A Neurobiological Study on Heterogeneity of Schizophrenia: Genetic Variations and Neurobiological Differentiations (SONPOS)

This study is enrolling participants by invitation only.
Sponsor:
Collaborator:
National Science Council, Taiwan
Information provided by:
National Taiwan University Hospital
ClinicalTrials.gov Identifier:
NCT01075373
First received: February 23, 2010
Last updated: March 4, 2010
Last verified: February 2010
  Purpose

Schizophrenia (SCH) is a devastating brain disorder with grave personal, family and social cost. SCH is a complex and heterogeneous (both genetic and clinical) disorder with oligogenetic endowed vulnerability risk of disease, which manifested as a clinical syndrome comprised of positive, negative and cognitive symptoms in late adolescent or young adulthood under the interaction with environmental stress. The fact that most positive psychotic symptoms can be well controlled by dopamine-blocking antipsychotics substantiates that dopamine hyperactivity is the pathophysiological model of SCH positive symptoms. This is the dopamine model of SCH.

The presence of negative and cognitive symptoms has not being fully explained by the dopamine model. The hypo-glutaminergic function was hypothesized to replace or to supplement the dopamine pathological model. The hypo-glutaminergic state was due to a neurodevelopmental disturbance in early-stage of life, and was coined as a pathophysiological mechanism of SCH.

The neurodevelopmental disturbance supports the hypo-glutamine model based on the cytoarchitecture abnormality in glutamate-pyramidal cells and reduced gray matter volume. We have found potential vulnerability genes of DISC1 and NRG1 in our Taiwanese SCH family samples. These two genes have functions on neurodevelopmental process. Besides, we, the investigators, also found two vulnerability genes of DRD2 receptor gene and COMT genes in our Taiwanese SCH families. The dopamine neurotransmission disturbance could be another pathophysiological mechanism of SCH.

With the awareness of confounding variables of antipsychotic treatment response revealed in pharmacogenetic studies, such as drug metabolism related genes and plasma HVA level, we intend to test the etiological genetic hypotheses in antipsychotic treatment response: (1) The group of neurodevelopmental etiology with risk variations in DISC1 and NRG1 genes is of poor treatment response group; (2) The group of pure hyperdopamine etiology with risk variation in DRD2 receptor and COMT genes is of good treatment group.

The potential treatment response related biomarkers, which are directly or indirectly induced by the etiological risk genetic variations, will be examined. These potential biomarkers include homovanillic acid (HVA), glutamate, serotonin, cytokines, and signaling proteins, the neurocognitive function, event-related evoked potential, Niacin skin test, and the AKT1 level in the peripheral lymphocytes.

After obtained the informed consult, we'll recruit 30 drug-naïve early schizophrenia (first episode or prodromal stage) patients for pre-treatment and post-treatment assessment on treatment response using positive and negative syndrome scale (PANSS), changes in biomarkers (including biochemical, electro-physiological and neuro-cognitive variables), and brain imaging (studies of component Project No.2 of this Integrated Program) of PET, fMRI, MRI, DSI and MRS (please refer to Project No.2) in addition to genotyping on DISC1, NRG1, DRD2 and COMT genes. The treatment agent is the dopamine stabilizing agent (aripiprazole, 15mg/day for 4 weeks) taking the advantage of dopamine activity balancing effect. Besides, we'll recruit 30 normal controls matched with age, gender, and education, who will receive genotyping and evaluations in all biomarker variables, and brain imaging studies.

In order to have adequate statistical power in the genetic analysis of 17 SNP variations in 4 vulnerability genes of DISC1, NRG1, DRD2, COMT, we'll recruit 200 more cases of schizophrenia with duration of illness less than 5 years, who have received regular clinical follow up and had good compliance on medication. The treatment response will be evaluated using PANSS. These cases will also receive all biomarker examinations and genotyping studies. For comparison, we'll also recruit 100 normal controls for study.

We'll delineate the heterogeneity issue of schizophrenia using genetic variation, neurobiological biomarkers. This study result will be beneficial for understanding pathogenesis of SCH, and for developing better treatment and prevention methods.


Condition
Schizophrenia

Study Type: Observational
Study Design: Observational Model: Case-Only
Time Perspective: Prospective
Official Title: A Neurobiological Study on Heterogeneity of Schizophrenia: Genetic Variations and Neurobiological Differentiations

Resource links provided by NLM:


Further study details as provided by National Taiwan University Hospital:

Biospecimen Retention:   Samples With DNA

Whole blood


Estimated Enrollment: 360
Study Start Date: March 2009
Estimated Study Completion Date: November 2010
Estimated Primary Completion Date: November 2010 (Final data collection date for primary outcome measure)
Detailed Description:

The project will use the early stage and drug naïve schizophrenic patients as the study subjects. The specific aims are:

  1. To test the hypothesis that the patient group with good antipsychotic treatment response mainly carries the risk polymorphism of DRD2 and COMT genes (the dopamine transmission genes) while the group with poor antipsychotic treatment response mainly carries the risk polymorphism of DISC1 and NRG1 genes (the neurodevelopmental genes). This association is controlled by the polymorphism of genes of drug metabolizing enzymes.
  2. The good vs. poor treatment response group will have different manifestation patterns in biomarkers directly or indirectly related to neurodevelopmental or dopamine neurotransmission genes. These potential biomarkers included biochemical parameters, electrophysiological and neurocognitive indicators.
  3. The good vs. poor responder group has differential changes of the response-related biomarkers comparing pre-treatment and post-treatment status in special sub-sample of the drug-naïve early schizophrenia patients.
  Eligibility

Ages Eligible for Study:   16 Years to 45 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

16-45 y/o early stage schizophrenia

Criteria

Inclusion Criteria:

  • early stage schizophrenia
  • drug naïve schizophrenia
  • no

Exclusion Criteria:

  • with mental retardation
  • with epilepsy
  • with alcohol or substance abuse
  • with panic or depressive disorder
  • not pregnant
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01075373

Locations
Taiwan
National Taiwan University Hospital
Taipei, Taiwan, 10002
Sponsors and Collaborators
National Taiwan University Hospital
National Science Council, Taiwan
Investigators
Principal Investigator: Hai-Gwo Hwu, Professor National Taiwan University Hopsital
  More Information

No publications provided

Responsible Party: Hai-Gwo Hwu, National Taiwan University Hospital
ClinicalTrials.gov Identifier: NCT01075373     History of Changes
Other Study ID Numbers: 200807021R, NSC 97-2321-B-002-041-, NSC 98-2321-B-002-008-
Study First Received: February 23, 2010
Last Updated: March 4, 2010
Health Authority: Taiwan: Department of Health

Keywords provided by National Taiwan University Hospital:
early stage schizophrenia
drug naïve schizophrenia
treatment response
Aripiprazole
pharmacogenetics
Disrupted-in-Schizophrenia 1 gene (DISC1)
Neuregulin 1 gene (NRG1)
Dopamine receptor type 2 gene (DRD2)
Catechol-O-Methyltransferase gene (COMT)
neurocognitive function
event-related evoked potential (ERP)
Niacin skin test
plasma neurotransmitter level
plasma cytokine level
plasma signaling protein level
AKT1 protein level in the peripheral lymphocytes
16-45 y/o
without mental retardation or epilepsy

Additional relevant MeSH terms:
Schizophrenia
Schizophrenia and Disorders with Psychotic Features
Mental Disorders

ClinicalTrials.gov processed this record on October 01, 2014