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

Phase 4

Completed

Conditions: Schizophrenia Spectrum and Other Psychotic Disorders

Interventions: Drug: Risperidone

Registration Number: NCT03323437

Lead Sponsor: Weill Medical College of Cornell University

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 available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 26

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Patient	Risperidone	Medication-free individuals during first-episode of psychosis who will receive 4 weeks of treatment with risperidone

Primary Outcome Measures

Name	Time	Method
Change in Biomarkers Reflecting Treatment Response: Medial Prefrontal Cortex (MPFC) Gamma Amino Butyric Acid (GABA)	Baseline and 4th week of treatment for patients, baseline only for controls	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.
Change in Biomarkers of Treatment Response: Dorsal Caudate (DCA) Gamma Amino Butyric Acid (GABA) Levels	Baseline and 4 weeks of treatment for patients, baseline for controls	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.
Change in Biomarkers of Treatment Response: Dorsal Caudate (DCA) Glx (Glutamate+Glutamine)	Baseline and 4th week of treatment for patients, baseline only for controls	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.
Change in Biomarkers Reflecting Treatment Response: Medial Prefrontal Cortex (MPFC) Glx (Glutamate+Glutamine)	Baseline and 4th week of treatment for patients, baseline for controls	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.

Secondary Outcome Measures

Name	Time	Method
Changes in Neurocognitive Performance: MATRICS Consensus Cognitive Battery (MCCB)	Baseline and 4th week of of treatment for patients, baseline only for controls	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.
WAMI (Wealth Asset and Income)	Baseline	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).
Changes in Clinical Severity: Clinical Global Impression Scale	Baseline and week 4 for patients; for controls this is a baseline measure only	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.
Recreational Substances Used by Patients as Recorded by the Substance Use Questionnaire	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, phencyclidine (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
Changes in Clinical Symptomatology: Positive and Negative Syndrome Scale (PANSS)	Baseline and week 4 for patients; for controls only baseline	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.
Changes in Motor Symptomatology: Abnormal Involuntary Movement Scale (AIMS)	Baseline and week 4	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).
Participants' Verbal I.Q (Intelligence Quotient) as Assessed by the WTAR (Wechsler Test of Adult Reading) to Determine Clinical Eligibility	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. The potential score range is 0-50. A higher score indicates better cognitive ability. There is only one total score.
Participants' Self-Reported Handedness as Recorded by the Edinburgh Handedness Scale (Predominantly Right)	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. Below we specifically report on the number of individuals who were predominantly right handed.
Changes in Global Functioning: Global Assessment of Functioning (GAF)	Baseline and week 4 for patients; for controls only baseline	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.