Mechanisms of Response to Therapeutic Intervention in Clinical High Risk (CHR) for Psychosis

Not Applicable

Recruiting

• Conditions: Healthy Controls; Psychosis; Schizophrenia-Like
• Interventions: Device: Sham rTMS; Device: Mb-rt-fMRI-NFB; Device: Sham mb-rt-fMRI-NFB; Device: rTMS

• Registration Number: NCT06542640
• Lead Sponsor: Beth Israel Deaconess Medical Center

Brief Summary

This study, "Psychobiological Follow-up Study of Transition from Prodrome to Early Psychosis", will be conducted in collaboration with the Shanghai Mental Health Center (SMHC) and several data processing sites in the United States. The current study builds on findings from the investigator's previous work that identified several biomarkers in participants at clinical high risk (CHR) for psychosis that may be related to clinical outcomes such as the development of psychosis. This study responds to the critical need to understand links between biomarkers (could be clinical, cognitive, biological or other abnormalities) and later clinical outcomes.

Participants will receive either one of two real interventions or one of two sham (a procedure that looks like the real treatment but is not) interventions, involving either: 1. repetitive transcranial magnetic stimulation (rTMS)1; or 2. mindfulness-based real time fMRI neurofeedback (mb-rt-fMRI-NFB). Both procedures will measure brain capacity for change in CHR individuals, thus paving the way forward for future therapeutic interventions.

The main hypotheses to be addressed by this study are:

1. - Following real interventions, novel biomarkers will be more effective predictors of clinical outcome than standard biomarkers in participants at CHR for psychosis

2. - Following real interventions, novel biomarkers will be more effective predictors of clinical outcomes in participants who received the real intervention than in participants who received sham treatments

3. - The novel interventions will reduce biomarker abnormalities in individuals with CHR relative to their own baselines and relative to healthy controls (HC)

4. - The sham interventions will will not reduce biomarker abnormalities in individuals with CHR relative to their own baselines or relative to HC

Detailed Description

This study builds upon our previous work, entitled "Psychobiological Follow-up Study of Transition from Prodrome to Early Psychosis" (R01MH111448). This study, titled Mechanisms of Response to Therapeutic Intervention in Clinical High Risk (CHR) for Psychosis: A bridge to treatment", focuses on two persistent needs in clinical high risk (CHR) for psychosis research: 1) the identification of novel biomarkers associated with transition to psychosis and other clinical outcomes; and 2) the identification of symptom-specific brain circuit targets that can be engaged in future clinical trials. The investigators hypothesize that clinically relevant biomarkers for participant-specific prognosis in CHR will be enhanced by the inclusion of biomarker measures that allow for the quantitative assessment of neural plasticity and are likely amenable to therapeutic change. In this view, CHR clinical outcomes are likely determined by both pathophysiology and by the brain's capacity to adapt and respond to pathophysiology via neural plasticity mechanisms. The investigators thus propose to examine brain circuit plasticity biomarkers relevant to CHR by administering non-invasive neuromodulation via two novel paradigms that, as they demonstrated previously in schizophrenia, engage brain networks involved in negative and positive psychiatric symptoms. These two novel interventional techniques are: 1. repetitive transcranial magnetic stimulation (rTMS); and 2. mindfulness-based real time functional magnetic resonance imaging (rt-fMRI) neurofeedback enhanced mindful meditation (mb-rt-fMRI-NFB) The investigators will also collect both traditional biomarkers (for example, clinical, neuropsychological, electrophysiological and neuroimaging biomarkers) and the novel biomarkers listed above (i.e., biomarkers that quantify neural changes pre- relative to post-intervention). These two interventions, which have not been used with CHR subjects before, will be tested in 200 CHR (50 CHR per experimental condition) and 100 HC over 5 years. Furthermore, the investigators will continue to enhance knowledge capacity at the Shanghai Mental Health Center (SMHC), where their Chinese collaborators are based. They will also examine the effectiveness of these interventions in CHR as a bridge to future therapeutic treatments and will test traditional and novel biomarkers as predictors of clinical and neurocognitive outcomes. Additionally, the investigators will significantly enhance research capacity by building on already established achievements and collaborations, and by extending their reach to new institutions (Aim 4). This competitive renewal capitalizes on a unique set of strengths at a single site (SMHC) and on a collaboration with the Shanghai research team, which has proven to be most productive in the current grant cycle. The investigators hypothesize that this highly novel study will contribute to the development of future therapeutic interventions in CHR, which will prevent this vulnerable population from developing adverse outcomes and, at the same time, will enrich the CHR field with new insights into the pathophysiology of this condition.

