Clinical Trials Logo

Clinical Trial Summary

The 2020 NIMH Strategic Plan for Research calls for investigations targeting neurobiology of mental illness across the lifespan. Growing evidence suggests that lifespan neurobiology of schizophrenia (SZ) incorporates two distinct dimensions: aging and disease course. However, their clinical correlates, associated biomarker trajectories, and implications for treatment are unknown. This study will investigate differential aspects of SZ neurobiology captured by aging and disease course, in order to develop specific biomarkers which may offer actionable targets for SZ stage-dependent intervention. The study is predicated on a novel mechanistic Model of SZ Trajectories across the Adult Lifespan, positing distinct biological fingerprints within the anterior limbic system for aging and disease course in SZ: (1) alterations in the circuit's function and structure that occur earlier in the lifespan and are larger in magnitude than the alterations expected with normal aging (accelerated aging dimension); and (2) regionally-specific anterior limbic "hyperactivity" in early SZ, with a subsequent transformation into "hypoactivity" in advanced SZ (disease course dimension). In a sample of SZ and matched healthy controls (n=168, 84/group) aged 18-75 years the investigators will ascertain a broad panel of biomarkers [via multimodal brain imaging: optimized 1H-MRS, high-resolution task-based fMRI, perfusion (Vascular Space Occupancy) and structural MRI], along with comprehensive cognitive and clinical assessments. All measures will be acquired at baseline and repeated at 2-year longitudinal follow-up. Using cutting-edge computational approaches, the study will examine (i) effects of aging and SZ course on anterior limbic system biomarkers; (ii) lifespan trajectories for different biomarkers; (iii) patterns of limbic system biomarkers in age- and SZ course-based subgroups (e.g., Younger vs. Older, Early-Course vs. Advanced SZ), as well as in data-driven subgroups (e.g., those with vs. without accelerated aging profiles); and (iv) associations between biomarkers and cognitive and clinical outcomes. This research will advance the field by providing novel biomarkers that capture unique neurobiological contributions of aging and disease course in SZ, and will motivate future studies on SZ mechanisms across the lifespan and development of precision treatments.


Clinical Trial Description

Specific Aims: In order to investigate aging and disease course dimensions in SZ, the study will ascertain a broad panel of biomarkers using multimodal brain imaging, along with comprehensive cognitive and clinical measures, which will allow integration of in vivo molecular; circuit structure and function; and clinical levels of system pathology. Aim 1. In vivo Molecular Biomarkers. Examine age- and disease course-dependent effects on excitatory and inhibitory 1H-MRS-based biomarkers in the anterior limbic system in SZ. SZ and CON (n=84/group) will undergo novel triple-refocusing 1H-MRS with Glutamate (Glu), GABA and broader metabolite measures from bilateral Hipp and mPFC. Hypothesis 1.1: SZ will show declines in Hipp-mPFC Glu and GABA along the lifespan, with significantly earlier and larger reductions than those observed in CON. Hypothesis 1.2: SZ will show distinct Hipp-mPFC Glu and GABA markers along the disease course, with significantly elevated or equivalent Glu, and reduced GABA levels, in early SZ, and reduced Glu and GABA in advanced SZ, compared to CON. Aim 2. Functional Circuit Biomarkers. Examine age- and disease course-dependent effects on intrinsic and task-based activation biomarkers in the anterior limbic circuit in SZ, using high resolution perfusion [Vascular Space Occupancy] and functional MRI with an episodic memory [Pattern Separation] task, respectively. Hypothesis 2.1: SZ will show declines in Hipp-mPFC intrinsic and task-based activity along the lifespan, with significantly earlier and larger reductions than those in CON. Hypothesis 2.2: SZ will show distinct Hipp-mPFC intrinsic and task-dependent activity signatures across the disease course, with significantly elevated or equivalent regional activation in early SZ, and reduced activation in advanced SZ, compared to CON. Aim 3. Structural Circuit Biomarkers. Examine age- and disease course-dependent effects on structural biomarkers in the anterior limbic system in SZ, using high resolution structural MRI. Hypothesis 3.1: SZ will show declines in cortical thickness and volume in Hipp, mPFC and broader fronto-temporal regions across the lifespan, with significantly earlier and larger reductions than those in CON. Hypothesis 3.2: SZ will show distinct fronto-temporal alterations along the disease course, with modestly reduced cortical thickness and volume measures in early SZ and larger reductions in advanced SZ, compared to CON. The investigators also predict that molecular, functional, and structural alterations in the anterior limbic system will be associated with impaired episodic memory and broader cognitive dysfunction in SZ, with declining cognition along both the lifespan and SZ course. This research will advance the field by providing novel biomarkers that capture unique neurobiological contributions of aging and disease course in SZ, and will motivate future studies on SZ mechanisms across the lifespan, and the development of relevant precision treatments. ;


