New treatment relieves depression in 90% of participants in small study

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A new form of magnetic brain stimulation rapidly relieved symptoms of severe depressioZn in 90% of participants in a small study conducted by researchers at the Stanford University School of Medicine. The researchers are conducting a larger, double-blinded trial in which half the participants are receiving fake treatment.

The researchers are optimistic the second trial will prove to be similarly effective in treating people whose condition hasn't improved with medication, talk therapy or other forms of electromagnetic stimulation.

The treatment is called Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT). It is a form of transcranial magnetic stimulation, which is approved by the US Food and Drug Administration for treatment of depression. The researchers reported that the therapy improves on current FDA-approved protocols by increasing the number of magnetic pulses, speeding up the pace of the treatment and targeting the pulses according to each individual's neuro-circuitry.

Before undergoing the therapy, all 21 study participants were severely depressed, according to several diagnostic tests for depression. Afterward, 19 of them scored within the nondepressed range. Although all of the participants had suicidal thoughts before the therapy, none of them reported having suicidal thoughts after treatment. All 21 participants had previously not experienced improvements with medications, FDA-approved transcranial magnetic stimulation or electroconvulsive therapy.

The only side effects of the new therapy were fatigue and some discomfort during treatment, the study reported.

"There's never been a therapy for treatment-resistant depression that's broken 55% remission rates in open-label testing," said Dr Nolan Williams, assistant professor of psychiatry and behavioural sciences and a senior author of the study. "Electroconvulsive therapy is thought to be the gold standard, but it has only an average 48% remission rate in treatment-resistant depression. No one expected these kinds of results."

When Deirdre Lehman, 60, woke up the morning of 30 June, 2018, she said she was hit by "a tsunami of darkness." Lehman had struggled with bipolar disorder all her adult life, but with medications and psychotherapy her mood had been stable for 15 years. "There was a constant chattering in my brain: It was my own voice talking about depression, agony, hopelessness," she said. "I told my husband, 'I'm going down and I'm heading toward suicide.' There seemed to be no other option."

Lehman's psychiatrist had heard of the SAINT study and referred her to Stanford. After researchers pinpointed the spot in her brain that would benefit from stimulation, Lehman underwent the therapy. "By the third round, the chatter started to ease," she said. "By lunch, I could look my husband in the eye. With each session, the chatter got less and less until it was completely quiet. "That was the most peace there's been in my brain since I was 16 and started down the path to bipolar disorder."

In transcranial magnetic stimulation, electric currents from a magnetic coil placed on the scalp excite a region of the brain implicated in depression. The treatment, as approved by the FDA, requires six weeks of once-daily sessions. Only about half of patients who undergo this treatment improve, and only about a third experience remission from depression.

Stanford researchers hypothesised that some modifications to transcranial magnetic stimulation could improve its effectiveness. Studies had suggested that a stronger dose, of 1,800 pulses per session instead of 600, would be more effective. The researchers were cautiously optimistic of the safety of the treatment, as that dose of stimulation had been used without harm in other forms of brain stimulation for neurological disorders, such as Parkinson's disease.

Other studies suggested that accelerating the treatment would help relieve patients' depression more rapidly. With SAINT, study participants underwent 10 sessions per day of 10-minute treatments, with 50-minute breaks in between. After a day of therapy, Lehman's mood score indicated she was no longer depressed; it took up to five days for other participants. On average, three days of the therapy were enough for participants to have relief from depression.

"The less treatment-resistant participants are, the longer the treatment lasts," said postdoctoral scholar Dr Eleanor Cole, a lead author of the study.

The researchers also conjectured that targeting the stimulation more precisely would improve the treatment's effectiveness. In transcranial magnetic stimulation, the treatment is aimed at the location where most people's dorsolateral prefrontal cortex lies. This region regulates executive functions, such as selecting appropriate memories and inhibiting inappropriate responses.