Study Timeline

• Study Start: 2024-01-01
• Study First Submitted: 2024-07-08
• Study First Submitted QC: 2024-08-05
• Study First Posted: 2024-08-07
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-16
• Last Update Posted: 2025-04-20
• Primary Completion: 2027-06-30
• Study Completion: 2027-06-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 300

Inclusion Criteria

Clinical High Risk (CHR):

1. Male or female between 15 and 35 years old.

2. Can understand and sign an informed consent (or assent for minors) document.

3. Must meet the substance use criteria:

   1. No Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) Alcohol or Drug Dependence in the past 3 months;
   2. No use on the day of assessment, clearly not intoxicated or hung-over.

4. Must meet diagnostic criteria for a prodromal syndrome. If under the age of 19 and meet diagnostic criteria for Schizotypal Personality Disorder or meet the diagnostic criteria called the Criteria for Prodromal Syndromes (COPS), which are operationalized as follows (a-c below):

   1. Genetic Risk and Deterioration Syndrome (GRDS): First degree biological relative with psychosis or subject with Schizotypal Personality Disorder and a 30% drop in Global Assessment of Functioning (GAF) score compared to one year ago, sustained over the past month.
   2. Attenuated Positive Symptoms Syndrome (APSS): Severity rating of moderate (rating of 3), moderately severe (4) or severe but not psychotic (5) on any one of the five Symptoms of Psychotic Disorders (SOPS) positive symptoms; symptom occurs at or above moderate severity level at an average frequency of at least once per week in the past month; symptom must have begun in the past year or currently rates at least one scale point higher than rated 12 months previously.
   3. Brief Intermittent Psychotic Syndrome (BIPS): Severity rating of psychotic intensity (6) on any of the 5 SOPS positive symptoms; symptom is present at least several minutes per day at a frequency of at least once per month; symptom(s) must have reached a psychotic intensity in the past 3 months; symptom is not seriously disorganizing or dangerous; symptom(s) do not last for more than 1 hour/day at an average frequency of 4 days/week over 1 month.

5. . Participant may be remitted from the CHR syndrome or may have converted to a full psychotic disorder since study entry and either is acceptable - they remain eligible to participate in follow-up procedures.

Exclusion Criteria

1. Meet criteria for current or lifetime Axis I psychotic disorder, including affective psychoses and psychosis Not Otherwise Specified (NOS) at the baseline assessment
2. Impaired intellectual functioning (i.e., Intelligence Quotient (IQ)<70) at baseline.
3. Past history of or current clinically significant central nervous system disorder that may contribute to prodromal symptoms or confound their assessment.
4. Traumatic Brain Injury that is rated as 7 or above on the Traumatic Brain Injury screening instrument (signifying a significant brain injury with persistent sequelae) or current concussion that interferes with any assessment measures.
5. Diagnostic prodromal symptoms that are clearly caused by one or more other psychiatric disorders, including substance use disorders, in the judgment of the evaluating clinician. Other non-psychotic Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) disorders will not be exclusionary (e.g., substance abuse disorder, major depression, anxiety disorders, personality disorders), as long as the disorder does not account for the diagnosis of prodromal symptoms.

Healthy Controls (HC):

1. Must meet subject inclusion criteria 1-2 and exclusion criteria 1-5. Must not meet criteria for any prodromal syndrome, any current or past psychotic disorder or Cluster A personality disorder diagnosis and must not be receiving any current treatment with psychotropic medication at the baseline assessment.
2. Must not have a family history (in first-degree relatives) of schizophrenia, schizoaffective disorder, schizotypal personality disorder, or any other disorder involving psychotic symptoms.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
CHR with sham rTMS Group	Sham rTMS	This CHR group will receive treatment via rTMS, but in a different, uninvolved brain region
CHR with mb-rt-fMRI-NFB Group	Mb-rt-fMRI-NFB	This CHR group will receive experimental treatment via mb-rt-fMRI-NFB, in a targeted frontal lobe region including the dorsolateral prefrontal cortex (DLPFC).
CHR with sham mb-rt-fMRI-NFB Group	Sham mb-rt-fMRI-NFB	This CHR group will receive treatment via mb-rt-fMRI-NFB, but in a different, uninvolved brain region
CHR with rTMS Group	rTMS	This CHR group will receive experimental treatment via rTMS, along a targeted neural pathway extending from the cerebellum to the midbrain to the dorsolateral prefrontal cortex (DLPFC)

