Testing a Transdiagnostic TMS Treatment Target

Depression Clinical Trial

— T5  

Official title:

Testing a Transdiagnostic TMS Treatment Target

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06282146
• Other study ID #: 2024P000252
• Status: Not yet recruiting
• Phase: Early Phase 1
• Start date: April 1, 2024
• Est. completion date: April 1, 2026

Study information

• Verified date: February 2024
• Source: Brigham and Women's Hospital
• Contact: Lauren Sanderson
• Phone: 617-525-3536
• Email: bwht5[@]bwh.harvard.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The goal of this clinical trial is to test a new brain stimulation treatment target for individuals with depression plus at least one additional psychiatric disorder. The main question is to understand the safety profile of a non-invasive form of brain stimulation called accelerated intermittent theta burst stimulation when it is targeting the posterior parietal cortex. Additional questions focus on whether this stimulation improves symptoms of depression and other psychiatric disorders as well as whether this stimulation changes brain function.

Description:

Psychiatric disorders are often studied individually. However, up to half of individuals who meet criteria for one psychiatric disorder also meet criteria for another. These individuals are difficult to diagnose and treat. Relative to those with one disorder, individuals with two or more have worse treatment outcomes, more functional impairment, and a greater risk of premature death. Neuromodulation treatments like transcranial magnetic stimulation (TMS) work when routine psychotherapy and medications have not worked, but they typically target one disorder at a time. In fact, the TMS field is largely focused on strategies to make TMS more precise by targeting individual symptoms within a diagnosis. This strategy is important, but it may be difficult to scale and optimize in the setting of real-world psychiatric comorbidity. For example, there are 227 possible ways to meet criteria for major depressive disorder, complicating precision TMS strategies for individuals with or without comorbid disorders. In this study, the investigators are moving in a different direction by targeting the brain network shared across psychiatric disorders in treatment-seeking individuals with more than one psychiatric disorder. This approach is based upon prior work. In a 2023 Nature Human Behavior study, the investigators analyzed four independent datasets with coordinate and lesion network mapping to test for a brain network shared across psychiatric disorders. They found that atrophy coordinates across six psychiatric disorders (193 studies) mapped to a common brain network defined by positive connectivity to the anterior cingulate and insula, and by negative connectivity to posterior parietal and lateral occipital cortices. The investigators verified that this transdiagnostic network was robust to leave-one-diagnosis-out cross validation and specific to atrophy coordinates from psychiatric versus neurodegenerative disorders (72 studies). Lesion-induced damage to this network correlated with the number of post-lesion psychiatric diagnoses in an independent dataset (194 patients). The transdiagnostic network also aligned with neurosurgical ablation targets for psychiatric disorders (4 targets), suggesting possible therapeutic relevance and generating testable hypotheses for neuromodulation. Importantly, the candidate TMS target that emerges from this transdiagnostic network is also a critical node of the convergent depression network that was derived across 14 independent datasets. This target has not been robustly tested for major depressive disorder (MDD) or transdiagnostic symptoms. In this open-label pilot trial, the investigators will test the hypothesis that modulating the transdiagnostic network with transcranial magnetic stimulation (TMS) will be safe and tolerable. Secondary outcomes will assess changes in the cumulative burden of psychopathology in individuals with MDD plus at least one additional psychiatric disorder. This approach is novel in three important ways: 1) This study will enroll, not exclude, individuals with multiple psychiatric illnesses. Most clinical trials selectively enroll individuals with a single diagnosis, a strategy that does not generalize to real-world settings where psychiatric comorbidity is common and difficult to treat. 2) The transdiagnostic target was validated with causal sources of information (i.e., brain lesions, neurosurgical ablation). In other words, this study will optimize the "where to stimulate" factor. TMS targets are usually derived from functional neuroimaging studies that identify correlates of illness. These correlates could cause, compensate for, or be epiphenomena of treatment or other variables, an interpretation that matters for TMS. 3) The investigators will use the most rapid-acting and robust TMS protocol. In other words, they will optimize the "how to stimulate" factor. Conventional TMS protocols require scalp-targeted treatments delivered weekdays for 6-8 weeks. By contrast, the accelerated intermittent theta burst (iTBS) protocol in this study is adapted from Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), which consists of MRI-guided treatment delivered 10 times a day for 5 days.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 10
• Est. completion date: April 1, 2026
• Est. primary completion date: April 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Age 18-65
• English proficiency sufficient for informed consent, questionnaires/tasks, and treatment
• Diagnosis of MDD per DSM-5 criteria (Quick Structured Clinical Interview for DSM-5

