“My therapist keeps telling me to do relaxing things like meditation, yoga, and mindfulness exercises. Why doesn’t she believe me when I tell her they make my anxiety worse?” I’m sure your therapist isn’t trying to be a meanie, but show her this article next session. Relaxation-induced anxiety is the real deal…
Since most of the things we worry about don’t happen, reinforced in the brain is, ‘See, I worried and nothing bad happened, so it makes sense that I should continue worrying.’
Why does it have to be so hard, right? I mean, sure makes sense that doing relaxing things would soothe the anxious beast. But, no, it doesn’t go that way for so many of us. Heck, the frustration factor is right up there with meds that work just great for others, but fail to do the job for us.
So what are we going to do? Can’t get all ticked-off, collect our toys, and leave the playground. Nah, it’s times like these that we need to learn all we can about our “eccentricities,” understand we’re not alone in them, make the indicated adjustments, and roll-on.
Speaking of which…
“People with Anxiety May Strategically Choose Worrying Over Relaxing”
I really enjoy finding cool stuff to bring your way. Believe me, there’s so much interesting and hopeful activity going-on out there. And so it is with new research from Penn State University, as detailed in the article, “People with anxiety may strategically choose worrying over relaxing,” written by Katie Bohn for Penn State News. The study was published in the Journal of Affective Disorders.
So, okay, those of us who wrestle with anxiety may actively resist relaxation in an effort to continue worrying. Why would we do that? According to psychology professor Dr. Michelle Newman and team, it’s to avoid a large jump in anxiety should something bad happen.
My personal experience has me buying what they’re selling. Still, let’s have a little bit more…
The team found that people who were more sensitive to shifts in negative emotion – for instance, quickly moving from a relaxed state to one of fear – were more likely to feel anxious while being led through relaxation exercises.
From Dr. Newman…
“People may be staying anxious to prevent a large shift in anxiety, but it’s actually healthier to let yourself experience those shifts. The more you do it, the more you realize you can do it and it’s better to allow yourself to be relaxed at times. Mindfulness training and other interventions can help people let go and live in the moment.”
By the way, can you relate to being sensitive to shifts in negative emotion?
Why Do Relaxation Treatments Ramp-Up Anxiety?
Dr. Newman says researchers have known about relaxation-induced anxiety since the 1980s, but the specific cause remains in the shadows. Actually, Newman believes she began shining some light on the matter when she developed the contrast avoidance theory in 2011.
I think you’ll find this very interesting and helpful. The contrast avoidance theory revolves around the notion that we may intentionally (perhaps without knowing it) make ourselves anxious as a way to avoid the letdown we might feel if something – anything – bad were to happen.
Of course, such thinking does us absolutely no good and only makes us more miserable. But here’s the biggie! Since most of the things we worry about don’t happen, reinforced in the brain is, “See, I worried and nothing bad happened, so it makes sense that I should continue worrying.”
Sure makes sense to me???
The Guts of the Study
The research team recruited some 100 participants, evenly split between generalized anxiety disorder (GAD) patients, major depressive disorder (MDD) patients, and a control group with neither disorder.
The participants were led through relaxation exercises before watching videos that held the potential to generate fear or sadness. Then it was on to answering questions designed to measure sensitivity to changes in emotional state.
Thing is, some may have found the negative emotions incited by the videos uncomfortable right after relaxation exercises. But others may have felt the exercises helped them deal with their negative emotions.
Well, the team led the participants through another relaxation exercise session before asking for the completion of a second survey.
Here’s the bottom-line: The GAD patients were more likely to be sensitive to sharp spikes in emotion – like going from feeling relaxed to being frightened or stressed. And the team linked the sensitivity to feeling anxious during sessions intended to induce relaxation.
Though not as strong, the same results were noted for the MDD patients.
According to graduate student Hanjoo Kim…
“Measuring relaxation-induced anxiety and implementing exposure techniques targeting the desensitization of negative contrast sensitivity may help patients reduce this anxiety. Also, it would be important to examine relaxation-induced anxiety in other disorders, such as panic disorder and persistent mild depression.”
