Schizophrenia
Schizophrenia & Cognitive Impairment:
High Unmet Treatment Needs
Schizophrenia is a complex neuropsychiatric disorders affecting around 24 million people worldwide*. This condition displays two main symptoms, which constitute the two main axes of Schizophrenia treatment:
- Positive symptoms – translating behaviors absent from healthy humans – such as hallucinations and delusions,
- Negative symptoms – that translate a lessening, absence of normal behavior – such as cognitive impairment and anhedonia.
Although quite a lot of compounds have already reached the clinic, amongst which the typical (e.g. haloperidol, olanzapine) and atypical antipsychotics (e.g. clozapine, aripiprazole), they are only mildly effective on negative symptoms and some of them may even worsen them. This lack of effective treatments for the negative symptoms is also due to the scarcity of robust and translational preclinical tests for cognitive deficits. Treating the negative symptoms of Schizophrenia is critical as it would allow an undeniable improvement in patient quality of life.
*According to the World Health Organization
MK-801 Model & 40HzASSR EEG Biomarker:
A Translational Model Coupled with a Clinical Readout
In order to support preclinical research in that particular area, SynapCell developed a chemically-induced model of Schizophrenia. It has been showed that injection of NMDA antagonists in rats or mice induce Cognitive Impairment Associated with Schizophrenia (CIAS) and deficits in information processing. In our hands, MK-801 induces robust and translational modifications in rodents in the 40Hz ASSR paradigm. As a matter of fact, the model reproduces the clinical features of patients suffering from Schizophrenia: reduced ASSR response and a difficulty to process auditory stimulus.
An Objective EEG Biomarker
In the field of psychiatric disorders, it is often challenging to identify objective biomarkers since the symptoms may be subjective. However, with the 40Hz ASSR assay, since it does not rely on the rodent’s attention, nor does it rely on complex behavioral measurements, we believe this is comes as close as possible to an objective EEG biomarker for this indication.
A Relevant Animal Model
PCP intoxication, which was shown to mimic both positive and negative schizophrenic symptoms in humans, helped uncover a relevant mechanism of action underlying schizophrenic symptoms. Indeed, PCP inhibits NMDA receptors, causing their hypofunction and therefore impairing transmission, plasticity and neuromodulation. Thus, modelling the disease using NMDA antagonists induces a phenotype close to what is happening in the clinic.
Beyond Schizophrenia
Although the deficit in the 40 Hz ASSR is often associated with Schizophrenia, it has been shown that it is more broadly related to a deficit in information processing and can be applied to other types of diseases and disorders. Based on recent studies, this paradigm was shown to translate not only schizophrenic symptoms but more generally a dysfunction in the cortical NMDA pathway (e.g. in Fragile X syndrome).
Key Features
of the MK-801 Model
The model is well accepted within the scientific community and well-known for its translational aspect.
Similarly to the clinic, there are still some progresses to be made in finding a relevant positive control as current standards of care fail to normalize the responses even in the clinic. This is not a biomarker sensitive to every compound and represents a real selection step for candidates.
This scientific design can be adapted to different compounds’ pharmacodynamic profile. Indeed, the protocol can be fine-tuned in order to hit the most effective time-window post-administration.
Drug Discovery Assays
with the MK-801 Model
This model is adapted to crossover (or latin square) designs. It allows for an efficacious way of screening compounds as it limits the total number of animals used as well as increases the statistical power of analysis, since all animals receive all conditions.
If a compound candidate stands out after a first crossover, or should you want to fine-tune directly the dose-range efficacy of one specific compound, you can also use the advantage of the crossover to find the right dose, powered here again by a strong and robust statistical analysis.
Finally, to make the most out of one study, we can tailor the experimental protocol to include baseline recording periods to perform quantitative EEG or to separate the different trains of stimulations to incorporate a different protocol of auditory stimulations and generate additional data.
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SynapCell’s MK-801 model and its associated EEG biomarker are processed on Cue®, our innovative translational in vivo EEG platform, which is designed to predict the in-human efficacy of your drug candidates during the preclinical step. Cue® is the result of decades of R&D, combining SynapCell’s know-how, expertise and scientific excellence in the fields of brain surgery and EEG signal recording, processing, and analysis.
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Auditory Steady-State Response (ASSR)
ASSR is widely used in the clinic and well-known in the field of psychiatric disorders as it is a relevant biomarker for the ability of the brain to coordinate a cortical response to an auditory stimulus. The paradigm consists in producing auditory stimulations over a specific time frame. In this case, the auditory stimulus is a 5 ms white noise click, repeated 80 times over 2 seconds at 40Hz. These 2 second trains are then repeated 360 times to generate enough data for robust statistical analysis and reproducibility. Responses will then be averaged to calculate different signal parameters and isolate the corresponding biomarkers.
EEG Response Overview
Here is an example of a typical 40Hz ASSR response. The first wave is called the evoked response while the rest of the oscillations are called entrainment responses. The second part, the entrainment responses, will eventually be used to quantify the different parameters, including the Inter-Trial Coherence (ITC).
Inter-Trial Coherence (ITC)
The ITC is one of the most used read-outs when it comes to the ASSR paradigm. It is a surrogate for the ability of the system to process the auditory signal in a relevant and consistent manner each time the animal hears a stimulus. The higher the ITC, the more consistent the brain responses to the auditory cues, translating a normal information processing process.
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