared on Medscape.com.
At Wayne State University’s Stress, Trauma, and Anxiety Research Clinic (STARC) in Michigan, researchers are developing novel interventions for treating some very ancient phobias hardwired into the human brain. By using augmented reality as means of conducting exposure therapy, STARC researchers – including Shantanu Madaboosi, Rakesh Ramaswamy, and Lana Grasser – and STARC director Arash Javanbakht, MD, have produced compelling evidence that they can free patients of their often debilitating fears of spiders, dogs, and snakes. Yet their work doesn’t stop there, and research into treating anxiety and posttraumatic stress disorder among first responders and others with high-stress occupations is ongoing.
This news organization spoke with Dr. Javanbakht, a psychiatrist, about the technological advances that have made this work possible; the future of remote-based psychiatry; and his tarantula colleague, Tony.
Augmenting exposure therapy
How did you begin using artificial intelligence as a way of delivering exposure therapy?
Exposure therapy is a very effective treatment for phobias, obsessive-compulsive disorder, and PTSD. But the problem we had is that, if someone comes to me and says they’re afraid of dogs, snakes, or spiders, I don’t have those in my office. Or, if its social phobia, I can’t create those scenarios. So, despite being such an effective treatment, it’s not utilized as much as it should be.
Several years ago, I saw a TED talk by the CEO of an augmented reality company who happened to be a neuroscientist. I thought the concept was amazing, because it offered a way to overcome those limitations.
Mixed augmented reality allows us to bring all those feared objects to the clinic. I can bring my Labrador to the office for someone who’s afraid of dogs, and they can get the exposure to that one dog. But we know good exposure therapy needs to be generalizable, with as many different breeds of dogs as possible, and is context dependent. If the patient sees a dog in their neighborhood, their fear response may come back. Doing it in a real-life context, and offering as many contexts as possible, makes it more effective.
Augmented reality allows all of these options because you can have as many different types of virtual objects as you want, and the difference between augmented reality and virtual reality is that augmented reality happens in a real-life context. You wear the goggles and you can walk around the environment and track the object, so the context is more realistic.
When did you begin researching augmented reality as a clinical tool?
I became a faculty member here in 2015, right out of my residency training, and I think it was around 2016 or 2017 that we began this work.
I’m very much involved in exposure therapy, utilize it myself, train others, and research how it works and changes the brain. I knew the ins and outs and what would make a better exposure therapy, based on my knowledge of neuroscience.
We spend time thinking about how we can apply these neuroscientific principles in software that can also be easily used by a not very technologically savvy therapist. Because that has been a big barrier when it comes to technology and human use in medicine.
Initially, we had a company create the software for us, but we’ve since brought all the programming inside.
The cool thing about these augmented reality devices is that they have excellent surface mapping. As soon as the person wears the goggles, it automatically maps the surfaces and provides a 3D view of the patient’s environment on the therapist’s computer. Say you’re treating a patient with a fear of spiders. Through drop-down menus, the therapist can choose what type of spider, its color and size, where it should be placed, and the motion. I can choose to move the spider from 6 feet away on the floor to the walls to the ceiling.
Virtual phobias, real fear
A big question for a lot of people was if the spiders are virtual, will they be scary, because it has to be realistic enough to create a fear response for the therapy to work. We use a couple of wires that you can put on a person’s finger and hook them up to a tablet or a cell phone. This provides an online measure of a person’s autonomic sympathetic response.
Like a lie detector test?
Exactly. We put that on their fingers and exposed them to a real-life tarantula and to our virtual tarantulas, and the fear response was no different. That means these do create an objective fear reaction in the body.
We also had people who said, “I know this is not real. I won’t be scared.” And when we started the therapy, it was with a tiny spider 5 meters away from them, and they’d lift their legs off the floor.
With the treatment, we’d come to one room and start with a very little spider, far from them. Then gradually we move them up to bigger, more diverse types of spiders, which are moving around. The patient comes near and tries to touch them.
Then at some point, I’d put a spiderweb on the door, put a few spiders on that, open the door, and have the patient walk through it. They kept walking through this spiderweb.
When they were desensitized to these spiders in this context – and as I said, context is important – we’d go to another room. This was darker, more like a basement, and we’d continue the same thing. That would actually take much less time because they already had desensitized a lot.
In our field, sense of control is very important, especially for when a patient goes home. So at the end, I’d leave the room and talk to the patient via a baby monitor. The patient was surrounded by 20 tarantulas, without the prompt moving around the environment.
Now that they’re desensitized to my virtual spiders, the question is, how would that apply to a real spider? So, we had a real live tarantula, whose name was Tony Stark, because we’re the STARC lab. We’d put Tony at the end of a long hallway before the treatment and see how close the patients could get to him.
It was only one treatment session; nobody’s was longer than 1 hour, and the average treatment time was 38 minutes.
That’s pretty effective.
It’s pretty good, compared with other studies. And I believe this is because of all the components I mentioned: being able to use your real environment; combining it with the real tarantula; the variety of the types of the feared objects; and, of course, giving the patient a sense of autonomy at the end.
Then we had to see how prolonged the effects are. We had them come in 1 week and 1 month after the treatment. I’d remind them of the principles of good exposure therapy and ask them to keep practicing at home between the sessions, looking at pictures and videos. But we never tested who did or did not do it.
After 1 week and 1 month, the effects were either the same or better. A larger number of people at 1 month were able to touch the tarantula than right after treatment.
Treating PTSD in first responders
Did you start with spiders and dogs because those are common fears?
We started with spiders because that worked with the initial goal of creating a prototype. Spiders’ behavior is simple enough for the programming, which takes a lot of time. Another reason for choosing spiders was that we had a lot of other studies of real and virtual reality exposure therapy to compare against.
I think another reason for our success is that, when you do real exposure therapy, you have just one scared tarantula in the corner of their tank, and they don’t listen to you. But my spiders listen to me and do exactly what I tell them.
After our initial success, we obtained more funds to expand it to other phobias. The cool thing is that we don’t need separate software for different phobias. You can choose dogs or snakes, add it to the person’s environment, and decide their behaviors.
We just started a clinical trial using dogs, and another group in Turkey is running a clinical trial with dogs. Eastern Michigan University is working with spiders. And a clinic at the University of Nebraska Medical Center is going to start using them in real-world clinics, not for research.
We have another project whose goal is helping reduce the impact of trauma and also treating PTSD in first responders, who are exposed to a lot of horrible things. Rates of PTSD are around 20%-30% among cops, firefighters, and EMS personnel.
They commonly find it very painful being in crowds because the fight-or-flight instinct in the brain is constantly screening for any sign of threat in their environment. We’re working on them walking into an empty room wearing the goggles, and then their therapist can scale the stimulus up and down.
There’ll be two people in front of you talking to each other, and then another group comes in, and people get louder. People can look at you and talk to you. There’s kids running, Fourth of July fireworks, and other things that might bother someone who’s been involved in gun- or explosion-related traumas. You gradually scale up when the person is next to their therapist.
Another thing we’re doing is related to cardiopulmonary resuscitation. If a young person dies in a CPR situation, that is really painful and traumatic. So, for exposure therapy to that, we’re creating a difficult CPR scenario when that person may die. The responder wears the goggles and basically watches a group of people doing CPR while standing next to a therapist who can help them navigate it and then scale it off.
Another goal is combining this with telemedicine, where the person can do it in their real-life environment. Imagine a person with military trauma. You can put them back in the barracks, connected with their psychiatrists via telemedicine. Then we would put humans in military fatigues near them and have them interact with them to feel comfortable with that situation.
What else is next for you and your group?
The next biggest challenge that we’re tackling is PTSD, because of course creating human-encounter scenarios is much more complicated than spiders and dogs. We’re in the midst of developing this so we can basically bring it to people’s homes.
We’ve been working with some military personnel to see if we can basically give a device to a veteran with PTSD, so they can go home and practice on their own.
There’s another possibility for training. Let’s take the example of a police force, which can have a lot of difficulties and mistakes because of lack of exposure and training. They can wear these goggles, get fully geared up, and be placed in encounters with people of different backgrounds, of different severity, with people who could be severely mentally ill or present different challenges for the officers.
Those situations can teach them a lot. I’m the creator of this thing, but even I’m often surprised by how realistic this technology can be. I find myself interacting with avatars the same way I would if they were real humans. I actually had one of my colleagues, when we started launching the programming with the dogs, immediately jump back. It’s just like the animal brain reacts to them.
Last question: Do you actually interact with Tony, the tarantula?
Oh, Tony is my friend. Unfortunately, he’s not with our lab at this moment. He’s on a sabbatical at Eastern Michigan University for their clinical trials. But yes, I’ve held him. He’s very friendly.
A version of this article first appeared on Medscape.com.
At Wayne State University’s Stress, Trauma, and Anxiety Research Clinic (STARC) in Michigan, researchers are developing novel interventions for treating some very ancient phobias hardwired into the human brain. By using augmented reality as means of conducting exposure therapy, STARC researchers – including Shantanu Madaboosi, Rakesh Ramaswamy, and Lana Grasser – and STARC director Arash Javanbakht, MD, have produced compelling evidence that they can free patients of their often debilitating fears of spiders, dogs, and snakes. Yet their work doesn’t stop there, and research into treating anxiety and posttraumatic stress disorder among first responders and others with high-stress occupations is ongoing.
This news organization spoke with Dr. Javanbakht, a psychiatrist, about the technological advances that have made this work possible; the future of remote-based psychiatry; and his tarantula colleague, Tony.
Augmenting exposure therapy
How did you begin using artificial intelligence as a way of delivering exposure therapy?
Exposure therapy is a very effective treatment for phobias, obsessive-compulsive disorder, and PTSD. But the problem we had is that, if someone comes to me and says they’re afraid of dogs, snakes, or spiders, I don’t have those in my office. Or, if its social phobia, I can’t create those scenarios. So, despite being such an effective treatment, it’s not utilized as much as it should be.
Several years ago, I saw a TED talk by the CEO of an augmented reality company who happened to be a neuroscientist. I thought the concept was amazing, because it offered a way to overcome those limitations.
Mixed augmented reality allows us to bring all those feared objects to the clinic. I can bring my Labrador to the office for someone who’s afraid of dogs, and they can get the exposure to that one dog. But we know good exposure therapy needs to be generalizable, with as many different breeds of dogs as possible, and is context dependent. If the patient sees a dog in their neighborhood, their fear response may come back. Doing it in a real-life context, and offering as many contexts as possible, makes it more effective.
Augmented reality allows all of these options because you can have as many different types of virtual objects as you want, and the difference between augmented reality and virtual reality is that augmented reality happens in a real-life context. You wear the goggles and you can walk around the environment and track the object, so the context is more realistic.
When did you begin researching augmented reality as a clinical tool?
I became a faculty member here in 2015, right out of my residency training, and I think it was around 2016 or 2017 that we began this work.
I’m very much involved in exposure therapy, utilize it myself, train others, and research how it works and changes the brain. I knew the ins and outs and what would make a better exposure therapy, based on my knowledge of neuroscience.
We spend time thinking about how we can apply these neuroscientific principles in software that can also be easily used by a not very technologically savvy therapist. Because that has been a big barrier when it comes to technology and human use in medicine.
Initially, we had a company create the software for us, but we’ve since brought all the programming inside.
The cool thing about these augmented reality devices is that they have excellent surface mapping. As soon as the person wears the goggles, it automatically maps the surfaces and provides a 3D view of the patient’s environment on the therapist’s computer. Say you’re treating a patient with a fear of spiders. Through drop-down menus, the therapist can choose what type of spider, its color and size, where it should be placed, and the motion. I can choose to move the spider from 6 feet away on the floor to the walls to the ceiling.
Virtual phobias, real fear
A big question for a lot of people was if the spiders are virtual, will they be scary, because it has to be realistic enough to create a fear response for the therapy to work. We use a couple of wires that you can put on a person’s finger and hook them up to a tablet or a cell phone. This provides an online measure of a person’s autonomic sympathetic response.
Like a lie detector test?
Exactly. We put that on their fingers and exposed them to a real-life tarantula and to our virtual tarantulas, and the fear response was no different. That means these do create an objective fear reaction in the body.
We also had people who said, “I know this is not real. I won’t be scared.” And when we started the therapy, it was with a tiny spider 5 meters away from them, and they’d lift their legs off the floor.
With the treatment, we’d come to one room and start with a very little spider, far from them. Then gradually we move them up to bigger, more diverse types of spiders, which are moving around. The patient comes near and tries to touch them.
Then at some point, I’d put a spiderweb on the door, put a few spiders on that, open the door, and have the patient walk through it. They kept walking through this spiderweb.
When they were desensitized to these spiders in this context – and as I said, context is important – we’d go to another room. This was darker, more like a basement, and we’d continue the same thing. That would actually take much less time because they already had desensitized a lot.
In our field, sense of control is very important, especially for when a patient goes home. So at the end, I’d leave the room and talk to the patient via a baby monitor. The patient was surrounded by 20 tarantulas, without the prompt moving around the environment.
Now that they’re desensitized to my virtual spiders, the question is, how would that apply to a real spider? So, we had a real live tarantula, whose name was Tony Stark, because we’re the STARC lab. We’d put Tony at the end of a long hallway before the treatment and see how close the patients could get to him.
It was only one treatment session; nobody’s was longer than 1 hour, and the average treatment time was 38 minutes.
That’s pretty effective.
It’s pretty good, compared with other studies. And I believe this is because of all the components I mentioned: being able to use your real environment; combining it with the real tarantula; the variety of the types of the feared objects; and, of course, giving the patient a sense of autonomy at the end.
Then we had to see how prolonged the effects are. We had them come in 1 week and 1 month after the treatment. I’d remind them of the principles of good exposure therapy and ask them to keep practicing at home between the sessions, looking at pictures and videos. But we never tested who did or did not do it.
After 1 week and 1 month, the effects were either the same or better. A larger number of people at 1 month were able to touch the tarantula than right after treatment.
Treating PTSD in first responders
Did you start with spiders and dogs because those are common fears?
We started with spiders because that worked with the initial goal of creating a prototype. Spiders’ behavior is simple enough for the programming, which takes a lot of time. Another reason for choosing spiders was that we had a lot of other studies of real and virtual reality exposure therapy to compare against.
I think another reason for our success is that, when you do real exposure therapy, you have just one scared tarantula in the corner of their tank, and they don’t listen to you. But my spiders listen to me and do exactly what I tell them.
After our initial success, we obtained more funds to expand it to other phobias. The cool thing is that we don’t need separate software for different phobias. You can choose dogs or snakes, add it to the person’s environment, and decide their behaviors.
We just started a clinical trial using dogs, and another group in Turkey is running a clinical trial with dogs. Eastern Michigan University is working with spiders. And a clinic at the University of Nebraska Medical Center is going to start using them in real-world clinics, not for research.
We have another project whose goal is helping reduce the impact of trauma and also treating PTSD in first responders, who are exposed to a lot of horrible things. Rates of PTSD are around 20%-30% among cops, firefighters, and EMS personnel.
They commonly find it very painful being in crowds because the fight-or-flight instinct in the brain is constantly screening for any sign of threat in their environment. We’re working on them walking into an empty room wearing the goggles, and then their therapist can scale the stimulus up and down.
There’ll be two people in front of you talking to each other, and then another group comes in, and people get louder. People can look at you and talk to you. There’s kids running, Fourth of July fireworks, and other things that might bother someone who’s been involved in gun- or explosion-related traumas. You gradually scale up when the person is next to their therapist.
Another thing we’re doing is related to cardiopulmonary resuscitation. If a young person dies in a CPR situation, that is really painful and traumatic. So, for exposure therapy to that, we’re creating a difficult CPR scenario when that person may die. The responder wears the goggles and basically watches a group of people doing CPR while standing next to a therapist who can help them navigate it and then scale it off.
Another goal is combining this with telemedicine, where the person can do it in their real-life environment. Imagine a person with military trauma. You can put them back in the barracks, connected with their psychiatrists via telemedicine. Then we would put humans in military fatigues near them and have them interact with them to feel comfortable with that situation.
What else is next for you and your group?
The next biggest challenge that we’re tackling is PTSD, because of course creating human-encounter scenarios is much more complicated than spiders and dogs. We’re in the midst of developing this so we can basically bring it to people’s homes.
We’ve been working with some military personnel to see if we can basically give a device to a veteran with PTSD, so they can go home and practice on their own.
There’s another possibility for training. Let’s take the example of a police force, which can have a lot of difficulties and mistakes because of lack of exposure and training. They can wear these goggles, get fully geared up, and be placed in encounters with people of different backgrounds, of different severity, with people who could be severely mentally ill or present different challenges for the officers.
Those situations can teach them a lot. I’m the creator of this thing, but even I’m often surprised by how realistic this technology can be. I find myself interacting with avatars the same way I would if they were real humans. I actually had one of my colleagues, when we started launching the programming with the dogs, immediately jump back. It’s just like the animal brain reacts to them.
Last question: Do you actually interact with Tony, the tarantula?
Oh, Tony is my friend. Unfortunately, he’s not with our lab at this moment. He’s on a sabbatical at Eastern Michigan University for their clinical trials. But yes, I’ve held him. He’s very friendly.
A version of this article first appeared on Medscape.com.
Therapeutic homework adherence improves tics in Tourette’s disorder
Homework adherence between behavior therapy sessions is a significant predictor of therapeutic improvement in patients with Tourette’s disorder (TD), a study of 119 youth and adults suggests.
