We all know how difficult treatment resistant depression (TRD) is for both the patient and the clinician. Wouldn’t it be great if we had a noninvasive method to treat these cases with better efficacy than ECT? What if I told you there is a new type of TMS that leads to remission in 80% of the most difficult to treat cases of depression? Would you be interested? Let’s Find out.
SAINT stands for Stanford Accelerated Intelligent Neuromodulation Therapy, try saying that one three times fast.
This is not a new concept as SAINT uses a noninvasive neuromodulation therapy (TMS) in patients with treatment resistant depression and it has shown some real promise in that area.
Treatment resistant depression (TRD) can affect up to 30% of patients with major depressive disorder and as you might expect it’s hard to treat these cases. When a patient reaches this point, things like off-label medication prescribing, ECT and Ketamine are used. However, the FDA just approved a new version of TMS that is reported to have an 80% remission rate in these patients.
The approval came quick as this device has received breakthrough status by the FDA based on the impressive results from study that included 22 participants with TRD. 19 of the 22 participants achieved remission which in terms of percentage was 86.4% of participants. This is substantially better than other treatments for TRD including ECT which come in around 50%-70% depending on the study you read.
What Is SAINT?
SAINT was first developed at Stanford University. What sets this TMS procedure apart from other methods of TMS is the intensity of treatment (10 sessions per day) carried out over the course of 5 days. Each session is 10 minutes in length. The intelligent portion of the name has to do with the use of MRI/fMRI-guided theta burst stimulation ensure proper placement of the coil on the dorsal lateral prefrontal cortex.
This device made it out of the academic arena and is now being distributed by a private start up company called Magnus Medical. You can get on the waiting list now to purchase one of these machines if you feel compelled to do so after this talk. To be clear I have no affiliations with the company.
What Research Lead to FDA Breakthrough Status Approval?
In general devices are not held to the same standard as medications when we are talking about FDA approval. It’s much easier to get a device approved.
The initial work was carried out with an open label format which is usually considered a lower form of evidence when compared to randomized controlled trials. The research group eventually published a randomized controlled trial in the American Journal of Psychiatry which is largely what allowed SAINT to gain FDA approval. In this study 32 participants with TRD were randomized to active treatment or sham. In this study they used percent reduction from baseline MADRS score 4 weeks after treatment which was found to be 52.5% in the SAINT group and 11.1% in the sham group. The remission rates in this study were 79% for the treatment group compared to 13.3% in the sham group.
These are significant results in the most difficult patient population to treat. It’s important to point out that these participants had 10 hours of contact with the treatment team per day and the number of participants in the study was small. Both are confounding factors, but using sham treatment helps because most participants were not able to tell if they received the treatment or sham. The one thing that was more common in the treatment group was headaches which may have altered them to which groups they were randomized into.
The authors justified the low number of participants because they achieved a very large effect size with statistical significance without additional participants. What is currently missing from the research is a large randomized controlled trial conducted independently of the research group who designed the protocol (something to look out for in the future).
Mechanism of Action (MOA)
One question you may have been thinking about is how does TMS work and what is the proposed mechanism of action for SAINT?
TMS is a noninvasive method of modulating specific areas of the brain by generating a magnetic field which induces neural cell membrane potentials to depolarize in the brain under the coil. Placing the coil in the correct location is critical and there is a 30% chance of missing that location when MRI is not used to map the exact location of the dorsal lateral prefrontal cortex.
SAINT is thought to alter brain connectivity and increase neuroplasticity in ways that traditional forms of TMS do not. The preliminary evidence suggests connectivity between the amygdala, insula, and medial frontal gyrus is altered in a meaningful way resulting in the improvement in depressive symptoms. Studies are underway to assess the MOA further.
How Does SAINT Differ From Other Forms of TMS?
First it differs in the time frame, it takes place only 5 days while most other forms of TMS take a full 6 weeks to complete. The treatments during those 5 days are intense, it requires 10 treatments per day while standard TMS is usually once per day.
The time for each treatment in the SAINT protocol is much shorter lasting approximately 10 minutes compared to the 20 to 45 minutes usually required.
There are three established types of TMS that differ in the time it takes to complete the treatment session.
-The first one on the market was the figure 8 coil which took 45 minutes to complete each session
-The H coils were invented by Brainsway and these sessions take 20 minutes
-Theta-burst stimulation: only take 3 minutes, and this is the one that the SAINT protocol uses
The next question is where to place the coil and how to place it. Traditionally the coil is moved around until the thumb twitches, this is the so-called thumb center, and we can look at the homunculus drawing and see how large the thumb center is. Traditionally we would measure 7 centimeters away from the thumb center and that should be the left dorsolateral prefrontal cortex. This method is not very accurate missing the mark approximately 30% of the time. To fix this problem the SAINT protocol uses MRI guided imaging to be sure the coil placement is accurate. You can also use EEG or PET scans to guide placement.
-While I’m glad there is innovation in TMS treatment, and the results thus far have been impressive we have to keep in mind this machine is now being marketed by a startup company and has left the world of academia.
-It’s unclear if you need their machine to produce similar results as theta burst TMS already exists and MRI guided placement of the coil on the dorsal lateral prefrontal cortex exists as well. The company claims they have developed an algorithm for placing the coil that is unique and this claim will need to be investigated further once the machines are available.
-Another concern is most of the research has been published by the same group that designed the protocol and has not been reproduced in large RCTs independently.
-My final concern is regarding the application of this treatment for the average patient. It requires a full 5 days and 10 hours of treatment over the course of the 5 days. This may or may not be feasible for the average patient with treatment resistant depression. We haven’t even talked about what this intensive treatment will cost and if insurers will pay for it, another potential barrier.
-I would also like to see this go head-to-head in a study with Ketamine infusions and ECT.
I’m one of the first couple 1000 to receive treatment. I was told outright ECT was a higher success ratio but I couldn’t miss that much work nor was I willing to take the risk of multiple anesthesias. I went from a PHQ9 on Monday to a 3 on Friday. 0 depression. And 0 side effects for 5 months. Going back for maintenance treatment. For many now FDA approved Insurance will cover all 50 sessions. Hoping to get to a point where I’m drug free one day