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

• ClinicalTrials.gov Identifier: NCT03323437
• Recruitment Status: Recruiting
• First Posted: October 27, 2017
• Last Update Posted: August 1, 2022
• Sponsor: Weill Medical College of Cornell University
• 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

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Schizophrenia Spectrum and Other Psychotic Disorders	Drug: Risperidone	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 90 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Biomarkers of Conversion Risk and Treatment Response in Early-Stage Schizophrenia
• Actual Study Start Date: September 15, 2017
• Estimated Primary Completion Date: October 2023
• Estimated Study Completion Date: October 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Patient; Medication-free individuals during first-episode of psychosis who will receive 4 weeks of treatment with risperidone	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.
No Intervention: Control; Healthy, psychosis-free controls who will not receive risperidone

Outcome Measures

Primary Outcome Measures :

1. 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.
2. 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.
3. 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.
4. 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.

Secondary Outcome Measures :

1. 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.
2. 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.
3. 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.

4. 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.

5. 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
6. 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

7. Recreational Substances Used by Patients as Recorded by the Substance Use Questionnaire [ Time Frame: This measure is administered on Day 1 of the study. ]
   This measure is a self-reported questionnaire which assesses for any use of the following substances within the past month prior to the initial research visit Tobacco (if the respondent indicates that they have used tobacco in the past month, they are additionally asked, "On average, how many cigarettes per day have you smoked in the past 7 days?" Alcohol, Cocaine, Marijuana, Opiates, Amphetamines, PCP Other Drugs of Abuse (if the respondent indicates they have used other drugs of abuse within the past month of the initial research visit, they are given the opportunity to "specify" which other drugs of abuse they used
8. Participants' Verbal I.Q as Assessed by the WTAR to Determine Clinical Eligibility [ Time Frame: This measure is completed on Day 1 of the study. ]
   This measure assesses a participant's verbal ability to determine whether they are cognitively able to complete the measures involved in the study. The participant will read from a list of 50 English words and the rater will record whether the pronunciation was correct on a score card for each word spoken. A standard score below the 70th percentile on this measure is indicative of an intellectual disability which would exclude a participant from being clinically and cognitively eligible to complete this study.
9. Participants' Self-Reported Handedness as Recorded by the Edinburgh Handedness Scale [ Time Frame: This measure is completed on Day 1 of the study. ]
   This measure assesses a participant's preference regarding which hand they would use to complete a specific task. They have the option to indicate whether they would use they would always or most of the time use their left, right, or both left and right hands to complete each task. This measure assesses handedness based on the amount of responses which indicate the participant is either left handed, right handed, or ambidextrous.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 35 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Contacts

Contact: Lawrence Kegeles, MD, Ph.D.; 646-774-5560; lsk5@columbia.edu

Contact: Ragy Girgis, MD; 646-774-5553; ragy.girgis@nyspi.columbia.edu

Locations

United States, New York

New York State Psychiatric Institute & Columbia University; Recruiting

New York, New York, United States, 10032

Contact: Lawrence Kegeles, M.D., Ph.D. 646-774-5560 lsk5@columbia.edu

Contact: Ragy Girgis, M.D. 646-774-5553 ragygir@nyspi.columbia.edu

Principal Investigator: Lawrence Kegeles, MD, PhD

Principal Investigator: Ragy Girgis, MD

Sub-Investigator: Roberto Lewis, MD

Sponsors and Collaborators

Weill Medical College of Cornell University

New York State Psychiatric Institute

Columbia University

National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Dikoma C. Shungu, Ph.D.; Weill Medical College of Cornell University

More Information

Publications:

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• Responsible Party: Weill Medical College of Cornell University
• ClinicalTrials.gov Identifier: NCT03323437
• Other Study ID Numbers: 1702018001; R01MH110270 ( U.S. NIH Grant/Contract )
• First Posted: October 27, 2017
• Last Update Posted: August 1, 2022
• Last Verified: July 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• 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

Additional relevant MeSH terms:

Schizophrenia; Mental Disorders; Psychotic Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Risperidone; Serotonin Antagonists; Serotonin Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Antipsychotic Agents; Tranquilizing Agents; Central Nervous System Depressants; Psychotropic Drugs; Dopamine Antagonists; Dopamine Agents