The assigning of “homework” to be completed between sessions – often used in cognitive-behavioral therapy – has been shown to reinforce learning but has not been well studied in TD.
“Understanding the relationship between homework adherence and therapeutic improvement from behavior therapy for TD may offer new insights for enhancing tic severity reductions achieved during this evidence-based treatment,” wrote Joey Ka-Yee Essoe, PhD, of the department of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, and colleagues.
To conduct the study, published in Behaviour Research and Therapy, the researchers recruited 70 youth and 49 adults with TD, ranging in age from 9 to 67 years, who underwent treatment at a single center. The average age was 21 years, and 80 participants were male. Treatment response was based on the Clinical Global Impressions of Improvement scale (CGI-I). Participants were assessed at baseline for tic severity and received eight sessions over 10 weeks. During those sessions, they were taught to perform a competing response to inhibit the expression of a tic when the tic or urge was detected.
Participants received homework at each weekly therapy session; most consisted of three to four practice sessions of about 30 minutes per week. Therapists reviewed the homework at the following session and adapted as needed to improve tic reduction skills.
After eight sessions of behavior therapy, overall greater homework adherence significantly predicted reduced tic severity and therapeutic improvement. However, early homework adherence predicted therapeutic improvement in youth, while late homework adherence predicted it in adults.
Overall,
However, homework adherence dipped midway through treatment in youth and showed a linear decline in adults, the researchers noted.
Among youth, baseline predictors of early homework adherence included lower levels of hyperactivity/impulsivity and caregiver strain. Among adults, baseline predictors of early homework adherence included lower anger scores, less social disability, and greater work disability.
The study findings were limited by several factors, including the absence of complete data on baseline predictors of homework adherence, reliance on a single measure of tic severity and improvement, and reliance on therapists’ reports of homework adherence, the researchers noted.
Future research should include objective measures of homework adherence, such as time-stamped videos, and different strategies may be needed for youth vs. adults, they added.
“Strategies that optimize homework adherence may enhance the efficacy of behavioral therapy, lead to greater tic severity reductions, and higher treatment response rates,” Dr. Essoe and colleagues wrote.
The study was supported by the Tourette Association of America, the National Institute of Mental Health, the American Academy of Neurology, and the American Psychological Foundation.
Homework adherence between behavior therapy sessions is a significant predictor of therapeutic improvement in patients with Tourette’s disorder (TD), a study of 119 youth and adults suggests.
The assigning of “homework” to be completed between sessions – often used in cognitive-behavioral therapy – has been shown to reinforce learning but has not been well studied in TD.
“Understanding the relationship between homework adherence and therapeutic improvement from behavior therapy for TD may offer new insights for enhancing tic severity reductions achieved during this evidence-based treatment,” wrote Joey Ka-Yee Essoe, PhD, of the department of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, and colleagues.
To conduct the study, published in Behaviour Research and Therapy, the researchers recruited 70 youth and 49 adults with TD, ranging in age from 9 to 67 years, who underwent treatment at a single center. The average age was 21 years, and 80 participants were male. Treatment response was based on the Clinical Global Impressions of Improvement scale (CGI-I). Participants were assessed at baseline for tic severity and received eight sessions over 10 weeks. During those sessions, they were taught to perform a competing response to inhibit the expression of a tic when the tic or urge was detected.
Participants received homework at each weekly therapy session; most consisted of three to four practice sessions of about 30 minutes per week. Therapists reviewed the homework at the following session and adapted as needed to improve tic reduction skills.
After eight sessions of behavior therapy, overall greater homework adherence significantly predicted reduced tic severity and therapeutic improvement. However, early homework adherence predicted therapeutic improvement in youth, while late homework adherence predicted it in adults.
Overall,
However, homework adherence dipped midway through treatment in youth and showed a linear decline in adults, the researchers noted.
Among youth, baseline predictors of early homework adherence included lower levels of hyperactivity/impulsivity and caregiver strain. Among adults, baseline predictors of early homework adherence included lower anger scores, less social disability, and greater work disability.
The study findings were limited by several factors, including the absence of complete data on baseline predictors of homework adherence, reliance on a single measure of tic severity and improvement, and reliance on therapists’ reports of homework adherence, the researchers noted.
Future research should include objective measures of homework adherence, such as time-stamped videos, and different strategies may be needed for youth vs. adults, they added.
“Strategies that optimize homework adherence may enhance the efficacy of behavioral therapy, lead to greater tic severity reductions, and higher treatment response rates,” Dr. Essoe and colleagues wrote.
The study was supported by the Tourette Association of America, the National Institute of Mental Health, the American Academy of Neurology, and the American Psychological Foundation.
Homework adherence between behavior therapy sessions is a significant predictor of therapeutic improvement in patients with Tourette’s disorder (TD), a study of 119 youth and adults suggests.
The assigning of “homework” to be completed between sessions – often used in cognitive-behavioral therapy – has been shown to reinforce learning but has not been well studied in TD.
“Understanding the relationship between homework adherence and therapeutic improvement from behavior therapy for TD may offer new insights for enhancing tic severity reductions achieved during this evidence-based treatment,” wrote Joey Ka-Yee Essoe, PhD, of the department of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, and colleagues.
To conduct the study, published in Behaviour Research and Therapy, the researchers recruited 70 youth and 49 adults with TD, ranging in age from 9 to 67 years, who underwent treatment at a single center. The average age was 21 years, and 80 participants were male. Treatment response was based on the Clinical Global Impressions of Improvement scale (CGI-I). Participants were assessed at baseline for tic severity and received eight sessions over 10 weeks. During those sessions, they were taught to perform a competing response to inhibit the expression of a tic when the tic or urge was detected.
Participants received homework at each weekly therapy session; most consisted of three to four practice sessions of about 30 minutes per week. Therapists reviewed the homework at the following session and adapted as needed to improve tic reduction skills.
After eight sessions of behavior therapy, overall greater homework adherence significantly predicted reduced tic severity and therapeutic improvement. However, early homework adherence predicted therapeutic improvement in youth, while late homework adherence predicted it in adults.
Overall,
However, homework adherence dipped midway through treatment in youth and showed a linear decline in adults, the researchers noted.
Among youth, baseline predictors of early homework adherence included lower levels of hyperactivity/impulsivity and caregiver strain. Among adults, baseline predictors of early homework adherence included lower anger scores, less social disability, and greater work disability.
The study findings were limited by several factors, including the absence of complete data on baseline predictors of homework adherence, reliance on a single measure of tic severity and improvement, and reliance on therapists’ reports of homework adherence, the researchers noted.
Future research should include objective measures of homework adherence, such as time-stamped videos, and different strategies may be needed for youth vs. adults, they added.
“Strategies that optimize homework adherence may enhance the efficacy of behavioral therapy, lead to greater tic severity reductions, and higher treatment response rates,” Dr. Essoe and colleagues wrote.
The study was supported by the Tourette Association of America, the National Institute of Mental Health, the American Academy of Neurology, and the American Psychological Foundation.
FROM BEHAVIOUR RESEARCH & THERAPY
Gut health ‘vitally important’ for mental health
Disturbances in gut microbiota are associated with depletion of anti-inflammatory bacteria and proliferation of proinflammatory bacteria, a pattern tied to several major psychiatric disorders including depression, bipolar disorder (BD), schizophrenia, and anxiety, new research shows.
A meta-analysis of 59 studies, encompassing roughly 2,600 patients with psychiatric conditions, showed a decrease in microbial richness in patients with psychiatric conditions versus controls.
In addition, those with depression, anxiety, BD, and psychosis had a similar set of abnormalities in the microbiota, particularly lower levels of Faecalibacterium and Coprococcus – two types of bacteria that have an anti-inflammatory effect in gut – and higher levels of Eggerthella, a bacterium with proinflammatory effects.
“The wealth of evidence we have summarized clearly demonstrates that the gut microbiota is vitally important to the wider mental health of individuals,” lead author Viktoriya Nikolova, MRes, Centre for Affective Disorders, King’s College London, said in an interview.
“While it is still too early to recommend specific interventions, it’s clear that clinicians need to place a greater awareness of gut health when considering the treatment of certain psychiatric disorders,” she said.
The study was published online Sept. 15, 2021, in JAMA Psychiatry.
Reliable biomarkers
“Evidence of gut microbiota perturbations has accumulated for multiple psychiatric disorders, with microbiota signatures proposed as potential biomarkers,” the authors wrote.
However, “while there is a wealth of evidence to suggest that abnormalities within the composition of the gut microbiota are connected to a number of psychiatric disorders, there haven’t been any attempts to evaluate the specificity of this evidence – that is, if these changes are unique to specific disorders or shared across many,” Ms. Nikolova said.
Previous research in individual disorders has identified “patterns that may be promising biomarker targets,” with the potential to “improve diagnostic accuracy, guide treatment, and assist the monitoring of treatment response,” the authors noted.
“We wanted to see if we could reliably establish biomarkers for individual conditions in an effort to further our understanding of the relationship between mental illness and gut microbiota,” said Ms. Nikolova.
The researchers wanted to “evaluate the specificity and reproducibility of gut microbiota alterations and delineate those with potential to become biomarkers.”
They identified 59 studies (64 case-control comparisons; n = 2,643 patients, 2,336 controls). Most (54.2%) were conducted in East Asia, followed by Westernized populations (40.7%) and Africa (1.7%).
These studies evaluated diversity or abundance of gut microbes in adult populations encompassing an array of psychiatric disorders: major depressive disorder (MDD), BD, psychosis and schizophrenia, eating disorders (anorexia nervosa and bulimia nervosa), anxiety, obsessive-compulsive disorder (OCD), PTSD, and ADHD.
Although studies were similar in exclusion criteria, few attempted to minimize dietary changes or control dietary intake. In addition, use of psychiatric medication also “varied substantially.”
The researchers conducted several analyses, with primary outcomes consisting of “community-level measures of gut microbiota composition (alpha and beta diversity) as well as taxonomic findings at the phylum, family, and genus levels (relative abundance).”
Alpha diversity provides a “summary of the microbial community in individual samples,” which “can be compared across groups to evaluate the role of a particular factor (in this case psychiatric diagnosis) on the richness (number of species) and evenness (how well each species is represented) in the sample.”
Beta diversity, on the other hand, “measures interindividual (between samples) diversity that assesses similarity of communities, compared with the other samples analyzed.”
Control samples consisted of participants without the relevant condition.
Biological overlap?
The alpha-diversity meta-analysis encompassed 34 studies (n = 1,519 patients, 1,429 controls). The researchers found significant decreases in microbial richness in patients, compared with controls (observed species standardized mean difference, −0.26; 95% CI, −0.47 to −0.06; Chao1 SMD, −0.5; 95% CI, −0.79 to −0.21). On the other hand, when they examined each diagnosis separately, they found consistent decreases only in bipolar disorder. There was a small, nonsignificant decrease in phylogenetic diversity between groups.
MDD, psychosis, and schizophrenia were the only conditions in which differences in beta diversity were consistently observed.
“These findings suggest there is reliable evidence for differences in the shared phylogenetic structure in MDD and psychosis and schizophrenia compared with controls,” the authors write.
However, “method of measurement and method of patient classification (symptom vs. diagnosis based) may affect findings,” they added.
When they focused on relative abundance, they found “little evidence” of disorder specificity, but rather a “transdiagnostic pattern of microbiota signatures.”
In particular, depleted levels of Faecalibacterium and Coprococcus and enriched levels of Eggerthella were “consistently shared” between MDD, BD, psychosis and schizophrenia, and anxiety, “suggesting these disorders are characterized by a reduction of anti-inflammatory butyrate-producing bacteria, while proinflammatory genera are enriched.”
“The finding that these perturbations do not appear to be disorder-specific suggests that the microbiota is affected in a similar manner by conditions such as depression, anxiety, bipolar disorder, and psychosis,” said Ms. Nikolova.
“We have seen similar findings from previous meta-analyses of inflammatory marker studies and genetic studies, for example, suggesting that there is a biological overlap between these conditions, which we have now also seen in the microbiota.”
The authors highlighted potential confounders, including study region and medication use.
Conditions such as MDD, psychosis, and schizophrenia were “largely investigated in the East,” while anorexia nervosa and OCD were primarily investigated in the West.
Moreover, comparing results from medication-free studies with those in which 80% or more of patients were taking psychiatric medication showed increases in bacterial families Lactobacillaceae, Klebsiella, Streptococcus, and Megasphaera only in medicated groups, and decreases in Dialister.
In light of these confounders, the findings should be considered “preliminary,” the investigators noted.
Greater standardization needed
Commenting on the study, Emeran Mayer, MD, director of the Oppenheimer Center for Neurobiology of Stress and Resilience at the University of California, Los Angeles, said it is “intriguing to speculate that low-grade immune activation due to reduced production of butyrate may be such a generalized factor affecting microbial composition shared similarly in several brain disorders. However, such a mechanism has not been confirmed in mechanistic studies to date.”
In addition, the study “lumps together a large number of studies and heterogeneous patient populations, with and without centrally acting medication, without adequate dietary history, studied in different ethnic populations, studied with highly variable collection and analysis methods, including highly variable sample and study sizes for different diseases, and using only measures of microbial composition but not function,” cautioned Dr. Mayer, who was not involved in the research.
Future studies “with much greater standardization of subject populations and clinical and biological analyses techniques should be performed to reevaluate the results of the current study and confirm or reject the main hypotheses,” asserted Dr. Mayer, who is also the founding director of the UCLA Brain Gut Microbiome Center.
Ms. Nikolova is funded by a Medical Research Council PhD Studentship. Other sources of funding include the National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King’s College London. Ms. Nikolova has disclosed no relevant financial relationships. Dr. Mayer is a scientific advisory board member of Danone, Axial Therapeutics, Viome, Amare, Mahana Therapeutics, Pendulum, Bloom Biosciences, and APC Microbiome Ireland.
A version of this article first appeared on Medscape.com .
Disturbances in gut microbiota are associated with depletion of anti-inflammatory bacteria and proliferation of proinflammatory bacteria, a pattern tied to several major psychiatric disorders including depression, bipolar disorder (BD), schizophrenia, and anxiety, new research shows.
A meta-analysis of 59 studies, encompassing roughly 2,600 patients with psychiatric conditions, showed a decrease in microbial richness in patients with psychiatric conditions versus controls.
In addition, those with depression, anxiety, BD, and psychosis had a similar set of abnormalities in the microbiota, particularly lower levels of Faecalibacterium and Coprococcus – two types of bacteria that have an anti-inflammatory effect in gut – and higher levels of Eggerthella, a bacterium with proinflammatory effects.
“The wealth of evidence we have summarized clearly demonstrates that the gut microbiota is vitally important to the wider mental health of individuals,” lead author Viktoriya Nikolova, MRes, Centre for Affective Disorders, King’s College London, said in an interview.
“While it is still too early to recommend specific interventions, it’s clear that clinicians need to place a greater awareness of gut health when considering the treatment of certain psychiatric disorders,” she said.
The study was published online Sept. 15, 2021, in JAMA Psychiatry.
Reliable biomarkers
“Evidence of gut microbiota perturbations has accumulated for multiple psychiatric disorders, with microbiota signatures proposed as potential biomarkers,” the authors wrote.
However, “while there is a wealth of evidence to suggest that abnormalities within the composition of the gut microbiota are connected to a number of psychiatric disorders, there haven’t been any attempts to evaluate the specificity of this evidence – that is, if these changes are unique to specific disorders or shared across many,” Ms. Nikolova said.
Previous research in individual disorders has identified “patterns that may be promising biomarker targets,” with the potential to “improve diagnostic accuracy, guide treatment, and assist the monitoring of treatment response,” the authors noted.
“We wanted to see if we could reliably establish biomarkers for individual conditions in an effort to further our understanding of the relationship between mental illness and gut microbiota,” said Ms. Nikolova.
The researchers wanted to “evaluate the specificity and reproducibility of gut microbiota alterations and delineate those with potential to become biomarkers.”
They identified 59 studies (64 case-control comparisons; n = 2,643 patients, 2,336 controls). Most (54.2%) were conducted in East Asia, followed by Westernized populations (40.7%) and Africa (1.7%).
These studies evaluated diversity or abundance of gut microbes in adult populations encompassing an array of psychiatric disorders: major depressive disorder (MDD), BD, psychosis and schizophrenia, eating disorders (anorexia nervosa and bulimia nervosa), anxiety, obsessive-compulsive disorder (OCD), PTSD, and ADHD.
Although studies were similar in exclusion criteria, few attempted to minimize dietary changes or control dietary intake. In addition, use of psychiatric medication also “varied substantially.”
The researchers conducted several analyses, with primary outcomes consisting of “community-level measures of gut microbiota composition (alpha and beta diversity) as well as taxonomic findings at the phylum, family, and genus levels (relative abundance).”
Alpha diversity provides a “summary of the microbial community in individual samples,” which “can be compared across groups to evaluate the role of a particular factor (in this case psychiatric diagnosis) on the richness (number of species) and evenness (how well each species is represented) in the sample.”
Beta diversity, on the other hand, “measures interindividual (between samples) diversity that assesses similarity of communities, compared with the other samples analyzed.”
Control samples consisted of participants without the relevant condition.
Biological overlap?
