Treatment Response in Schizophrenia: Bridging Imaging and Postmortem Studies
Condition: Schizophrenia
MeSH terms: Schizophrenia
Study type: Observational

Summary: 
      The overarching goal is to identify imaging markers that will predict treatment response, and
      to confirm or validate these biomarkers using anatomical studies of postmortem tissue. Early
      detection of drug response would yield specific treatment strategies that are tailored to the
      individual, thus improving both the quality of life of the patients and drastically reducing
      the costs associated with unsuccessful treatment strategies.
    

Detailed description: 
      Our past brain imaging and Positron Emission Tomography (PET) studies have contributed to the
      understanding of specific brain regions related to treatment response to antipsychotic drugs
      in schizophrenia. We have found that treatment response to antipsychotic medication is
      related to blood-flow patterns in specific regions (such as the ventral striatum, anterior
      cingulate cortex, and hippocampus). In addition, functional changes in these regions
      following one week of antipsychotic drug therapy are predictive of treatment response. Dr.
      Roberts, a neuroanatomist, has studied the post mortem (after death) brains of patients with
      schizophrenia while working in association with the Maryland Brain Collection. Her studies
      have indicated an increased number of dopaminergic synapses (that is, neurons that produce
      the neurotransmitter dopamine) in these regions in patients who were known to have had a
      favorable response to antipsychotic drug therapy. In addition, from this post-mortem work we
      know the number of glutamate synapses in these regions were significantly different between
      good treatment responders and poor responders.

      From these studies we have hypothesized that in schizophrenia an over-abundance of dopamine
      in the ventral striatum interferes with normal functioning by limiting the transmission of
      glutamate. Putatively, antipsychotic medications may decrease the symptoms of schizophrenia
      by restoring glutamatergic activity in the ventral striatum and projected areas, such as the
      anterior cingulate cortex and hippocampus. We have hypothesized that those individuals
      responding favorably to antipsychotic drug therapy will display greater glutamate activity in
      the ventral striatum (due to dopamine blockade) and the other regions receiving glutamate
      projections. This should lead to restored neuronal functioning in good responders when
      compared to treatment resistant and poor responders to antipsychotic drug treatment. We will
      test this hypothesis using complementary imaging and postmortem studies yielding data that
      will permit the formulation of a comprehensive model for antipsychotic drug responses in
      subjects with severe mental illness.

      Magnetic Resonance is a technique for probing atoms and molecules based upon their
      interaction with an external magnetic field. Magnetic Resonance does not use ionizing
      radiation. The most familiar example of this is Magnetic Resonance Imaging (MRI). Another
      application of Magnetic Resonance is called functional Magnetic Resonance Imaging (fMRI).
      Functional Magnetic Resonance Imaging (fMRI) allows us to measure the Blood Oxygenation
      Level-Dependent (BOLD) response, a measure of blood flow in the brain that is known to
      correlate with neuronal activity. Another application of Magnetic Resonance is Magnetic
      Resonance Spectroscopy (MRS), which allows the measurements of specific metabolites such as
      N-acetyl aspartate (NAA), a measure of neuronal integrity, and Glutamate, which is involved
      in neurotransmission and metabolism. We will seek to replicate and extend our past Positron
      Emission Tomography (PET) findings with functional magnetic resonance imaging (fMRI) using
      cognitive tasks that are known to activate the hippocampus (Episodic memory task) and the
      anterior cingulate cortex (Stroop task). This aim will further seek to parse out the
      differential contribution of the hippocampus and the anterior cingulate cortex to treatment
      response. At the same time, N-acetylaspartate, a marker of neuronal integrity, and glutamate
      measurements obtained with magnetic resonance spectroscopy in the anterior cingulate cortex
      and hippocampus will directly probe in the living brain the relation between neuronal
      integrity, glutamate function, and treatment response. In parallel, the postmortem work of
      Dr. Roberts (UAB IRB exemption: NO70813001, IRB#F080306003) will concentrate on the study of
      the anterior cingulate cortex in post mortem brains of schizophrenic patients. These studies
      should allow the development of hypotheses about the pathophysiology of treatment response
      and provide a basis for the interpretation of functional imaging data. The overarching goal
      is to identify imaging markers that will predict treatment response, and to confirm or
      validate these biomarkers using anatomical studies of postmortem tissue. Early detection of
      drug response would yield specific treatment strategies that are tailored to the individual,
      thus improving both the quality of life of the patients and drastically reducing the costs
      associated with unsuccessful treatment strategies.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        We will recruit fifty patients with a diagnosis of schizophrenia presenting at UAB clinics
        who have stopped taking APD medication for at least 10 days and agree to antipsychotic
        treatment, and twenty-five matched healthy volunteers.
      
Biospecimen description: 
      Specimens will be tested for dopamine, serotonin, norepinephrine, and glutamine-related
      genes. In previous studies, all of these neurotransmitters have been associated with
      schizophrenia and/or schizoaffective disorder.
    
Keywords: schizophrenia; treatment response; risperidone; functional magnetic resonance; functional magnetic spectroscopy