Imagine a new treatment for people with major depression who have not responded to existing treatments—one that acts rapidly and helps a much larger fraction of such patients than any current treatment.

The new treatment has the following characteristics. It is optimized for each patient who receives it. It takes a total of 5 days to receive the full treatment dose. Antidepressant effects are felt by most patients between days 2 and 3. By the end of the 5th day, when the treatment course is completed, 90% of patients are in remission—they are no longer clinically depressed. Those who had reported suicidal thoughts prior to treatment no longer report having such thoughts. The treatment appears to have no serious or lasting side effects. One month after being treated, 70% of patients continue to experience an antidepressant “response”—defined as a reduction in initial symptoms of at least 50%.

This is not a fantasy. It’s a summary of the results of a small, preliminary clinical test of a protocol called the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) for treatment-resistant depression. SAINT is a new approach to delivering non-invasive brain stimulation—via a magnetic coil placed just above the scalp and focused on a precise spot in the brain. The results, based on an “open-label” clinical trial involving 21 patients with refractory depression, were reported in the American Journal of Psychiatry in April.

Leading the research team that developed SAINT is Nolan R. Williams, M.D., Assistant Professor of Psychiatry and Behavioral Sciences at the Stanford University Medical Center. Dr. Williams developed the protocol with the help of his two BBRF Young Investigator grants, received in 2016 and 2018. In 2019, Dr. Williams was the recipient of BBRF’s Klerman Prize for Exceptional Clinical Research.

Dr. Williams trained with Mark S. George, M.D., a BBRF Scientific Council member, two-time grantee and 2008 Falcone Prize winner at the Medical University of South Carolina who in the 1990s pioneered the non-invasive brain stimulation method called rTMS (repetitive transcranial magnetic stimulation). In 2008, rTMS was approved by the FDA for treatmentresistant depression, and is now used more broadly in depression, as well as in obsessive-compulsive disorder.

The SAINT protocol developed by Dr. Williams and Stanford colleagues, including Alan Schatzberg, M.D., a senior team member who is also a member of the BBRF Scientific Council, is a refinement of a variant form of rTMS called intermittent theta-burst stimulation, or iTBS. iTBS has been validated in a number of clinical trials, including one led by 2010 BBRF Young Investigator Daniel M. Blumberger, M.D., of the University of Toronto. In iTBS, the patient receives the same “dose” of brain stimulation as in FDAapproved rTMS, but receives it in much shorter treatment sessions, lasting 3 minutes per session as compared with 37 minutes in conventional rTMS. iTBS is now FDA-approved for treating patients with refractory major depression.

THREE IMPORTANT ‘TWEAKS’

Dr. Williams set out to improve upon iTBS—which has been shown to be just as effective as rTMS, enabling about one-third of patients with treatment-resistant depression to achieve remission. Dr. Williams wanted to test the hypothesis that iTBS could be much more effective if three “tweaks” were made.

These tweaks are actually major changes in the protocol, involving giving a refractory patient five times as much total stimulation over a 5-day period than iTBS or rTMS delivers over the FDA-approved treatment course of 6 weeks. Dr. Williams also wanted to see if he could optimize the targeting of the iTBS stimulation in SAINT in each patient, individually, to boost its effectiveness.

While increasing the stimulation dose five-fold and decreasing the treatment course from a month and half to only 5 days may seem radical, there were both practical and scientific reasons for developing SAINT and receiving institutional approval to test it on patients. The first reason has to do with the intended beneficiaries: Dr. Williams, as a neurologist and psychiatrist, is deeply concerned with the dire situation faced by the “mostdifficult- to-treat patients,” he says. These are individuals whose major depression not only renders them non-functional, unable to hold jobs or conduct conventional lives when in the throes of a depressive episode, but who also have a significantly elevated risk of suicide.

Their condition, therefore, is lifethreatening in many cases, he notes. Dr. Williams refers to people who have tried and not been helped by multiple courses of conventional antidepressant medicines of various types, but who also have not been helped by rTMS or conventional iTBS, and who in some cases have even not been helped by electroconvulsive therapy (ECT), a procedure performed under anesthesia that involves inducing a brief seizure and which is sometimes accompanied by short-term memory loss. An alternative for such patients is ketamine, a powerful anesthetic delivered at very low dose that doesn’t induce anesthesia. It has proven very effective in many instances and acts within hours, although a single treatment works only for about a week. An FDA-approved derivative of ketamine called esketamine is now available, but like ketamine, its therapeutic impact is short-term following discontinuation. More research is being conducted to further enhance its effectiveness.

The still unaddressed needs of such patients were therefore an important motivation for SAINT’s development. But there were specific scientific reasons to pursue it as well. Dr. Williams and colleagues built upon a decade of research studies that have provided a sense of why conventional rTMS and iTBS appear to help many patients feel better.

In summarizing his take-away from this body of research, Dr. Williams explains the aim of SAINT treatments in terms of three targets in the brain, which for convenience he calls A, B and C. He wants to focus stimulation on A to cause an effect upon B, which in turn induces a change in C.

“A” is an area of the cerebral cortex positioned in the skull just above the left eye. It’s called the dorsolateral prefrontal cortex, or DLPFC, and it has been the target of rTMS treatments since the pioneering days of Dr. George. Dr. Williams says he wanted SAINT to target a specific portion of the DLPFC—one defined by its function. He wanted his iTBS pulses to focus on that spot in the DLPFC which induces the maximum possible effect upon a second spot. This spot, which he calls “B” for convenience, is the subgenual anterior cingulate cortex, or sgACC. Why is “B” important? Because the change in “B” caused by focusing iTBS pulses upon “A” causes an impact upon a third entity in the brain, “C”—the Default Mode Network (DMN).