The alpha-diversity meta-analysis encompassed 34 studies (n = 1,519 patients, 1,429 controls). The researchers found significant decreases in microbial richness in patients, compared with controls (observed species standardized mean difference, −0.26; 95% CI, −0.47 to −0.06; Chao1 SMD, −0.5; 95% CI, −0.79 to −0.21). On the other hand, when they examined each diagnosis separately, they found consistent decreases only in bipolar disorder. There was a small, nonsignificant decrease in phylogenetic diversity between groups.
MDD, psychosis, and schizophrenia were the only conditions in which differences in beta diversity were consistently observed.
“These findings suggest there is reliable evidence for differences in the shared phylogenetic structure in MDD and psychosis and schizophrenia compared with controls,” the authors write.
However, “method of measurement and method of patient classification (symptom vs. diagnosis based) may affect findings,” they added.
When they focused on relative abundance, they found “little evidence” of disorder specificity, but rather a “transdiagnostic pattern of microbiota signatures.”
In particular, depleted levels of Faecalibacterium and Coprococcus and enriched levels of Eggerthella were “consistently shared” between MDD, BD, psychosis and schizophrenia, and anxiety, “suggesting these disorders are characterized by a reduction of anti-inflammatory butyrate-producing bacteria, while proinflammatory genera are enriched.”
“The finding that these perturbations do not appear to be disorder-specific suggests that the microbiota is affected in a similar manner by conditions such as depression, anxiety, bipolar disorder, and psychosis,” said Ms. Nikolova.
“We have seen similar findings from previous meta-analyses of inflammatory marker studies and genetic studies, for example, suggesting that there is a biological overlap between these conditions, which we have now also seen in the microbiota.”
The authors highlighted potential confounders, including study region and medication use.
Conditions such as MDD, psychosis, and schizophrenia were “largely investigated in the East,” while anorexia nervosa and OCD were primarily investigated in the West.
Moreover, comparing results from medication-free studies with those in which 80% or more of patients were taking psychiatric medication showed increases in bacterial families Lactobacillaceae, Klebsiella, Streptococcus, and Megasphaera only in medicated groups, and decreases in Dialister.
In light of these confounders, the findings should be considered “preliminary,” the investigators noted.
Greater standardization needed
Commenting on the study, Emeran Mayer, MD, director of the Oppenheimer Center for Neurobiology of Stress and Resilience at the University of California, Los Angeles, said it is “intriguing to speculate that low-grade immune activation due to reduced production of butyrate may be such a generalized factor affecting microbial composition shared similarly in several brain disorders. However, such a mechanism has not been confirmed in mechanistic studies to date.”
In addition, the study “lumps together a large number of studies and heterogeneous patient populations, with and without centrally acting medication, without adequate dietary history, studied in different ethnic populations, studied with highly variable collection and analysis methods, including highly variable sample and study sizes for different diseases, and using only measures of microbial composition but not function,” cautioned Dr. Mayer, who was not involved in the research.
Future studies “with much greater standardization of subject populations and clinical and biological analyses techniques should be performed to reevaluate the results of the current study and confirm or reject the main hypotheses,” asserted Dr. Mayer, who is also the founding director of the UCLA Brain Gut Microbiome Center.
Ms. Nikolova is funded by a Medical Research Council PhD Studentship. Other sources of funding include the National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King’s College London. Ms. Nikolova has disclosed no relevant financial relationships. Dr. Mayer is a scientific advisory board member of Danone, Axial Therapeutics, Viome, Amare, Mahana Therapeutics, Pendulum, Bloom Biosciences, and APC Microbiome Ireland.
A version of this article first appeared on Medscape.com .
Disturbances in gut microbiota are associated with depletion of anti-inflammatory bacteria and proliferation of proinflammatory bacteria, a pattern tied to several major psychiatric disorders including depression, bipolar disorder (BD), schizophrenia, and anxiety, new research shows.
A meta-analysis of 59 studies, encompassing roughly 2,600 patients with psychiatric conditions, showed a decrease in microbial richness in patients with psychiatric conditions versus controls.
In addition, those with depression, anxiety, BD, and psychosis had a similar set of abnormalities in the microbiota, particularly lower levels of Faecalibacterium and Coprococcus – two types of bacteria that have an anti-inflammatory effect in gut – and higher levels of Eggerthella, a bacterium with proinflammatory effects.
“The wealth of evidence we have summarized clearly demonstrates that the gut microbiota is vitally important to the wider mental health of individuals,” lead author Viktoriya Nikolova, MRes, Centre for Affective Disorders, King’s College London, said in an interview.
“While it is still too early to recommend specific interventions, it’s clear that clinicians need to place a greater awareness of gut health when considering the treatment of certain psychiatric disorders,” she said.
The study was published online Sept. 15, 2021, in JAMA Psychiatry.
Reliable biomarkers
“Evidence of gut microbiota perturbations has accumulated for multiple psychiatric disorders, with microbiota signatures proposed as potential biomarkers,” the authors wrote.
However, “while there is a wealth of evidence to suggest that abnormalities within the composition of the gut microbiota are connected to a number of psychiatric disorders, there haven’t been any attempts to evaluate the specificity of this evidence – that is, if these changes are unique to specific disorders or shared across many,” Ms. Nikolova said.
Previous research in individual disorders has identified “patterns that may be promising biomarker targets,” with the potential to “improve diagnostic accuracy, guide treatment, and assist the monitoring of treatment response,” the authors noted.
“We wanted to see if we could reliably establish biomarkers for individual conditions in an effort to further our understanding of the relationship between mental illness and gut microbiota,” said Ms. Nikolova.
The researchers wanted to “evaluate the specificity and reproducibility of gut microbiota alterations and delineate those with potential to become biomarkers.”
They identified 59 studies (64 case-control comparisons; n = 2,643 patients, 2,336 controls). Most (54.2%) were conducted in East Asia, followed by Westernized populations (40.7%) and Africa (1.7%).
These studies evaluated diversity or abundance of gut microbes in adult populations encompassing an array of psychiatric disorders: major depressive disorder (MDD), BD, psychosis and schizophrenia, eating disorders (anorexia nervosa and bulimia nervosa), anxiety, obsessive-compulsive disorder (OCD), PTSD, and ADHD.
Although studies were similar in exclusion criteria, few attempted to minimize dietary changes or control dietary intake. In addition, use of psychiatric medication also “varied substantially.”
The researchers conducted several analyses, with primary outcomes consisting of “community-level measures of gut microbiota composition (alpha and beta diversity) as well as taxonomic findings at the phylum, family, and genus levels (relative abundance).”
Alpha diversity provides a “summary of the microbial community in individual samples,” which “can be compared across groups to evaluate the role of a particular factor (in this case psychiatric diagnosis) on the richness (number of species) and evenness (how well each species is represented) in the sample.”
Beta diversity, on the other hand, “measures interindividual (between samples) diversity that assesses similarity of communities, compared with the other samples analyzed.”
Control samples consisted of participants without the relevant condition.
Biological overlap?
The alpha-diversity meta-analysis encompassed 34 studies (n = 1,519 patients, 1,429 controls). The researchers found significant decreases in microbial richness in patients, compared with controls (observed species standardized mean difference, −0.26; 95% CI, −0.47 to −0.06; Chao1 SMD, −0.5; 95% CI, −0.79 to −0.21). On the other hand, when they examined each diagnosis separately, they found consistent decreases only in bipolar disorder. There was a small, nonsignificant decrease in phylogenetic diversity between groups.
MDD, psychosis, and schizophrenia were the only conditions in which differences in beta diversity were consistently observed.
“These findings suggest there is reliable evidence for differences in the shared phylogenetic structure in MDD and psychosis and schizophrenia compared with controls,” the authors write.
However, “method of measurement and method of patient classification (symptom vs. diagnosis based) may affect findings,” they added.
When they focused on relative abundance, they found “little evidence” of disorder specificity, but rather a “transdiagnostic pattern of microbiota signatures.”
In particular, depleted levels of Faecalibacterium and Coprococcus and enriched levels of Eggerthella were “consistently shared” between MDD, BD, psychosis and schizophrenia, and anxiety, “suggesting these disorders are characterized by a reduction of anti-inflammatory butyrate-producing bacteria, while proinflammatory genera are enriched.”
“The finding that these perturbations do not appear to be disorder-specific suggests that the microbiota is affected in a similar manner by conditions such as depression, anxiety, bipolar disorder, and psychosis,” said Ms. Nikolova.
“We have seen similar findings from previous meta-analyses of inflammatory marker studies and genetic studies, for example, suggesting that there is a biological overlap between these conditions, which we have now also seen in the microbiota.”
The authors highlighted potential confounders, including study region and medication use.
Conditions such as MDD, psychosis, and schizophrenia were “largely investigated in the East,” while anorexia nervosa and OCD were primarily investigated in the West.
Moreover, comparing results from medication-free studies with those in which 80% or more of patients were taking psychiatric medication showed increases in bacterial families Lactobacillaceae, Klebsiella, Streptococcus, and Megasphaera only in medicated groups, and decreases in Dialister.
In light of these confounders, the findings should be considered “preliminary,” the investigators noted.
Greater standardization needed
Commenting on the study, Emeran Mayer, MD, director of the Oppenheimer Center for Neurobiology of Stress and Resilience at the University of California, Los Angeles, said it is “intriguing to speculate that low-grade immune activation due to reduced production of butyrate may be such a generalized factor affecting microbial composition shared similarly in several brain disorders. However, such a mechanism has not been confirmed in mechanistic studies to date.”
In addition, the study “lumps together a large number of studies and heterogeneous patient populations, with and without centrally acting medication, without adequate dietary history, studied in different ethnic populations, studied with highly variable collection and analysis methods, including highly variable sample and study sizes for different diseases, and using only measures of microbial composition but not function,” cautioned Dr. Mayer, who was not involved in the research.
Future studies “with much greater standardization of subject populations and clinical and biological analyses techniques should be performed to reevaluate the results of the current study and confirm or reject the main hypotheses,” asserted Dr. Mayer, who is also the founding director of the UCLA Brain Gut Microbiome Center.
Ms. Nikolova is funded by a Medical Research Council PhD Studentship. Other sources of funding include the National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King’s College London. Ms. Nikolova has disclosed no relevant financial relationships. Dr. Mayer is a scientific advisory board member of Danone, Axial Therapeutics, Viome, Amare, Mahana Therapeutics, Pendulum, Bloom Biosciences, and APC Microbiome Ireland.
A version of this article first appeared on Medscape.com .
Toward ‘superhuman cognition’: The future of brain-computer interfaces
The brain is inarguably the most complex and mysterious organ in the human body.
As the epicenter of intelligence, mastermind of movement, and song for our senses, the brain is more than a 3-lb organ encased in shell and fluid. Rather, it is the crown jewel that defines the self and, broadly, humanity.
For decades now, researchers have been exploring the potential for connecting our own astounding biological “computer” with actual physical mainframes. These so-called “brain-computer interfaces” (BCIs) are showing promise in treating an array of conditions, including paralysis, deafness, stroke, and even psychiatric disorders.
Among the big players in this area of research is billionaire entrepreneur Elon Musk, who in 2016 founded Neuralink. The company’s short-term mission is to develop a brain-to-machine interface to help people with neurologic conditions (for example, Parkinson’s disease). The long-term mission is to steer humanity into the era of “superhuman cognition.”
But first, some neuroscience 101.
Neurons are specialized cells that transmit and receive information. The basic structure of a neuron includes the dendrite, soma, and axon. The dendrite is the signal receiver. The soma is the cell body that is connected to the dendrites and serves as a structure to pass signals. The axon, also known as the nerve fiber, transmits the signal away from the soma.
Neurons communicate with each other at the synapse (for example, axon-dendrite connection). Neurons send information to each other through action potentials. An action potential may be defined as an electric impulse that transmits down the axon, causing the release of neurotransmitters, which may consequently either inhibit or excite the next neuron (leading to the initiation of another action potential).
So how will the company and other BCI companies tap into this evolutionarily ancient system to develop an implant that will obtain and decode information output from the brain?
The Neuralink implant is composed of three parts: The Link, neural threads, and the charger.
A robotic system, controlled by a neurosurgeon, will place an implant into the brain. The Link is the central component. It processes and transmits neural signals. The micron-scale neural threads are connected to the Link and other areas of the brain. The threads also contain electrodes, which are responsible for detecting neural signals. The charger ensures the battery is charged via wireless connection.
The invasive nature of this implant allows for precise readouts of electric outputs from the brain – unlike noninvasive devices, which are less sensitive and specific. Additionally, owing to its small size, engineers and neurosurgeons can implant the device in very specific brain regions as well as customize electrode distribution.
The Neuralink implant would be paired with an application via Bluetooth connection. The goal is to enable someone with the implant to control their device or computer by simply thinking. The application offers several exercises to help guide and train individuals on how to use the implant for its intended purpose. , as well as partake in creative activities such as photography.
Existing text and speech synthesis technology are already underway. For example, Synchron, a BCI platform company, is investigating the use of Stentrode for people with severe paralysis. This neuroprosthesis was designed to help people associate thought with movement through Bluetooth technology (for example, texting, emailing, shopping, online banking). Preliminary results from a study in which the device was used for patients with amyotrophic lateral sclerosis showed improvements in functional independence via direct thinking.
Software intended to enable high-performance handwriting utilizing BCI technology is being developed by Francis R. Willett, PhD, at Stanford (Calif.) University. The technology has also shown promise.
“We’ve learned that the brain retains its ability to prescribe fine movements a full decade after the body has lost its ability to execute those movements,” says Dr. Willett, who recently reported on results from a BCI study of handwriting conversion in an individual with full-body paralysis. Through a recurrent neural networking decoding approach, the BrainGate study participant was able to type 90 characters per minute – with an impressive 94.1% raw accuracy – using thoughts alone.
Although not a fully implantable brain device, this percutaneous implant has also been studied of its capacity to restore arm function among individuals who suffered from chronic stroke. Preliminary results from the Cortimo trials, led by Mijail D. Serruya, MD, an assistant professor at Thomas Jefferson University, Philadelphia, have been positive. Researchers implanted microelectrode arrays to decode brain signals and power motor function in a participant who had experienced a stroke 2 years earlier. The participant was able to use a powered arm brace on their paralyzed arm.
Neuralink recently released a video demonstrating the use of the interface in a monkey named Pager as it played a game with a joystick. Company researchers inserted a 1024-Electrode neural recording and data transmission device called the N1 Link into the left and right motor cortices. Using the implant, neural activity was sent to a decoder algorithm. Throughout the process, the decoder algorithm was refined and calibrated. After a few minutes, Pager was able to control the cursor on the screen using his mind instead of the joystick.
Mr. Musk hopes to develop Neuralink further to change not only the way we treat neurological disorders but also the way we interact with ourselves and our environment. It’s a lofty goal to be sure, but one that doesn’t seem outside the realm of possibility in the near future.
Known unknowns: The ethical dilemmas
One major conundrum facing the future of BCI technology is that researchers don’t fully understand the science regarding how brain signaling, artificial intelligence (AI) software, and prostheses interact. Although offloading computations improves the predictive nature of AI algorithms, there are concerns of identity and personal agency.
How do we know that an action is truly the result of one’s own thinking or, rather, the outcome of AI software? In this context, the autocorrect function while typing can be incredibly useful when we’re in a pinch for time, when we’re using one hand to type, or because of ease. However, it’s also easy to create and send out unintended or inappropriate messages.
These algorithms are designed to learn from our behavior and anticipate our next move. However, a question arises as to whether we are the authors of our own thoughts or whether we are simply the device that delivers messages under the control of external forces.
“People may question whether new personality changes they experience are truly representative of themselves or whether they are now a product of the implant (e.g., ‘Is that really me?’; ‘Have I grown as a person, or is it the technology?’). This then raises questions about agency and who we are as people,” says Kerry Bowman, PhD, a clinical bioethicist and assistant professor at the Temerty Faculty of Medicine of the University of Toronto.
It’s important to have safeguards in place to ensure the privacy of our thoughts. In an age where data is currency, it’s crucial to establish boundaries to preserve our autonomy and prevent exploitation (for example, by private companies or hackers). Although Neuralink and BCIs generally are certainly pushing the boundaries of neural engineering in profound ways, it’s important to note the biological and ethical implications of this technology.
As Dr. Bowman points out, “throughout the entire human story, under the worst of human circumstances, such as captivity and torture, the one safe ground and place for all people has been the privacy of one’s own mind. No one could ever interfere, take away, or be aware of those thoughts. However, this technology challenges one’s own privacy – that this technology (and, by extension, a company) could be aware of those thoughts.”
A version of this article first appeared on Medscape.com.
The brain is inarguably the most complex and mysterious organ in the human body.
As the epicenter of intelligence, mastermind of movement, and song for our senses, the brain is more than a 3-lb organ encased in shell and fluid. Rather, it is the crown jewel that defines the self and, broadly, humanity.
For decades now, researchers have been exploring the potential for connecting our own astounding biological “computer” with actual physical mainframes. These so-called “brain-computer interfaces” (BCIs) are showing promise in treating an array of conditions, including paralysis, deafness, stroke, and even psychiatric disorders.
Among the big players in this area of research is billionaire entrepreneur Elon Musk, who in 2016 founded Neuralink. The company’s short-term mission is to develop a brain-to-machine interface to help people with neurologic conditions (for example, Parkinson’s disease). The long-term mission is to steer humanity into the era of “superhuman cognition.”
But first, some neuroscience 101.