For SAINT, the researchers used magnetic-resonance imaging of brain activity to locate not only the dorsolateral prefrontal cortex, but a particular subregion within it. They pinpointed the subregion in each participant that has a relationship with the sub-genual cingulate, a part of brain that is overactive in people experiencing depression.

In people who are depressed, the connection between the two regions is weak, and the sub-genual cingulate becomes overactive, said Dr Keith Sudheimer, clinical assistant professor of psychiatry and a senior author of the study. Stimulating the subregion of the dorsolateral prefrontal cortex reduces activity in the sub-genual cingulate, he said.

To test safety, the researchers evaluated the participants' cognitive function before and after treatment. They found no negative side effects; in fact, they discovered that the participants' ability to switch between mental tasks and to solve problems had improved – a typical outcome for people who are no longer depressed. One month after the therapy, 60% of participants were still in remission from depression. Follow-up studies are underway to determine the duration of the antidepressant effects.

The researchers plan to study the effectiveness of SAINT on other conditions, such as obsessive-compulsive disorder, addiction and autism spectrum disorders.

The depression Lehman woke up to almost two years ago was the worst episode she had ever experienced. Today, she said, she is happy and calm. Since undergoing SAINT treatment, she has completed a bachelor's degree at the University of California-Santa Barbara; she had dropped out as a young woman when her bipolar symptoms overwhelmed her studies. "I used to cry over the slightest thing," she said. "But when bad things happen now, I'm just resilient and stable. I'm in a much more peaceful state of mind, able to enjoy the positive things in life with the energy to get things done."

Abstract
Objective: New antidepressant treatments are needed that are effective, rapid acting, safe, and tolerable. Intermittent theta-burst stimulation (iTBS) is a noninvasive brain stimulation treatment that has been approved by the U.S. Food and Drug Administration for treatment-resistant depression. Recent methodological advances suggest that the current iTBS protocol might be improved through 1) treating patients with multiple sessions per day at optimally spaced intervals, 2) applying a higher overall pulse dose of stimulation, and 3) precision targeting of the left dorsolateral prefrontal cortex (DLPFC) to subgenual anterior cingulate cortex (sgACC) circuit. The authors examined the feasibility, tolerability, and preliminary efficacy of Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), an accelerated, high-dose resting-state functional connectivity MRI (fcMRI)–guided iTBS protocol for treatment-resistant depression.

Methods: Twenty-two participants with treatment-resistant depression received open-label SAINT. fcMRI was used to individually target the region of the left DLPFC most anticorrelated with sgACC in each participant. Fifty iTBS sessions (1,800 pulses per session, 50-minute intersession interval) were delivered as 10 daily sessions over 5 consecutive days at 90% resting motor threshold (adjusted for cortical depth). Neuropsychological testing was conducted before and after SAINT.
Results: One participant withdrew, leaving a sample size of 21. Nineteen of 21 participants (90.5%) met remission criteria (defined as a score <11 on the Montgomery-Åsberg Depression Rating Scale). In the intent-to-treat analysis, 19 of 22 participants (86.4%) met remission criteria. Neuropsychological testing demonstrated no negative cognitive side effects.
Conclusions: SAINT, an accelerated, high-dose, iTBS protocol with fcMRI-guided targeting, was well tolerated and safe. Double-blinded sham-controlled trials are needed to confirm the remission rate observed in this initial study.

Authors
Eleanor J Cole, Katy H Stimpson, Brandon S Bentzley, Merve Gulser, Kirsten Cherian, Claudia Tischler, Romina Nejad, Heather Pankow, Elizabeth Choi, Haley Aaron, Flint M Espil, Jaspreet Pannu, Xiaoqian Xiao, Dalton Duvio, Hugh B Solvason, Jessica Hawkins, Austin Guerra, Booil Jo, Kristin S Raj, Angela L Phillips, Fahim Barmak, James H Bishop, John P Coetzee, Charles DeBattista, Jennifer Keller, Alan F Schatzberg, Keith D Sudheimer, Nolan R Williams

Stanford Medicine material

American Journal of Psychiatry abstract

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