SAINT® Therapy for Memory Problems in Older Adults With Treatment-Resistant Depression

This is a prospective, open-label, single-arm feasibility study of the Magnus Neuromodulation System using Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT®) in older adults with treatment-resistant depression (TRD) and memory concerns. The study will evaluate the feasibility, safety, tolerability, and preliminary clinical effects of an accelerated, individualized transcranial magnetic stimulation (TMS) treatment course.

TRD is associated with ongoing depressive symptoms despite prior antidepressant treatment. In older adults, depression may occur with concerns about memory, thinking, and ability to perform daily activities. Transcranial magnetic stimulation is a noninvasive treatment that uses magnetic pulses to stimulate targeted areas of the brain. The SAINT® approach uses magnetic resonance imaging (MRI)-guided targeting to personalize the stimulation location for each participant. The treatment is directed to a region of the left prefrontal cortex that is involved in mood regulation and connected brain networks.

The Magnus Neuromodulation System includes a TMS stimulator, stimulation coil, neuronavigation system, and software that uses each participant's structural and functional MRI information to identify an individualized treatment target. The study uses an accelerated intermittent theta-burst stimulation schedule. Participants receive 10 stimulation sessions per day over 5 consecutive days, for a total of 50 sessions. Each session lasts approximately 10 minutes, with approximately 50 minutes between sessions.

This study does not include a placebo or comparison group. All enrolled participants receive the study treatment. The study is designed to provide early information about whether this treatment approach can be delivered as planned in this population and to describe changes over time in memory, mood, global clinical status, and daily functioning. Findings will help inform the design of future controlled studies.

The primary efficacy assessment focuses on change in global cognitive function from before treatment to approximately 5 days after completing the treatment course. The study also evaluates depressive symptoms, clinician-rated overall improvement and severity, self-reported cognitive concerns, and ability to carry out daily activities during follow-up. Researchers will explore whether treatment effects differ according to amyloid or tau-related biomarker status from testing performed as part of participants' clinical care.

Safety monitoring includes assessment of adverse events, physical examinations, vital signs, and structured evaluations of mood symptoms and suicidal thoughts or behaviors. During the active treatment period, trained staff observe participants during stimulation sessions and assess them daily for neurological symptoms, mood elevation or destabilization, worsening depression, and other safety concerns. Hearing protection is used during all stimulation sessions. The study includes predefined rules for stopping treatment for an individual participant or pausing the study if important safety concerns arise.

The SAINT® Neuromodulation System is used clinically for TRD. In this study, researchers are evaluating whether this approach may also affect memory and thinking in older adults with depression and memory concerns.

• Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT®) with the Magnus Neuromodulation System (Device), also known as SAINT, accelerated intermittent theta-burst stimulation (aiTBS), repetitive transcranial magnetic stimulation (rTMS): MRI-guided, individualized accelerated intermittent theta-burst stimulation delivered with the Magnus Neuromodulation System to a personalized left dorsolateral prefrontal cortex target. Participants receive 10 stimulation sessions per day for 5 consecutive days (50 total sessions). Each 10-minute session delivers 1,800 magnetic pulses at 90% of motor threshold with depth adjustment, using 50-Hz triplet bursts at 5 Hz (2-second trains, 8-second inter-train intervals). Sessions are separated by approximately 50 minutes. Total planned exposure is 90,000 pulses. Participants wear hearing protection during stimulation.

Primary outcomes

• Change From Baseline in Mini-Mental State Examination (MMSE) Score at 5 Days Post-Stimulation [Baseline and 5 days after completion of SAINT stimulation]: The Mini-Mental State Examination (MMSE) is a clinician-administered 30-item screening measure of global cognitive function, assessing orientation, memory, attention, language, and visuoconstructional abilities. Total scores range from 0 to 30, with higher scores indicating better cognitive function.

Secondary outcomes

• Change in Clinical Global Impression-Improvement and Clinical Global Impression-Severity Scores [Baseline through 12 months post-stimulation]: Clinician-rated global clinical status will be assessed using the Clinical Global Impression-Improvement (CGI-I) scale and Clinical Global Impression-Severity (CGI-S) scale. CGI-I rates overall improvement or worsening relative to baseline; CGI-S rates illness severity at each assessment. Scores will be summarized descriptively and evaluated longitudinally across post-baseline visits.
• Change From Baseline in Cognitive Function Index (CFI) Score at 12 Months [Baseline and 12 months post-stimulation]: The Cognitive Function Index (CFI) is a questionnaire assessing perceived change in everyday cognitive functioning, including memory and other cognitive concerns. The participant responds to items regarding cognitive change compared with approximately one year earlier. Total scores range from 0 to 14, with higher scores indicating greater perceived cognitive decline or concern. Change is calculated as the 12-month score minus the baseline score; a negative change indicates improvement.
• Change From Baseline in Alzheimer's Disease Cooperative Study-Mild Cognitive Impairment Activities of Daily Living (ADCS-MCI-ADL) Score Through 12 Months [Baseline; 5 days post-stimulation; and 3, 6, 9, and 12 months post-stimulation]: The ADCS-MCI-ADL is an informant-based questionnaire that evaluates functional ability in activities of daily living relevant to individuals with mild cognitive impairment. The total score ranges from 0 to 53, with higher scores indicating greater functional independence. Change is calculated as each post-baseline score minus the baseline score; a positive change indicates improved functioning, and a negative change indicates functional decline.