Neurons are specialized cells that transmit and receive information. The basic structure of a neuron includes the dendrite, soma, and axon. The dendrite is the signal receiver. The soma is the cell body that is connected to the dendrites and serves as a structure to pass signals. The axon, also known as the nerve fiber, transmits the signal away from the soma.
Neurons communicate with each other at the synapse (for example, axon-dendrite connection). Neurons send information to each other through action potentials. An action potential may be defined as an electric impulse that transmits down the axon, causing the release of neurotransmitters, which may consequently either inhibit or excite the next neuron (leading to the initiation of another action potential).
So how will the company and other BCI companies tap into this evolutionarily ancient system to develop an implant that will obtain and decode information output from the brain?
The Neuralink implant is composed of three parts: The Link, neural threads, and the charger.
A robotic system, controlled by a neurosurgeon, will place an implant into the brain. The Link is the central component. It processes and transmits neural signals. The micron-scale neural threads are connected to the Link and other areas of the brain. The threads also contain electrodes, which are responsible for detecting neural signals. The charger ensures the battery is charged via wireless connection.
The invasive nature of this implant allows for precise readouts of electric outputs from the brain – unlike noninvasive devices, which are less sensitive and specific. Additionally, owing to its small size, engineers and neurosurgeons can implant the device in very specific brain regions as well as customize electrode distribution.
The Neuralink implant would be paired with an application via Bluetooth connection. The goal is to enable someone with the implant to control their device or computer by simply thinking. The application offers several exercises to help guide and train individuals on how to use the implant for its intended purpose. , as well as partake in creative activities such as photography.
Existing text and speech synthesis technology are already underway. For example, Synchron, a BCI platform company, is investigating the use of Stentrode for people with severe paralysis. This neuroprosthesis was designed to help people associate thought with movement through Bluetooth technology (for example, texting, emailing, shopping, online banking). Preliminary results from a study in which the device was used for patients with amyotrophic lateral sclerosis showed improvements in functional independence via direct thinking.
Software intended to enable high-performance handwriting utilizing BCI technology is being developed by Francis R. Willett, PhD, at Stanford (Calif.) University. The technology has also shown promise.
“We’ve learned that the brain retains its ability to prescribe fine movements a full decade after the body has lost its ability to execute those movements,” says Dr. Willett, who recently reported on results from a BCI study of handwriting conversion in an individual with full-body paralysis. Through a recurrent neural networking decoding approach, the BrainGate study participant was able to type 90 characters per minute – with an impressive 94.1% raw accuracy – using thoughts alone.
Although not a fully implantable brain device, this percutaneous implant has also been studied of its capacity to restore arm function among individuals who suffered from chronic stroke. Preliminary results from the Cortimo trials, led by Mijail D. Serruya, MD, an assistant professor at Thomas Jefferson University, Philadelphia, have been positive. Researchers implanted microelectrode arrays to decode brain signals and power motor function in a participant who had experienced a stroke 2 years earlier. The participant was able to use a powered arm brace on their paralyzed arm.
Neuralink recently released a video demonstrating the use of the interface in a monkey named Pager as it played a game with a joystick. Company researchers inserted a 1024-Electrode neural recording and data transmission device called the N1 Link into the left and right motor cortices. Using the implant, neural activity was sent to a decoder algorithm. Throughout the process, the decoder algorithm was refined and calibrated. After a few minutes, Pager was able to control the cursor on the screen using his mind instead of the joystick.
Mr. Musk hopes to develop Neuralink further to change not only the way we treat neurological disorders but also the way we interact with ourselves and our environment. It’s a lofty goal to be sure, but one that doesn’t seem outside the realm of possibility in the near future.
Known unknowns: The ethical dilemmas
One major conundrum facing the future of BCI technology is that researchers don’t fully understand the science regarding how brain signaling, artificial intelligence (AI) software, and prostheses interact. Although offloading computations improves the predictive nature of AI algorithms, there are concerns of identity and personal agency.
How do we know that an action is truly the result of one’s own thinking or, rather, the outcome of AI software? In this context, the autocorrect function while typing can be incredibly useful when we’re in a pinch for time, when we’re using one hand to type, or because of ease. However, it’s also easy to create and send out unintended or inappropriate messages.
These algorithms are designed to learn from our behavior and anticipate our next move. However, a question arises as to whether we are the authors of our own thoughts or whether we are simply the device that delivers messages under the control of external forces.
“People may question whether new personality changes they experience are truly representative of themselves or whether they are now a product of the implant (e.g., ‘Is that really me?’; ‘Have I grown as a person, or is it the technology?’). This then raises questions about agency and who we are as people,” says Kerry Bowman, PhD, a clinical bioethicist and assistant professor at the Temerty Faculty of Medicine of the University of Toronto.
It’s important to have safeguards in place to ensure the privacy of our thoughts. In an age where data is currency, it’s crucial to establish boundaries to preserve our autonomy and prevent exploitation (for example, by private companies or hackers). Although Neuralink and BCIs generally are certainly pushing the boundaries of neural engineering in profound ways, it’s important to note the biological and ethical implications of this technology.
As Dr. Bowman points out, “throughout the entire human story, under the worst of human circumstances, such as captivity and torture, the one safe ground and place for all people has been the privacy of one’s own mind. No one could ever interfere, take away, or be aware of those thoughts. However, this technology challenges one’s own privacy – that this technology (and, by extension, a company) could be aware of those thoughts.”
A version of this article first appeared on Medscape.com.
The brain is inarguably the most complex and mysterious organ in the human body.
As the epicenter of intelligence, mastermind of movement, and song for our senses, the brain is more than a 3-lb organ encased in shell and fluid. Rather, it is the crown jewel that defines the self and, broadly, humanity.
For decades now, researchers have been exploring the potential for connecting our own astounding biological “computer” with actual physical mainframes. These so-called “brain-computer interfaces” (BCIs) are showing promise in treating an array of conditions, including paralysis, deafness, stroke, and even psychiatric disorders.
Among the big players in this area of research is billionaire entrepreneur Elon Musk, who in 2016 founded Neuralink. The company’s short-term mission is to develop a brain-to-machine interface to help people with neurologic conditions (for example, Parkinson’s disease). The long-term mission is to steer humanity into the era of “superhuman cognition.”
But first, some neuroscience 101.
Neurons are specialized cells that transmit and receive information. The basic structure of a neuron includes the dendrite, soma, and axon. The dendrite is the signal receiver. The soma is the cell body that is connected to the dendrites and serves as a structure to pass signals. The axon, also known as the nerve fiber, transmits the signal away from the soma.
Neurons communicate with each other at the synapse (for example, axon-dendrite connection). Neurons send information to each other through action potentials. An action potential may be defined as an electric impulse that transmits down the axon, causing the release of neurotransmitters, which may consequently either inhibit or excite the next neuron (leading to the initiation of another action potential).
So how will the company and other BCI companies tap into this evolutionarily ancient system to develop an implant that will obtain and decode information output from the brain?
The Neuralink implant is composed of three parts: The Link, neural threads, and the charger.
A robotic system, controlled by a neurosurgeon, will place an implant into the brain. The Link is the central component. It processes and transmits neural signals. The micron-scale neural threads are connected to the Link and other areas of the brain. The threads also contain electrodes, which are responsible for detecting neural signals. The charger ensures the battery is charged via wireless connection.
The invasive nature of this implant allows for precise readouts of electric outputs from the brain – unlike noninvasive devices, which are less sensitive and specific. Additionally, owing to its small size, engineers and neurosurgeons can implant the device in very specific brain regions as well as customize electrode distribution.
The Neuralink implant would be paired with an application via Bluetooth connection. The goal is to enable someone with the implant to control their device or computer by simply thinking. The application offers several exercises to help guide and train individuals on how to use the implant for its intended purpose. , as well as partake in creative activities such as photography.
Existing text and speech synthesis technology are already underway. For example, Synchron, a BCI platform company, is investigating the use of Stentrode for people with severe paralysis. This neuroprosthesis was designed to help people associate thought with movement through Bluetooth technology (for example, texting, emailing, shopping, online banking). Preliminary results from a study in which the device was used for patients with amyotrophic lateral sclerosis showed improvements in functional independence via direct thinking.
Software intended to enable high-performance handwriting utilizing BCI technology is being developed by Francis R. Willett, PhD, at Stanford (Calif.) University. The technology has also shown promise.
“We’ve learned that the brain retains its ability to prescribe fine movements a full decade after the body has lost its ability to execute those movements,” says Dr. Willett, who recently reported on results from a BCI study of handwriting conversion in an individual with full-body paralysis. Through a recurrent neural networking decoding approach, the BrainGate study participant was able to type 90 characters per minute – with an impressive 94.1% raw accuracy – using thoughts alone.
Although not a fully implantable brain device, this percutaneous implant has also been studied of its capacity to restore arm function among individuals who suffered from chronic stroke. Preliminary results from the Cortimo trials, led by Mijail D. Serruya, MD, an assistant professor at Thomas Jefferson University, Philadelphia, have been positive. Researchers implanted microelectrode arrays to decode brain signals and power motor function in a participant who had experienced a stroke 2 years earlier. The participant was able to use a powered arm brace on their paralyzed arm.
Neuralink recently released a video demonstrating the use of the interface in a monkey named Pager as it played a game with a joystick. Company researchers inserted a 1024-Electrode neural recording and data transmission device called the N1 Link into the left and right motor cortices. Using the implant, neural activity was sent to a decoder algorithm. Throughout the process, the decoder algorithm was refined and calibrated. After a few minutes, Pager was able to control the cursor on the screen using his mind instead of the joystick.
Mr. Musk hopes to develop Neuralink further to change not only the way we treat neurological disorders but also the way we interact with ourselves and our environment. It’s a lofty goal to be sure, but one that doesn’t seem outside the realm of possibility in the near future.
Known unknowns: The ethical dilemmas
One major conundrum facing the future of BCI technology is that researchers don’t fully understand the science regarding how brain signaling, artificial intelligence (AI) software, and prostheses interact. Although offloading computations improves the predictive nature of AI algorithms, there are concerns of identity and personal agency.
How do we know that an action is truly the result of one’s own thinking or, rather, the outcome of AI software? In this context, the autocorrect function while typing can be incredibly useful when we’re in a pinch for time, when we’re using one hand to type, or because of ease. However, it’s also easy to create and send out unintended or inappropriate messages.
These algorithms are designed to learn from our behavior and anticipate our next move. However, a question arises as to whether we are the authors of our own thoughts or whether we are simply the device that delivers messages under the control of external forces.
“People may question whether new personality changes they experience are truly representative of themselves or whether they are now a product of the implant (e.g., ‘Is that really me?’; ‘Have I grown as a person, or is it the technology?’). This then raises questions about agency and who we are as people,” says Kerry Bowman, PhD, a clinical bioethicist and assistant professor at the Temerty Faculty of Medicine of the University of Toronto.
It’s important to have safeguards in place to ensure the privacy of our thoughts. In an age where data is currency, it’s crucial to establish boundaries to preserve our autonomy and prevent exploitation (for example, by private companies or hackers). Although Neuralink and BCIs generally are certainly pushing the boundaries of neural engineering in profound ways, it’s important to note the biological and ethical implications of this technology.
As Dr. Bowman points out, “throughout the entire human story, under the worst of human circumstances, such as captivity and torture, the one safe ground and place for all people has been the privacy of one’s own mind. No one could ever interfere, take away, or be aware of those thoughts. However, this technology challenges one’s own privacy – that this technology (and, by extension, a company) could be aware of those thoughts.”
A version of this article first appeared on Medscape.com.
Neuropsychiatry affects pediatric OCD treatment
Treatment of pediatric obsessive-compulsive disorder (OCD) has evolved in recent years, with more attention given to some of the neuropsychiatric underpinnings of the condition and how they can affect treatment response.
At the Focus on Neuropsychiatry 2021 meeting, Jeffrey Strawn, MD, outlined some of the neuropsychiatry affecting disease and potential mechanisms to help control obsessions and behaviors, and how they may fit with some therapeutic regimens.
Dr. Strawn discussed the psychological construct of cognitive control, which can provide patients an “out” from the cycle of obsession/fear/worry and compulsion/avoidance. In the face of distress, compulsion and avoidance lead to relief, which reinforces the obsession/fear/worry; this in turn leads to more distress.
“We have an escape door for this circuit” in the form of cognitive control, said Dr. Strawn, who is an associate professor of pediatrics at Cincinnati Children’s Hospital Medical Center.
Cognitive control is linked to insight, which can in turn increase adaptive behaviors that help the patient resist the compulsion. Patients won’t eliminate distress, but they can be helped to make it more tolerable. Therapists can then help them move toward goal-directed thoughts and behaviors. Cognitive control is associated with several neural networks, but Dr. Strawn focused on two: the frontoparietal network, associated with top-down regulation; and the cingular-opercular network. Both of these are engaged during cognitive control processes, and play a role inhibitory control and error monitoring.
Dr. Strawn discussed a recent study that explored the neurofunctional basis of treatment. It compared the effects of a stress management therapy and cognitive-behavioral therapy (CBT) in children and adults with OCD at 6 and 12 weeks. The study found similar symptom reductions in both adults and adolescents in both intervention groups.
Before initiating treatment, the researchers conducted functional MRI scans of participants while conducting an incentive flanker task, which reveals brain activity in response to cognitive control and reward processing.
A larger therapeutic response was found in the CBT group among patients who had a larger pretreatment activation within the right temporal lobe and rostral anterior cingulate cortex during cognitive control, as well as those with more activation within the medial prefrontal, orbitofrontal, lateral prefrontal, and amygdala regions during reward processing. On the other hand, within the stress management therapy group, treatment responses were better among those who had lower pretreatment activation among overlapping regions.
“There was a difference in terms of the neurofunctional predictors of treatment response. One of the key regions is the medial prefrontal cortex as well as the rostral anterior cingulate,” said Dr. Strawn, at the meeting presented by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.
On the neuropharmacology side, numerous medications have been approved for OCD. Dr. Strawn highlighted some studies to illustrate general OCD treatment concepts. That included the 2004 Pediatric OCD Treatment Study, which was one of the only trials to compare placebo with an SSRI, CBT, and the combination of SSRI and CBT. It showed the best results with combination therapy, and the difference appeared early in the treatment course.
That study had aggressive dosing, which led to some issues with sertraline tolerability. Dr. Strawn showed results of a study at his institution which showed that the drug levels of pediatric patients treated with sertraline depended on CYP2C19 metabolism, which affects overall exposure and peak dose concentration. In pediatric populations, some SSRIs clear more slowly and can have high peak concentrations. SSRIs have more side effects than serotonin and norepinephrine reuptake inhibitors in both anxiety disorders and OCD. A key difference between the two is that SSRI treatment is associated with greater frequency of activation, which is difficult to define, but includes restlessness and agitation and insomnia in the beginning stages of treatment.
SSRIs also lead to improvement early in the course of treatment, which was shown in a meta-analysis of nine trials. However, the same study showed that clomipramine is associated with a faster and greater magnitude of improvement, compared with SSRIs, even when the latter are dosed aggressively.
Clomipramine is a potent inhibitor of both serotonin and norepinephrine reuptake. It is recommended to monitor clomipramine levels in pediatric OCD patients, and Dr. Strawn suggested that monitoring should include both the parent drug and its primary metabolite, norclomipramine. At a given dose, there can be a great deal of variation in drug level. The clomipramine/norclomipramine ratio can provide information about the patient’s metabolic state, as well as drug adherence.
Dr. Strawn noted that peak levels occur around 1-3 hours after the dose, “and we really do want at least a 12-hour trough level.” EKGs should be performed at baseline and after any titration of clomipramine dose.
He also discussed pediatric OCD patients with OCD and tics. About one-third of Tourette syndrome patients experience OCD at some point. Tics often improve, whereas OCD more often persists. Tics that co-occur with OCD are associated with a lesser response to SSRI treatment, but not CBT treatment. Similarly, patients with hoarding tendencies are about one-third less likely to respond to SSRIs, CBT, or combination therapy.
Dr. Strawn discussed the concept of accommodation, in which family members cope with a patient’s behavior by altering routines to minimize distress and impairment. This may take the form of facilitating rituals, providing reassurance about a patient’s fears, acquiescing to demands, reducing the child’s day-to-day responsibilities, or helping the child complete tasks. Such actions are well intentioned, but they undermine cognitive control, negatively reinforce symptom engagement, and are associated with functional impairment. Reassurance is the most important behavior, occurring in more than half of patients, and it’s measurable. Parental involvement with rituals is also a concern. “This is associated with higher levels of child OCD severity, as well as parental psychopathology, and lower family cohesion. So
New developments in neurobiology and neuropsychology have changed the view of exposure. The old model emphasized the child’s fear rating as an index of corrective learning. The idea was that habituation would decrease anxiety and distress from future exposures. The new model revolves around inhibitory learning theory, which focuses on the variability of distress and aims to increase tolerance of distress. Another goal is to develop new, non-threat associations.
Finally, Dr. Strawn pointed out predictors of poor outcomes in pediatric OCD, including factors such as compulsion severity, oppositional behavior, frequent handwashing, functional impairment, lack of insight, externalizing symptoms, and possibly hoarding. Problematic family characteristics include higher levels of accommodation, parental anxiety, low family cohesion, and high levels of conflict. “The last three really represent a very concerning triad of family behaviors that may necessitate specific family work in order to facilitate the recovery of the pediatric patient,” Dr. Strawn said.
