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

Schizophrenia Spectrum and Other Psychotic Disorders Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03323437
• Other study ID #: 1702018001
• Secondary ID: R01MH110270
• Status: Completed
• Phase: Phase 4
• Start date: September 15, 2017
• Est. completion date: May 31, 2023

Study information

• Verified date: May 2024
• Source: Weill Medical College of Cornell University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 26
• Est. completion date: May 31, 2023
• Est. primary completion date: May 31, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 35 Years

Eligibility

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

Related Conditions & MeSH terms

• Psychotic Disorders
• Schizophrenia
• Schizophrenia Spectrum and Other Psychotic Disorders

Intervention

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.

Locations

Country	Name	City	State
United States	New York State Psychiatric Institute & Columbia University	New York	New York

Sponsors (4)

Lead Sponsor	Collaborator
Weill Medical College of Cornell University	Columbia University, National Institute of Mental Health (NIMH), New York State Psychiatric Institute

Country where clinical trial is conducted

United States, 

References & Publications (21)

Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M, van Dyck CH, Charney DS, Innis RB, Laruelle M. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry. 1998 Jun;155(6):761-7. doi: 10.1176/ajp.155.6.761. — View Citation

CARLSSON A, LINDQVIST M. EFFECT OF CHLORPROMAZINE OR HALOPERIDOL ON FORMATION OF 3METHOXYTYRAMINE AND NORMETANEPHRINE IN MOUSE BRAIN. Acta Pharmacol Toxicol (Copenh). 1963;20:140-4. doi: 10.1111/j.1600-0773.1963.tb01730.x. No abstract available. — View Citation

Carlsson A, Waters N, Holm-Waters S, Tedroff J, Nilsson M, Carlsson ML. Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence. Annu Rev Pharmacol Toxicol. 2001;41:237-60. doi: 10.1146/annurev.pharmtox.41.1.237. — View Citation

Coyle JT. The glutamatergic dysfunction hypothesis for schizophrenia. Harv Rev Psychiatry. 1996 Jan-Feb;3(5):241-53. doi: 10.3109/10673229609017192. — View Citation

Davis KL, Kahn RS, Ko G, Davidson M. Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry. 1991 Nov;148(11):1474-86. doi: 10.1176/ajp.148.11.1474. — View Citation

Farooq S, Large M, Nielssen O, Waheed W. The relationship between the duration of untreated psychosis and outcome in low-and-middle income countries: a systematic review and meta analysis. Schizophr Res. 2009 Apr;109(1-3):15-23. doi: 10.1016/j.schres.2009.01.008. Epub 2009 Feb 23. — View Citation

Fusar-Poli P, Bonoldi I, Yung AR, Borgwardt S, Kempton MJ, Valmaggia L, Barale F, Caverzasi E, McGuire P. Predicting psychosis: meta-analysis of transition outcomes in individuals at high clinical risk. Arch Gen Psychiatry. 2012 Mar;69(3):220-9. doi: 10.1001/archgenpsychiatry.2011.1472. — View Citation

Fusar-Poli P, Borgwardt S, Bechdolf A, Addington J, Riecher-Rossler A, Schultze-Lutter F, Keshavan M, Wood S, Ruhrmann S, Seidman LJ, Valmaggia L, Cannon T, Velthorst E, De Haan L, Cornblatt B, Bonoldi I, Birchwood M, McGlashan T, Carpenter W, McGorry P, Klosterkotter J, McGuire P, Yung A. The psychosis high-risk state: a comprehensive state-of-the-art review. JAMA Psychiatry. 2013 Jan;70(1):107-20. doi: 10.1001/jamapsychiatry.2013.269. — View Citation

Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry. 1991 Oct;148(10):1301-8. doi: 10.1176/ajp.148.10.1301. — View Citation

Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994 Mar;51(3):199-214. doi: 10.1001/archpsyc.1994.03950030035004. — View Citation

Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D'Souza CD, Erdos J, McCance E, Rosenblatt W, Fingado C, Zoghbi SS, Baldwin RM, Seibyl JP, Krystal JH, Charney DS, Innis RB. Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):9235-40. doi: 10.1073/pnas.93.17.9235. — View Citation

Laruelle M, Abi-Dargham A. Dopamine as the wind of the psychotic fire: new evidence from brain imaging studies. J Psychopharmacol. 1999 Dec;13(4):358-71. doi: 10.1177/026988119901300405. — View Citation

Lodge DJ, Grace AA. Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia. J Neurosci. 2007 Oct 17;27(42):11424-30. doi: 10.1523/JNEUROSCI.2847-07.2007. — View Citation

Moghaddam B, Adams B, Verma A, Daly D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci. 1997 Apr 15;17(8):2921-7. doi: 10.1523/JNEUROSCI.17-08-02921.1997. — View Citation

Olney JW, Farber NB. Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry. 1995 Dec;52(12):998-1007. doi: 10.1001/archpsyc.1995.03950240016004. — View Citation

Olsen KA, Rosenbaum B. Prospective investigations of the prodromal state of schizophrenia: review of studies. Acta Psychiatr Scand. 2006 Apr;113(4):247-72. doi: 10.1111/j.1600-0447.2005.00697.x. — View Citation

Perkins DO, Gu H, Boteva K, Lieberman JA. Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a critical review and meta-analysis. Am J Psychiatry. 2005 Oct;162(10):1785-804. doi: 10.1176/appi.ajp.162.10.1785. — View Citation

Snyder SH. The dopamine hypothesis of schizophrenia: focus on the dopamine receptor. Am J Psychiatry. 1976 Feb;133(2):197-202. doi: 10.1176/ajp.133.2.197. — View Citation

Tamminga CA, Holcomb HH, Gao XM, Lahti AC. Glutamate pharmacology and the treatment of schizophrenia: current status and future directions. Int Clin Psychopharmacol. 1995 Sep;10 Suppl 3:29-37. — View Citation

Tamminga CA. Schizophrenia and glutamatergic transmission. Crit Rev Neurobiol. 1998;12(1-2):21-36. doi: 10.1615/critrevneurobiol.v12.i1-2.20. — View Citation

Yung AR, Yuen HP, Berger G, Francey S, Hung TC, Nelson B, Phillips L, McGorry P. Declining transition rate in ultra high risk (prodromal) services: dilution or reduction of risk? Schizophr Bull. 2007 May;33(3):673-81. doi: 10.1093/schbul/sbm015. Epub 2007 Apr 2. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Baseline and 4 weeks of treatment for patients, baseline for controls
Primary	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.	Baseline and 4th week of treatment for patients, baseline only for controls
Primary	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.	Baseline and 4th week of treatment for patients, baseline only for controls
Primary	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.	Baseline and 4th week of treatment for patients, baseline for controls
Secondary	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.	Baseline and 4th week of of treatment for patients, baseline only for controls
Secondary	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).	Baseline
Secondary	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; (Absent); (Minimal); (Mild); (Moderate); (Moderate severe); (Severe); (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.	Baseline and week 4 for patients; for controls only baseline
Secondary	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; Minimal; Mild; Moderate; 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).	Baseline and week 4
Secondary	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; (Normal, not at all ill); (Borderline mentally ill); (Mildly ill); (Moderately ill); (Markedly ill); (Severely ill); (Among the most extremely ill patients); Improvement - The second item assesses how much the patient's symptomatology has changed since the last clinical visit.; Very much improved; Much improved; Minimally improved; No change; Minimally worse; Much worse; 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.	Baseline and week 4 for patients; for controls this is a baseline measure only
Secondary	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.	Baseline and week 4 for patients; for controls only baseline
Secondary	Recreational Substances Used by Patients as Recorded by the Substance Use Questionnaire	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	This measure is administered on Day 1 of the study.
Secondary	Participants' Verbal I.Q (Intelligence Quotient) as Assessed by the WTAR (Wechsler Test of Adult Reading) to Determine Clinical Eligibility	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.	This measure is completed on Day 1 of the study.
Secondary	Participants' Self-Reported Handedness as Recorded by the Edinburgh Handedness Scale (Predominantly Right)	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.	This measure is completed on Day 1 of the study.