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

Weill Medical College of Cornell University26 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Enrollment

Eligibility

Sex: ALLMin age: 18 YearsMax age: 35 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Change in Biomarkers of Treatment Response: Dorsal Caudate (DCA) Gamma Amino Butyric Acid (GABA) Levels

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. This is a measure of GABA levels, over water, in the dorsal caudate. For patients this is a change measure. For control subjects, this is a one time measure. The values can range from 0 to infinity for controls and -infinity to infinity for patients.

Time frame: Baseline and 4 weeks of treatment for patients, baseline for controls

Change in Biomarkers of Treatment Response: Dorsal Caudate (DCA) Glx (Glutamate+Glutamine)

Dorsal Caudate (DCA) Glx levels will be ascertained at baseline and after 4 weeks of treatment using MRI scan with 1H MRS to assess treatment response. This is a measure of the levels of Glx over water in the dorsal caudate. For patients this is a change measure. For control subjects, this is a one time measure. The values can range from 0 to infinity for controls and -infinity to infinity for patients.

Time frame: Baseline and 4th week of treatment for patients, baseline only for controls

Change in Biomarkers Reflecting Treatment Response: Medial Prefrontal Cortex (MPFC) Gamma Amino Butyric Acid (GABA)

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. This is a measure of GABA levels, over water, in the mPFC. For patients this is a change measure. For control subjects, this is a one time measure. The values can range from 0 to infinity for controls and -infinity to infinity for patients.

Time frame: Baseline and 4th week of treatment for patients, baseline only for controls

Change in Biomarkers Reflecting Treatment Response: Medial Prefrontal Cortex (MPFC) Glx (Glutamate+Glutamine)

Medial Prefrontal Cortex (MPFC) Glx levels will be ascertained at baseline and after 4 weeks of treatment using MRI scan with 1H MRS to assess treatment response. This is a measure of glx levels, over water, in the mPFC. For patients this is a change measure. For control subjects, this is a one time measure. The values can range from 0 to infinity for controls and -infinity to infinity for patients.

Time frame: Baseline and 4th week of treatment for patients, baseline for controls

Secondary Outcomes

Changes in Neurocognitive Performance: MATRICS Consensus Cognitive Battery (MCCB)

Memory, attention, reasoning, emotional intelligence, and verbal ability will be assessed using the MCCB before and after 4 weeks of treatment. MATRICS Consensus Cognitive Battery (MCCB) as measure of Neurocognitive/Functional Measures is a standardized battery designed to measure cognitive functioning in people with schizophrenia. The MCCB is represented as a percentile score. This score can go from 0 to 100 where a higher score indicates a better performance. For patients this is a change measure. For control subjects, this is a one time measure.

Time frame: Baseline and 4th week of of treatment for patients, baseline only for controls

WAMI (Wealth Asset and Income)

The WAMI Score at Baseline is a measure of socioeconomic status across countries and culture. The index scale goes from 0 (lower socioeconomic situation) to 1 (highest socioeconomic situation).

Time frame: Baseline

Changes in Clinical Symptomatology: Positive and Negative Syndrome Scale (PANSS)

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. For patients this is a change measure. For control subjects, this is a one time measure.

Time frame: Baseline and week 4 for patients; for controls only baseline

Changes in Motor Symptomatology: Abnormal Involuntary Movement Scale (AIMS)

Motor symptomatology associated with tardive dyskinesia (TD) assessed using the AIMS. The measure consists of 10 items with scale/scores for each item of: 0 None 1. Minimal 2. Mild 3. Moderate 4. Severe Higher ratings = higher levels of motor symptoms which is worse. This scale assesses abnormal movements for parts of the body. The total score is a sum score of items 1-10 and can be 0-40, with 40 being the most symptomatic (i.e., most extrapyramidal side effects, or worse).

Changes in Clinical Severity: Clinical Global Impression Scale

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 For patients this is a change measure. For control subjects, this is a one time measure. The possible score range is 1-7 with 1 being least and 7 being most symptomatic.

Time frame: Baseline and week 4 for patients; for controls this is a baseline measure only

Changes in Global Functioning: Global Assessment of Functioning (GAF)

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 For patients this is a change measure. For control subjects, this is a one time measure.