That’s All, Folks
I’ve been on a mission for decades to negate the freak-factor involved with living with an emotional or mental health disorder. I’ve said it time and again: knowing others were in the same boat provided tons of comfort in the early years of my disorder experience.
Does your anxiety spike when you attempt to do something relaxing? Well, you aren’t alone, and now you have some insight into why it happens, and what to do about it.
The state of mood and anxiety disorder diagnosis and treatment sure isn’t anything to write home about. I know, most emotional and mental health practitioners do the best they can with what they have; however, even they’ll admit it isn’t nearly enough. Good news is there’s a lot cookin’ that’s changing the landscape. Let’s talk artificial intelligence…
‘The algorithm was able to identify children with a diagnosis of an internalizing disorder (anxiety, depression) with 80 percent accuracy.’
If we were to poll one-hundred individuals who are participating in some form of treatment for a mood or anxiety disorder, I’m guessing only five would say everything was hunky-dory.
And, of course, the remaining ninety-five are wishing, hoping, praying for something – anything – promising from the world of research, eyes and ears fixed upon the meds pipeline. But I’ve said many times, hope isn’t only about meds.
Get yourself comfortable as we chat artificial intelligence…
Artificial Intelligence: What Is It?
Artificial intelligence (AI) is often misunderstood, even feared. So let’s start with some defining.
Very simply, within the context of computer science, AI, often referred to as machine intelligence, is the term used to describe machines that mimic the cognitive functions we humans associate with other human minds. That would include learning and problem solving.
Now, let’s take our definition one step further. AI is a system’s ability to correctly interpret external data, learn from it, and use the learning to achieve specific goals and tasks through flexible adaptation. By the way, AI isn’t really anything new, as the term was coined during a Dartmouth College workshop back in 1956.
Okay, the changing the landscape info you’re about to read comes from three articles, which we’ll discuss one-by-one. I’ll present links at the end.
“Can AI Help Doctors Treat Depression? These Startups Think So”
In “Can AI Help Doctors Treat Depression? These Startups Think So,” Yaron Carni and Danielle Shapira get us off to a great start by pointing-out that though AI is assisting in powering the “digital health boom,” its relationship with emotional and mental health is new. And much of that has to do with the fact that understanding human thoughts and feelings is much more difficult than dealing with a potentially damaged kidney. Add to the difficulty factor the reality that boosting one’s mood or lowering their anxiety, within the framework of personalized medicine, is a daunting task.
Still, Carni and Shapira go on to mention several startups that are coming out with a variety of AI-based tools designed to help psychiatrists and family docs optimize depression and anxiety care sooner.
Here are two…
Taliaz is developing an AI-driven decision support tool, PREDICTIX, that’ll help docs identify the right antidepressant for any given patient. The tool uses data based upon the results of the epic STAR*D study. And catch this. After developing the algorithms, PREDICTIX was able to predict efficacy and adverse effects of antidepressants with as high as 75% accuracy. To get the ball rolling, a DNA sample, as well as a demographic and clinical history, are collected online.
Carni and Shapira go on to mention the startup Elminda, whose brain analytics product, BNA-PREDICT, forecasts responsiveness to antidepressant med and neurostimulation treatments. And the tool allows docs to monitor the chosen treatment’s impact directly in the patient’s brain.
“Can Artificial Intelligence Help with Depression?”
Jodi Clarke opens her article, “Can Artificial Intelligence Help with Depression?,” bringing the sad news that according to the National Institute of Mental Health, only 63% of those having had a major depressive episode received any kind of treatment. And the numbers are worse for teens.
According to Clarke, AI-based programs (apps) offer significant treatment assistance because they directly address convenience, connection, and anonymity. She provides three examples…
WoeBot: A conversational agent (“chatbot”) that offers self-help related guidance and companionship. It can share all sorts of information and resources and can facilitate mood tracking. Cool thing is, part of its guidance are cognitive behavioral therapy (CBT) techniques.
Wysa: An emotionally intelligent bot that assists with managing emotions and thoughts. From their website, “…your private reflective space for when you need to get your head straight.” Like WoeBot, Wysa uses CBT, even DBT, guidance.
Tess: Also a chatbot, it touts itself as “a psychological AI that administers highly personalized psycho-education and health-related reminders on demand.” They call themselves a “transformative digital behavioral change program.”
By the way, do you think any of the above are popular? You’d better believe it. Tess says eight-million people have paid access. Wow!
“Artificial Intelligence Can Detect Depression in a Child’s Speech”
Opening her piece, “Artificial Intelligence Can Detect Depression in a Child’s Speech,” Anna Versai observes that 20% of children endure “internalizing disorders” – anxiety and depression. And since both may be difficult to detect, especially for children under eight years of age, late treatment onset is a major problem.
But Versai cites a study published in the Journal of Biomedical and Health Informatics. The work was conducted at the Vermont Center for Children, Youth and Families, University of Vermont Medical Center. And how ’bout this? The study team came up with an AI algorithm that can detect signs of anxiety and depression by using the speech patterns of children.
In the words of the study’s senior author Ryan McGinnis, “The algorithm was able to identify children with a diagnosis of an internalizing disorder with 80 percent accuracy.”
And, of course, that means treatment can commence so much sooner.
That’s All, Folks
Okay, most anyone in any way involved with a mood or anxiety disorder knows we have a long way to go in terms of diagnosis and treatment. So holding onto hope is essential. But I’m telling you, hope extends well beyond meds in the development pipeline.
Artificial intelligence is quickly changing the mental health landscape. And keep in mind, the two haven’t been pals for all that long.
I believe there’s so much more to come. You just wait and see.
Your brother’s depression has improved on SSRIs. So has your wife’s best friend’s. Go figure, not yours. Understandably, you’re frustrated – angry. Yeah, “So why not me?” Well, before you come up with a goofy reason to blame yourself, let’s take a look at some enlightening new research…
The team discovered that the actual production of serotonin has nothing to do with it…And the efficiency of the reuptake process itself wasn’t implicated. So what the heck is the problem?
We’ve discussed depression not responding to an antidepressant too many times. But it’s a tough fact of life in the mood and anxiety disorder neck of the woods, and merits continued action-oriented chat.
Okay, you know how I am, always snooping-around for hot scoops on what we wrestle with. Over the weekend an article title jumped out at me and I had to dig-in. I mean, what would you have done if you read “When Neurons Are Out of Shape, Antidepressants May Not Work?”
So there it was on the Salk Institute’s website, a summary of their new study, just published in the journal, Molecular Psychiatry. In bringing you the information, I used the journal piece as reference. Actually, had to pay to access it, so I’ll hit you a link to the Salk article at the end.
One additional – important – piece of business before we jump-in. I really believe you’ll find this research enlightening. I mean, the science is stunning. But the point goes well beyond just that.
Sure, what you’re about to read isn’t going to solve the SSRI-resistance problem – today. But I find it encouraging and hopeful that scientists are considering so many depression treatment angles. New meds, or meds in development, often steal the headlines, but it’s “back-page” work like this that may well bring relief to millions by, say, solving the resistance issue or directing patients to other antidepressant (AD) classes or non-ADs.
Well, let’s see what you think…
“Altered serotonergic circuitry in SSRI-resistant major depressive disorder patient-derived neurons”
Some title, right? Well, straight from the journal. And I’m telling you, the info was impressively, um, brainy.
Couple of heads-ups going-in, just in case. “Serotonergic” means anything having to do with the neurotransmitter serotonin. SSRIs are selective serotonin reuptake inhibitor ADs (brand names Celexa, Lexapro, Prozac, Luvox, Paxil, Zoloft).
The Salk brain-trust sets the table for their study by stating disrupted serotonergic neurotransmission has long been implicated in the generation of major depressive disorder (MDD). And they go on to say that SSRIs are the first line of treatment, as well as the most prescribed class of ADs.
But then they deliver the bad news: some 30% of MDD patients fail to show improvement with SSRI intervention, even after multiple treatment steps. One more bummer. Even though the mechanisms contributing to MDD are becoming much better understood, such hasn’t been the case for SSRI-resistance.