Other outcomes

• Durability of Cognitive, Clinical, and Functional Outcomes Following Stimulation [Baseline through 12 months following completion of stimulation; follow-up assessments at 3, 6, 9, and 12 months]: Descriptive evaluation of changes from baseline in cognitive, mood, clinical, and functional outcomes following SAINT® stimulation. Measures include the Mini-Mental State Examination (MMSE), Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impression-Improvement (CGI-I), Clinical Global Impression-Severity (CGI-S), and Alzheimer's Disease Cooperative Study-Mild Cognitive Impairment-Activities of Daily Living (ADCS-MCI-ADL). Outcomes will be assessed longitudinally to characterize the persistence of effects after the acute treatment period.
• Association Between Change in Depressive Symptoms and Cognitive and Functional Outcomes [Baseline through 12 months following completion of stimulation]: Exploratory correlations between change in depressive symptom severity, measured by the Montgomery-Asberg Depression Rating Scale (MADRS), and change in cognitive and functional outcomes, measured by the MMSE, Cognitive Function Index (CFI), and ADCS-MCI-ADL. Associations will be evaluated descriptively at post-treatment visits.
• Differences in Cognitive, Mood, Clinical, and Functional Outcomes by Amyloid and/or Tau Biomarker Status [Baseline through 12 months following completion of stimulation]: Exploratory descriptive comparisons of change from baseline in MMSE, MADRS, CGI-I, CGI-S, and ADCS-MCI-ADL between participants who are amyloid- and/or tau-positive and those who are amyloid- and/or tau-negative. Biomarker status will be based on amyloid PET imaging and/or Lumipulse G pTau217/Amyloid 1-42 plasma-ratio results obtained as part of clinical care.
• Incidence, Severity, and Relatedness of Treatment-Emergent Adverse Events [From first SAINT® stimulation session through 12 months post-stimulation]: A treatment-emergent adverse event (TEAE) is any untoward medical occurrence that begins or worsens after initiation of SAINT® stimulation, regardless of relationship to treatment. All adverse events and serious adverse events will be collected and recorded. Each event will be assessed for severity using CTCAE version 5.0 and for relationship to SAINT® stimulation as definite, probable, possible, unlikely, or unrelated. Incidence will be summarized as the number and percentage of participants with one or more TEAEs, including serious adverse events.

Sex: All, ages: 65 Years to any

Inclusion Criteria:

* Age 65 years or older
* Diagnosis of treatment-resistant depression
* Current depressive symptoms, with a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or higher
* A memory concern reported by the participant or caregiver
* A Mini-Mental State Examination (MMSE) score between 10 and 28
* Able to understand the study, provide written informed consent, and complete study assessments
* Determined by an independent treating clinician to be an appropriate candidate for accelerated SAINT treatment, consisting of 10 treatment sessions per day for 5 consecutive days
* Completed an amyloid PET scan and/or Lumipulse G pTau217/Amyloid 1-42 blood test as part of usual medical care within 6 months before the baseline visit
* Health insurance coverage confirmed for rTMS/SAINT treatment for treatment-resistant depression
* Willing to follow study requirements, including medication restrictions and study visits

Exclusion Criteria:

* Pregnancy
* Unable or unwilling to use an acceptable method of birth control during the 5-day treatment period and for 30 days afterward, if of childbearing potential or sexually active with a partner of childbearing potential
* Non-removable metal or an implanted medical device in or near the head that is not safe for transcranial magnetic stimulation or magnetic resonance imaging, such as a cochlear implant, aneurysm clip, stent, or metal fragment
* An implanted neurostimulator in or near the head, such as a deep brain stimulator or vagus nerve stimulator
* History of epilepsy or a seizure disorder, except for isolated febrile seizures during childhood
* A brain condition that may increase seizure risk, such as prior brain surgery, skull defect, stroke-related brain disease, or brain tumor
* Any other contraindication to transcranial magnetic stimulation listed in the device instructions for use that the study doctor believes would increase risk
* A clinically significant abnormal magnetic resonance imaging (MRI) result
* A current psychiatric diagnosis other than major depressive disorder that could affect safe participation, including schizophrenia, schizoaffective disorder, bipolar disorder, or post-traumatic stress disorder
* A diagnosis of borderline, paranoid, histrionic, schizotypal, schizoid, or antisocial personality disorder
* Substance abuse or dependence within the past year, including alcohol or benzodiazepines, except caffeine or nicotine
* High current risk of suicide or a suicide attempt within the past 6 months
* A serious or unstable medical condition that could make participation unsafe or affect interpretation of the study results
* Resting heart rate below 40 beats per minute or above 110 beats per minute at the clinic visit
* Use of a medication or procedure that the study doctor determines may significantly interfere with transcranial magnetic stimulation treatment
* Any other condition that, in the study doctor's judgment, would make participation unsafe or prevent completion of the study requirements

• Robert Bota, Principal investigator, BrainHealth Solutions, Inc.