Schizophrenia Clinical Trial
Official title:
A Neurobiological Study on Heterogeneity of Schizophrenia: Genetic Variations and Neurobiological Differentiations
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.
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.
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Observational Model: Case-Only, Time Perspective: Prospective
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