Stanford Accelerated Intelligent Neuromodulation Therapy and Depression Remission

doctor near MRI machine
Hispanic doctor using digital tablet in MRI room
In patients with treatment-resistant depression, use of SAINT—a high-dose, resting-state, fcMRI–guided iTBS protocol is safe and well tolerated, and is associated with a high rate of remission from depression.

In patients with treatment-resistant depression, use of the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT)—a high-dose, resting-state, functional connectivity magnetic resonance imaging (fcMRI)–guided intermittent theta-burst stimulation (iTBS) protocol—is safe and well tolerated, and is associated with a high rate of remission from depression. These results were published in The American Journal of Psychiatry.

The investigators sought to examine the feasibility, tolerability, and preliminary efficacy of an accelerated, high-dose iTBS protocol using fcMRI-guided targeting in individuals with treatment-resistant depression. In an open-label study, they explored improving the current iTBS protocol via use of the following: (1) treating patients using multiple sessions per day at optimally spaced intervals between treatments; (2) applying a higher overall pulse dose of stimulation; and (3) precision targeting of the left dorsolateral prefrontal cortex (DLPFC) to subgenual anterior cingulate context (sgACC) circuit.

The protocol involved 5 consecutive days—Monday through Friday—with a total of 10 iTBS sessions occurring per day (ie, 1800 pulses per session, with 50-minute intervals between sessions). The treatments were delivered at 90% resting motor threshold. The protocol was called SAINT, in order to differentiate it from other attempts at accelerating transcranial magnetic stimulation protocols without individualized targeting, high pulse dose, or 50-minute intersession intervals. Neuropsychological testing was performed both before and after SAINT.

All study enrollees needed to be currently experiencing a nonpsychotic major depressive episode, as part of either major depressive disorder (MDD) or bipolar II disorder, and to have not responded to ≥1 antidepressant medication. All participants were required to have a

17-item Hamilton Depression Rating Scale (HAM-D) score of ≥20, a negative urine drug screen, and a negative pregnancy test (in women).

The primary outcome measure was change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to immediately after receiving SAINT. MADRS scores were utilized to measure remission and response rates. Reductions in scores on the 17-item and 6-item HAM-D, as well as on the Beck Depression Inventory-II (BDI-II), were secondary outcome measures of severity of depression. Response was defined as having a reduction of ≥50% on these scales. Remission was defined as attaining a score of <11 on the MADRS, a score of <8 on the 17-item HAM-D, a score of <5 on the 6-item HAM-D, and a score of <13 on the BDI-II.

Overall, the final study sample comprised 21 individuals (ages 19-78, 12 female). A diagnosis of MDD was reported in 19 of the patients, whereas 2 participants had a diagnosis of bipolar II disorder and were currently experiencing a depressive episode (for >1 year). All of the participants needed to maintain their antidepressant medication regimen throughout study enrollment.

In each of the participants, fcMRI was used to individually target the region of the left DLPFC most anticorrelated with sgACC. Overall, 90.5% (19 of 21) of the study participants met remission criteria, which were defined as a score of <11 on the MADRS.

Per generalized linear mixed-model analysis, a significant effect of day on mean 6-item HAM-D score and a significant of week on mean MADRS scores (P <.001 for both) were demonstrated, with scores at all follow-up time points significantly lower than those at baseline (P <.001). The same results were repeated for the 17-item HAM-D and the

BDI-II (P <.001 for both).  Limitations of the study included a small sample size and an open-label design.

The investigators concluded that double-blinded, sham-controlled studies are warranted, in order to verify the remission rate observed in this initial analysis.


Cole EJ, Stimpson KH, Bentzley BS, et al. Stanford Accelerated Intelligent Neuromodulation Therapy for treatment-resistant depression [published online April 7, 2020]. Am J Psychiatry. doi: 10.1176/appi.ajp.2019.19070720