Synopsis: Transcranial Magnetic Stimulation (TMS) therapy is one of the newest and most effective treatments for major depression, especially treatment-resistant depression. This article reviews recent research that supports Stanford’s revolutionary approach, which may improve the effectiveness and accessibility of TMS for depression.

BY LEN LANTZ, MD / 11.7.21; No. 52 / 7 min read

Disclaimer: Yes, I am a physician, but I’m not your doctor, and this article does not create a doctor-patient relationship. This article is for educational purposes and should not be seen as medical advice. You should consult with your physician before you rely on this information. This post might also contain affiliate links. Please click this LINK for the full disclaimer.

A quick refresher on TMS for depression

Transcranial magnetic stimulation (TMS) therapy is a treatment for major depression that works when traditional treatments, such as antidepressant medications and psychotherapy, have failed to fully lift a person’s depression (also known as achieving remission). TMS was approved for the treatment of major depression by the US Food & Drug Administration (FDA) in 2008, and the treatment is effective for other conditions such as obsessive-compulsive disorder (FDA approved in 2018), bipolar depression (FDA provided breakthrough designation in 2020), and addictions (FDA clearance in 2020 with approval pending for smoking cessation). TMS therapy works for kids who have major depression and also is effective at preventing the recurrence of depression (maintenance treatment), however, the FDA has been slow to approve uses of TMS compared to new medication treatments for depression, such as esketamine.

Researchers have been studying TMS with intense interest because it is a new way of treating depression and understanding the mechanisms that drive depression. TMS has minimal side effects and when depression improves with the standard treatment protocols, the improvement usually lasts. On a single day of treatment, TMS therapy involves a person receiving hundreds of magnetic pulses over the left front scalp that stimulate the area of the brain known as the DLPFC (dorsolateral prefrontal cortex), which is underactive in depression. One of the limitations of TMS is that it involves daily treatment for weeks, so researchers have been trying to find ways to shorten the daily treatment window (such as the iTBS protocol, which takes 3 minutes compared to 20-minute standard TMS) and the number of weeks that a person has to come in for treatment (such as in the 2020 Stanford SAINT protocol).

Another area of research in TMS regards accurately targeting the magnetic pulses to the DLPFC. Research has shown since 2001 (Herwig et al. Biol Psychiatry. 2001) that the DLPFC is frequently missed using routine targeting, and imprecise targeting of the DLPFC in TMS treatments results in worsened outcomes (Fitzgerald, et al. Neuropsychopharmacology. 2009). Using a procedure called neuronavigation improves the accuracy of TMS in delivering the magnetic pulses to the DLPFC. For more background on TMS therapy for depression, please see my article, “Transcranial Magnetic Stimulation (TMS) – the Best New Depression Treatment.”

What Stanford did in its revolutionary SAINT study

In a small study in 2020 (Cole et al. Am J Psychiatry. 2020), Dr. Nolan Williams and his group of Stanford researchers combined all of the best new TMS strategies and added in a few game-changers. In their SAINT study, the researchers used fMRI brain scans to accurately determine the location of the DLPFC, because determining the location of the DLPFC with a normal MRI is still just guessing at its location. Once they found the precise location of the DLPFC, the researchers were able to use the neuronavigation process to deliver the magnetic pulses to the proper area.

Next, the researchers delivered a TMS treatment (involving hundreds of magnetic pulses) 10 separate times per day for 5 days. For comparison, a standard TMS treatment schedule involves 30 to 36 treatments over 6 or more weeks. The researchers provided many more treatments over a much shorter timeframe, and their results were far better than those of standard TMS treatments. The best outcomes of standard TMS, which are far better than antidepressants and psychotherapy for treatment-resistant depression, have approached a 50% remission rate. In their 2020 study, Stanford achieved a jaw-dropping 90% remission rate. For a more thorough review of the 2020 SAINT study, please see my article, “Stanford’s SAINT Study: a TMS Breakthrough for Depression?.”

What is new in Stanford’s 2021 SNT study?

Other than the SAINT study being a small study, one of its biggest limitations was that there was no placebo/sham group. Depression research studies show that remission rates are not as impressive once a placebo/sham is added in, and that is what Stanford did in this new study. In addition to changing the name of their approach from SAINT to SNT (Stanford Neuromodulation Therapy), they added the placebo/sham component to their approach.

In the 2020 SAINT study that did not have a sham/placebo, Stanford achieved a 90% remission rate for depression. In this 2021 SNT study report titled “Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial” (Cole et al. Am J Psychiatry. 2021), the researchers achieved a 79% remission in the active treatment group and a 13% remission rate in the placebo/sham group. This is exactly the outcome everyone was hoping for. The SNT study had an amazing outcome even after the placebo/sham was added. This research provides further evidence that the treatment outcomes are real and the results are reproducible. It opens the door for larger studies of this treatment strategy and takes us one step closer to widespread clinical use.

