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On 9/6/22 the FDA approved Stanford’s SAINT Neuromodulation, an accelerated version of TMS that has raised hopes with unusually high remission rates.

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Published On: 09/12/22

Duration: 14 minutes, 00 seconds

Transcript: 

Kellie Newsome: Treatment resistant depression is – by definition – hard to treat, but new version of TMS brought 80% of patients to remission, it just got cleared by the FDA.  

Chris Aiken:Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report. 

Kellie Newsome: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

Chris Aiken: Last week, on September 6 the FDA granted a new clearance for TMS. This is the 8th in a long line of FDA approvals for TMS, and it’s a big one. You may have heard of it as Stanford Neuromodulation Therapy, but the new brand name is SAINT Neuromodulation. The approval came quickly, because the FDA granted the device breakthrough status based on impressive results from two open label trials. In those trials, 86% of patients with treatment resistant depression achieved full remission. Let me repeat that: 86%. That’s almost double the remission rate we see with ECT in treatment resistant cases. 

But open label trials are not enough, so the Stanford group went on to test this out in a controlled trial. That study was published last February in the American Journal of Psychiatry, and it’s on this study that the FDA approval largely rests. The remission rates were once again high: 79% achieved remission at some point in the 4 weeks after the treatment was completed, compared to only 13.3% in the placebo “sham” group. And those remission rates were fairly stable in the month after treatment ended – fluctuating between 70-84% without any clear pattern of declining results. 

Shortly after the paper came out we interviewed Charles DeBattista, who coauthored the paper with Nolan William’s team. Dr. DeBattista shared that he was surprised to see these kinds of results in patients with this level of treatment resistance.

Dr. DeBattista: “They’re reporting really high remission rates in a treatment-resistant population that’s pretty treatment resistant. They’re the kind of patients that we historically would have sent to ECT.

I don’t know what to make of that, to be honest with you. Knowing this population as I have over the past 25-plus years, when somebody’s reporting an 80% remission rate in a highly treatment-resistant population, I always scratch my head a bit and am skeptical.”

Chris Aiken: The rest of the research team was also surprised by the results. They had planned for a larger trial, but they halted it midway through because achieved statistical significance with a large effect size with only 29 subjects. The study used sham TMS – a fake treatment – as the placebo, which is important because it’s quite possible that some psychotherapeutic effects might slip through the cracks when the treatment team is interacting with the patient 10 hours a day. And – importantly – when asked which treatment they thought they received, patients were not able to tell if they had the placebo or the real thing, meaning the blind was maintained. The side effects were similar between the two groups with slightly more headache in the ones who got the real treatment. 

Clearly these kinds of results need replication, and we’re aware of one study that is underway – also at Stanford – that will look at the effects of SAINT TMS on suicidality. And recently two open label studies of SAINT from independent groups outside of Stanford came out – one in postpartum depression and another in primary insomnia – and while these studies showed benefits they weren’t designed to test the treatment but rather to look into its mechanism using functional MRI.

They suggest the treatment normalizes connectivity between the amygdala, insula, and medial frontal gyrus, and that is the general consensus of earlier investigations, that the SAINT protocol alters brain connections – neuroplasticity – in ways that regular TMS does not.

The SAINT protocol differs from regular TMS in a lot of important ways. First, it takes place over 5 days while regular TMS takes 6 weeks. And treatments during those 5 days are much more intense – patients receive 10 treatments a day, one brief 3 minute treatment.

Regular TMS has only 1 treatment a day, with longer sessions, 20 to 45 minutes. Before the Stanford protocol, there were three types of TMS. They don’t differ much in efficacy, but rather in how long it takes to deliver them. Here’s the line up:

• Figure 8 coils, the first TMS, now off patent but originally known as Neurostar: 45 minutes/day
• H coils, a brand-only innovation known as Brainsway’s Deep TMS: 20 minutes/day
• Theta-burst stimulation:  Originally released by MagVenture as “Express TMS” but now available through several machines, this treatment takes only 3 minutes.

