Psychosis; Schizophrenia-LikeNCT06542640
Mechanisms of Response to Therapeutic Intervention in Clinical High Risk (CHR) for Psychosis
A study testing Mb-rt-fMRI-NFB and rTMS in people with Psychosis; Schizophrenia-Like and Healthy Controls, run by Beth Israel Deaconess Medical Center at 1 site in China.
Trial 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. Read more about this study
- Who is it for?
- Ages 15 to 35 yearsHealthy volunteers can take part
- Conditions the study is for
- Psychosis; Schizophrenia-Like, Healthy Controls
- What is being tested?
- Mb-rt-fMRI-NFB and rTMS
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 300 participants
- Where
- 1 siteChina
- Study dates
- 1 Jan 2024to 30 Jun 2027
- Phase
- Interventional
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 15 to 35 years
- All sexes
- Healthy volunteers accepted
- Child, Adult
Who may be able to join
- Clinical High Risk (CHR):
- Male or female between 15 and 35 years old.
- Can understand and sign an informed consent (or assent for minors) document.
- Must meet the substance use criteria:
- No Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) Alcohol or Drug Dependence in the past 3 months;
- No use on the day of assessment, clearly not intoxicated or hung-over.
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- 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):
- 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.
- 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.
- 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.
- . 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.
Who cannot join
- Meet criteria for current or lifetime Axis I psychotic disorder, including affective psychoses and psychosis Not Otherwise Specified (NOS) at the baseline assessment
- Impaired intellectual functioning (i.e., Intelligence Quotient (IQ)<70) at baseline.
- Past history of or current clinically significant central nervous system disorder that may contribute to prodromal symptoms or confound their assessment.
- 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.
- 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):
- 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.
- Must not have a family history (in first-degree relatives) of schizophrenia, schizoaffective disorder, schizotypal personality disorder, or any other disorder involving psychotic symptoms.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
China1 site, 1 recruiting
- Recruiting
Shanghai Mental Health Center
Shanghai, Shanghai Municipality
Jijun Wang, MD
About this study
Official title: Identifying Mechanisms of Response to Therapeutic Intervention in Clinical High Risk (CHR) for Psychosis: a Bridge to Treatment
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.
Read more
The main hypotheses to be addressed by this study are:
- - Following real interventions, novel biomarkers will be more effective predictors of clinical outcome than standard biomarkers in participants at CHR for psychosis
- - 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
- - The novel interventions will reduce biomarker abnormalities in individuals with CHR relative to their own baselines and relative to healthy controls (HC)
- - The sham interventions will will not reduce biomarker abnormalities in individuals with CHR relative to their own baselines or relative to HC
Read the 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.
- Conditions
- Psychosis; Schizophrenia-Like, Healthy Controls
- Being tested
- Mb-rt-fMRI-NFB, Sham mb-rt-fMRI-NFB, rTMS, Sham rTMS
- Keywords
- real-time fMRI neurofeedback (rt-fMRI-NFB), mindfulness-based (mb), mb rt-fMRI-NFB (mb-rt-fMRI-NFB), repet. transcran mag stim (rTMS), neuropsycho (NP), diffusion tensor imaging (DTI), clinical high risk (CHR), healthy control (HC), MATRICS Consenus Cog Batt (MCCB)
- Medical subject headings
- Psychotic Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Mb-rt-fMRI-NFBDevice
The MRI and TMS interventions described below will yield measures of change in the targeted brain regions in post- relative to pre- intervention comparisons. These change measures will be compared relative to changes in the sham/control group and the HC group. Furthermore, they will be compared to HC to assess improvement or normalization of brain function in the targeted brain regions. In addition, the investigators will examine treatment effects on traditional biomarkers that are likely to be impacted by such interventions: ERP, NP and NLP measures. Here, mindfulness meditation practiced during a real-time fMRI NFB session will be used to bring connectivity changes to brain structures involved in positive psychiatric symptoms (e.g. attenuated psychotic symptoms) in order to to reduce them.