Interesting Brain-Systems Realities
The study team shared a few brain-systems realities that I found interesting. The 5-HT (5-hydroxytryptamine, serotonin’s chemical name) transporter, which is highly expressed in serotonergic neurons, is the primary target of the SSRIs.
But in making sense of all of this, you have to keep in mind that the 300,000 or so serotonergic neurons in the brain are difficult to work with. That’s because they constitute a small fraction of our 86 billion total brain neurons. And then there’s their location in the raphe nuclei, deep within the brain stem. That makes serotonergic neurons terribly inaccessible.
Barriers & Findings
So facing barriers, the team had to come up with creative methods to take care of biz. They turned to something known as induced pluripotent stem cell technology (iPSC, and we aren’t going there), which allowed them to generate neural subtypes of SSRI-responsive and resistant study participants (800 total).
This is huge, because there had never been a study that used patient-derived neurons in vitro (outside of their normal biological context). This was human-live.
So what causes SSRI-resistance?
The team discovered that the actual production of serotonin has nothing to do with it. The same applies to SSRI concentrations in the blood. And the efficiency of the reuptake process itself wasn’t implicated.
So what the heck is the problem?
Well, the team discovered that altered serotonergic neuron growth, form and structure, and circuitry “downstream” of what are called protocadherin alpha genes (not going there either) are associated with SSRI-resistance.
Thing is, serotonergic neurites (projections) have to travel quite a distance from the raphe nuclei to innervate nearly all forebrain structures (cerebral hemispheres, thalamus, hypothalamus, etc.). Of course, then, inadequate serotonergic innervation is a big contributor to psychiatric disease.
Still, longer serotonergic cell neurites may be associated with SSRI-resistance, as it seems longer neurites aren’t necessarily better. The team observed that altered levels of two protocadherins may be associated with this phenomenon, and lowering them regulates length.
People, I could go on and on about the study, but I’ve worked-up a sweat. How ’bout this from study senior author and Salk president Dr. Rusty Gage?
“This paper, along with another we recently published, not only provides insights into this common treatment, but also suggests that other drugs, such as serotonergic antagonists, could be additional options for some patients.”
That’ll Do It
The Salk work is impressive, but, as always, let’s not lose the forest for the trees. Sure, gummed-up serotonergic wiring may generate maladaptive circuitry that contributes to SSRI-resistance in major depressive disorder patients.
But that revelation isn’t going to provide relief today if you’re SSRI-resistant. In the meantime, be hopeful about the science, talk with your doc and pursue other treatment options, and most important of all…
Don’t blame yourself!
(Serotonin pathway image: Wikipedia, Serotonergic neuron image: Salk Institute. Thanks!)
When it comes to the development of new interventions for depression, as well as other mood and anxiety disorders, drugs typically get the spotlight. Makes sense, because they can make the fastest impact. But there’s more in the pipeline than just meds. For instance, deep brain stimulation…
So though the science and technique are still developing for the treatment of depression, in my opinion we’re not talking lobotomies with ice-picks.
Lots of depression treatment hubbub these days, what with the FDA approval of the nasal spray esketamine (Spravato). And I believe there’s more in the immediate future with rapastinel. Of course, both are meds.
But as we look with great hope to new interventions for depression – all mood and anxiety disorders – meds aren’t the only players.
Let’s have a very basic chat about deep brain stimulation (DBS)…
Deep Brain Stimulation
Interesting: I posted an article about deep brain stimulation for the treatment of depression here on Chipur seven years ago. And, go figure, development continues. Funny how that pipeline works, right?
Okay, let’s begin our discussion by talking about what DBS isn’t. That list includes transcranial magnetic stimulation (TMS), transcranial direct current stimulation (TDCS), and electroconvulsive therapy (ECT). By the way, you can enter any of them in the search box above and find some solid information.
