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Biomarkers of Conversion Risk and Treatment Response in Early-Stage Schizophrenia

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ClinicalTrials.gov Identifier: NCT03323437
Recruitment Status : Recruiting
First Posted : October 27, 2017
Last Update Posted : July 22, 2019
Sponsor:
Collaborators:
New York State Psychiatric Institute
Columbia University
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
Weill Medical College of Cornell University

Tracking Information
First Submitted Date  ICMJE October 2, 2017
First Posted Date  ICMJE October 27, 2017
Last Update Posted Date July 22, 2019
Actual Study Start Date  ICMJE September 15, 2017
Estimated Primary Completion Date October 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 25, 2017)
  • Change in biomarkers of treatment response: Dorsal Caudate (DCA) GABA levels [ Time Frame: Baseline and 4 weeks of treatment ]
    Dorsal Caudate (DCA) GABA levels will be ascertained at baseline and after 4 weeks of treatment using MRI scan with 1H MRS to assess treatment response.
  • Change in biomarkers of treatment response: Dorsal Caudate (DCA) Glutamate [ Time Frame: Baseline and 4th week of treatment ]
    Dorsal Caudate (DCA) Glutamate levels will be ascertained at baseline and after 4 weeks of treatment using MRI scan with 1H MRS to assess treatment response.
  • Change in biomarkers reflecting treatment response: Medial Prefrontal Cortex (MPFC) GABA [ Time Frame: Baseline and 4th week of treatment ]
    Medial Prefrontal Cortex (MPFC) GABA levels will be ascertained at baseline and after 4 weeks of treatment using MRI scan with 1H MRS to assess treatment response.
  • Change in biomarkers reflecting treatment response: Medial Prefrontal Cortex (MPFC) Glutamate [ Time Frame: Baseline and 4th week of treatment ]
    Medial Prefrontal Cortex (MPFC) Glutamate levels will be ascertained at baseline and after 4 weeks of treatment using MRI scan with 1H MRS to assess treatment response.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 25, 2017)
  • Changes in neurocognitive performance: MATRICS Consensus Cognitive Battery (MCCB) [ Time Frame: Baseline and 4th week of of treatment ]
    Memory, attention, reasoning, emotional intelligence, and verbal ability will be assessed using the MCCB before and after 4 weeks of treatment.
  • Changes in everyday functioning: University of California San Diego (UCSD) Performance-based Skills Assessment (UPSA) [ Time Frame: Baseline and 4th week of treatment ]
    Ability to function in a variety of everyday tasks from six domains (Financial Skills, Communication, Comprehension/Planning, Transportation, Household Management and Medication Management) will be assessed using the University of California San Diego Performance-based Skills Assessment (UPSA) before and after 4 weeks of treatment.
  • Changes in clinical symptomatology: Positive and Negative Syndrome Scale (PANSS) [ Time Frame: Treatment week 1, treatment week 2, treatment week 3 ]
    Changes in Positive and Negative Symptoms will be assessed across the treatment period using the PANSS. Participants are rated on a scale of
    1. (Absent)
    2. (Minimal)
    3. (Mild)
    4. (Moderate)
    5. (Moderate severe)
    6. (Severe)
    7. (Extreme)
    to describe Positive, Negative and General symptomatology. Items from each subscale (Positive, Negative, and General) are summed for their respective scales, with lower numbers indicating less severe or absent symptomatology, and higher scores indicating more severe symptoms. A total sum of all subscales is also computed to reflect overall symptom severity. Positive Subscale: 7 items, minimum score = 7, maximum score = 49 Negative Subscale: 7 items, minimum score = 7, maximum score = 49 General Subscale: `16 items, minimum score = 16, maximum score = 112 Total Score: 30 items, minimum score = 30, maximum score = 210.
  • Changes in motor symptomatology: Abnormal Involuntary Movement Scale (AIMS) [ Time Frame: Treatment week 1, treatment week 2, treatment week 3 ]
    Changes in motor symptomatology associated with tardive dyskinesia (TD) assessed using the Abnormal Involuntary Movement Scale (AIMS). The measure consists of 14 items with scale 0 None
    1. Minimal
    2. Mild
    3. Moderate
    4. Severe Higher ratings -> higher levels of motor symptoms. Items 1-7 assess abnormal movements for parts of the body. Ratings are summed to produce a score of total motor symptomatology (min 0, max 28).
    Item 8 = rating of overall symptom severity based on observation, using the same scale as above. Item 9 = rating of the incapacity of the subject due to abnormal movements, using the same scale as above. Item 10 = rating of the level of awareness and distress in the participant over the abnormal movements, with 0 =No Awareness
    1. = Aware, no distress
    2. = ~, mild ~
    3. = ~, moderate ~
    4. = ~, severe ~ Item 11-13 = yes/no, rule out dental problems that can lead to a mistaken diagnosis of TD.