During the question-and-answer session after the talk, Dr. Strawn was asked whether there might be an inflammatory component to OCD, and whether pediatric autoimmune neuropsychiatric disorders associated with streptococcus (PANDAS) might be a prodromal condition. He noted that some studies have shown a relationship, but results have been mixed, with lots of heterogeneity within the studied populations. To be suspicious that a patient had OCD resulting from PANDAS would require a high threshold, including an acute onset of symptoms. “This is a situation also where I would tend to involve consultation with some other specialties, including neurology. And obviously there would be follow-up in terms of the general workup,” he said.
Dr. Strawn has received research funding from Allergan, Otsuka, and Myriad Genetics. He has consulted for Myriad Genetics, and is a speaker for CMEology and the Neuroscience Education Institute.
Treatment of pediatric obsessive-compulsive disorder (OCD) has evolved in recent years, with more attention given to some of the neuropsychiatric underpinnings of the condition and how they can affect treatment response.
At the Focus on Neuropsychiatry 2021 meeting, Jeffrey Strawn, MD, outlined some of the neuropsychiatry affecting disease and potential mechanisms to help control obsessions and behaviors, and how they may fit with some therapeutic regimens.
Dr. Strawn discussed the psychological construct of cognitive control, which can provide patients an “out” from the cycle of obsession/fear/worry and compulsion/avoidance. In the face of distress, compulsion and avoidance lead to relief, which reinforces the obsession/fear/worry; this in turn leads to more distress.
“We have an escape door for this circuit” in the form of cognitive control, said Dr. Strawn, who is an associate professor of pediatrics at Cincinnati Children’s Hospital Medical Center.
Cognitive control is linked to insight, which can in turn increase adaptive behaviors that help the patient resist the compulsion. Patients won’t eliminate distress, but they can be helped to make it more tolerable. Therapists can then help them move toward goal-directed thoughts and behaviors. Cognitive control is associated with several neural networks, but Dr. Strawn focused on two: the frontoparietal network, associated with top-down regulation; and the cingular-opercular network. Both of these are engaged during cognitive control processes, and play a role inhibitory control and error monitoring.
Dr. Strawn discussed a recent study that explored the neurofunctional basis of treatment. It compared the effects of a stress management therapy and cognitive-behavioral therapy (CBT) in children and adults with OCD at 6 and 12 weeks. The study found similar symptom reductions in both adults and adolescents in both intervention groups.
Before initiating treatment, the researchers conducted functional MRI scans of participants while conducting an incentive flanker task, which reveals brain activity in response to cognitive control and reward processing.
A larger therapeutic response was found in the CBT group among patients who had a larger pretreatment activation within the right temporal lobe and rostral anterior cingulate cortex during cognitive control, as well as those with more activation within the medial prefrontal, orbitofrontal, lateral prefrontal, and amygdala regions during reward processing. On the other hand, within the stress management therapy group, treatment responses were better among those who had lower pretreatment activation among overlapping regions.
“There was a difference in terms of the neurofunctional predictors of treatment response. One of the key regions is the medial prefrontal cortex as well as the rostral anterior cingulate,” said Dr. Strawn, at the meeting presented by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.
On the neuropharmacology side, numerous medications have been approved for OCD. Dr. Strawn highlighted some studies to illustrate general OCD treatment concepts. That included the 2004 Pediatric OCD Treatment Study, which was one of the only trials to compare placebo with an SSRI, CBT, and the combination of SSRI and CBT. It showed the best results with combination therapy, and the difference appeared early in the treatment course.
That study had aggressive dosing, which led to some issues with sertraline tolerability. Dr. Strawn showed results of a study at his institution which showed that the drug levels of pediatric patients treated with sertraline depended on CYP2C19 metabolism, which affects overall exposure and peak dose concentration. In pediatric populations, some SSRIs clear more slowly and can have high peak concentrations. SSRIs have more side effects than serotonin and norepinephrine reuptake inhibitors in both anxiety disorders and OCD. A key difference between the two is that SSRI treatment is associated with greater frequency of activation, which is difficult to define, but includes restlessness and agitation and insomnia in the beginning stages of treatment.
SSRIs also lead to improvement early in the course of treatment, which was shown in a meta-analysis of nine trials. However, the same study showed that clomipramine is associated with a faster and greater magnitude of improvement, compared with SSRIs, even when the latter are dosed aggressively.
Clomipramine is a potent inhibitor of both serotonin and norepinephrine reuptake. It is recommended to monitor clomipramine levels in pediatric OCD patients, and Dr. Strawn suggested that monitoring should include both the parent drug and its primary metabolite, norclomipramine. At a given dose, there can be a great deal of variation in drug level. The clomipramine/norclomipramine ratio can provide information about the patient’s metabolic state, as well as drug adherence.
Dr. Strawn noted that peak levels occur around 1-3 hours after the dose, “and we really do want at least a 12-hour trough level.” EKGs should be performed at baseline and after any titration of clomipramine dose.
He also discussed pediatric OCD patients with OCD and tics. About one-third of Tourette syndrome patients experience OCD at some point. Tics often improve, whereas OCD more often persists. Tics that co-occur with OCD are associated with a lesser response to SSRI treatment, but not CBT treatment. Similarly, patients with hoarding tendencies are about one-third less likely to respond to SSRIs, CBT, or combination therapy.
Dr. Strawn discussed the concept of accommodation, in which family members cope with a patient’s behavior by altering routines to minimize distress and impairment. This may take the form of facilitating rituals, providing reassurance about a patient’s fears, acquiescing to demands, reducing the child’s day-to-day responsibilities, or helping the child complete tasks. Such actions are well intentioned, but they undermine cognitive control, negatively reinforce symptom engagement, and are associated with functional impairment. Reassurance is the most important behavior, occurring in more than half of patients, and it’s measurable. Parental involvement with rituals is also a concern. “This is associated with higher levels of child OCD severity, as well as parental psychopathology, and lower family cohesion. So
New developments in neurobiology and neuropsychology have changed the view of exposure. The old model emphasized the child’s fear rating as an index of corrective learning. The idea was that habituation would decrease anxiety and distress from future exposures. The new model revolves around inhibitory learning theory, which focuses on the variability of distress and aims to increase tolerance of distress. Another goal is to develop new, non-threat associations.
Finally, Dr. Strawn pointed out predictors of poor outcomes in pediatric OCD, including factors such as compulsion severity, oppositional behavior, frequent handwashing, functional impairment, lack of insight, externalizing symptoms, and possibly hoarding. Problematic family characteristics include higher levels of accommodation, parental anxiety, low family cohesion, and high levels of conflict. “The last three really represent a very concerning triad of family behaviors that may necessitate specific family work in order to facilitate the recovery of the pediatric patient,” Dr. Strawn said.
During the question-and-answer session after the talk, Dr. Strawn was asked whether there might be an inflammatory component to OCD, and whether pediatric autoimmune neuropsychiatric disorders associated with streptococcus (PANDAS) might be a prodromal condition. He noted that some studies have shown a relationship, but results have been mixed, with lots of heterogeneity within the studied populations. To be suspicious that a patient had OCD resulting from PANDAS would require a high threshold, including an acute onset of symptoms. “This is a situation also where I would tend to involve consultation with some other specialties, including neurology. And obviously there would be follow-up in terms of the general workup,” he said.
Dr. Strawn has received research funding from Allergan, Otsuka, and Myriad Genetics. He has consulted for Myriad Genetics, and is a speaker for CMEology and the Neuroscience Education Institute.
Treatment of pediatric obsessive-compulsive disorder (OCD) has evolved in recent years, with more attention given to some of the neuropsychiatric underpinnings of the condition and how they can affect treatment response.
At the Focus on Neuropsychiatry 2021 meeting, Jeffrey Strawn, MD, outlined some of the neuropsychiatry affecting disease and potential mechanisms to help control obsessions and behaviors, and how they may fit with some therapeutic regimens.
Dr. Strawn discussed the psychological construct of cognitive control, which can provide patients an “out” from the cycle of obsession/fear/worry and compulsion/avoidance. In the face of distress, compulsion and avoidance lead to relief, which reinforces the obsession/fear/worry; this in turn leads to more distress.
“We have an escape door for this circuit” in the form of cognitive control, said Dr. Strawn, who is an associate professor of pediatrics at Cincinnati Children’s Hospital Medical Center.
Cognitive control is linked to insight, which can in turn increase adaptive behaviors that help the patient resist the compulsion. Patients won’t eliminate distress, but they can be helped to make it more tolerable. Therapists can then help them move toward goal-directed thoughts and behaviors. Cognitive control is associated with several neural networks, but Dr. Strawn focused on two: the frontoparietal network, associated with top-down regulation; and the cingular-opercular network. Both of these are engaged during cognitive control processes, and play a role inhibitory control and error monitoring.
Dr. Strawn discussed a recent study that explored the neurofunctional basis of treatment. It compared the effects of a stress management therapy and cognitive-behavioral therapy (CBT) in children and adults with OCD at 6 and 12 weeks. The study found similar symptom reductions in both adults and adolescents in both intervention groups.
Before initiating treatment, the researchers conducted functional MRI scans of participants while conducting an incentive flanker task, which reveals brain activity in response to cognitive control and reward processing.
A larger therapeutic response was found in the CBT group among patients who had a larger pretreatment activation within the right temporal lobe and rostral anterior cingulate cortex during cognitive control, as well as those with more activation within the medial prefrontal, orbitofrontal, lateral prefrontal, and amygdala regions during reward processing. On the other hand, within the stress management therapy group, treatment responses were better among those who had lower pretreatment activation among overlapping regions.
“There was a difference in terms of the neurofunctional predictors of treatment response. One of the key regions is the medial prefrontal cortex as well as the rostral anterior cingulate,” said Dr. Strawn, at the meeting presented by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.
On the neuropharmacology side, numerous medications have been approved for OCD. Dr. Strawn highlighted some studies to illustrate general OCD treatment concepts. That included the 2004 Pediatric OCD Treatment Study, which was one of the only trials to compare placebo with an SSRI, CBT, and the combination of SSRI and CBT. It showed the best results with combination therapy, and the difference appeared early in the treatment course.
That study had aggressive dosing, which led to some issues with sertraline tolerability. Dr. Strawn showed results of a study at his institution which showed that the drug levels of pediatric patients treated with sertraline depended on CYP2C19 metabolism, which affects overall exposure and peak dose concentration. In pediatric populations, some SSRIs clear more slowly and can have high peak concentrations. SSRIs have more side effects than serotonin and norepinephrine reuptake inhibitors in both anxiety disorders and OCD. A key difference between the two is that SSRI treatment is associated with greater frequency of activation, which is difficult to define, but includes restlessness and agitation and insomnia in the beginning stages of treatment.
SSRIs also lead to improvement early in the course of treatment, which was shown in a meta-analysis of nine trials. However, the same study showed that clomipramine is associated with a faster and greater magnitude of improvement, compared with SSRIs, even when the latter are dosed aggressively.
Clomipramine is a potent inhibitor of both serotonin and norepinephrine reuptake. It is recommended to monitor clomipramine levels in pediatric OCD patients, and Dr. Strawn suggested that monitoring should include both the parent drug and its primary metabolite, norclomipramine. At a given dose, there can be a great deal of variation in drug level. The clomipramine/norclomipramine ratio can provide information about the patient’s metabolic state, as well as drug adherence.
Dr. Strawn noted that peak levels occur around 1-3 hours after the dose, “and we really do want at least a 12-hour trough level.” EKGs should be performed at baseline and after any titration of clomipramine dose.
He also discussed pediatric OCD patients with OCD and tics. About one-third of Tourette syndrome patients experience OCD at some point. Tics often improve, whereas OCD more often persists. Tics that co-occur with OCD are associated with a lesser response to SSRI treatment, but not CBT treatment. Similarly, patients with hoarding tendencies are about one-third less likely to respond to SSRIs, CBT, or combination therapy.
Dr. Strawn discussed the concept of accommodation, in which family members cope with a patient’s behavior by altering routines to minimize distress and impairment. This may take the form of facilitating rituals, providing reassurance about a patient’s fears, acquiescing to demands, reducing the child’s day-to-day responsibilities, or helping the child complete tasks. Such actions are well intentioned, but they undermine cognitive control, negatively reinforce symptom engagement, and are associated with functional impairment. Reassurance is the most important behavior, occurring in more than half of patients, and it’s measurable. Parental involvement with rituals is also a concern. “This is associated with higher levels of child OCD severity, as well as parental psychopathology, and lower family cohesion. So
New developments in neurobiology and neuropsychology have changed the view of exposure. The old model emphasized the child’s fear rating as an index of corrective learning. The idea was that habituation would decrease anxiety and distress from future exposures. The new model revolves around inhibitory learning theory, which focuses on the variability of distress and aims to increase tolerance of distress. Another goal is to develop new, non-threat associations.
Finally, Dr. Strawn pointed out predictors of poor outcomes in pediatric OCD, including factors such as compulsion severity, oppositional behavior, frequent handwashing, functional impairment, lack of insight, externalizing symptoms, and possibly hoarding. Problematic family characteristics include higher levels of accommodation, parental anxiety, low family cohesion, and high levels of conflict. “The last three really represent a very concerning triad of family behaviors that may necessitate specific family work in order to facilitate the recovery of the pediatric patient,” Dr. Strawn said.
During the question-and-answer session after the talk, Dr. Strawn was asked whether there might be an inflammatory component to OCD, and whether pediatric autoimmune neuropsychiatric disorders associated with streptococcus (PANDAS) might be a prodromal condition. He noted that some studies have shown a relationship, but results have been mixed, with lots of heterogeneity within the studied populations. To be suspicious that a patient had OCD resulting from PANDAS would require a high threshold, including an acute onset of symptoms. “This is a situation also where I would tend to involve consultation with some other specialties, including neurology. And obviously there would be follow-up in terms of the general workup,” he said.
Dr. Strawn has received research funding from Allergan, Otsuka, and Myriad Genetics. He has consulted for Myriad Genetics, and is a speaker for CMEology and the Neuroscience Education Institute.
FROM FOCUS ON NEUROPSYCHIATRY 2021
Early data for experimental THC drug ‘promising’ for Tourette’s
Oral delta-9-tetrahydracannabinol (delta-9-THC) and palmitoylethanolamide (PEA), in a proprietary combination known as THX-110, is promising for reducing tic symptoms in adults with Tourette syndrome (TS), new research suggests.
In a small phase 2 trial, investigators administered THX-110 to 16 adults with treatment-resistant TS for 12 weeks. Results showed a reduction of more than 20% in tic symptoms after the first week of treatment compared with baseline.
“We conducted an uncontrolled study in adults with severe TS and found that their tics improved over time while they took THX-110,” lead author Michael Bloch, MD, associate professor and co-director of the Tic and OCD Program at the Child Study Center, Yale University, New Haven, Conn., told this news organization.
Dr. Bloch added that the next step in this line of research will be to conduct a placebo-controlled trial of the compound in order to assess whether tic improvement observed over time in this study “was due to the effects of the medication and not related to the natural waxing-and-waning course of tic symptoms or treatment expectancy.”
The findings were published online August 2 in the Journal of Neuropsychiatry and Clinical Neurosciences.
‘Entourage effect’
“Several lines of evidence from clinical observation and even randomized controlled trials” suggest that cannabis (cannabis sativa) and delta-9-THC may be effective in treatment of tic disorders, Dr. Bloch said.
“Cannabinoid receptors are present in the motor regions important for tics, and thus, there is a potential mechanism of action to lead to improvement of tics,” he added.
However, “the major limitations of both cannabis and dronabinol [a synthetic form of delta-9-THC] use are the adverse psychoactive effects they induce in higher doses,” he said.
Dr. Bloch noted that PEA is a lipid messenger “known to mimic several endocannabinoid-driven activities.”
For this reason, combining delta-9-THC with PEA is hypothesized to reduce the dose of delta-9-THC needed to improve tics and also potentially lessen its side effects.
This initial open-label trial examined safety and tolerability of THX-110, as well as its effect on tic symptoms in adults with TS. The researchers hoped to “use the entourage effect to deliver the therapeutic benefits of delta-9-THC in reducing tics with decrease psychoactive effects by combining with PEA.”
The “entourage effect” refers to “endocannabinoid regulation by which multiple endogenous cannabinoid chemical species display a cooperative effect in eliciting a cellular response,” they write.
The investigators conducted a 12-week uncontrolled trial of THX-110, used at its maximum daily dose of delta-9-THC (10 mg) and a constant 800-mg dose of PEA in 16 adults with TS (mean age, 35 years; mean TS illness duration, 26.6 years).
Participants had a mean baseline Yale Global Tic Severity Scale (YGTSS) score of 38.1 and a mean worst-ever total tic score of 45.4.
All participants were experiencing persistent tics, despite having tried an array of previous evidence-based treatments for TS, including antipsychotics, alpha-2 agonists, VMAT2 inhibitors, benzodiazepines, and topiramate (Topamax).
Significant improvement
Results showed significant improvement in tic symptoms with TXH-110 treatment over time (general linear model time factor: F = 3.06, df = 7.91, P = .006).
At first assessment point, mean YGTSS improvement was 3.5 (95% confidence interval, 0.1-6.9; P = .047). The improvement not only remained significant but continued to increase throughout the 12-week trial period.
