The End of Trial-and-Error Psychiatry?

Written by Reece Jones

Illustration by Hrishita Das

Let’s set the scene: you’re recently diagnosed with a small and easily removable cancer. However, instead of immediately removing the tumor, your doctor prescribes a series of medications in the hopes that one will eventually work. After months and potentially years of testing different treatments, you’ve finally moved into surgery to remove a tumor that has become significantly worse since its discovery. Any reasonable person would have done the surgery from the start, right? 

It’s such an egregious example that it’s hard to imagine such malpractice in the 21st century. However, this is the exact approach taken to treating psychological conditions such as depression. For years, doctors have followed a strategy known as “STAR*D” (Sequenced Treatment Alternatives to Relieve Depression), wherein if you bring a patient through several low-effect-size antidepressants, one will work at some point. With that view, the patient will sometimes spend years in a depressive episode until they find, by random chance, the proper treatment. But what if we had a high-effect-size therapy with the same directness we use for physical ailments? Turns out it already exists.

Approved for the treatment of major depressive disorder (MDD) in 2022, SAINT (Stanford Accelerated Intelligent Neuromodulation Therapy) is a protocol with a remission rate of ~90% after 5 days of treatment and, in some cases, less than 3 days. SAINT is an improved version of transcranial magnetic stimulation (TMS), which has existed since the 1980s. TMS uses an electromagnetic coil to stimulate nerve cells in the brain. In depression, the areas of the brain involved in mood control are believed to have decreased activity and decreased communication with other brain regions. Externally stimulating these lesser-used regions seeks to restore or normalize their activity. However, traditional TMS therapy for depression stimulates a broad area of the brain, typically involving 20-30 sessions over 4-6 weeks, with a remission rate of ~30%. With such marked improvements in treatment time and remission, how did a seemingly outdated protocol become one of our most promising avenues for treating depression?

“Both ethically and economically, getting people to the right treatment as fast as possible is the only answer,” says Dr. Nolan Williams, an Associate Professor of Psychiatry and Behavioral Sciences at Stanford School of Medicine, Director of the school’s Brain Stimulation Lab, and one of the lead inventors of SAINT. “The three things we asked were (1) where, (2) how, and (3) how much? Where (1) is: where in that person’s neural network?” Unlike old TMS protocols, which base the “where” on a position on the skull, SAINT uses functional MRI (fMRI) imaging to pinpoint where exactly to stimulate in each patient’s brain. The stimulated region for each patient was determined as the location in the left dorsolateral prefrontal cortex (LDPFC) (the front left of the brain) most anticorrelated with the subgenual anterior cingulate cortex (sgACC) (a structure in the front middle of the brain). In other words, when one region’s activity increased, the other decreased, and vice versa. “Next, how (2) am I stimulating so that the information I’m trying to transmit comes through?” Says Williams. “Finally, how much (3)? We need to do it enough that it sticks.” The SAINT protocol delivers a significantly higher dose than standard TMS treatment (90,000 pulses versus 18,000), with a higher pulse dose associated with greater antidepressant efficacy. This level of precision in treatment has led to yet another breakthrough–the discovery of potential biomarkers for MDD. 

The development of treatments for MDD has primarily been impeded by our lack of a detectable biomarker associated with the condition. Unlike physical ailments that can be treated through direct pharmacological or genetic manipulation, many psychological conditions still lack a definitive biological signature to assess and treat. Despite SAINT’s effectiveness in the acute treatment of MDD, the biological basis for this efficacy remained unknown until recently. In 2023, Dr. Williams’ team published a paper in the Proceedings of the National Academy of Sciences, suggesting MDD is partly caused by abnormally early signaling in an area of the brain called the “salience network.” The salience network has primarily been linked to emotional processing, and previous research has broadly linked this network to the physiology of MDD and the target for SAINT’s treatment success. Similar to the anticorrelation between the DLPFC and sgACC that SAINT uses for targeting, the DLPFC is also anticorrelated to a region known as the dorsal anterior cingulate cortex (dACC). Through SAINT treatment to the left DLPFC, stimulation can alter activity in both anticorrelated regions. The Stanford Brain Stimulation Lab found that in patients with MDD, signaling in the ACC is abnormally earlier than in the anterior insula (a structure in the salience network) and the DLPFC. Furthermore, they found that through SAINT therapy, temporally shifting this abnormal signaling in the anterior cingulate cortex is correlated with symptomatic improvement. While this discovery marks a significant step forward in understanding and treating MDD, another pressing question remains: how accessible is SAINT therapy to those who need it?

Already FDA-approved for the treatment of MDD, the SAINT® neuromodulation system is being deployed clinically and in research protocols in laboratories and hospitals worldwide. Even better, as of 2024, SAINT is now covered by Medicare, with private insurers following suit. With the success of SAINT, Dr. Williams and the Stanford Brain Stimulation Lab continue to explore the biological basis of SAINT and other minimally invasive technologies for psychological treatment. “We’re interested in making it successful for everybody,” says Williams. “Maybe that’s a take-home device that can provide this same sort of stimulation chronically and conveniently. Scaling this out to the masses is our priority.” 

With SAINT, the landscape of depression treatment is shifting from trial-and-error prescribing to precise, targeted intervention. By identifying a biomarker for MDD and refining neuromodulation techniques, Dr. Williams and the Stanford Brain Stimulation Lab are improving current treatments and reimagining the future of psychiatric care. The ultimate goal? Accessibility, efficiency, and lasting impact. As Dr. Williams puts it, “If you have a treatment for depression like SAINT therapy, then there’s a world where most people can be well in a week.”

CITATIONS

U.S. Department of Health and Human Services. (n.d.). Questions and answers about the NIMH sequenced treatment alternatives to relieve depression (STAR*d) study - all medication levels. National Institute of Mental Health. https://www.nimh.nih.gov/funding/clinical-research/practical/stard/allmedicationlevels

Cole, E. J., Phillips, A. L., Bentzley, B. S., Stimpson, K. H., Nejad, R., Barmak, F., Veerapal, C., Khan, N., Cherian, K., Felber, E., Brown, R., Choi, E., King, S., Pankow, H., Bishop, J. H., Azeez, A., Coetzee, J., Rapier, R., Odenwald, N., … Williams, N. R. (2022). Stanford Neuromodulation therapy (SNT): A double-blind randomized controlled trial. American Journal of Psychiatry, 179(2), 132–141. https://doi.org/10.1176/appi.ajp.2021.20101429

TMS history. Los Angeles TMS Therapy and Depression Treatment | TMS History. (n.d.). https://pulsetms.com/resources/tms-history/

Mayo Foundation for Medical Education and Research. (2023, April 7). Transcranial magnetic stimulation. Mayo Clinic. http://www.mayoclinic.org/tests-procedures/transcranial-magnetic-stimulation/about/pac-20384625

Mitra, A., Raichle, M. E., Geoly, A. D., Kratter, I. H., & Williams, N. R. (2023). Targeted neurostimulation reverses a spatiotemporal biomarker of treatment-resistant depression. Proceedings of the National Academy of Sciences, 120(21). https://doi.org/10.1073/pnas.2218958120

CAP Profiles. (n.d.). Nolan Williams: Stanford Medicine. https://med.stanford.edu/profiles/nolan-williams#:~:text=SAINT%20received%20FDA%20Breakthrough%20Device,depression%20within%20inpatient%20psychiatric%20units