Disorders) and currently experiencing a moderate to severe episode:

• >20 on Beck Depression Inventory (BDI)
• >20 on the Montgomery-Åsberg Depression Rating Scale (MADRS) 14, 15
• Moderate to severe level of treatment resistance (Maudsley Staging Method)16, 17
• Diagnosis of at least one or more of the following psychiatric conditions per DSM-5

criteria (Quick Structured Clinical Interview for DSM-5 Disorders):

• Generalized anxiety disorder (GAD), panic disorder (PD), or social anxiety disorder (SAD)
• Obsessive compulsive disorder (OCD)
• Post-traumatic stress disorder (PTSD)
• Physician referral for individuals with either schizophrenia or schizoaffective disorder
• Stable psychiatric medication regimen, or remain medication free, for 4 weeks prior to treatment and to remain on this regimen throughout the study until the two-week post-treatment visit
• Primary clinician (e.g. psychiatrist, therapist, psychologist, APRN, PA, etc.) responsible for psychiatric care before, during, and after the trial
• Agreement to lifestyle considerations
• Abstain from becoming pregnant from time of screening to two weeks after treatment (post-treatment MRI visit)
• Continue usual intake patterns of caffeine- or xanthine-containing products (e.g. coffee, tea, soft drinks, chocolate) throughout treatment
• Abstain from alcohol, tobacco, and recreational drugs for at least 24 hours before the start of each MRI and each TMS session

Exclusion Criteria:

• Active pregnancy as determined by a urine pregnancy test
• Positive urine drug screen for illicit substances (not including THC)
• Depressive symptoms refractory to 8 sessions of electroconvulsive therapy (ECT)
• Recent (within 4 weeks) or concurrent use of rapid acting antidepressant agent (ketamine/esketamine/ECT)
• Receiving or planning to receive other TMS treatments during course of participation
• History of
• Autism spectrum disorder
• Neurosurgical intervention for depression
• Intellectual disability
• Severe cognitive impairment
• Significant neurological illness (e.g., dementia, Parkinson's, Huntington's, brain tumor, seizure disorder, subdural hematoma, multiple sclerosis, brain lesion)
• Untreated or insufficiently treated endocrine disorder
• Treatment with investigational drug or intervention during the study period
• Depth-adjusted TMS treatment dose > 65% maximum stimulator output
• Existing tinnitus (ringing in the ears)
• Current evidence of:
• Mania or hypomania
• Active suicidal ideation or a suicide attempt (defined by C-SSRS) within the past year
• Neurological lesion
• Contraindications to either TMS or MRI (e.g., metallic implants, severe insomnia > 4 hours per night with hypnotic, etc.).
• Moderate or severe substance use disorder or demonstrating signs of acute substance withdrawal (not including cannabis or nicotine use disorders)
• Bipolar I disorder
• For participants with schizophrenia or schizoaffective disorder referred by a

physician:

• Total PANSS score >90
• Score >4 (moderate-severe) on any positive PANSS item
• Active substance use disorder (other than nicotine)
• Hospitalization for psychosis in the past 6 months
• Severe borderline personality disorder
• Any other condition deemed by the PI to interfere with the study or increase risk to the participant

Related Conditions & MeSH terms

• Anxiety Disorders
• Depression
• Depressive Disorder
• Depressive Disorder, Major
• Major Depressive Disorder
• Mental Disorder
• Mental Disorders
• Mood Disorders
• OCD
• Problem Behavior
• Psychiatric Disorder
• PTSD

Intervention

Procedure:
• transcranial magnetic stimulation
non-invasive form of brain stimulation

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Brigham and Women's Hospital