At 12 weeks, the maximal improvement in tic symptoms was observed, with a mean YGTSS improvement at endpoint of 7.6 (95% CI, 2.5-12.8; P = .007).
Four patients experienced a greater than 35% improvement in tic symptoms during the trial, whereas 6 experienced a 25% or greater improvement. The mean improvement in tic symptoms over the course of the trial was 20.6%.
There was also a significant improvement between baseline and endpoint on other measures of tic symptoms – but not on premonitory urges.
The patients experienced “modest” but not significant improvement in comorbid symptoms, including attentional, anxiety, depressive, and obsessive-compulsive symptoms.
Adverse events
All participants experienced some mild side effects for “a couple hours” after taking the medication, particularly during the course of dose escalation and maintenance. However, these were not serious enough to warrant stopping the medication.
These effects typically included fatigue/drowsiness, feeling “high,” dry mouth, dizziness/lightheadedness, and difficulty concentrating.
Side effects of moderate or greater severity necessitating changes in medication dosing were “less common,” the investigators report. No participants experienced significant laboratory abnormalities.
One patient discontinued the trial early because he felt that the study medication was not helpful, and a second discontinued because of drowsiness and fatigue related to the study medication.
Twelve participants elected to continue treatment with THX-110 during an open extension phase and 7 of these completed the additional 24 weeks.
“THX-110 treatment led to an average improvement in tic symptoms of roughly 20%, or a 7-point decrease in the YGTSS total tic score. This improvement translates to a large effect size (d = 0.92) of improvement over time,” the investigators write.
More data needed
Commenting on the findings, Yolanda Holler-Managan, MD, assistant professor of pediatrics (neurology), Northwestern University, Chicago, cautioned that this was not a randomized, double-blind, parallel-group placebo-controlled study.
Instead, it was a clinical study to prove safety, tolerability, and dosing of the combination medication in adult patients with TS and “does not provide as much weight, since we do not have many studies on the efficacy of cannabinoids,” said Dr. Holler-Managan, who was not involved with the research.
She noted that the American Academy of Neurology’s 2019 practice guideline recommendations for treatment of tics in individuals with TS and tic disorders reported “limited evidence” that delta-9-THC is “possibly more likely than placebo to reduce tic severity in adults with TS, therefore we need more data.”
The current investigators agree. “Although these initial data are promising, future randomized double-blind placebo-controlled trials are necessary to demonstrate efficacy of TXH-110 treatment,” they write.
They add that the psychoactive properties of cannabis-derived compounds make it challenging to design a properly blinded trial.
“Incorporation of physiologic biomarkers and objective measures of symptoms (e.g., videotaped tic counts by blinded raters) may be particularly important when examining these medications with psychoactive properties that may be prone to reporting bias,” the authors write.
The study was supported by an investigator-initiated grant to Dr. Bloch from Therapix Biosciences. The state of Connecticut also provided resource support via the Abraham Ribicoff Research Facilities at the Connecticut Mental Health Center. Dr. Bloch serves on the scientific advisory boards of Therapix Biosciences, and he receives research support from Biohaven Pharmaceuticals, Janssen Pharmaceuticals, NARSAD, Neurocrine Biosciences, NIH, and the Patterson Foundation. The other investigators and Dr. Holler-Managan have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Oral delta-9-tetrahydracannabinol (delta-9-THC) and palmitoylethanolamide (PEA), in a proprietary combination known as THX-110, is promising for reducing tic symptoms in adults with Tourette syndrome (TS), new research suggests.
In a small phase 2 trial, investigators administered THX-110 to 16 adults with treatment-resistant TS for 12 weeks. Results showed a reduction of more than 20% in tic symptoms after the first week of treatment compared with baseline.
“We conducted an uncontrolled study in adults with severe TS and found that their tics improved over time while they took THX-110,” lead author Michael Bloch, MD, associate professor and co-director of the Tic and OCD Program at the Child Study Center, Yale University, New Haven, Conn., told this news organization.
Dr. Bloch added that the next step in this line of research will be to conduct a placebo-controlled trial of the compound in order to assess whether tic improvement observed over time in this study “was due to the effects of the medication and not related to the natural waxing-and-waning course of tic symptoms or treatment expectancy.”
The findings were published online August 2 in the Journal of Neuropsychiatry and Clinical Neurosciences.
‘Entourage effect’
“Several lines of evidence from clinical observation and even randomized controlled trials” suggest that cannabis (cannabis sativa) and delta-9-THC may be effective in treatment of tic disorders, Dr. Bloch said.
“Cannabinoid receptors are present in the motor regions important for tics, and thus, there is a potential mechanism of action to lead to improvement of tics,” he added.
However, “the major limitations of both cannabis and dronabinol [a synthetic form of delta-9-THC] use are the adverse psychoactive effects they induce in higher doses,” he said.
Dr. Bloch noted that PEA is a lipid messenger “known to mimic several endocannabinoid-driven activities.”
For this reason, combining delta-9-THC with PEA is hypothesized to reduce the dose of delta-9-THC needed to improve tics and also potentially lessen its side effects.
This initial open-label trial examined safety and tolerability of THX-110, as well as its effect on tic symptoms in adults with TS. The researchers hoped to “use the entourage effect to deliver the therapeutic benefits of delta-9-THC in reducing tics with decrease psychoactive effects by combining with PEA.”
The “entourage effect” refers to “endocannabinoid regulation by which multiple endogenous cannabinoid chemical species display a cooperative effect in eliciting a cellular response,” they write.
The investigators conducted a 12-week uncontrolled trial of THX-110, used at its maximum daily dose of delta-9-THC (10 mg) and a constant 800-mg dose of PEA in 16 adults with TS (mean age, 35 years; mean TS illness duration, 26.6 years).
Participants had a mean baseline Yale Global Tic Severity Scale (YGTSS) score of 38.1 and a mean worst-ever total tic score of 45.4.
All participants were experiencing persistent tics, despite having tried an array of previous evidence-based treatments for TS, including antipsychotics, alpha-2 agonists, VMAT2 inhibitors, benzodiazepines, and topiramate (Topamax).
Significant improvement
Results showed significant improvement in tic symptoms with TXH-110 treatment over time (general linear model time factor: F = 3.06, df = 7.91, P = .006).
At first assessment point, mean YGTSS improvement was 3.5 (95% confidence interval, 0.1-6.9; P = .047). The improvement not only remained significant but continued to increase throughout the 12-week trial period.
At 12 weeks, the maximal improvement in tic symptoms was observed, with a mean YGTSS improvement at endpoint of 7.6 (95% CI, 2.5-12.8; P = .007).
Four patients experienced a greater than 35% improvement in tic symptoms during the trial, whereas 6 experienced a 25% or greater improvement. The mean improvement in tic symptoms over the course of the trial was 20.6%.
There was also a significant improvement between baseline and endpoint on other measures of tic symptoms – but not on premonitory urges.
The patients experienced “modest” but not significant improvement in comorbid symptoms, including attentional, anxiety, depressive, and obsessive-compulsive symptoms.
Adverse events
All participants experienced some mild side effects for “a couple hours” after taking the medication, particularly during the course of dose escalation and maintenance. However, these were not serious enough to warrant stopping the medication.
These effects typically included fatigue/drowsiness, feeling “high,” dry mouth, dizziness/lightheadedness, and difficulty concentrating.
Side effects of moderate or greater severity necessitating changes in medication dosing were “less common,” the investigators report. No participants experienced significant laboratory abnormalities.
One patient discontinued the trial early because he felt that the study medication was not helpful, and a second discontinued because of drowsiness and fatigue related to the study medication.
Twelve participants elected to continue treatment with THX-110 during an open extension phase and 7 of these completed the additional 24 weeks.
“THX-110 treatment led to an average improvement in tic symptoms of roughly 20%, or a 7-point decrease in the YGTSS total tic score. This improvement translates to a large effect size (d = 0.92) of improvement over time,” the investigators write.
More data needed
Commenting on the findings, Yolanda Holler-Managan, MD, assistant professor of pediatrics (neurology), Northwestern University, Chicago, cautioned that this was not a randomized, double-blind, parallel-group placebo-controlled study.
Instead, it was a clinical study to prove safety, tolerability, and dosing of the combination medication in adult patients with TS and “does not provide as much weight, since we do not have many studies on the efficacy of cannabinoids,” said Dr. Holler-Managan, who was not involved with the research.
She noted that the American Academy of Neurology’s 2019 practice guideline recommendations for treatment of tics in individuals with TS and tic disorders reported “limited evidence” that delta-9-THC is “possibly more likely than placebo to reduce tic severity in adults with TS, therefore we need more data.”
The current investigators agree. “Although these initial data are promising, future randomized double-blind placebo-controlled trials are necessary to demonstrate efficacy of TXH-110 treatment,” they write.
They add that the psychoactive properties of cannabis-derived compounds make it challenging to design a properly blinded trial.
“Incorporation of physiologic biomarkers and objective measures of symptoms (e.g., videotaped tic counts by blinded raters) may be particularly important when examining these medications with psychoactive properties that may be prone to reporting bias,” the authors write.
The study was supported by an investigator-initiated grant to Dr. Bloch from Therapix Biosciences. The state of Connecticut also provided resource support via the Abraham Ribicoff Research Facilities at the Connecticut Mental Health Center. Dr. Bloch serves on the scientific advisory boards of Therapix Biosciences, and he receives research support from Biohaven Pharmaceuticals, Janssen Pharmaceuticals, NARSAD, Neurocrine Biosciences, NIH, and the Patterson Foundation. The other investigators and Dr. Holler-Managan have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Oral delta-9-tetrahydracannabinol (delta-9-THC) and palmitoylethanolamide (PEA), in a proprietary combination known as THX-110, is promising for reducing tic symptoms in adults with Tourette syndrome (TS), new research suggests.
In a small phase 2 trial, investigators administered THX-110 to 16 adults with treatment-resistant TS for 12 weeks. Results showed a reduction of more than 20% in tic symptoms after the first week of treatment compared with baseline.
“We conducted an uncontrolled study in adults with severe TS and found that their tics improved over time while they took THX-110,” lead author Michael Bloch, MD, associate professor and co-director of the Tic and OCD Program at the Child Study Center, Yale University, New Haven, Conn., told this news organization.
Dr. Bloch added that the next step in this line of research will be to conduct a placebo-controlled trial of the compound in order to assess whether tic improvement observed over time in this study “was due to the effects of the medication and not related to the natural waxing-and-waning course of tic symptoms or treatment expectancy.”
The findings were published online August 2 in the Journal of Neuropsychiatry and Clinical Neurosciences.
‘Entourage effect’
“Several lines of evidence from clinical observation and even randomized controlled trials” suggest that cannabis (cannabis sativa) and delta-9-THC may be effective in treatment of tic disorders, Dr. Bloch said.
“Cannabinoid receptors are present in the motor regions important for tics, and thus, there is a potential mechanism of action to lead to improvement of tics,” he added.
However, “the major limitations of both cannabis and dronabinol [a synthetic form of delta-9-THC] use are the adverse psychoactive effects they induce in higher doses,” he said.
Dr. Bloch noted that PEA is a lipid messenger “known to mimic several endocannabinoid-driven activities.”
For this reason, combining delta-9-THC with PEA is hypothesized to reduce the dose of delta-9-THC needed to improve tics and also potentially lessen its side effects.
This initial open-label trial examined safety and tolerability of THX-110, as well as its effect on tic symptoms in adults with TS. The researchers hoped to “use the entourage effect to deliver the therapeutic benefits of delta-9-THC in reducing tics with decrease psychoactive effects by combining with PEA.”
The “entourage effect” refers to “endocannabinoid regulation by which multiple endogenous cannabinoid chemical species display a cooperative effect in eliciting a cellular response,” they write.
The investigators conducted a 12-week uncontrolled trial of THX-110, used at its maximum daily dose of delta-9-THC (10 mg) and a constant 800-mg dose of PEA in 16 adults with TS (mean age, 35 years; mean TS illness duration, 26.6 years).
Participants had a mean baseline Yale Global Tic Severity Scale (YGTSS) score of 38.1 and a mean worst-ever total tic score of 45.4.
All participants were experiencing persistent tics, despite having tried an array of previous evidence-based treatments for TS, including antipsychotics, alpha-2 agonists, VMAT2 inhibitors, benzodiazepines, and topiramate (Topamax).
Significant improvement
Results showed significant improvement in tic symptoms with TXH-110 treatment over time (general linear model time factor: F = 3.06, df = 7.91, P = .006).
At first assessment point, mean YGTSS improvement was 3.5 (95% confidence interval, 0.1-6.9; P = .047). The improvement not only remained significant but continued to increase throughout the 12-week trial period.
At 12 weeks, the maximal improvement in tic symptoms was observed, with a mean YGTSS improvement at endpoint of 7.6 (95% CI, 2.5-12.8; P = .007).
Four patients experienced a greater than 35% improvement in tic symptoms during the trial, whereas 6 experienced a 25% or greater improvement. The mean improvement in tic symptoms over the course of the trial was 20.6%.
There was also a significant improvement between baseline and endpoint on other measures of tic symptoms – but not on premonitory urges.
The patients experienced “modest” but not significant improvement in comorbid symptoms, including attentional, anxiety, depressive, and obsessive-compulsive symptoms.
Adverse events
All participants experienced some mild side effects for “a couple hours” after taking the medication, particularly during the course of dose escalation and maintenance. However, these were not serious enough to warrant stopping the medication.
These effects typically included fatigue/drowsiness, feeling “high,” dry mouth, dizziness/lightheadedness, and difficulty concentrating.
Side effects of moderate or greater severity necessitating changes in medication dosing were “less common,” the investigators report. No participants experienced significant laboratory abnormalities.
One patient discontinued the trial early because he felt that the study medication was not helpful, and a second discontinued because of drowsiness and fatigue related to the study medication.
Twelve participants elected to continue treatment with THX-110 during an open extension phase and 7 of these completed the additional 24 weeks.
“THX-110 treatment led to an average improvement in tic symptoms of roughly 20%, or a 7-point decrease in the YGTSS total tic score. This improvement translates to a large effect size (d = 0.92) of improvement over time,” the investigators write.
More data needed
Commenting on the findings, Yolanda Holler-Managan, MD, assistant professor of pediatrics (neurology), Northwestern University, Chicago, cautioned that this was not a randomized, double-blind, parallel-group placebo-controlled study.
Instead, it was a clinical study to prove safety, tolerability, and dosing of the combination medication in adult patients with TS and “does not provide as much weight, since we do not have many studies on the efficacy of cannabinoids,” said Dr. Holler-Managan, who was not involved with the research.
She noted that the American Academy of Neurology’s 2019 practice guideline recommendations for treatment of tics in individuals with TS and tic disorders reported “limited evidence” that delta-9-THC is “possibly more likely than placebo to reduce tic severity in adults with TS, therefore we need more data.”
The current investigators agree. “Although these initial data are promising, future randomized double-blind placebo-controlled trials are necessary to demonstrate efficacy of TXH-110 treatment,” they write.
They add that the psychoactive properties of cannabis-derived compounds make it challenging to design a properly blinded trial.
“Incorporation of physiologic biomarkers and objective measures of symptoms (e.g., videotaped tic counts by blinded raters) may be particularly important when examining these medications with psychoactive properties that may be prone to reporting bias,” the authors write.
The study was supported by an investigator-initiated grant to Dr. Bloch from Therapix Biosciences. The state of Connecticut also provided resource support via the Abraham Ribicoff Research Facilities at the Connecticut Mental Health Center. Dr. Bloch serves on the scientific advisory boards of Therapix Biosciences, and he receives research support from Biohaven Pharmaceuticals, Janssen Pharmaceuticals, NARSAD, Neurocrine Biosciences, NIH, and the Patterson Foundation. The other investigators and Dr. Holler-Managan have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Psychiatric genomics has a diversity problem
In combing the genome, scientists can use genetic clues to determine a person’s risk for psychiatric disease and even identify new drug targets. But the benefits of these discoveries will be limited to people of European descent.
Nearly 90% of participants in genome-wide association studies (GWASs), which search for gene variants linked to disease, are of European ancestry. This Eurocentric focus threatens to widen existing disparities in racial and ethnic mental health.
“If you develop certain interventions based on only a single population profile, then you’ll be leaving out the rest of the populations in the world,” says Solomon Teferra, MD, PhD, associate professor of psychiatry at Addis Ababa University, Ethiopia. In a growing trend, psychiatric researchers are diverging from the field’s European bias and are working to correct the imbalance in DNA databases.
The significant downsides of genomics’ one-track mind
One obstacle hindering therapeutic advances in psychiatry is a shallow understanding of the mechanisms of disorders. “The biggest problem in terms of advancing research for mental health conditions is that we don’t understand the underlying biology,” says Laramie Duncan, PhD, assistant professor of psychiatry and behavioral sciences at Stanford (Calif.) University. “Genetics is one of the best ways to systematically look for new clues about the underlying biology.”
At the advent of genomic research, scientists thought it best to study DNA from people of a single ancestry from one continent. “Researchers for a long time held the idea that it was going to be too complicated to include multiple ancestries in the first rounds of genetic analyses,” says Dr. Duncan.
Studying DNA from someone with ancestors from multiple parts of the world wasn’t compatible with methods used in the early days of GWASs. “Individual parts of a person’s DNA can be linked back to one region of the world or another, and most of our methods essentially assume that all of a person’s DNA came from one region of the world,” says Dr. Duncan.