Study Design


Related Conditions & MeSH terms


NCT number NCT04951700
Study type Observational [Patient Registry]
Source University of Texas Southwestern Medical Center
Contact Elena I. Ivleva, MD, PhD
Phone 214-645-8942
Email elena.ivleva@utsouthwestern.edu
Status Recruiting
Phase
Start date July 1, 2021
Completion date April 30, 2027

See also
  Status Clinical Trial Phase
Recruiting NCT05039489 - A Study on the Brain Mechanism of cTBS in Improving Medication-resistant Auditory Hallucinations in Schizophrenia N/A
Completed NCT05111548 - Brain Stimulation and Cognitive Training - Efficacy N/A
Completed NCT05321602 - Study to Evaluate the PK Profiles of LY03010 in Patients With Schizophrenia or Schizoaffective Disorder Phase 1
Completed NCT04503954 - Efficacy of Chronic Disease Self-management Program in People With Schizophrenia N/A
Completed NCT02831231 - Pilot Study Comparing Effects of Xanomeline Alone to Xanomeline Plus Trospium Phase 1
Completed NCT05517460 - The Efficacy of Auricular Acupressure on Improving Constipation Among Residents in Community Rehabilitation Center N/A
Completed NCT03652974 - Disturbance of Plasma Cytokine Parameters in Clozapine-Resistant Treatment-Refractory Schizophrenia (CTRS) and Their Association With Combination Therapy Phase 4
Recruiting NCT04012684 - rTMS on Mismatch Negativity of Schizophrenia N/A
Recruiting NCT04481217 - Cognitive Factors Mediating the Relationship Between Childhood Trauma and Auditory Hallucinations in Schizophrenia N/A
Completed NCT00212784 - Efficacy and Safety of Asenapine Using an Active Control in Subjects With Schizophrenia or Schizoaffective Disorder (25517)(P05935) Phase 3
Completed NCT04092686 - A Clinical Trial That Will Study the Efficacy and Safety of an Investigational Drug in Acutely Psychotic People With Schizophrenia Phase 3
Completed NCT01914393 - Pediatric Open-Label Extension Study Phase 3
Recruiting NCT03790345 - Vitamin B6 and B12 in the Treatment of Movement Disorders Induced by Antipsychotics Phase 2/Phase 3
Recruiting NCT05956327 - Insight Into Hippocampal Neuroplasticity in Schizophrenia by Investigating Molecular Pathways During Physical Training N/A
Terminated NCT03261817 - A Controlled Study With Remote Web-based Adapted Physical Activity (e-APA) in Psychotic Disorders N/A
Terminated NCT03209778 - Involuntary Memories Investigation in Schizophrenia N/A
Completed NCT02905604 - Magnetic Stimulation of the Brain in Schizophrenia or Depression N/A
Recruiting NCT05542212 - Intra-cortical Inhibition and Cognitive Deficits in Schizophrenia N/A
Completed NCT04411979 - Effects of 12 Weeks Walking on Cognitive Function in Schizophrenia N/A
Terminated NCT03220438 - TMS Enhancement of Visual Plasticity in Schizophrenia N/A