A New Paradigm for Treating ‘Treatment-Resistant’ Depression

Contemporary research on the human brain is shedding new light on how to treat illnesses like depression. Researchers are using neuroimaging to take pictures of the brain to gain a better understanding of how it functions. They are also investigating biomarkers and exploring precision targeting, the latter of which has helped extend remission rates and generate faster patient responses.¹ These new research pathways also present opportunities to use “old” technologies—electrical currents and magnetic fields in particular—in novel ways.

In the article “Tackling Depression: A New Treatment Offers Hope for Those Hardest to Treat,” I discussed the causes and impacts of depression and major depressive disorder (MDD). I also touched on the role neural networks play in depression. Neural networks are, in essence, the brain’s circuitry and are proving to be integral in developing new and better treatments for MDD, among others. As Nolan Williams, M.D., explained in a recent podcast, we are currently in the “circuit era” of psychiatry.² Dr. Williams, who is an associate professor of psychiatry and behavioral science at Stanford University and director of the Stanford Brain Stimulation Lab, explained that reframing severe depression as a “circuit problem” and focusing on miswiring/misfiring within the brain,³ is enabling scientists to devise ways to reroute signals to help patients become well. While at Stanford BSL, I collaborated with Dr. Williams to pioneer the development of SAINT® therapy, which has proven to be effective in treating treatment-resistant depression.⁴ Neuromodulation entails stimulating the brain’s nerve cells with electrical or magnetic fields using a variety of methods and devices. Magnus Medical has the exclusive license to further develop and commercialize the SAINT neuromodulation system, which we launched in April 2024.

Currently, the SAINT neuromodulation system uses structural and resting-state functional connectivity MRI (fcMRI) scans to inform a proprietary algorithm that identifies the optimal anatomic target for focused neurostimulation in people with MDD. In the future, the SAINT platform will evolve to treat many more brain disorders.

Functional MRI helps identify the most strongly connected portions of the left dorsolateral prefrontal cortex (DLPFC) with respect to the subgenual anterior cingulate cortex (sgACC), a deeper subregion of the brain.⁵ People with MDD have an underactive DLPFC and an overactive sgACC, which impedes their ability to stop or block out inwardly directed negative thoughts.⁶ Imaging a patient using both structural MRI and resting-state functional connectivity MRI allows us to precisely locate the spot where the DLPFC is connected to the deeper network.⁷ In 2021, Magnus Medical was granted Breakthrough Device Designation and received 510(k) clearance in 2022 by the U.S. Food & Drug Administration (FDA) for the treatment of MDD in adults who have failed to achieve satisfactory improvement from a prior antidepressant medication in the current episode.

In 2023, Mitra et al. published findings from an important study about biomarkers in the brain.⁸ They noted that the biological signatures of MDD are not well understood, even with decades of data from neuroimaging research. What neuroimaging has revealed, Mitra et al. (2023) argue, is that the neural mechanisms of MDD “likely involve aberrant function across brain-wide networks.”⁹ Although researchers’ inability to detect “mechanistic biomarkers” has hindered the development of effective treatments for MDD, Mitra et al.’s (2023) study results “suggest spatiotemporal biomarker of MDD on the basis of aberrant directed signaling between the ACC, anterior insula, lateral prefrontal cortex, and temporoparietal junction.”¹⁰ Stated more simply, the investigators saw that in depression, the signals in the brain were going in the wrong direction. Mitra et al.’s study builds on the results of earlier clinical trials studying treatment using SAINT for MDD, which showed that SAINT relieved symptoms for 80–90 percent of participants after only five days of treatment, with no serious adverse events.^11,12 In a double-blind clinical trial, researchers “observed a large antidepressant effect of SAINT. After five days of treatment, 79% of participants in the active SAINT group (11 of 14 participants) achieved remission from their depressive episodes at some point during the 4-week follow-up, compared with 13% (two of 15 participants) in the sham treatment group.”¹³ Side effects included fatigue and headaches, but they were minimal. Using advanced imaging technologies combined with personalized targeting and novel stimulation patterns, SAINT presents a new form of individualized neurostimulation for people with treatment-resistant depression.

Targeted therapy, the use of neuroimaging, novel stimulation patterns, and ongoing research into the biology of the brain have enabled researchers to revisit how electromagnetic energy can be used to treat mental illness. TMS is gaining traction and recognition as a viable treatment for patients with MDD, and an opportunity exists to explore its use in combination with other therapies. Further research in the form of additional clinical trials is needed to fine-tune treatment protocols, to understand more deeply why TMS is more effective for some patients than for others, and to ascertain whether TMS can be introduced earlier before a patient’s MDD becomes debilitating. Nevertheless, brain stimulation holds great promise—and hope—for those hardest to treat.