NCT06542640

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

Identifying Mechanisms of Response to Therapeutic Intervention in Clinical High Risk (CHR) for Psychosis: a Bridge to Treatment

• Status: Recruiting
• Phase: N/A
• Study type: Interventional
• Enrollment: 300 (estimated)
• Sponsor: Beth Israel Deaconess Medical Center · Academic / Other
• Sex: All
• Age: 15 Years – 35 Years
• Healthy volunteers: Accepted

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.

Conditions

• Psychosis; Schizophrenia-Like
• Healthy Controls

Interventions

Type	Name	Description
DEVICE	Mb-rt-fMRI-NFB	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.
DEVICE	Sham mb-rt-fMRI-NFB	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.
DEVICE	rTMS	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.
DEVICE	Sham rTMS	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.

Timeline

• Start date: 2024-01-01
• Primary completion: 2027-06-30
• Completion: 2027-06-30
• First posted: 2024-08-07
• Last updated: 2025-04-20

Locations

1 site across 1 country: China