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Beck Depression Inventory (BDI)	Depression severity rating scales (0-63, higher numbers indicate higher severity)	Before treatment, daily throughout treatment, two weeks after treatment ends, and 3, 6, 9, and 12 months after treatment
Other	Beck Anxiety Inventory (BAI)	Anxiety severity rating scale (0-63, higher numbers indicate higher severity)	Before treatment, daily throughout treatment and two weeks after treatment ends, and 3, 6, 9, and 12 months after treatment
Other	Adult Attention Deficit/Hyperactivity Disorder Self-Report Scale (AARS)	ADHD rating scale (each question rated 1-5)	Before treatment and two weeks after treatment
Other	Clinical Global Impression Scale (CGI)	Global assessment of current symptoms, behavior, and function (1-7)	Before treatment and two weeks after treatment
Other	Illness Intrusiveness Rating Scale (IIRS)	13 item scale measuring how illness affects function. Scored 13-91, higher score indicates higher illness intrusiveness severity	Before treatment, two weeks after treatment, and 3, 6, 9, and 12 months after treatment
Other	Perceived Stress Scale (PSS)	Stress assessment scored 0-40, higher scores indicate higher stress	Before treatment and two weeks after treatment
Other	Positive and Negative Symptom Scale (PANSS)	14 item scale that measures positive and negative symptoms of psychotic disorders. Each question is scored 1-7. Each subscale (positive and negative) is scored 7-49, or total PANSS is scored 14-98. Higher scores indicate greater severity of psychotic symptoms.	Before treatment and two weeks after treatment
Other	Post Traumatic Stress Disorder Checklist for DSM-5 (PCL-5)	20 item PTSD scale, scored 0-80, higher scores indicate worse symptoms	Before treatment and two weeks after treatment
Other	Social Readjustment Rating Scale (SRRS)	Stress self-assessment tool with 43 items. Each item has a different impact score. Can be scored 0 - 300+, with potential scores >1000 depending on the frequency and impact score of stressful events. any score of 300+ indicates a high level of stress.	Before treatment and two weeks after treatment
Other	Yale Brown Obsessive-Compulsive Scale (Y-BOCS)	OCD assessment tool scored 0-40, higher scores indicate worse outcomes	Before treatment and two weeks after treatment
Other	Temperament and Character Inventory, Revised 140-item	Psychobiologically-based personality inventory which measures seven personality dimensions (harm avoidance, novelty seeking, reward dependence, persistence, self-directedness, cooperativeness, and persistence). For each dimension, this yields a scaled T-score (mean score of 50 with standard deviation of 10). This is an overall estimate of personality traits, and there are no "better" or "worse" traits.	Before treatment and two weeks after treatment
Other	Emotional Conflict Resolution Test	Computer task measuring accuracy and reaction time to emotional faces	Before treatment and two weeks after treatment
Other	Learning, Multi-Source Interference Task (MSIT)	Computer task measuring accuracy and reaction time	Before treatment and two weeks after treatment
Other	Penn Emotion Recognition Task (ER-40)	Computer task measuring accuracy and reaction time to emotional faces	Before treatment and two weeks after treatment
Other	Death Suicide IAT	Computer task measuring reaction time	Before treatment and two weeks after treatment
Other	Young Mania Rating Scale (YMRS)	11 item scale evaluating mania. Scored 0-60. Higher score indicates worse outcome/higher mania	before treatment, daily during treatment, and two weeks after treatment
Primary	Tolerability as measured by incidence of side effects on an accelerated TMS sensations and adverse events questionnaire	Questionnaire asking about the incidence, frequency, and severity of common TMS-related side effects such as headache, tinnitus, and neck pain.; Higher severity and frequency of side effects indicates lower tolerability	Each morning before treatment and afternoon after treatment during the 5 days of treatment
Primary	Feasibility as measured by number of the 50 treatments completed	0-50 treatments more treatments completed: higher feasibility	Throughout the 5 days of treatment
Secondary	Montgomery-Åsberg Depression Rating Scale (MADRS)	Depression severity rating scale (0-60, higher numbers indicate higher severity)	Before treatment and two weeks after treatment ends
Secondary	Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision, Level 1 Self-Rated Cross-Cutting Symptom Measure (DSM-5-XC)	Transdiagnostic rating scale (each question rated 0-4) Minimum score: 0 Maximum score: 92 Higher score indicates worse outcome or worse overall psychiatric burden	Before treatment, two weeks after treatment ends, and 3, 6, 9, and 12 months after treatment
Secondary	World Health Organization Disability Assessment Schedule II (WHODAS 2.0)	36-item functional assessment (each question rated 1-5) Minimum: 36 Maximum: 180 Can also be scored by percentiles Higher score indicates more disability	Before treatment, two weeks after treatment ends, and 3, 6, 9, and 12 months after treatment