Because many genes are usually involved in psychiatric disorders, scientists need large numbers of participants to detect uncommon, influential variants. Early research was concentrated in North America and Europe so that scientists could readily collect samples from people of European ancestry.
“It then went out of hand because it became routine practice to use only this one group, essentially White, European ancestry people,” says Karoline Kuchenbaecker, PhD, associate professor of psychiatry at University College London.
Yet findings from one population won’t necessarily translate to others. “And that’s exactly what has been shown,” says Dr. Teferra. Polygenic risk scores developed for schizophrenia from European samples, for example, perform poorly among people of African ancestry, although among Europeans, they are strongly effective at differentiating European individuals with and those without schizophrenia. Moreover, drugs that target a gene identified from studies in European populations may be harmful to other groups.
Studies drawn from a diverse pool of participants would benefit a wider swath of humanity. They would also allow scientists to discover small areas of overlap in genomes of different populations, which would help them close in on the true biology of diseases and ensure that “we’re all benefiting from more diverse data in genetics and psychiatric genetics,” says Dr. Kuchenbaecker.
New efforts aim at filling the gaps
, not African, Latin American, or Indigenous ancestry.
Efforts to increase representation of persons of African ancestry have largely focused on African Americans; fewer efforts have extended to the African continent, home to the most genetically diverse populations. Even fewer have focused on mental health. “The little that was being done was on a very small scale,” says Karestan Koenen, PhD, a professor at Harvard School of Public Health, Boston.
With this in mind, researchers from institutions in Kenya, Uganda, South Africa, and Ethiopia partnered with researchers at the Broad Institute of the Massachusetts Institute of Technology and Harvard to conduct the largest GWAS of psychiatric disorders in Africa. Dr. Koenen leads the project, Neuropsychiatric Genetics of African Populations–Psychosis (NeuroGAP-Psychosis), which will analyze DNA from over 35,000 people of African ancestry in each of these four countries. Investigators will compare the half of participants who have no history of psychosis with the half with schizophrenia or bipolar disorder in the hopes of identifying the genetic determinants of psychosis.
“Then any potential intervention or therapeutics that will be developed will also be useful for Africans,” says Dr. Teferra, a NeuroGAP principal investigator. Because of the tremendous degree of genetic diversity among people on the continent, however, findings still might not translate to all African populations.
But correcting equity problems in genomics isn’t as simple as recruiting people with non-European backgrounds, especially if those people are unfamiliar with research or have been subject to scientific exploitation. “Special care needs to be taken to, first of all, provide information that’s appropriate [to participants], but also motivate people to take part and then find ways to keep these communities involved and understand what they’re interested in,” says Dr. Kuchenbaecker, who is not involved with NeuroGAP.
For NeuroGAP, the team needed to work with ethical committees at all of the institutions involved, ensure research materials were appropriate for each community’s cultural context, and gain the trust of local communities.
“One of the biggest criticisms within the scientific world is that people from more endowed countries just fly in, bully everyone, collect the data, and leave, with no credit to the local scientists or communities,” says NeuroGAP principal investigator Lukoye Atwoli, MMed, PhD, professor of psychiatry and dean of the Medical College, East Africa, at the Aga Khan University, Nairobi, Kenya. “That is one of the biggest pitfalls we had to grapple with.”
To address that concern, NeuroGAP is training local researchers and is providing them with requested resources so they can carry out similar studies in the future. “We will be looking to address a real need in the academic community and in clinical service delivery,” says Dr. Atwoli.
Dr. Kuchenbaecker says that NeuroGAP demonstrates features necessary for projects seeking to improve equity in psychiatric genomics. “What they’re doing right is recruiting really large numbers, recruiting from different African countries, and involving African investigators,” she says.
In the Americas, Janitza Montalvo-Ortiz, PhD, assistant professor in the Division of Genetics, department of psychiatry, Yale University, New Haven, Conn., and her colleagues are expanding psychiatric genomics projects in Latin America. She co-founded the Latin American Genomics Consortium in 2019, a network of scientists supporting psychiatric genomic research in the region. The consortium also involves the Neuropsychiatric Genetics in Mexican Populations project, which is similar to NeuroGAP and is also led by Dr. Koenan.
The study of Latin American populations is complicated, because genes in these populations reflect Indigenous American, European, and African ancestries. Even when investigators sampled DNA from Latin American individuals, that data often went unused. “Now with new methods emerging to allow us to properly analyze admixed populations in GWAS studies, we’re making efforts to compile different datasets scattered across different large-scale cohorts,” says Dr. Montalvo-Ortiz. “Our ultimate goal is to conduct the first large-scale LatinX GWAS of psychiatry,” she says.
With these projects, researchers hope that new psychiatric research will produce clinical advances for people historically left on the sidelines of genomic studies. By involving their communities in genomic research, “whatever is going to be developed will also benefit our community,” says Dr. Teferra. “We will not be left out.”
A version of this article first appeared on Medscape.com.
In combing the genome, scientists can use genetic clues to determine a person’s risk for psychiatric disease and even identify new drug targets. But the benefits of these discoveries will be limited to people of European descent.
Nearly 90% of participants in genome-wide association studies (GWASs), which search for gene variants linked to disease, are of European ancestry. This Eurocentric focus threatens to widen existing disparities in racial and ethnic mental health.
“If you develop certain interventions based on only a single population profile, then you’ll be leaving out the rest of the populations in the world,” says Solomon Teferra, MD, PhD, associate professor of psychiatry at Addis Ababa University, Ethiopia. In a growing trend, psychiatric researchers are diverging from the field’s European bias and are working to correct the imbalance in DNA databases.
The significant downsides of genomics’ one-track mind
One obstacle hindering therapeutic advances in psychiatry is a shallow understanding of the mechanisms of disorders. “The biggest problem in terms of advancing research for mental health conditions is that we don’t understand the underlying biology,” says Laramie Duncan, PhD, assistant professor of psychiatry and behavioral sciences at Stanford (Calif.) University. “Genetics is one of the best ways to systematically look for new clues about the underlying biology.”
At the advent of genomic research, scientists thought it best to study DNA from people of a single ancestry from one continent. “Researchers for a long time held the idea that it was going to be too complicated to include multiple ancestries in the first rounds of genetic analyses,” says Dr. Duncan.
Studying DNA from someone with ancestors from multiple parts of the world wasn’t compatible with methods used in the early days of GWASs. “Individual parts of a person’s DNA can be linked back to one region of the world or another, and most of our methods essentially assume that all of a person’s DNA came from one region of the world,” says Dr. Duncan.
Because many genes are usually involved in psychiatric disorders, scientists need large numbers of participants to detect uncommon, influential variants. Early research was concentrated in North America and Europe so that scientists could readily collect samples from people of European ancestry.
“It then went out of hand because it became routine practice to use only this one group, essentially White, European ancestry people,” says Karoline Kuchenbaecker, PhD, associate professor of psychiatry at University College London.
Yet findings from one population won’t necessarily translate to others. “And that’s exactly what has been shown,” says Dr. Teferra. Polygenic risk scores developed for schizophrenia from European samples, for example, perform poorly among people of African ancestry, although among Europeans, they are strongly effective at differentiating European individuals with and those without schizophrenia. Moreover, drugs that target a gene identified from studies in European populations may be harmful to other groups.
Studies drawn from a diverse pool of participants would benefit a wider swath of humanity. They would also allow scientists to discover small areas of overlap in genomes of different populations, which would help them close in on the true biology of diseases and ensure that “we’re all benefiting from more diverse data in genetics and psychiatric genetics,” says Dr. Kuchenbaecker.
New efforts aim at filling the gaps
, not African, Latin American, or Indigenous ancestry.
Efforts to increase representation of persons of African ancestry have largely focused on African Americans; fewer efforts have extended to the African continent, home to the most genetically diverse populations. Even fewer have focused on mental health. “The little that was being done was on a very small scale,” says Karestan Koenen, PhD, a professor at Harvard School of Public Health, Boston.
With this in mind, researchers from institutions in Kenya, Uganda, South Africa, and Ethiopia partnered with researchers at the Broad Institute of the Massachusetts Institute of Technology and Harvard to conduct the largest GWAS of psychiatric disorders in Africa. Dr. Koenen leads the project, Neuropsychiatric Genetics of African Populations–Psychosis (NeuroGAP-Psychosis), which will analyze DNA from over 35,000 people of African ancestry in each of these four countries. Investigators will compare the half of participants who have no history of psychosis with the half with schizophrenia or bipolar disorder in the hopes of identifying the genetic determinants of psychosis.
“Then any potential intervention or therapeutics that will be developed will also be useful for Africans,” says Dr. Teferra, a NeuroGAP principal investigator. Because of the tremendous degree of genetic diversity among people on the continent, however, findings still might not translate to all African populations.
But correcting equity problems in genomics isn’t as simple as recruiting people with non-European backgrounds, especially if those people are unfamiliar with research or have been subject to scientific exploitation. “Special care needs to be taken to, first of all, provide information that’s appropriate [to participants], but also motivate people to take part and then find ways to keep these communities involved and understand what they’re interested in,” says Dr. Kuchenbaecker, who is not involved with NeuroGAP.
For NeuroGAP, the team needed to work with ethical committees at all of the institutions involved, ensure research materials were appropriate for each community’s cultural context, and gain the trust of local communities.
“One of the biggest criticisms within the scientific world is that people from more endowed countries just fly in, bully everyone, collect the data, and leave, with no credit to the local scientists or communities,” says NeuroGAP principal investigator Lukoye Atwoli, MMed, PhD, professor of psychiatry and dean of the Medical College, East Africa, at the Aga Khan University, Nairobi, Kenya. “That is one of the biggest pitfalls we had to grapple with.”
To address that concern, NeuroGAP is training local researchers and is providing them with requested resources so they can carry out similar studies in the future. “We will be looking to address a real need in the academic community and in clinical service delivery,” says Dr. Atwoli.
Dr. Kuchenbaecker says that NeuroGAP demonstrates features necessary for projects seeking to improve equity in psychiatric genomics. “What they’re doing right is recruiting really large numbers, recruiting from different African countries, and involving African investigators,” she says.
In the Americas, Janitza Montalvo-Ortiz, PhD, assistant professor in the Division of Genetics, department of psychiatry, Yale University, New Haven, Conn., and her colleagues are expanding psychiatric genomics projects in Latin America. She co-founded the Latin American Genomics Consortium in 2019, a network of scientists supporting psychiatric genomic research in the region. The consortium also involves the Neuropsychiatric Genetics in Mexican Populations project, which is similar to NeuroGAP and is also led by Dr. Koenan.
The study of Latin American populations is complicated, because genes in these populations reflect Indigenous American, European, and African ancestries. Even when investigators sampled DNA from Latin American individuals, that data often went unused. “Now with new methods emerging to allow us to properly analyze admixed populations in GWAS studies, we’re making efforts to compile different datasets scattered across different large-scale cohorts,” says Dr. Montalvo-Ortiz. “Our ultimate goal is to conduct the first large-scale LatinX GWAS of psychiatry,” she says.
With these projects, researchers hope that new psychiatric research will produce clinical advances for people historically left on the sidelines of genomic studies. By involving their communities in genomic research, “whatever is going to be developed will also benefit our community,” says Dr. Teferra. “We will not be left out.”
A version of this article first appeared on Medscape.com.
In combing the genome, scientists can use genetic clues to determine a person’s risk for psychiatric disease and even identify new drug targets. But the benefits of these discoveries will be limited to people of European descent.
Nearly 90% of participants in genome-wide association studies (GWASs), which search for gene variants linked to disease, are of European ancestry. This Eurocentric focus threatens to widen existing disparities in racial and ethnic mental health.
“If you develop certain interventions based on only a single population profile, then you’ll be leaving out the rest of the populations in the world,” says Solomon Teferra, MD, PhD, associate professor of psychiatry at Addis Ababa University, Ethiopia. In a growing trend, psychiatric researchers are diverging from the field’s European bias and are working to correct the imbalance in DNA databases.
The significant downsides of genomics’ one-track mind
One obstacle hindering therapeutic advances in psychiatry is a shallow understanding of the mechanisms of disorders. “The biggest problem in terms of advancing research for mental health conditions is that we don’t understand the underlying biology,” says Laramie Duncan, PhD, assistant professor of psychiatry and behavioral sciences at Stanford (Calif.) University. “Genetics is one of the best ways to systematically look for new clues about the underlying biology.”
At the advent of genomic research, scientists thought it best to study DNA from people of a single ancestry from one continent. “Researchers for a long time held the idea that it was going to be too complicated to include multiple ancestries in the first rounds of genetic analyses,” says Dr. Duncan.
Studying DNA from someone with ancestors from multiple parts of the world wasn’t compatible with methods used in the early days of GWASs. “Individual parts of a person’s DNA can be linked back to one region of the world or another, and most of our methods essentially assume that all of a person’s DNA came from one region of the world,” says Dr. Duncan.
Because many genes are usually involved in psychiatric disorders, scientists need large numbers of participants to detect uncommon, influential variants. Early research was concentrated in North America and Europe so that scientists could readily collect samples from people of European ancestry.
“It then went out of hand because it became routine practice to use only this one group, essentially White, European ancestry people,” says Karoline Kuchenbaecker, PhD, associate professor of psychiatry at University College London.
Yet findings from one population won’t necessarily translate to others. “And that’s exactly what has been shown,” says Dr. Teferra. Polygenic risk scores developed for schizophrenia from European samples, for example, perform poorly among people of African ancestry, although among Europeans, they are strongly effective at differentiating European individuals with and those without schizophrenia. Moreover, drugs that target a gene identified from studies in European populations may be harmful to other groups.
Studies drawn from a diverse pool of participants would benefit a wider swath of humanity. They would also allow scientists to discover small areas of overlap in genomes of different populations, which would help them close in on the true biology of diseases and ensure that “we’re all benefiting from more diverse data in genetics and psychiatric genetics,” says Dr. Kuchenbaecker.
New efforts aim at filling the gaps
, not African, Latin American, or Indigenous ancestry.
Efforts to increase representation of persons of African ancestry have largely focused on African Americans; fewer efforts have extended to the African continent, home to the most genetically diverse populations. Even fewer have focused on mental health. “The little that was being done was on a very small scale,” says Karestan Koenen, PhD, a professor at Harvard School of Public Health, Boston.
With this in mind, researchers from institutions in Kenya, Uganda, South Africa, and Ethiopia partnered with researchers at the Broad Institute of the Massachusetts Institute of Technology and Harvard to conduct the largest GWAS of psychiatric disorders in Africa. Dr. Koenen leads the project, Neuropsychiatric Genetics of African Populations–Psychosis (NeuroGAP-Psychosis), which will analyze DNA from over 35,000 people of African ancestry in each of these four countries. Investigators will compare the half of participants who have no history of psychosis with the half with schizophrenia or bipolar disorder in the hopes of identifying the genetic determinants of psychosis.
“Then any potential intervention or therapeutics that will be developed will also be useful for Africans,” says Dr. Teferra, a NeuroGAP principal investigator. Because of the tremendous degree of genetic diversity among people on the continent, however, findings still might not translate to all African populations.
But correcting equity problems in genomics isn’t as simple as recruiting people with non-European backgrounds, especially if those people are unfamiliar with research or have been subject to scientific exploitation. “Special care needs to be taken to, first of all, provide information that’s appropriate [to participants], but also motivate people to take part and then find ways to keep these communities involved and understand what they’re interested in,” says Dr. Kuchenbaecker, who is not involved with NeuroGAP.
For NeuroGAP, the team needed to work with ethical committees at all of the institutions involved, ensure research materials were appropriate for each community’s cultural context, and gain the trust of local communities.
“One of the biggest criticisms within the scientific world is that people from more endowed countries just fly in, bully everyone, collect the data, and leave, with no credit to the local scientists or communities,” says NeuroGAP principal investigator Lukoye Atwoli, MMed, PhD, professor of psychiatry and dean of the Medical College, East Africa, at the Aga Khan University, Nairobi, Kenya. “That is one of the biggest pitfalls we had to grapple with.”
To address that concern, NeuroGAP is training local researchers and is providing them with requested resources so they can carry out similar studies in the future. “We will be looking to address a real need in the academic community and in clinical service delivery,” says Dr. Atwoli.
Dr. Kuchenbaecker says that NeuroGAP demonstrates features necessary for projects seeking to improve equity in psychiatric genomics. “What they’re doing right is recruiting really large numbers, recruiting from different African countries, and involving African investigators,” she says.
In the Americas, Janitza Montalvo-Ortiz, PhD, assistant professor in the Division of Genetics, department of psychiatry, Yale University, New Haven, Conn., and her colleagues are expanding psychiatric genomics projects in Latin America. She co-founded the Latin American Genomics Consortium in 2019, a network of scientists supporting psychiatric genomic research in the region. The consortium also involves the Neuropsychiatric Genetics in Mexican Populations project, which is similar to NeuroGAP and is also led by Dr. Koenan.
The study of Latin American populations is complicated, because genes in these populations reflect Indigenous American, European, and African ancestries. Even when investigators sampled DNA from Latin American individuals, that data often went unused. “Now with new methods emerging to allow us to properly analyze admixed populations in GWAS studies, we’re making efforts to compile different datasets scattered across different large-scale cohorts,” says Dr. Montalvo-Ortiz. “Our ultimate goal is to conduct the first large-scale LatinX GWAS of psychiatry,” she says.