DBS is an invasive (no craniotomy) procedure involving the implantation of electrodes in target areas deep within the brain. The electrodes produce electrical impulses that regulate abnormalities, including those of impulse, neurons, and brain chemicals. A pacemaker-like device is implanted under the skin in the upper chest, which governs the amount of stimulation. Go ahead, reference the featured image.
DBS is currently FDA-approved for the treatment of dystonia, epilepsy, essential tremor, OCD (some very cool things going-on), and Parkinson’s disease. And it continues to be studied for a variety of challenges, such as depression, addiction, chronic pain, multiple sclerosis, dementia, and Tourette syndrome.
So though the science and technique are still developing for the treatment of depression, in my opinion we’re not talking lobotomies with ice-picks.
DBS for Depression
As you likely assumed, DBS becomes a treatment option only after the failure of multiple interventions. So this is about treatment-resistant depression (TRD). Yes, DBS for depression is not FDA-approved, though procedures are being performed “off-label.” It’s a similar arrangement to using ketamine infusions for TRD.
By the way, many clinical trials are in the works. If you’re interested in that sort of info, including participation, head over to clinicaltrials.gov, enter the necessary info into the search box, and have at it.
Now, before we continue, keep in mind that DBS for depression is considered an investigational treatment. Also understand that results over the years have been extremely mixed. That includes complete remission, moderate improvement, no impact at all, and major cognitive and mood disasters.
DBS for Depression: Targets
At this time, the DBS treatment approach for depression is definitely not optimized; however, the numero uno consideration is the stimulation site. Makes a ton of sense, right?
Looking at the image to the left, the red sites are current targets and the green are candidates. We’re not going to review all of them, but among the current targets, the subgenual anterior cingulate cortex (sACC), ventral capsule/ventral striatum (VC/VS), and nucleus accumbens (NAcc) are three of the most used. If you’d like to review them all, check-out the article I looked to for reference. I’ll hit you a link at the end.
Of course, selecting a target site isn’t like playing pin the tail on the donkey. Taken into account are neuroimaging, human and animal studies, and anatomical and functional position based upon what are believed to be the dysfunctional neural circuits in mood disorders – or of their role in neurotransmitter systems. Well, let’s just say some thought goes into it.
DBS for Depression: The Future
DBS for depression will continue to be performed and studied, with a goal of completely removing the functional abnormalities that generate treatment-resistant depression. And the most important consideration will remain target selection.
And how ’bout this important takeaway from DBS research? Scientists believe that the fact that DBS has produced anti-depressant effects, using assorted targets, supports the notion that depression is a neurocircuitry disease involving the gumming-up of multiple neural networks. That, as opposed to the issue being just one brain structure.
I mean, that’s huge.
Other important considerations in the ongoing development of DBS for depression include the realities of personalized medicine, which takes into account the specific needs of each patient. That means each DBS procedure will be unique. Refined study design is also key to future efficacy.
So There You Have It
The depression – mood and anxiety disorders – intervention development pipeline is the highway of hope. And, sure, it’s dominated by drugs, but procedures such as deep brain stimulation have to be taken into account.
Absolutely, deep brain stimulation will be an ongoing highway star. And, I might add, who’s to say its efficacy won’t go beyond treatment-resistant, to any depressive presentation?
Okay, here we go. If you had all the money in the world – right now – would you do it?
Anxiety disorders are just plain nasty. Trust me, I’ve shared my life with a couple. Yeah, there are plenty of meds available that may provide relief, but count-on-it effectiveness remains a disappointing problem. So is there any hope? Let’s do an update on drugs in development for anxiety…
You may find this baby to be a real gas. Actually, it is. Nobilis Therapeutics is developing NBTX-101, its active ingredient being xenon – an odorless, colorless gas…
Last week we discussed drugs in development for depression. There were some impressive prospects. So now it’s about anxiety. Again, some very hopeful things on the horizon, but I have to say a smidge less impressive than the depression side of the fence.
If I’m right, why do you suppose that is?
You know, I’ve given it a lot of thought and came up with three angles. First, the anxiety disorders aren’t as “cool” as depression. What?! It’s true. I’ve noticed over the years that depression garners a lot more public, as well as research, attention – though it still isn’t nearly enough.
