Translational Investigation of the Glutamatergic and GABAergic System in Schizophrenia

Study Overview
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Brief Summary
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In the last years, the imbalance between excitatory and inhibitory neuronal activity has come to the fore as a possible molecular disease mechanism of schizophrenia . Pharmacological studies have suggested different fMRI and EEG markers of that molecular dysfunction (resting state connectivity changes, auditory mismatch and steady state deficits). However, previous research is inconclusive regarding their genetic basis, their reliability, inter-individual relationship as well as disease specificity. Therefore, in this study we aim at estimating the effect sizes, test-retest-reliability and clinical correlates of the respective markers in a comparative fashion in patients with schizophrenia, their relatives and healthy control subject. To assess their molecular validity, we will assess their relationship with glutamatergic and GABAergic genotypes and cellular disease models. The proof of such a relation would give the opportunity of detecting a glutamatergic and GABAergic imbalance throughout non-invasive imaging. Furthermore, it would help deepening our understanding of the molecular pathophysiology of mental disorders which will be essential for the development of more effective drugs.

Detailed Description
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The participant collective will include 3 groups of 200 persons, consisting of patients with schizophrenia, their healthy relatives and healthy controls that are not related to the patients. The patients must be diagnosed of schizophrenia according to DSM-5 to be included in the study and will be excluded when there is a further psychiatric comorbidity that dominates in the clinical appearance. All participants have to be aged from 18 to 80 years, be mentally and contractually capable to give their consent to study participation and may not be pregnant or have a structural neurological disease. The healthy participants must not suffer from a psychiatric disorder themselves and, additionally, the control subjects must not have psychiatric disorders in the family history of their first-degree relatives. Every participant will undergo the same examinations, tests and measurements. All subjects will be taken a blood sample of 30 milliliters of blood that will be tested for antibodies against the NMDA receptor, neuronal growth factors, components of the glutamatergic and GABAergic metabolism and markers for the integrity of the blood brain barrier. In addition to that, a genetic analysis to identify risk alleles for schizophrenia and important glutamatergic and GABAergic genes will be performed. A medical history of every subject will be taken, including medication, somatic and psychiatric disorders. Furthermore, a row of psychiatric ratings scales as well as neuropsychological and neurological tests will be performed. These will include Structured Clinical Interview for DSM Disorders (SCID) Mini-RDoC Short Form Health 36 (SF-36) Personal and Social Performance Scale (PSP) Positive and Negative Syndrome Scale Berner Psychopathologie-Skala Calgary Depression Rating Scale for Schizophrenia Conners' Adult ADHD Rating Scales (CAARS) Wender Utah Rating Scale (WURS-k) Clinical Global Impression (CGI) Global Assessment of Functioning (GAF) Extrapyramidal Symptom Rating Scale (EPS) Heidelberg Neurological Soft Signs Scale Brief Assessment of Cognition in Schizophrenia d2 test Every study participant must undergo an EEG measurement while different, neutral visual (fixation cross or movies without sound) and auditive stimuli (tones or clic trains) will be presented to them. They will be instructed to ignore the auditive stimuli. Resting state, auditory steady state response (ASSR) and two different auditory mismatch paradigms will be used. Without contradiction for the conduction of an MRI measurement, a combined EEG/ MRI measurement and a pure MRI measurement (without EEG) using the same paradigms are intended. It will also include structural (T1, T2 and diffusion tensor imaging) MRI and MR spectroscopy of glutamate and GABA. All the previously mentioned examinations are planned to take place on the same day with an approximate expenditure of time of five hours. If necessary, the examinations may also take place on different days, providing that there will be a maximum of three weeks between the first and the last measurement. Except from the blood withdrawal, we intend repeating all the measurements for a second time. This repetition must take place at least one day and not later than three years after the first measurement. It will not be necessary to repeat the clinical and neuropsychological tests if the first testing does not date back more than 6 weeks. In a second part of the study, we want to generate induced pluripotent stem cells (iPS cells) from 15 participants of every study group. For this purpose, a further blood sample of 20 milliliters of blood must be taken. The participants of the second part of the study will be selected based on special genetic, EEG or fMRI characteristics revealed in the first part of the study if they agree to be contacted again.