The DMN is not a spot in the brain but rather a circuit that links a number of brain areas. The aim, says Dr. Williams, is to impact the connection between the sgACC and the default mode network. In depression, researchers have discovered that the sgACC is “hyperconnected” to the DMN. By sending pulses into the DLPFC, one can indirectly diminish this hyperactivity—which is thought to be at least one cause of what doctors call “dysphoria” in depression, the symptoms of depressed mood, a state of unease or dissatisfaction.

Dr. Williams explains that one can seek to direct rTMS or iTBS pulses either at a spot on the skull, or a spot in the brain beneath. There is a subtle distinction. One wants to hit the precise spot in the DLPFC that has the greatest functional effect on the sgACC, but one must allow that each person is slightly different. The question then becomes: how does one hit this spot in the brain precisely when its position, relative to the outer skull, varies a bit from person to person?

For this reason, SAINT begins with each patient getting an MRI brain scan. Specifically, a functional scan of the brain in its resting state, when the individual is not focused on any particular mental task. This enabled Dr. Williams’ team to increase the specificity of the iTBS pulses “to the person’s actual functional anatomy”—the spot in that person’s DLPFC that would induce the maximum effect on the sgACC that would in turn impact the functional connection between the sgACC and the DMN (reducing hyperconnectivity). It is thought that these changes in connectivity contribute to the strengthening of synapses, the connections between neurons, which may correlate with diminishing depression symptoms.

As for the other key innovations in SAINT: it was Dr. Williams’ hypothesis that the patients most resistant to treatment would do better if the intervals between iTBS session were radically decreased and the total number of sessions were substantially increased. This is accomplished by reducing the interval between sessions, termed the “intersession interval,” from 24 hours to 50 minutes. Ten sessions are given per day. This timing is based on research that has given rise to what is called “spaced learning theory.” The reduction in the intervals between iTBS sessions allows for a substantial increase in total dose per day, Dr. Williams explains, and in the reduction of the number of days of stimulation to just 5 days. In short, the idea behind SAINT is that patients who weren’t being helped by conventional rTMS or iTBS were not receiving enough stimulation quick enough in the FDA-approved protocols to reduce their depression.

Drs. Williams, Schatzberg and others had already gotten a preliminary reading that this approach might work: in another open-label study published in Brain in 2018, they showed that 5 of 6 highly refractory patients receiving 10 conventional iTBS treatments per day, each separated by 50 minutes, over a 5-day period, achieved remission.

This was the basis for the test in 21 patients just reported, which generated results that were quite similar, with 19 of the 21 (90.4%) achieving remission by the end of the 5th day.

WHY CAUTION IS ADVISED

While highly gratified by the newly reported results, including the remarkable 90% remission rate, Dr. Williams urges that they be viewed as preliminary. The same SAINT protocol, he stresses, must be tested in larger patient populations and in trials that involve two things that the preliminary trials did not: patient randomization and placebo-control.

Each of the 21 patients who took part in the just-reported trial knew that they were going to receive the experimental treatment protocol, as did the doctors who administered the treatments. Thus, there was no blinded control group against which to compare the results of an “active treatment” group. This is the gold standard for such trials, since knowledge that one is receiving an experimental treatment tends to spur what researchers call the placebo effect: a natural desire of patients (and sometimes doctors, too) to believe the treatment is working.

Even so, a 90% remission rate over just 5 days in a clinical test of an antidepressant treatment in a group of patients who have “failed” one or multiple prior antidepressant courses is extraordinary—and hence, the great hope that the preliminary SAINT results hold up when put to the goldstandard test.

Safety is an important factor. Conventional rTMS and iTBS have very strong safety profiles; neither is associated with anything more than temporary headaches or a tingling sensation while the treatments are being administered. This has proven the case so far in patients who have received SAINT treatments. As an extra measure of caution, the team gave some participants in the SAINT trails a full battery of cognitive tests before and after receiving treatment. “In addition to not seeing any cognitive deficits from treatments, we actually saw improvements in certain cognitive domains,” Dr. Williams says.

The observed durability of the antidepressant effect in the preliminary SAINT trials is also encouraging to Dr. Williams. While not all refractory depression patients have access to ketamine or eskemtaine, those who are helped by these agents usually don’t hold their remissions for more than a few weeks, which means they need repeated doses.

The 70% continued repose rate at one month posttreatment in the preliminary SAINT trial will be significant if replicated in subsequent studies.

The impact would be especially felt, Dr. Williams says, in inpatient situations. “ECT is available in only about 10% of U.S. psychiatric hospitals, and ketamine availability on inpatient units is spotty,” he says. For patients at suicide risk, he adds, conventional rTMS is impractical because it takes too long to deliver; the average length of stay in hospital for such patients is only about 12 days for those who don’t get ECT, he points out. “We’ve got something that works in 5 days. We’ve tested it on inpatients, and we’re preparing a paper on how SAINT works in these acutely suicidal patients.”

If results are positive, it is possible, Dr. Williams says, that SAINT could “rapidly transform the landscape of inpatient psychiatry for suicidal depression.” Beyond that application, there will likely be others, for less acute depression cases and for other indications. There is a place in the brain to focus iTBS pulses to address anxiety, for example, and that might be one subject of future clinical trials.

Written By Peter Tarr, Ph.D.

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