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

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

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.

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