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ARRA Investments in Schizophrenia


Public Health Burden
Schizophrenia is a chronic, severe, and disabling brain disorder that affects about 1.1 percent of the U.S. population age 18 and older in a given year. Symptoms usually develop in men in their late teens or early twenties and in women in their twenties and thirties. People with schizophrenia have significant rates of co-occurring health problems including other mental illnesses and medical conditions. About 5 percent of people with schizophrenia commit suicide. Schizophrenia is responsible for enormous losses in productivity and income, both for patients and caregivers.

Causes
The identical twin of a person with schizophrenia has a 40 to 65 percent chance of developing the disease. This suggests that much, but not all, of the risk is a result of genes, but environmental factors also play a role. No one gene causes schizophrenia. Variants of many genes involved in shaping brain function contribute to schizophrenia risk and the effect of any one gene may be small. ARRA funding is enabling scientists to conduct research aimed at identifying risk genes and determining how they interact with each other and with the environment to alter brain physiology and shape risk. The goal is both to understand schizophrenia, and to identify targets for future pharmacotherapies.
  • A five-center project is making use of an existing collaboration to examine the heritability of schizophrenia-associated epigenetic changes to genes: changes that affect the activity, but not the underlying sequential structure of genes. The investigators will examine how these changes relate to cognitive deficits in people with schizophrenia and family members.1
  • Determining the connections between gene variation and mental illness requires meticulously detailed information on behavior and brain function. A collaborative project will assemble behavioral, cognitive, emotional, and genomic profiles of 10,000 children and adolescents to create a dataset to serve as a resource for investigating the contributions of genes to aspects of brain function, and ultimately, health and disease.2
  • Another ARRA project investigates the activity of two susceptibility genes previously shown to have an impact on schizophrenia risk during brain development. The aim is to clarify how variants in these genes can interact to disrupt the neurochemical pathways involved in the development of brain circuitry.3
Interventions
Available treatments, such as antipsychotic medications and social skills training, can relieve many of the disorder's symptoms and help people with schizophrenia function, but most people with the disease must cope with some residual symptoms as long as they live. People with schizophrenia frequently drop out of school, lose the ability to work competitively, and become increasingly isolated from friends and family. Important research goals include development of ways to identify those at risk for developing psychosis early, and determining whether early intervention could prevent the inexorable decline that follows the onset of the disease.
  • The RAISE project (Recovery After an Initial Schizophrenia Episode) is a large-scale clinical study testing whether early, comprehensive treatment can reduce the lifelong disability associated with schizophrenia and the resulting costs to individuals and society.4
  • An existing consortium of eight centers aims to track people at risk for schizophrenia in order to develop the means to accurately predict the onset of psychosis, key information for intervention. The study will include analyses of genetic and neurobiological risk factors, stress hormones, electrophysiology, and clinical signs.5
  • By seeing how brain cell activity in mice tracks with cognitive function, one team aims to create a rodent model of schizophrenia with which to test new therapies. The goal is to be able to directly measure the effects of candidate drugs on basic aspects of brain activity that are relevant to attention and working memory.6
  • A biomarker of psychosis would be a valuable aid to tailoring treatment for individuals with schizophrenia. In one project, scientists will follow up on a finding that a marker related to a known schizophrenia-related gene is elevated during active psychosis and determine whether it could be used as a marker of therapeutic effectiveness.7
  • Evidence suggests that reduced activity of a key neurotransmitter may be a factor in the deterioration of brain function seen after the onset of schizophrenia. A study in people who have recently experienced a first psychosis will test whether a drug that can augment signaling by this neurotransmitter could help prevent this deterioration and ameliorate symptoms of schizophrenia, including problems with cognition.8



  1. 1RC2MH089859-01, -- Family-based genome-wide methylation scan in neurocognition and schizophrenia -- Nimgaonkar, Vishwajit (PA); 1RC2MH090221-01 -- Perry, Rodney (AL); 1RC2MH089984-01 -- Braff, David (CA); 1RC2MH090043-01 -- Feinberg, Andres (MD); 1RC2MH089973-01 -- Gur, Raquel (PA)
  2. 1RC2MH089983-01 -- Neurodevelopmental genomics -- Gur, Raquel (PA); RC2MH089924- Hakonarson, Hakon (PA)
  3. 1RC1MH088753-01 -- Defining of neurodevelopment pathways regulated by neuregulin-DISC1 interactions -- Anton, Eva (NC)
  4. HHSN271200900019C-0-0-1, --Recoveryafteraninitialschizophreniaepisode--KaneJohn(NY);HHSN271200900019C-0-0-1 -- Lieberman, Jeffrey (NY)
  5. 5U01MH081902-02S1 -- Predictors and mechanisms of conversion to psychosis -- Cannon, Tyrone (CA)
  6. 1RC1MH088617-01 -- In vivo methods for preclinical analysis of cognitive therapies for schizophrenia-Levenson, Jonathan (MA)
  7. 1RC1MH088735-01 -- Characterization of a treatment-response biomarker in patients with schizophrenia -- Gault, Judith— (CO)
  8. 1R21MH082235-0A1 -- GABA and early intervention of schizophrenia -- Woo, Tsung-ung (MA)


 
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