Official Title
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Translational Investigation of the Glutamatergic and GABAergic System in Schizophrenia - a Combined EEG-, fMRI-, Genetic, Serological and Cell Biological Study

Conditions
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Schizophrenia

Intervention / Treatment
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* Genetic: Genotyping


Participation Criteria
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Eligibility Criteria
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PATIENTS Inclusion Criteria: diagnosis of schizophrenia according to DSM-5 aged 18 to 80 being mentally and contractually capable to give their consent to study participation Exclusion Criteria: pregnancy structural neurological disease a further psychiatric comorbidity that dominates in the clinical appearance HEALTHY PARTICIPANTS Inclusion Criteria: aged 18 to 80 being mentally and contractually capable to give their consent to study participation Exclusion Criteria: pregnancy structural neurological disease psychiatric disorder for healthy controls: psychiatric disorders in the family history of first-degree relatives

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| patients with schizophrenia<br>200 patients with a DSM 5- diagnosis of schizophrenia | Genetic: Genotyping<br>* Genotyping of glutamatergic, GABAergic, dopaminergic and other CNS-related genes<br>|
| healthy relatives of patients with schizophrenia<br>200 healthy relatives of the patients with schizophrenia | Genetic: Genotyping<br>* Genotyping of glutamatergic, GABAergic, dopaminergic and other CNS-related genes<br>|
| healthy control subjects<br>healthy control subjects without relatives with mental disorders | Genetic: Genotyping<br>* Genotyping of glutamatergic, GABAergic, dopaminergic and other CNS-related genes<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MMN | Mismatch negativity amplitude | 1 day to maximum 3 years | 
| ASSR Power | 40-Hz auditory steady state response spectral power | 1 day to maximum 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ASSR Phase Locking | 40-Hz auditory steady state response phase locking | 1 day to maximum 3 years | 
| Functional connectivity | Whole brain resting state functional connectivity matrix | 1 day to maximum 3 years | 
| Psychopathology as assessed with the PANSS | Positive and negative syndrome scale (Minimum: 30, Maximum: 210, higher scores mean worse outcome) | 1 day to maximum 3 years | 
| Psychopathology as assessed with the BPP | Berner Psychopathologie-Skala (Minimum: -3, Maximum: +3, higher positive scores mean excessive speech, movements or higher positive affect, higher negative scores mean a lack of speech, movements or higher negative affect, | 1 day to maximum 3 years | 
| Psychopathology as assessed with the CGI | Clinical Global Impression (CGI) (Minimum: 1, Maximum: 7, higher scores mean worse outcome) | 1 day to maximum 3 years | 
| Electrophysiology | Electrophysiology assessed in iPSC derived neurons obtained from subsamples using patch clamp and microelectrode array recordings | one appointment of additional blood sampling to isolate cells for iPSC reprogramming | 
| Expression of neural markers in iPSC derived neurons | quantitative polymerase chain reaction (qPCR), immunofluorescence, western blot | one appointment of additional blood sampling to isolate cells for iPSC reprogramming | 
| Neurological status as assessed with the EPS | Extrapyramidal Symptom Rating Scale (Minimum: 0, Maximum: 4, higher scores mean worse outcome) | 1 day to maximum 3 years | 
| Neurological soft signs assessed with the Heidelberg Scale | Heidelberg Neurological Soft Signs Scale (Minimum: 0, Maximum: 75, higher scores mean worse outcome) | 1 day to maximum 3 years | 
| Psychopathology as assessed with the SCID | Structured Clinical Interview for DSM Disorders (SCID) | 1 day to maximum 3 years | 
| Psychopathology as assessed with the Mini-RDoC | Minimum data set Research Domain Criteria | 1 day to maximum 3 years | 
| Psychopathology as assessed with the SF-36 | Short Form Health (Minimum: 0, Maximum: 100, higher scores mean better outcome) | 1 day to maximum 3 years | 
| Psychopathology as assessed with the PSP | Personal and Social Performance Scale (Minimum: 1, Maximum: 100, higher scores mean better outcome) | 1 day to maximum 3 years | 
| Psychopathology as assessed with the CDSS | Calgary Depression Rating Scale for Schizophrenia (Minimum: 0, Maximum: 27, higher scores mean worse outcome) | 1 day to maximum 3 years | 
| Psychopathology as assessed with the CAARS (Minimum: 0, Maximum: 198, higher scores mean worse outcome) | Conners' Adult ADHD Rating Scales | 1 day to maximum 3 years | 
| Psychopathology as assessed with the WURS-k (Minimum: 0, Maximum: 84, higher scores mean worse outcome) | Wender Utah Rating Scale | 1 day to maximum 3 years | 
| Psychopathology as assessed with the GAF | Global Assessment of Functioning | 1 day to maximum 3 years | 
| Neuropsychology assessed with BACS | Brief Assessment of Cognition in Schizophrenia | 1 day to maximum 3 years | 
| Neuropsychology assessed with d2 test | d2 test | 1 day to maximum 3 years |