With these projects, researchers hope that new psychiatric research will produce clinical advances for people historically left on the sidelines of genomic studies. By involving their communities in genomic research, “whatever is going to be developed will also benefit our community,” says Dr. Teferra. “We will not be left out.”
A version of this article first appeared on Medscape.com.
Health anxiety common as COVID restrictions loosen
As restrictions lift and mask mandates become scarce, Americans are filling their social calendars and booking vacations. While some are rejoicing, health care professionals say others are emerging from the pandemic with more health-related fears.
COVID-19 has caused more anxiety and depression for many over the course of the pandemic. A survey from the CDC and the Census Bureau found the percentage of adults with symptoms of an anxiety or depressive disorder increased from 36.4% to 41.5% from August 2020 to February 2021.
But this phenomenon will not just disappear as COVID-19 cases decrease, said Reese Druckenmiller, a clinical social worker for the Mayo Clinic Health System.
“There are still people out there not wanting to leave home,” she said. “Some folks inherently struggle with anxiety more than others, and we know anxiety can come from different experiences and traumas.
Though there is little research on the psychological effects of pandemic outbreaks, scientists are beginning to explore this. A recent review published in the International Journal of Cognitive Therapy concluded that, based on available research and the effects of previous pandemics, COVID-19 will likely have a significant effect on people’s mental health, particularly those who already have obsessive-compulsive disorder and health anxiety, along with people on the front line of health care.
According to the authors, since the virus doesn’t have symptoms among certain populations, there’s more anxiety about becoming infected and unknowingly spreading it to vulnerable people.
Not to mention the influx of anxiety-provoking news over the past year, Ms. Druckenmiller noted.
“One thing I noticed during the pandemic: The news changed. There were still regular news stories, but at the forefront of every single newscast was the numbers, how many people have died, how many people are hospitalized,” she said.
Some of Ms. Druckenmiller’s own patients who are more health-focused saw this as an added burden – another source of anxiety.
For those still uncomfortable with an abrupt reentry into public spaces, Ms. Druckenmiller recommended taking small steps. Start leaving the house every day, she suggested, even if it’s just for a walk. It is also important to be honest with loved ones about your own comfort level.
“Our brain is very flexible and fluid, but it also doesn’t just switch on a dime,” she said. “If I’ve been told over the past year this is a horrible thing that could kill me, my brain can’t adjust that fast. We need evidence through experience.”
A version of this article first appeared on WebMD.com.
As restrictions lift and mask mandates become scarce, Americans are filling their social calendars and booking vacations. While some are rejoicing, health care professionals say others are emerging from the pandemic with more health-related fears.
COVID-19 has caused more anxiety and depression for many over the course of the pandemic. A survey from the CDC and the Census Bureau found the percentage of adults with symptoms of an anxiety or depressive disorder increased from 36.4% to 41.5% from August 2020 to February 2021.
But this phenomenon will not just disappear as COVID-19 cases decrease, said Reese Druckenmiller, a clinical social worker for the Mayo Clinic Health System.
“There are still people out there not wanting to leave home,” she said. “Some folks inherently struggle with anxiety more than others, and we know anxiety can come from different experiences and traumas.
Though there is little research on the psychological effects of pandemic outbreaks, scientists are beginning to explore this. A recent review published in the International Journal of Cognitive Therapy concluded that, based on available research and the effects of previous pandemics, COVID-19 will likely have a significant effect on people’s mental health, particularly those who already have obsessive-compulsive disorder and health anxiety, along with people on the front line of health care.
According to the authors, since the virus doesn’t have symptoms among certain populations, there’s more anxiety about becoming infected and unknowingly spreading it to vulnerable people.
Not to mention the influx of anxiety-provoking news over the past year, Ms. Druckenmiller noted.
“One thing I noticed during the pandemic: The news changed. There were still regular news stories, but at the forefront of every single newscast was the numbers, how many people have died, how many people are hospitalized,” she said.
Some of Ms. Druckenmiller’s own patients who are more health-focused saw this as an added burden – another source of anxiety.
For those still uncomfortable with an abrupt reentry into public spaces, Ms. Druckenmiller recommended taking small steps. Start leaving the house every day, she suggested, even if it’s just for a walk. It is also important to be honest with loved ones about your own comfort level.
“Our brain is very flexible and fluid, but it also doesn’t just switch on a dime,” she said. “If I’ve been told over the past year this is a horrible thing that could kill me, my brain can’t adjust that fast. We need evidence through experience.”
A version of this article first appeared on WebMD.com.
As restrictions lift and mask mandates become scarce, Americans are filling their social calendars and booking vacations. While some are rejoicing, health care professionals say others are emerging from the pandemic with more health-related fears.
COVID-19 has caused more anxiety and depression for many over the course of the pandemic. A survey from the CDC and the Census Bureau found the percentage of adults with symptoms of an anxiety or depressive disorder increased from 36.4% to 41.5% from August 2020 to February 2021.
But this phenomenon will not just disappear as COVID-19 cases decrease, said Reese Druckenmiller, a clinical social worker for the Mayo Clinic Health System.
“There are still people out there not wanting to leave home,” she said. “Some folks inherently struggle with anxiety more than others, and we know anxiety can come from different experiences and traumas.
Though there is little research on the psychological effects of pandemic outbreaks, scientists are beginning to explore this. A recent review published in the International Journal of Cognitive Therapy concluded that, based on available research and the effects of previous pandemics, COVID-19 will likely have a significant effect on people’s mental health, particularly those who already have obsessive-compulsive disorder and health anxiety, along with people on the front line of health care.
According to the authors, since the virus doesn’t have symptoms among certain populations, there’s more anxiety about becoming infected and unknowingly spreading it to vulnerable people.
Not to mention the influx of anxiety-provoking news over the past year, Ms. Druckenmiller noted.
“One thing I noticed during the pandemic: The news changed. There were still regular news stories, but at the forefront of every single newscast was the numbers, how many people have died, how many people are hospitalized,” she said.
Some of Ms. Druckenmiller’s own patients who are more health-focused saw this as an added burden – another source of anxiety.
For those still uncomfortable with an abrupt reentry into public spaces, Ms. Druckenmiller recommended taking small steps. Start leaving the house every day, she suggested, even if it’s just for a walk. It is also important to be honest with loved ones about your own comfort level.
“Our brain is very flexible and fluid, but it also doesn’t just switch on a dime,” she said. “If I’ve been told over the past year this is a horrible thing that could kill me, my brain can’t adjust that fast. We need evidence through experience.”
A version of this article first appeared on WebMD.com.
APA, AMA, others move to stop insurer from overturning mental health claims ruling
The American Psychiatric Association has joined with the American Medical Association and other medical societies to oppose United Behavioral Health’s (UBH) request that a court throw out a ruling that found the insurer unfairly denied tens of thousands of claims for mental health and substance use disorder services.
Wit v. United Behavioral Health, in litigation since 2014, is being closely watched by clinicians, patients, providers, and attorneys.
Reena Kapoor, MD, chair of the APA’s Committee on Judicial Action, said in an interview that the APA is hopeful that “whatever the court says about UBH should be applicable to all insurance companies that are providing employer-sponsored health benefits.”
In a friend of the court (amicus curiae) brief, the APA, AMA, the California Medical Association, Southern California Psychiatric Society, Northern California Psychiatric Society, Orange County Psychiatric Society, Central California Psychiatric Society, and San Diego Psychiatric Society argue that “despite the availability of professionally developed, evidence-based guidelines embodying generally accepted standards of care for mental health and substance use disorders, managed care organizations commonly base coverage decisions on internally developed ‘level of care guidelines’ that are inappropriately restrictive.”
The guidelines “may lead to denial of coverage for treatment that is recommended by a patient’s physician and even cut off coverage when treatment is already being delivered,” said the groups.
The U.S. Department of Labor also filed a brief in support of the plaintiffs who are suing UBH. Those individuals suffered injury when they were denied coverage, said the federal agency, which regulates employer-sponsored insurance plans.
California Attorney General Rob Bonta also made an amicus filing supporting the plaintiffs.
“When insurers limit access to this critical care, they leave Californians who need it feeling as if they have no other option than to try to cope alone,” said Mr. Bonta in a statement.
‘Discrimination must end’
Mr. Bonta said he agreed with a 2019 ruling by the U.S. District Court for the Northern District of California that UBH had violated its fiduciary duties by wrongfully using its internally developed coverage determination guidelines and level of care guidelines to deny care.
The court also found that UBH’s medically necessary criteria meant that only “acute” episodes would be covered. Instead, said the court last November, chronic and comorbid conditions should always be treated, according to Maureen Gammon and Kathleen Rosenow of Willis Towers Watson, a risk advisor.
In November, the same Northern California District Court ruled on the remedies it would require of United, including that the insurer reprocess more than 67,000 claims. UBH was also barred indefinitely from using any of its guidelines to make coverage determinations. Instead, it was ordered to make determinations “consistent with generally accepted standards of care,” and consistent with state laws.
The District Court denied a request by UBH to put a hold on the claims reprocessing until it appealed the overall case. But the Ninth Circuit Court of Appeals in February granted that request.
Then, in March, United appealed the District Court’s overall ruling, claiming that the plaintiffs had not proven harm.
The U.S. Chamber of Commerce has filed a brief in support of United, agreeing with its arguments.
However, the APA and other clinician groups said there is no question of harm.
“Failure to provide appropriate levels of care for treatment of mental illness and substance use disorders leads to relapse, overdose, transmission of infectious diseases, and death,” said APA CEO and Medical Director Saul Levin, MD, MPA, in a statement.
APA President Vivian Pender, MD, said guidelines that “are overly focused on stabilizing acute symptoms of mental health and substance use disorders” are not treating the underlying disease. “When the injury is physical, insurers treat the underlying disease and not just the symptoms. Discrimination against patients with mental illness must end,” she said.
No court has ever recognized the type of claims reprocessing ordered by the District Court judge, said attorneys Nathaniel Cohen and Joseph Laska of Manatt, Phelps & Phillips, in an analysis of the case.
Mr. Cohen and Mr. Laska write. “Practitioners, health plans, and health insurers would be wise to track UBH’s long-awaited appeal to the Ninth Circuit.”
This article first appeared on Medscape.com.
The American Psychiatric Association has joined with the American Medical Association and other medical societies to oppose United Behavioral Health’s (UBH) request that a court throw out a ruling that found the insurer unfairly denied tens of thousands of claims for mental health and substance use disorder services.
Wit v. United Behavioral Health, in litigation since 2014, is being closely watched by clinicians, patients, providers, and attorneys.
Reena Kapoor, MD, chair of the APA’s Committee on Judicial Action, said in an interview that the APA is hopeful that “whatever the court says about UBH should be applicable to all insurance companies that are providing employer-sponsored health benefits.”
In a friend of the court (amicus curiae) brief, the APA, AMA, the California Medical Association, Southern California Psychiatric Society, Northern California Psychiatric Society, Orange County Psychiatric Society, Central California Psychiatric Society, and San Diego Psychiatric Society argue that “despite the availability of professionally developed, evidence-based guidelines embodying generally accepted standards of care for mental health and substance use disorders, managed care organizations commonly base coverage decisions on internally developed ‘level of care guidelines’ that are inappropriately restrictive.”
The guidelines “may lead to denial of coverage for treatment that is recommended by a patient’s physician and even cut off coverage when treatment is already being delivered,” said the groups.
The U.S. Department of Labor also filed a brief in support of the plaintiffs who are suing UBH. Those individuals suffered injury when they were denied coverage, said the federal agency, which regulates employer-sponsored insurance plans.
California Attorney General Rob Bonta also made an amicus filing supporting the plaintiffs.
“When insurers limit access to this critical care, they leave Californians who need it feeling as if they have no other option than to try to cope alone,” said Mr. Bonta in a statement.
‘Discrimination must end’
Mr. Bonta said he agreed with a 2019 ruling by the U.S. District Court for the Northern District of California that UBH had violated its fiduciary duties by wrongfully using its internally developed coverage determination guidelines and level of care guidelines to deny care.
The court also found that UBH’s medically necessary criteria meant that only “acute” episodes would be covered. Instead, said the court last November, chronic and comorbid conditions should always be treated, according to Maureen Gammon and Kathleen Rosenow of Willis Towers Watson, a risk advisor.
In November, the same Northern California District Court ruled on the remedies it would require of United, including that the insurer reprocess more than 67,000 claims. UBH was also barred indefinitely from using any of its guidelines to make coverage determinations. Instead, it was ordered to make determinations “consistent with generally accepted standards of care,” and consistent with state laws.
The District Court denied a request by UBH to put a hold on the claims reprocessing until it appealed the overall case. But the Ninth Circuit Court of Appeals in February granted that request.
Then, in March, United appealed the District Court’s overall ruling, claiming that the plaintiffs had not proven harm.
The U.S. Chamber of Commerce has filed a brief in support of United, agreeing with its arguments.
However, the APA and other clinician groups said there is no question of harm.
“Failure to provide appropriate levels of care for treatment of mental illness and substance use disorders leads to relapse, overdose, transmission of infectious diseases, and death,” said APA CEO and Medical Director Saul Levin, MD, MPA, in a statement.
APA President Vivian Pender, MD, said guidelines that “are overly focused on stabilizing acute symptoms of mental health and substance use disorders” are not treating the underlying disease. “When the injury is physical, insurers treat the underlying disease and not just the symptoms. Discrimination against patients with mental illness must end,” she said.
No court has ever recognized the type of claims reprocessing ordered by the District Court judge, said attorneys Nathaniel Cohen and Joseph Laska of Manatt, Phelps & Phillips, in an analysis of the case.
Mr. Cohen and Mr. Laska write. “Practitioners, health plans, and health insurers would be wise to track UBH’s long-awaited appeal to the Ninth Circuit.”
This article first appeared on Medscape.com.
The American Psychiatric Association has joined with the American Medical Association and other medical societies to oppose United Behavioral Health’s (UBH) request that a court throw out a ruling that found the insurer unfairly denied tens of thousands of claims for mental health and substance use disorder services.
Wit v. United Behavioral Health, in litigation since 2014, is being closely watched by clinicians, patients, providers, and attorneys.
Reena Kapoor, MD, chair of the APA’s Committee on Judicial Action, said in an interview that the APA is hopeful that “whatever the court says about UBH should be applicable to all insurance companies that are providing employer-sponsored health benefits.”
In a friend of the court (amicus curiae) brief, the APA, AMA, the California Medical Association, Southern California Psychiatric Society, Northern California Psychiatric Society, Orange County Psychiatric Society, Central California Psychiatric Society, and San Diego Psychiatric Society argue that “despite the availability of professionally developed, evidence-based guidelines embodying generally accepted standards of care for mental health and substance use disorders, managed care organizations commonly base coverage decisions on internally developed ‘level of care guidelines’ that are inappropriately restrictive.”
The guidelines “may lead to denial of coverage for treatment that is recommended by a patient’s physician and even cut off coverage when treatment is already being delivered,” said the groups.
The U.S. Department of Labor also filed a brief in support of the plaintiffs who are suing UBH. Those individuals suffered injury when they were denied coverage, said the federal agency, which regulates employer-sponsored insurance plans.
California Attorney General Rob Bonta also made an amicus filing supporting the plaintiffs.
“When insurers limit access to this critical care, they leave Californians who need it feeling as if they have no other option than to try to cope alone,” said Mr. Bonta in a statement.
‘Discrimination must end’
Mr. Bonta said he agreed with a 2019 ruling by the U.S. District Court for the Northern District of California that UBH had violated its fiduciary duties by wrongfully using its internally developed coverage determination guidelines and level of care guidelines to deny care.
The court also found that UBH’s medically necessary criteria meant that only “acute” episodes would be covered. Instead, said the court last November, chronic and comorbid conditions should always be treated, according to Maureen Gammon and Kathleen Rosenow of Willis Towers Watson, a risk advisor.
In November, the same Northern California District Court ruled on the remedies it would require of United, including that the insurer reprocess more than 67,000 claims. UBH was also barred indefinitely from using any of its guidelines to make coverage determinations. Instead, it was ordered to make determinations “consistent with generally accepted standards of care,” and consistent with state laws.
The District Court denied a request by UBH to put a hold on the claims reprocessing until it appealed the overall case. But the Ninth Circuit Court of Appeals in February granted that request.
Then, in March, United appealed the District Court’s overall ruling, claiming that the plaintiffs had not proven harm.
The U.S. Chamber of Commerce has filed a brief in support of United, agreeing with its arguments.
However, the APA and other clinician groups said there is no question of harm.
“Failure to provide appropriate levels of care for treatment of mental illness and substance use disorders leads to relapse, overdose, transmission of infectious diseases, and death,” said APA CEO and Medical Director Saul Levin, MD, MPA, in a statement.
APA President Vivian Pender, MD, said guidelines that “are overly focused on stabilizing acute symptoms of mental health and substance use disorders” are not treating the underlying disease. “When the injury is physical, insurers treat the underlying disease and not just the symptoms. Discrimination against patients with mental illness must end,” she said.
No court has ever recognized the type of claims reprocessing ordered by the District Court judge, said attorneys Nathaniel Cohen and Joseph Laska of Manatt, Phelps & Phillips, in an analysis of the case.
Mr. Cohen and Mr. Laska write. “Practitioners, health plans, and health insurers would be wise to track UBH’s long-awaited appeal to the Ninth Circuit.”
This article first appeared on Medscape.com.