    Item 14 = yes/no if symptoms disappear or persist during sleep.
  • Changes in clinical severity: Clinical Global Impression Scale [ Time Frame: treatment week 1, treatment week 2, treatment week 3 ]
    Changes in clinical severity over the course of treatment will be monitored using the The Clinical Global Impression Scale (CGI) consists of two items.- Severity scale (CGI-S). Severity - The first item assesses the patient's current level of mental health symptomatology compared to the clinician's experience with other patients with the same diagnosis. The scale ranges from
    1. (Normal, not at all ill)
    2. (Borderline mentally ill)
    3. (Mildly ill)
    4. (Moderately ill)
    5. (Markedly ill)
    6. (Severely ill)
    7. (Among the most extremely ill patients)
    Improvement - The second item assesses how much the patient's symptomatology has changed since the last clinical visit.
    1. Very much improved
    2. Much improved
    3. Minimally improved
    4. No change
    5. Minimally worse
    6. Much worse
    7. Very much worse
  • Changes in global functioning: Global Assessment of Functioning (GAF) [ Time Frame: Treatment week 1, treatment week 2, treatment week 3 ]
    Changes in global functioning over the course of treatment will be assessed using the Global Assessment of Functioning (GAF). Participants are rated 1-100 on their level of functioning, according to clinical observation: 91 - 100 No symptoms. 81 - 90 Absent or minimal symptoms 71 - 80 If symptoms are present, they expected reactions to stressors 61 - 70 Some mild symptoms 51 - 60 Moderate symptoms 41 - 50 Serious symptoms 31 - 40 Impairment in reality testing or communication or major impairment in several areas 21-30 Behavior influenced by delusions or hallucinations or serious impairment in communication/judgment/inability to function in almost all areas 11-20 Some danger of hurting self or others or occasionally fails to maintain minimal personal hygiene or gross impairment in communication 1-10 Persistent violence risk or lack of self-care 0 No info
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Biomarkers of Conversion Risk and Treatment Response in Early-Stage Schizophrenia
Official Title  ICMJE Biomarkers of Conversion Risk and Treatment Response in Early-Stage Schizophrenia
Brief Summary Schizophrenia (SZ) is a highly debilitating neuropsychiatric disorder of young adulthood onset and a leading cause of disability worldwide. While treatments delivered at early stages of the disorder may be effective at reducing psychosis or altering the course of the disease, there are currently no biomarkers capable of identifying subjects in early stages of SZ who are likely to respond to treatment and would be good candidates for available proactive, symptomatic or future disease-modifying treatments; or those who would not respond and can be spared unnecessary medication exposure. The lack of these vitally important biomarkers provides a compelling rationale for the present multidisciplinary research project, which aims to develop and validate highly promising noninvasive and objective proton magnetic resonance spectroscopy (1H MRS)-based biomarkers for monitoring treatment response in early stages of SZ. In support of the viability of this overall objective is a large body of data, reported by the applicants and others, that show (a) that levels of glutamate (Glu) and - aminobutyric acid (GABA) - respectively, the major excitatory and inhibitory amino acid neurotransmitter systems - are abnormally elevated in medication-naïve and unmedicated first episode and chronic SZ patients; (b) that the effect of treatment with antipsychotic medications in these populations may be to lower or normalize brain levels of both Glu and GABA. To investigate the potential of these in vivo brain Glu and GABA abnormalities to serve as biomarkers of treatment response in early-stage SZ, the applicants propose to use 1H MRS to measure Glu and GABA levels in the largest cohort of medication-free SZ subjects to date, at baseline and following 4 weeks of antipsychotic treatment.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE Schizophrenia Spectrum and Other Psychotic Disorders
Intervention  ICMJE Drug: Risperidone
Participants will meet with a study doctor physician once per week (about 3 times total) to monitor progress and side-effects of risperidone, which includes taking 4 assessments each time. After 4 weeks of taking Risperidone, participant will be assessed and scanned with the MRI/MRS scanner again.
Study Arms  ICMJE
  • Experimental: Patient
    Medication-free individuals during first-episode of psychosis who will receive 4 weeks of treatment with risperidone
    Intervention: Drug: Risperidone
  • No Intervention: Control
    Healthy, psychosis-free controls who will not receive risperidone
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 25, 2017)
90
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 2022
Estimated Primary Completion Date October 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria (Patients):