Sham mb-rt-fMRI-NFBDevice
Individuals with CHR who are randomly assigned to this arm will receive mb-rt-fMRI-NFB, as do the experimental group, but it will be aimed at a motor cortex location that is not part of the prefrontal neural networks targeted in the experimental group.
rTMSDevice
In previous work, the investigators used a multivariate pattern analysis to identify functional connectivity correlates of negative symptom severity in a schizophrenia (SZ) group. DLPFC-cerebellum hypo-connectivity was strongly correlated with negative symptoms. In a separate SZ cohort, the investigators used rTMS targeting the cerebellum to manipulate this circuit. The rTMS-induced increase in functional connectivity in a cerebellar-midbrain-DLPFC circuit was strongly linked to negative symptom severity reduction. Furthermore, individuals varied in the degree of change in functional connectivity in response to rTMS. This variation strongly predicted variation in post-rTMS symptom severity. The investigators predict that rTMS based intervention, but not sham rTMS, will similarly impact the cerebellar-midbrain-dorsolateral prefrontal cortex (DLPFC) network in the CHR group receiving real but not sham rTMS.
Sham rTMSDevice
Individuals with CHR who are randomly assigned to this arm will receive rTMS, as do the experimental group, but it will be aimed at a motor cortex location that is not part of the prefrontal neural networks targeted in the experimental group.
| Study group | Role | What they receive |
|---|---|---|
| CHR with mb-rt-fMRI-NFB Group | Experimental | This CHR group will receive experimental treatment via mb-rt-fMRI-NFB, in a targeted frontal lobe region including the dorsolateral prefrontal cortex (DLPFC). Receives: Device: Mb-rt-fMRI-NFB |
| CHR with sham mb-rt-fMRI-NFB Group | Sham comparator | This CHR group will receive treatment via mb-rt-fMRI-NFB, but in a different, uninvolved brain region Receives: Device: Sham mb-rt-fMRI-NFB |
| CHR with rTMS Group | Experimental | 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) Receives: Device: rTMS |
| CHR with sham rTMS Group | Sham comparator | This CHR group will receive treatment via rTMS, but in a different, uninvolved brain region Receives: Device: Sham rTMS |
| Healthy Control Group | No intervention | The healthy control group will not receive any treatment, but will be used as a comparison for the 2 experimental and 2 sham groups. |
What is being measured
The primary outcome is the main question the study is designed to answer.
mb-rt-fMRI-NFB intervention: functional connectivity
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)
Measured: 1 month, 1 year, 2 years
rTMS intervention: functional connectivity
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)
Measured: 1 month, 1 year, 2 years
Secondary outcomes (14)
Clinical
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
Measured: 1 month, 1 year, 2 years
Neuropsychological function: verbal learning
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
Measured: 1 month, 1 year, 2 years
Neuropsychological function: visual learning
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
Measured: 1 month, 1 year, 2 years
Neuropsychological function: visual-spatial / speed of processing
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
Measured: 1 month, 1 year, 2 years
Neuropsychological function: verbal fluency / speed of processing
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
Measured: 1 month, 1 year, 2 years
Neuropsychological function: visual-motor / speed of processing
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
Measured: 1 month, 1 year, 2 years
Neuropsychological function: attention
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
Measured: 1 month, 1 year, 2 years
Neuropsychological function: working memory
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
Measured: 1 month, 1 year, 2 years
Neuropsychological function: reasoning and problem solving
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
Measured: 1 month, 1 year, 2 years
Event Related Potentials
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
Measured: 1 month, 1 year, 2 years
Natural Language Processing: Linguistic
Changes in Clinical High Risk participant's natural language function from baseline will be measured linguistically using machine learning: semantic coherence
Measured: 1 month, 1 year, 2 years
Natural Language Processing: Acoustic
Changes in Clinical High Risk participant's natural language function from baseline will be measured acoustically using machine learning: pauses in words
Measured: 1 month, 1 year, 2 years
Structural MRI
Changes in Clinical High Risk participant's cortical gray matter brain function will be measured through cortical thickness
Measured: 1 month, 1 year, 2 years
Diffusion Tensor Imaging
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
Measured: 1 month, 1 year, 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Aug 2024
- Study start1 Jan 2024
- Primary completion30 Jun 2027 (estimated)
- Study completion30 Jun 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Psychosis; Schizophrenia-LikeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- The study will consist of two interventions and 2 full assessments, (pre- and post-intervention) (year 1) followed by two clinical/NP/NLP/ERP assessments in years 2 and 3 relative to a CHR's entry to the study. To minimize the time lag between HC's assessment and the last follow-up assessment of the CHR, 50 HC participants will be recruited at the study onset and 50 additional HC will be recruited at years 3 and 4 of the grant. Baseline assessments will be followed by random assignment of CHR subjects to either an intervention group (100 CHR) or sham group (100 CHR). The intervention group will receive either the TMS (50 CHR) or rt-fMRI NFB (50 CHR), with the random CHR assignment to the arm of the study. The sham groups will also be counterbalanced across subjects, with 50 CHR in the TMS-sham and 50 CHR in the rt-fMRI NFB-first group. The two interventions will be delivered over two-week period, followed by post-intervention assessments.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 300 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Beth Israel Deaconess Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Shanghai Jiao Tong University School of Medicine, Florida A&M University, Brigham and Women's Hospital, Massachusetts General Hospital, VA Boston Healthcare System, National Institute of Mental Health (NIMH)
- Responsible party
- Principal investigator, William Stone, Beth Israel Deaconess Medical Center
- Investigators
- William S Stone, Ph.D., Principal investigator, Beth Israel Deaconess Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06542640
- Sponsor's protocol ID
- 2023P001089
- Other IDs
- 2R01MH111448
- Status last verified
- Apr 2025
- First submitted
- 8 Jul 2024
- Last updated
- 20 Apr 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Only de-identified data, which will not contain Protected Health Information (PHI), will be transmitted from the Shanghai site to the U.S. sites. All human-subjects data provided will include a Global Unique Identifier (GUID) and will not include personally identifiable information (PII). Descriptive/raw data are data used to characterize a research subject, will include data from standard diagnostic assessments, standard clinical measures, demographic data, and will be submitted to New Drug and Clinical Trials rules (NDCT). Analyzed data will be submitted prior to publication/public dissemination (whether the findings are positive or negative). Even if a publication focuses on only part of an analyzed dataset, the entire analyzed dataset will be submitted when the first paper/finding is published or communicated. The data that are not part of the paper will not be immediately shared, but rather along the time frame described below.
Publications
Brady RO Jr, Gonsalvez I, Lee I, Ongur D, Seidman LJ, Schmahmann JD, Eack SM, Keshavan MS, Pascual-Leone A, Halko MA. Cerebellar-Prefrontal Network Connectivity and Negative Symptoms in Schizophrenia. Am J Psychiatry. 2019 Jul 1;176(7):512-520. doi: 10.1176/appi.ajp.2018.18040429. Epub 2019 Jan 30.
PubMed 30696271Okano K, Bauer CCC, Ghosh SS, Lee YJ, Melero H, de Los Angeles C, Nestor PG, Del Re EC, Northoff G, Whitfield-Gabrieli S, Niznikiewicz MA. Real-time fMRI feedback impacts brain activation, results in auditory hallucinations reduction: Part 1: Superior temporal gyrus -Preliminary evidence. Psychiatry Res. 2020 Apr;286:112862. doi: 10.1016/j.psychres.2020.112862. Epub 2020 Feb 10.
PubMed 32113035Bauer CCC, Okano K, Ghosh SS, Lee YJ, Melero H, Angeles CL, Nestor PG, Del Re EC, Northoff G, Niznikiewicz MA, Whitfield-Gabrieli S. Real-time fMRI neurofeedback reduces auditory hallucinations and modulates resting state connectivity of involved brain regions: Part 2: Default mode network -preliminary evidence. Psychiatry Res. 2020 Feb;284:112770. doi: 10.1016/j.psychres.2020.112770. Epub 2020 Jan 14.
PubMed 32004893Niznikiewicz MA, Brady RO, Whitfield-Gabrieli S, Keshavan MS, Zhang T, Li H, Pasternak O, Shenton ME, Wang J, Stone WS. Dynamic intervention-based biomarkers may reduce heterogeneity and motivate targeted interventions in clinical high risk for psychosis. Schizophr Res. 2022 Aug;246:60-62. doi: 10.1016/j.schres.2022.05.004. Epub 2022 Jun 13. No abstract available.
PubMed 35709648