ANXIETY & AGITATION
A Key Challenge: Treating Anxiety and Agitation without Compromising Patients' Awareness
Anxiety disorders affected 301 million people in 2019*, with numbers rising after the Covid-19 crisis. Agitation often associated with mental disorders such as Alzheimer’s disease, also poses significant challenges. Current medications typically induce sedation, reducing patients’ awareness and quality of life. A key challenge is to develop solutions that manage acute anxiety and agitation effectively without compromising cognitive functioning.
In order to test new molecules, drug developers use preclinical animal models replicating acute anxiety and agitation with Yohimbine, an alpha2 adrenergic antagonist, in behavioral tests like the elevated plus maze, with some positive controls showing effects on the induced behaviors. However, behavioral tests alone are insufficient. More objective and accurate biomarkers are needed. This is where EEG biomarkers come into play!
*According to the World Health Organization
Combining the Yohimbine Model with Robust EEG Biomarkers for Objective Results at Preclinical Stage
At SynapCell, we adopted a different approach to identify a robust and objective biomarker as a surrogate for acute anxiety and agitation. Measuring this metric through behavior alone is challenging, as patients are often unable to answer questions or express their feelings, which underscores the need for an objective biomarker.
We chose to focus on EEG biomarker and locomotor activity, as they are directly associated with agitation. Specifically, the EEG biomarker we target is the Epsilon frequency band (90-140 Hz), which is linked to higher processes and locomotion.
A Serendipitous Discovery
Based on its mechanism of action, yohimbine was initially used to treat blood circulation issues in conditions such as hypotension and Raynaud’s disease, aiming to increase blood pressure and enhance its peripheral effects on the nervous system. However, some patients experienced unexpected effects related to its actions on the central nervous system, which provided new insights into its broader physiological impact.
EEG: An Objective Metric in Both Clinical and Preclinical Studies
So far, measuring anxiety has been challenging because it leaves patients unable to express their feelings or clarify their thoughts. This is where EEG can help, providing a new metric that does not require patients to speak or communicate during a panic attack.
At preclinical stage, yohimbine also affects brain activity, which can be measured using preclinical in vivo EEG.
The Epsilon Power EEG Biomarker: An Objective and Translational Preclinical Metric
The robust EEG biomarker (Epsilon Power) derived from this model provides translational endpoints aligned with human studies.
This enables the objective evaluation of compounds targeting anxiety and agitation at the preclinical stage, offering predictive insights into their potential clinical effectiveness.
Key Features of the Yohimbine Model
SynapCell’s yohimbine model includes not only the EEG biomarker but also locomotor activity, which serves as a complementary readout. This can also act as an indirect marker of sedation, providing insight into the animals’ mobility under the influence of the drug.
This scientific design is adaptable to different compound pharmacodynamics, as the protocol can be initiated at various times after the test compound’s injection to target the optimal time window when the asset is most effective.
Additionally, depending on the therapeutic strategy (rescue or prevention), yohimbine administration can be performed concurrently with, before or after the candidate compound.
Drug Discovery Assays with the Yohimbine Model
SynapCell’s yohimbine model is compatible with a crossover (or Latin square) design. This setup provides an efficient method for screening compounds, as it reduces the total number of animals required and enhances statistical power by ensuring that all animals are exposed to all conditions.
If a candidate compound shows promise after an initial crossover study, or if you want to directly fine-tune the dose-range efficacy of a specific compound, you can leverage the crossover design to identify the optimal dose. This approach is further supported by strong and robust statistical analysis.
Powered by Cue®, SynapCell's Predictive In Vivo EEG Platform
SynapCell’s yohimbine model and its associated EEG biomarker (Epsilon Power) 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.
Using Cue®, we transform preclinical data into actionable insights, offering end-to-end support for informed decision-making in CNS drug discovery.
THE SCIENCE CORNER
Epsilon Power (ranging 90 to 140Hz):
SynapCell's EEG Biomarker for the Yohimbine Model
Higher frequency ranges are often related to locomotor activity and higher processes both in human and in rodents. Particularly in rodents, Epsilon is associated with the active state (including locomotor activities). Moreover, pharmacological modulations of the locomotor activity also induces an increase in the high frequency oscillations.
Hansen et al. 2019.
Locomotor Activity
Using a telemetric receiver, animals can be recorded in their home cage, allowing their locomotor activity to be monitored. Since the animals are recorded in a familiar environment, we can assess that any increase in locomotor activity can be attributed directly to the injection of yohimbine rather than environmental exploration. Alternatively, a reduction in locomotor activity caused by a candidate compound may serve as an indirect marker of sedation, which is an undesirable side effect in this assay.
Locomotor activity is recorded alongside the EEG system and aligned with the pharmacodynamic effects of yohimbine observed in the EEG spectrum.
Let's Talk About Your Research Project!
More than a CRO, a team of collaborators – we are your dream neuroscience team specialized in preclinical EEG! We don’t just produce data, we are your partners from conceptualization to conclusion. We translate raw EEG data into meaningful, clinically-relevant endpoints, delivering clear insights to allow data-based decision-making. Choose SynapCell, a leading preclinical CNS-specialized CRO for cutting-edge EEG expertise combined with an irresistible touch of fun.
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