What are the limitations of the Stanford SNT approach?

One of the biggest concerns of the Stanford SNT study is that we do not know the duration of improvement past the 5 weeks of the study. If I had to guess, the long-term durability is not great, as in the 2021 SNT article, the authors state, “We propose a treatment model in which SNT is used to achieve rapid remission from depression and is then followed by a less intensive maintenance treatment that can be of any effective and acceptable modality—medication, psychotherapy, brain stimulation, and other treatments. Under this model of care, all patients who enter remission in the month after treatment would be able to transition to a maintenance treatment.” Research from longer treatment protocols shows a duration of remission and response (meaningful improvement) at the 1-year mark of 62% (Dunner et al. J Clin Psychiatry. 2014).

Another limitation of this study is that its reliance on fMRI makes it less scalable due to the cost and specialized technical expertise required. Not only do radiology departments struggle to get insurance company reimbursement for fMRI in clinical settings, running an fMRI service requires expensive software, a team of professionals trained in its use, and an experienced neuroradiologist.

After the 2020 SAINT study was published, I actually called every neuroradiology department in the state of Montana. Neither the larger hospitals nor the private MRI clinic that I called were willing to do fMRI testing to find the DLPFC even with out-of-pocket payment. The use of fMRI is a significant barrier for states like Montana to overcome if the SNT protocol becomes the new gold standard treatment for severe and treatment-resistant depression.

There might be easier and cheaper ways to find the DLPFC. For example, functional Near-Infrared Spectroscopy (fNIRS) has been used to measure the activity of the DLPFC (Schaal et al. Sci Rep. 2019). Also, high-density EEG (HD-EEG) with LORETA reconstruction has been used to study the DLPFC (Brown et al. Pain. 2008; Lamm et al. Dev Sci. 2014). A recent study also showed 92% success in localizing the DLPFC using TMS stimulation while the patient performed a cognitive task (Wang, et al. Exp Brain Res. 2021). Possibly the Stanford team could add these other techniques to future research with an eye toward widespread clinical accessibility to the SNT treatment protocol.

Another possible solution would be to bypass the fMRI localization altogether and just run the SNT protocol with a BrainsWay TMS device. The SNT study relied on a device with a figure-8 treatment coil that treats a smaller and more targeted area. The BrainsWay TMS device, on the other hand, is unlikely to miss the DLPFC target, as the H-shaped coil stimulates both broadly and deeply, thereby removing the need for neuronavigation.

What rural America needs from the SNT

Stanford’s SNT protocol has the possibility of better meeting the needs of rural Americans with depression because it compresses a 6-week treatment down to 5 days and offers better results. If you take Montanans, for example, our farmers and ranchers cannot leave their crops and cattle to drive to Helena or Billings every day for standard TMS therapy for 6 weeks. However, there is a good chance that they could travel into the city for 5 days of SNT, especially if there is a very high likelihood of the treatment being effective.

Stanford’s SNT remains experimental, but its outcomes are very encouraging. One of the greatest future barriers to making SNT available for widespread clinical use in places like Montana is its reliance on fMRI. If we had fMRI available in Montana, we would be much closer to having this treatment readily available to Montanans. Montana has one of the highest suicide rates in the nation and depression is by far the largest contributor to our high suicide rate. Federal funding or large private donations could potentially make fMRI-reliant treatment possible in Montana. Once we get the right supports and treatments in place, we truly will help the people who need it the most.

The Stanford SNT provides realistic hope for people who struggle with depression

The SNT team at Stanford has provided tremendously important, high-caliber research on depression and given hope to people with severe depression, their loved ones, and their mental health caregivers. The SNT study is offering new insights into how to best deliver TMS therapy and may become the new gold standard in the treatment of refractory depression. Imagine already having this treatment available in your community. This 2021 SNT study provides realistic hope with actionable results and is an excellent example of why the US needs to promote medical research on depression and the prevention of suicide. Conventional TMS treatment protocols already are a big improvement over treatment as usual. Stanford’s SNT is a great sign of even better treatments to come for those with depression.

For further reading, check out:

• Len’s Article, “Stanford’s SAINT Study: a TMS Breakthrough for Depression?”

• Len’s Article, “Transcranial Magnetic Stimulation (TMS) – the Best New Depression Treatment”

• Len’s Article, “The Most Important New Findings in Depression”

• Transcranial Magnetic Stimulation: Clinical Applications for Psychiatric Practice by Drs. Bermudes, Lanocha and Janicak

• Network Neuroscience by Dr. Frohlich

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