  1. Male or females between the ages of 18-35
  2. less than five years (<60 months) of active Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnosis of schizophrenia, schizophreniform, or schizoaffective disorder
  3. Capacity to provide informed consent
  4. No major medical or neurological illness
  5. Medication free (3 weeks without antipsychotic medications)

Exclusion Criteria (Patients):

  1. Current alcohol or drug abuse (<1 month) or substance dependence (<6 months) or substances used within one day of the imaging study.
  2. Pregnant or lactating women or women of child-bearing potential, who are either not surgically-sterile or, for outpatients, not using appropriate methods of birth control.
  3. Intelligence Quotient (IQ) <70
  4. Acute risk for suicide or violence
  5. Presence of pacemaker or any metallic objects in the body that would interfere with the MRS or cause MRI safety problems
  6. Claustrophobia
  7. Any organic brain disorder (including epilepsy, mental retardation, or a medical condition whose pathology or treatment would likely alter the presentation or treatment of SZ
  8. Individuals on anti-epileptic medications (e.g., valproate, carbamazepine) that may affect GABA or Glu
  9. Unstable medical or neurological condition
  10. DSM-V diagnosis of bipolar disorder I
  11. DSM-V diagnosis of major depression with psychotic features
  12. History of non-response to or non-tolerance of Risperidone

Inclusion Criteria (Healthy Controls)

  1. Male or females between the ages of 18-35
  2. less than five years (<60 months) of active DSM diagnosis of schizophrenia, schizophreniform, or schizoaffective disorder
  3. No major medical or neurological illness

Exclusion Criteria (Healthy Controls)

  1. Current alcohol or drug abuse (<1 month) or substance dependence (<6 months) or substances used within one day of the imaging study.
  2. Pregnant or lactating women or women of child-bearing potential, who are either not surgically-sterile or, for outpatients, not using appropriate methods of birth control.
  3. IQ<70
  4. Acute risk for suicide or violence
  5. Presence of pacemaker or any metallic objects in the body that would interfere with the MRS or cause MRI safety problems
  6. Claustrophobia
  7. History of psychotropic medication use such as antipsychotics or antidepressants
  8. Any first-degree family history of psychotic illness
  9. Personal history of any DSM Axis I disorder
  10. Individuals on anti-epileptic medications (e.g., valproate, carbamazepine) that may affect GABA or Glu
  11. Unstable medical or neurological condition
  12. Any organic brain disorder (including epilepsy, mental retardation, or a medical condition whose pathology or treatment would likely alter the presentation or treatment of SZ
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 35 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Lawrence Kegeles, MD, Ph.D. 646-774-5560 lsk5@columbia.edu
Contact: Ragy Girgis, MD 646-774-5553 ragy.girgis@nyspi.columbia.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03323437
Other Study ID Numbers  ICMJE 1702018001
R01MH110270 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Weill Medical College of Cornell University
Study Sponsor  ICMJE Weill Medical College of Cornell University
Collaborators  ICMJE
  • New York State Psychiatric Institute
  • Columbia University
  • National Institute of Mental Health (NIMH)
Investigators  ICMJE
Principal Investigator: Dikoma C. Shungu, Ph.D. Weill Cornell Medicine
PRS Account Weill Medical College of Cornell University
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP