Association of the Amisulpride Treatment Response in Patients With Schizophrenia With the Findings of Brain Structural Magnetic Resonance Imaging

1. Study rationale 1-1.

• Predicting the treatment response of antipsychotic drug in schizophrenia patients has been an issue in psychiatry. However, it is not clear if the findings of structural magnetic resonance imaging (MRI) such as brain gray matter volumes and white matter connectivities, are related to the treatment response of antipsychotic drugs.
• The cognitive and behavioural symptoms of patients with schizophrenia are hypothesized to involve a disruption of neuronal interactions resulting in dysfunctional cognitive integration (Friston et al., 1995, 1996). This hypothesis is supported by reports about a decrease in white matter anatomic connections (Mitelman et al. 2006; Skudlarski et al. 2010; Zalesky et al. 2011) and brain structure alterations, especially decrease in volumes of specific brain regions for patients with schizophrenia. Several studies of brain connectivity have shown that functional connectivity depends strongly on the underlying anatomic structure (Sporns O et al. 2004). At the anatomic level, the pathology of schizophrenia has been related to a wide range of anatomic abnormalities, including ventricular enlargement, associated with anomalous neurodevelopment or neurodegenerative alterations (Shenton ME et al 2001). And schizophrenia is likely to be the result of both general and specific localized changes in both grey and white matter (Knochel C et al. 2012; Konrad A et al. 2008). Savas HA et al. found that responders to risperidone had greater hippocampal volumes than patients who failed to respond to risperidone (Savas HA et al., 2002). Vicente M et al. found an inverse association between striatal size and the degree of clinical improvement, and a direct association between the degree of insular volume deficit and its improvement. The non-responders to risperidone or olanzapine showed a significant decrease in their left rectal gyrus as compared with the responder group. (Vicente M et al., 2010).
• Nielsen et al reported that after 6 weeks of amisulpride treatment, patients with schizophrenia showed an increase in the anticipation-related functional MRI signal (Nielsen et al., 2012). This suggested that amisulpride could affect the brain structures and that responses to amisulpride could be associated by the brain structures as seen previous studies about treatment response to antipsychotics and brain structures. But to date, no study has examined the impact of brain structure alterations on amisulpride treatment for schizophrenia and its potential clinical significance..

2. Study type: Clinical Study Phase IV
3. Number of centers: a single center in Korea
4. Number of subjects: N= 20 patients
5. Study duration and dates (format date : dd/mmm/yyyy) 5-1. Protocol planned date: 01/Apr/2013 5-2. First patient In: 01/Nov/2013 5-3. Last patient In: 01/Oct/2015 5-4. Last patient Out: 01/Dec/2015 5-5. Estimated enrollment duration: 2 years 5-6. Estimated average treatment duration: 8 weeks 5-7. Database lock planned date: 15/Dec/2015 5-8. Estimated Report/Publication date: 31/Dec/2015
6. Indication: Schizophrenia
7. Study Objectives (Primary / Most Important Secondary):

7-1. Primary: To show the differences of the baseline brain structures on the structural MRI between the Solian® treatment responders and the non-responders 7-2. Secondary:

• To show the differences of the baseline polymorphisms of COMT and BDNF with molecular genetic analysis between the Solian® treatment responders and the non-responders; responder defined by PANSS
• To find out the correlates of baseline brain structures with symptom severity of schizophrenia at baseline; symptom severity defined by CGI-S and PANSS
• To assess psychotic symptom improvement after 8th week of Solian® treatment using positive and negative syndrome scale (PANSS), scale for the assessment of negative symptoms (SANS), scale for the assessment of positive symptoms (SAPS) and clinical global impression scale (CGI)
• To assess safety after 8th week of Solian® treatment with Barnes Akathisia Scale, Simpson-Angus scale and vital signs
• To report all serious adverse event (SAE) within 24hrs regardless of relationship to investigational product. SAE or expedited reports are completed including: death, Requiring/prolonging hospitalization, Congenital anomaly/Birth defect, Life-threatening, Persistent/significant disability/incapacity, A procedure result only if symptomatic, considered by the investigator as clinically significant or meaningful or leading to permanent investigational product discontinuation or requiring corrective treatment, A symptomatic overdose, A pregnancy, AESI (adverse event special interest with immediate notification) in AEs( serious or non-serious) that need to be monitored, documented, and managed in a pre-specified manner described in the protocol.

8. Inclusion Criteria:

8-1. between 21 and 60 years of age 8-2. diagnosed with schizophrenia, based on the Structured Clinical Interview for DSM-IV(SCID) 8-3. first or second episode of schizophrenia patient 8-4. the presence of positive or negative symptoms or both, resulting in illness of at least mild severity (≥3 on the Clinical Global Impression (CGI) severity scale 9. Exclusion Criteria:

9-1. evidence of organic mental disorder or mental retardation 9-2. severe drug or alcohol dependence that required inpatient treatment and/or detoxification 9-3. other conditions, such as a serious medical condition, a history of bipolar or schizoaffective disorder, suicidality, possibility of pregnancy, lactation, or inability/unwillingness to use contraception 9-4. contraindicated with Solian® by the product label 10. Study Design: Prospective/ Open label/ Interventional/ Controlled 11. Treatments: