Clinical trial NCT03323437: Biomarkers of Conversion Risk and Treatment Response in Early-Stage Schizophrenia
Official title: Biomarkers of Conversion Risk and Treatment Response in Early-Stage Schizophrenia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Schizophrenia Spectrum and Other Psychotic Disorders
Lead sponsor: Weill Medical College of Cornell University
Sponsor class: OTHER
Collaborators: name: New York State Psychiatric Institute
name: Columbia University
name: National Institute of Mental Health (NIMH)
First posted: 2017-10-27
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.


Eligibility 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

Primary outcomes:
measure: Change in Biomarkers of Treatment Response: Dorsal Caudate (DCA) Gamma Amino Butyric Acid (GABA) Levels
timeFrame: Baseline and 4 weeks of treatment for patients, baseline for controls
measure: Change in Biomarkers of Treatment Response: Dorsal Caudate (DCA) Glx (Glutamate+Glutamine)
timeFrame: Baseline and 4th week of treatment for patients, baseline only for controls
measure: Change in Biomarkers Reflecting Treatment Response: Medial Prefrontal Cortex (MPFC) Gamma Amino Butyric Acid (GABA)
timeFrame: Baseline and 4th week of treatment for patients, baseline only for controls
measure: Change in Biomarkers Reflecting Treatment Response: Medial Prefrontal Cortex (MPFC) Glx (Glutamate+Glutamine)
timeFrame: Baseline and 4th week of treatment for patients, baseline for controls
Secondary outcomes:
measure: Changes in Neurocognitive Performance: MATRICS Consensus Cognitive Battery (MCCB)
timeFrame: Baseline and 4th week of of treatment for patients, baseline only for controls
measure: WAMI (Wealth Asset and Income)
timeFrame: Baseline
measure: Changes in Clinical Symptomatology: Positive and Negative Syndrome Scale (PANSS)
timeFrame: Baseline and week 4 for patients; for controls only baseline
measure: Changes in Motor Symptomatology: Abnormal Involuntary Movement Scale (AIMS)
timeFrame: Baseline and week 4
measure: Changes in Clinical Severity: Clinical Global Impression Scale
timeFrame: Baseline and week 4 for patients; for controls this is a baseline measure only
measure: Changes in Global Functioning: Global Assessment of Functioning (GAF)
timeFrame: Baseline and week 4 for patients; for controls only baseline
measure: Recreational Substances Used by Patients as Recorded by the Substance Use Questionnaire
timeFrame: This measure is administered on Day 1 of the study.
measure: Participants' Verbal I.Q (Intelligence Quotient) as Assessed by the WTAR (Wechsler Test of Adult Reading) to Determine Clinical Eligibility
timeFrame: This measure is completed on Day 1 of the study.
measure: Participants' Self-Reported Handedness as Recorded by the Edinburgh Handedness Scale (Predominantly Right)
timeFrame: This measure is completed on Day 1 of the study.
Other outcomes:
Locations:
city: New York
country: United States
facility: New York State Psychiatric Institute & Columbia University
state: New York
Study officials:
affiliation: Weill Medical College of Cornell University
name: Dikoma C. Shungu, Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
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.
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.
citation: Coyle JT. The glutamatergic dysfunction hypothesis for schizophrenia. Harv Rev Psychiatry. 1996 Jan-Feb;3(5):241-53. doi: 10.3109/10673229609017192.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
citation: Tamminga CA. Schizophrenia and glutamatergic transmission. Crit Rev Neurobiol. 1998;12(1-2):21-36. doi: 10.1615/critrevneurobiol.v12.i1-2.20.
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.
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.