The SAINT protocol uses theta-burst stimulation, but instead of delivering it once a day they give it for 3 minutes every hour, 10 hours a day. Another unique thing about the SAINT is in how they place the magnet.

For TMS to work, they have to target a specific area of the brain, the left dorsolateral prefrontal cortex. In traditional TMS, this region is located through anatomical markers. They move the magnet around until they see the patient’s thumb twitch, once they know where they thumb-center is in the brain – you might remember that from the homunculus drawings that show how different parts of the body are mapped on the motor cortex – the thumb occupies a lot of space there so it’s easy to map, and once you find the thumb you can expect that the so-called mood center – the dorsolateral prefrontal cortex – is about 7 centimeters away.

The problem is that this is an approximation, and close doesn’t count. If you miss the target, the patient is not going to respond much to the TMS. Using more advanced methods to guide the magnet, like EEG, PET scan, or MRI, they find that the old-fashioned thumb rule misses the mark about 30% of the time.

We expect the SAINT machines to roll out in 2023, and the company has a waitlist you can join if you want to be an early adopter – go to Magnus Med.com. One thing that’s not clear to me is whether you absolutely need the SAINT machines. We already have devices that can deliver MRI-guided theta burst stimulation, like Nexstim and Soterix. Magnus claims their device uses a proprietary algorithm to target the dorsolateral prefrontal cortex, and that’s a claim we’ll be looking into.

We will be back in a few weeks with our next episode of the 10 commandments of psychopharmacology. Our first episode which was on doing no harm with psychotropic medications got a lot of questions and feedback from readers that I’d like to share two of them here. One reader asked if it’s OK to give antidepressants along with antipsychotics as opposed to mood stabilizers in bipolar disorder. Well as we talked about in that episode it’s never exactly OK to give an antidepressant in bipolar disorder there’s always some risk there, you just got to measure how risky it is, but yes to your point, antipsychotics are much like mood stabilizers in how they prevent mania, so that would be OK. You know I have a particular bias towards using the classical mood stabilizers, lithium and the anticonvulsants, and we covered the reasons why in our podcast series on antipsychotics last fall. To sum it up briefly, for a long time antipsychotics were meant to be used short-term to get quick relief in bipolar mania and they weren’t used long term because they could cause depression and other long-term side effects like metabolic and tardive dyskinesia. The whole idea of using antipsychotics long-term without a traditional mood stabilizer in bipolar is relatively new and it’s not as well tested as we’d like it to be. Most of the antipsychotics do not have good robust preventative data in bipolar disorder. There are controversies about the kind of data that they do have because there are other explanations for the preventions that we’re seeing. We covered that in our fall podcast series. 

Another reader sent a real-life description of the kind of problem we were talking about, that on the surface sounded absurd, like who would do that, but yet if you look closely we see it all the time, which is starting an antidepressant in someone who’s acutely manic. The reader described a case of a man who was admitted and diagnosed for bipolar one mania. He had symptoms of racing thoughts that he described as psychotic and out of control. He was agitated and restless and not sleeping. The patient was already taking one antidepressant when he was admitted and the treatment plan was not to add a mood stabilizer, but to add another antidepressant, in this case mirtazapine, with the rationale of targeting symptoms of insomnia and anxiety. The problem with this approach is it uses symptomatic treatments rather than using meds the way they were developed and researched for, which is to treat disease states. Yes in mania, anxiety and insomnia are very common chief complaints, but mirtazapine is not going to treat those things unless the underlying disease state is major depression. Finally, one thing more. In the chart the clinical team wrote that they had warned the patient about potential adverse events with mirtazapine including mania which strangely was exactly what their diagnosis was.  Thank you for sending those comments in. It is this kind of feedback that inspires us to keep doing these 10 commandments

Kellie Newsome: Got ideas you’d like us to cover on the podcast? Email [email protected], or connect with us directly through linked in – Chris Aiken MD – or his twitter handle @chrisaikenmd.  Dr. Aiken is posting one research study a day on those social media streams, and listeners are sharing questions and ideas to improve the podcast.