Primary Outcome Measures

Name	Time	Method
mb-rt-fMRI-NFB intervention: functional connectivity	1 month, 1 year, 2 years	Context-dependent changes in functional connectivity (i.e., coupling) between brain regions will be measured by statistical software programs as Pearson correlation coefficients between brain regions whose activity depends on an interaction between psychological context (the task) and physiological state (the time course of brain activity)
rTMS intervention: functional connectivity	1 month, 1 year, 2 years	Context-dependent changes in functional connectivity (i.e., coupling) between brain regions will be measured by statistical software programs as Pearson correlation coefficients between brain regions whose activity depends on an interaction between psychological context (the task) and physiological state (the time course of brain activity)

Secondary Outcome Measures

Name	Time	Method
Neuropsychological function: verbal learning	1 month, 1 year, 2 years	Changes in verbal learning from baseline will be measured in the Clinical High Risk participants using the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery: Hopkins Verbal Learning Test - Revised
Structural MRI	1 month, 1 year, 2 years	Changes in Clinical High Risk participant's cortical gray matter brain function will be measured through cortical thickness
Neuropsychological function: visual learning	1 month, 1 year, 2 years	Changes in visual learning from baseline will be measured in the Clinical High Risk participants using the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery: Brief Visuospatial Memory Test - Revised
Neuropsychological function: verbal fluency / speed of processing	1 month, 1 year, 2 years	Changes in verbal fluency / speed of processing from baseline will be measured in the Clinical High Risk participants using the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery: Category Fluency: Animal Naming Test
Neuropsychological function: visual-motor / speed of processing	1 month, 1 year, 2 years	Changes in visual-motor / speed of processing from baseline will be measured in the Clinical High Risk participants using the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery: Brief Assessment of Cognition in Schizophrenia: Symbol Coding
Neuropsychological function: attention	1 month, 1 year, 2 years	Changes in attention from baseline will be measured in the Clinical High Risk participants using the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery: Continuous Performance Test: Identical Pairs Version
Event Related Potentials	1 month, 1 year, 2 years	Changes in Clinical High Risk participant's electrophysiological function from baseline will be measured through measures of wave amplitudes and latencies in 'P300 Oddball' and 'P300 Novel' paradigms
Clinical	1 month, 1 year, 2 years	Changes in Clinical High Risk clinical function from baseline will measured using the Structured Interview for Psychosis Risk Syndromes, specifically the Scale for Psychosis Risk Symptoms and the Criteria for Psychosis Risk Syndromes
Diffusion Tensor Imaging	1 month, 1 year, 2 years	Changes in Clinical High Risk participant's brain white matter function will be measured using 'fractional anisotropy', which is a measurement of the directionality of water diffusion in white matter, which is used in diffusion imaging to assess the density of white matter fibers, axonal diameter, and myelination
Neuropsychological function: visual-spatial / speed of processing	1 month, 1 year, 2 years	Changes in visual-spatial speed of processing from baseline will be measured in the Clinical High Risk participants using the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery: Trail Making Test
Neuropsychological function: reasoning and problem solving	1 month, 1 year, 2 years	Changes in reasoning and problem solving from baseline will be measured in the Clinical High Risk participants using the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery: Neuropsychological Assessment Battery: Mazes
Neuropsychological function: working memory	1 month, 1 year, 2 years	Changes in working memory from baseline will be measured in the Clinical High Risk participants using the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery: Wechsler Memory Scale - Third Edition: Spatial Span
Natural Language Processing: Linguistic	1 month, 1 year, 2 years	Changes in Clinical High Risk participant's natural language function from baseline will be measured linguistically using machine learning: semantic coherence
Natural Language Processing: Acoustic	1 month, 1 year, 2 years	Changes in Clinical High Risk participant's natural language function from baseline will be measured acoustically using machine learning: pauses in words

Trial Locations

Locations (1)

Shanghai Mental Health Center; 🇨🇳 Shanghai, Shanghai, China