Clinical trial NCT06542640: Mechanisms of Response to Therapeutic Intervention in Clinical High Risk (CHR) for Psychosis
Official title: Identifying Mechanisms of Response to Therapeutic Intervention in Clinical High Risk (CHR) for Psychosis: a Bridge to Treatment
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Psychosis; Schizophrenia-Like
Healthy Controls
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)
Lead sponsor: Beth Israel Deaconess Medical Center
Sponsor class: OTHER
Collaborators: name: Shanghai Jiao Tong University School of Medicine
name: Florida A&M University
name: Brigham and Women's Hospital
name: Massachusetts General Hospital
name: VA Boston Healthcare System
name: National Institute of Mental Health (NIMH)
First posted: 2024-08-07
Enrollment: 300
Sex: ALL
Minimum age (years): 15
Maximum age (years): 35
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: 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.

Primary outcomes:
measure: mb-rt-fMRI-NFB intervention: functional connectivity
timeFrame: 1 month, 1 year, 2 years
measure: rTMS intervention: functional connectivity
timeFrame: 1 month, 1 year, 2 years
Secondary outcomes:
measure: Clinical
timeFrame: 1 month, 1 year, 2 years
measure: Neuropsychological function: verbal learning
timeFrame: 1 month, 1 year, 2 years
measure: Neuropsychological function: visual learning
timeFrame: 1 month, 1 year, 2 years
measure: Neuropsychological function: visual-spatial / speed of processing
timeFrame: 1 month, 1 year, 2 years
measure: Neuropsychological function: verbal fluency / speed of processing
timeFrame: 1 month, 1 year, 2 years
measure: Neuropsychological function: visual-motor / speed of processing
timeFrame: 1 month, 1 year, 2 years
measure: Neuropsychological function: attention
timeFrame: 1 month, 1 year, 2 years
measure: Neuropsychological function: working memory
timeFrame: 1 month, 1 year, 2 years
measure: Neuropsychological function: reasoning and problem solving
timeFrame: 1 month, 1 year, 2 years
measure: Event Related Potentials
timeFrame: 1 month, 1 year, 2 years
measure: Natural Language Processing: Linguistic
timeFrame: 1 month, 1 year, 2 years
measure: Natural Language Processing: Acoustic
timeFrame: 1 month, 1 year, 2 years
measure: Structural MRI
timeFrame: 1 month, 1 year, 2 years
measure: Diffusion Tensor Imaging
timeFrame: 1 month, 1 year, 2 years
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Shanghai Mental Health Center
state: Shanghai
Study officials:
affiliation: Beth Israel Deaconess Medical Center
name: William S Stone, Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Okano 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 Feb 10;286:112862. doi: 10.1016/j.psychres.2020.112862. Online ahead of print.
citation: Bauer 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.
citation: Niznikiewicz 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.