Stanford Neuromodulation Therapy: A Revolutionary Treatment for Depression

A new type of magnetic brain stimulation brought rapid remission to ~80% of participants with severe depression.

The leading cause of disability worldwide is still major depressive disorder (MDD), with half of those patients meeting the criteria for treatment-resistant depression (TRD). However, current therapies and addictive antidepressants do produce not the desired effects.

Therefore, repetitive transcranial magnetic stimulation (rTMS), a brain stimulation treatment, is approved by the U.S. Food and Drug Administration (FDA) for treatment-resistant depression. Most research targets the dorsolateral prefrontal cortex (DLPFC), a key area in the neural circuitry underlying depressive symptoms that have been shown to be hypoactive in major depressive disorder.

Present-day FDA-approved protocols for stimulation of the DLPFC are showing limited results due to a few reasons:

• Long duration of the treatment course (6 weeks)
• Modestly effective
• Induces remission after 4–6 weeks of treatment in ~17% of patients who have not shown response to three prior antidepressant treatments

You can comprehend why new treatments had to be invented.

Stanford Neuromodulation Therapy

The non-invasive rTMS treatment involves passing an electrical current through a magnetic coil placed superficial — located near the surface — to the scalp, producing a high-intensity magnetic field that passes through the scalp, skull, and meninges to excite neuronal tissue.

A more efficient form of rTMS, known as intermittent theta-burst stimulation (iTBS), recently approved by the FDA, has significantly shortened the duration of rTMS treatment sessions from 37 minutes to 3 minutes and produces equivalent antidepressant responses.

Researchers developed a new protocol, previously termed Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), and now entitled Stanford neuromodulation therapy (SNT).

The SNT protocol is an accelerated version of the rTMS protocol and includes:

• Intermittent theta-burst stimulation (iTBS)
• 5 consecutive days (Monday through Friday)
• 10 iTBS sessions per day (1,800 pulses per session, 50-minute intersession intervals)
• A higher stimulation pulse dose
• Personalized targeting for application of the stimulation of the left DLPFC to subgenual anterior cingulate cortex (sgACC) circuit

Encouraging Results

Because this accelerated protocol of rTMS is recently invented, studies using this protocol in a clinical setting are scarce. Studies that did use this protocol have their limitations such as, small sample sizes, however, the preliminary results are way too incredible not to investigate.

Based on a study investigating the effects of iTBS on the human motor cortex, which suggested it could be safely applied, the FDA-approved approved one of the first comparative studies of rTMS and iTBS courses involving daily stimulation sessions (600 iTBS pulses) for 6 weeks.

This study revealed an antidepressant response rate of 49% and a remission rate of 32% following iTBS treatment for treatment-resistant depression. This is encouraging and clinically meaningful, given that these participants had not responded to an average of one to two adequate antidepressant medication trials and about 50% of the participants had failed two adequate trials.

Moreover, researchers from the University of Ghent examined the effects and safety of iTBS (20 iTBS sessions over 4 days) on suicide risk in a group of treatment-resistant unipolar depressed patients.

One study revealed a significant decrease in suicide risk which lasted up for at least a month, findings that other treatments for suicidal ideation did not show. Moreover, after 2 months, 39% of therapy-resistant depressed patients still observed a reduction in depressive symptoms.

The other study from Ghent revealed that 38% of the patients showed a 50% reduction of their Depression Rating Scale score at the end of the two-week procedure. Additionally, 30% of the respondents were considered in clinical remission.

The first application of SAINT, using the left DLPFC as the primary target area, in highly refractory depressed patients showed encouraging results. In a small cohort of participants, there was a mean 76% reduction in depression ratings.

Based on this study, the researchers decided to apply precisely targetting of the left DLPFC of each individual using fMRI, i.e., the functional connectivity–guided targeting method, for their next study.

With incredible results.

In the first analysis, nineteen of 21 participants (90.5%) met remission criteria, however, after the intent-to-treat analysis, 19 of 22 participants (86.4%) met remission criteria after 5 days of open-label treatment.

Because the study revealed incredible results in treatment-resistant individuals, researchers wanted to repeat the experiment but now with more accurately targetting the left DLPFC to subgenual anterior cingulate cortex (sgACC) circuitry. Earlier research showed that this network is implicated in patients with MDD.

The recently published study from Stanford University School of Medicine observed a large antidepressant effect of SNT:

After 5 days of treatment, 79% of participants in the active SNT 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.

Here again, the small sample sizes influence the power of study — increasing the margin of error — however, a larger antidepressant effect size — the strength of a relationship of two variables — of SNT was observed despite the high severity of depressive symptoms and the level of treatment resistance in the participant sample as well as calculation at 1-month follow-up.

Future perspectives

During the last decade, researchers have refined the transcranial magnetic stimulation protocol for TRD patients. First off, they developed an accelerated protocol of stimulation, i.e., iTBS, delivering 1800 pulses per session in comparison to the 600 pulses in rTMS studies.

Then, the personalized targeting for the application of the stimulation became more specific. The last above-mentioned study used individualized functional connectivity MRI–guided target locations to precisely stimulate the left DLPFC-sgACC network.

Both improvements of the transcranial stimulation protocol revealed remarkable positive results in TRD patients. Most TRD patients had an average of three to five previous adequate antidepressant medication trials. Moreover, conventional rTMS protocols have been found to induce remission in only 17% of individuals who have shown no response to three prior antidepressant treatments.

In short, the SNT lead to high antidepressant efficacy and the first results of the protocol look very promising. However, future studies need to investigate this protocol with larger sample sizes in a wider population.

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