Then there’s the reality that with the exception of unipolar and bipolar, depression is, well, depression. But anxiety can be generalized, separation, social, phobias, panic, agoraphobia, PTSD, and OCD (the last two are now in different DSM-5 diagnostic categories). And though there may be significant anatomical and biochemical common ground, just as significant variations remain.
Finally, there’s the dough. As much as they may sincerely want to help, pharma companies aren’t going to invest $2.5 billion (shockingly realistic) to bring a drug from invention to pharmacy shelves without a healthy profit opportunity. I’m thinking depression meds’ potential is stronger.
Okay, so much for the warm-up. Let’s get busy…
Drugs in Development for Anxiety
There are a good number of drugs in development for the treatment of assorted anxiety disorders. Can’t review them all, but here are five that merit attention. I’ll slip you a link at the end where you can find more…
Being developed by Avineuro Pharmaceuticals, AVN-101 is in Phase 2 (of 3) of FDA-approval clinical trials for the treatment of generalized anxiety. It primarily targets specific serotonin receptors; however, it also influences histamine and adrenergic (epinephrine/norepinephrine) receptors. It’s being called a serotonin receptor modulator.
Tonix Pharmaceuticals is developing Tonmya (TNX-102-SL), a sublingual product for the treatment of PTSD. It’s in Phase 3 clinical trials. Tonmya targets the mechanisms associated with disturbed sleep and nightmares. So it’s believed that increasing sleep quality in those dealing with PTSD may flip the switch on the body’s adaptive ability to recover from severe trauma – equating to improved daytime symptoms.
What’s especially interesting about Tonmya is it’s low-dose cyclobenzaprine. You may know it as Flexeril, used for sudden onset muscle spasms. It targets serotonin, alpha-1-adrenergic, and histamine receptors. The sublingual application is designed to optimize delivery and absorption, as well as minimize side effects.
Being developed by Azevan Pharmaceuticals, SRX246 is an oral medication for the treatment of PTSD and generalized anxiety. It’s in Phase 3 trials for PTSD and Phase 1 for anxiety. SRX246s target is the hormone vasopressin. The idea is that working with V1A receptors may reduce overall stress or neural circuitry dysregulation.
You may find this baby to be a real gas. Actually, it is. Nobilis Therapeutics is developing NBTX-101, its active ingredient being xenon – an odorless, colorless gas with very low chemical reactivity. It’s in Phase 2 trials for the treatment of PTSD. I might add, giving it a go for the treatment of panic attacks is producing very promising results in Russia.
Now, I typically include the neurotransmitter, hormone, etc. the drug targets; however, this one’s really complicated and I don’t want to gum things up. Let’s just say the action begins on glutamate’s NMDA receptors and it ends up reducing excitatory, and increasing inhibitory, neurotransmission. So how well will it work? Well, rodents that had been exposed to xenon immediately after fear memory reactivation showed a significant reduction in freezing – and I don’t mean temperature.
Pherin Pharmaceuticals is developing Aloradine (PH94B), an as-needed nasal spray for the treatment of social anxiety – primarily in women. Men? Sorry guys, it’s not looking good. It’s in Phase 3 trials. Aloradine is also being investigated for the treatment of generalized anxiety. Yes, primarily in women. Another roundabout and complicated chemical journey, but the bottom-line is the ultimate target seems to be GABAA receptors – same as the benzodiazepines. So there you have the anxiolytic-like effect.
Just a Few More
Before we close, I want to mention just a few more med possibilities beyond the present-day roster of antidepressants and benzos. Maybe you’re familiar with hydroxyzine (Atarax, Rezine, Vistaril) and buspirone (Buspar). Certainly no guaranteed scores, but both are worth a look-see and chat with your doc.
Well that’s going to do it, people. Yep, anxiety is nasty, awful business. And though there are plenty of meds available, just like drugs for depression, efficacy is a problem.
So for the sake of hope we need to keep our eyes on the development pipeline. And while we’re waiting for our ships to come in, we have to stay focused on therapy, lifestyle habits, yoga, meditation, supplements, and more.