ANXIETY & AGITATION
A Key Challenge: Treating Anxiety and Agitation without Compromising Patients' Alertness
Anxiety disorders affected 301 million people worldwide in 2019*, with numbers rising after the Covid-19 epidemic. Agitation is frequently associated with mental disorders such as Alzheimer’s disease, and also poses significant challenges. Current medications to treat these two disorders typically induce sedation, reducing patients’ alertness and quality of life. A key challenge is to develop solutions that manage acute anxiety and agitation effectively without compromising cognitive function.
To test new molecules, drug developers use preclinical animal models replicating acute anxiety and agitation by treatment with Yohimbine, an alpha2 adrenergic antagonist. Animals then perform behavioral tests, like the elevated plus maze. Positive controls treatments show effects on the induced behaviors. However, behavioral tests alone are insufficient. More accurate objective 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 Preclinical Results
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 based on behavior alone is challenging, as patients are often unable to answer questions or express their feelings, which further 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, we target the Epsilon frequency band (90-140 Hz) EEG biomarker. This biomarker 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, with the aim of increasing blood pressure and inducing peripheral effects on the nervous system.
However, some patients experienced unexpected effects related to its effects on the central nervous system, which provided new insights into its broader physiological impact.
The Epsilon Power EEG Biomarker: An Objective Translational Preclinical Metric
The robust EEG biomarker (Epsilon Power) derived from this model provides translational endpoints aligned with human studies.
By monitoring the Epsilon frequency band, compounds targeting anxiety and agitation can be objectively evaluated at the preclinical stage, offering predictive insights into their potential clinical effectiveness.
EEG: An Objective Metric in Both Clinical and Preclinical Studies
So far, anxiety has been challenging to measure because it often leaves patients unable to express their feelings or clarify their thoughts. EEG, by providing a new metric that does not require patients to speak or communicate during a panic attack, can be of significant help.
At the preclinical stage, our approach involves inducing a panic state using yohimbine and testing pharmacological references, such as diazepam, which reduces the alterations induced on the Epsilon frequency band.
Key Features of the Yohimbine Model
SynapCell’s yohimbine model includes assessment not only of the EEG biomarker but also of locomotor activity, which serves as a complementary readout. Locomotor activity can also act as an indirect marker of sedation, providing insight into the animals’ mobility under the influence of the drug.
The scientific design can be adapted to make it compatible with distinct compound pharmacodynamics, for example initiating the protocol at various times after the test compound’s injection to target the optimal time window when the candidate compound is most effective.
Additionally, depending on the therapeutic strategy (rescue or prevention), yohimbine can be administrated concurrently with, before or after the candidate compound.
Drug Discovery Assays with the Yohimbine Model
SynapCell’s yohimbine model is compatible with crossover (or Latin square) study designs. This setup provides an efficient method to screen 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 during 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 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 (90 to 140Hz):
SynapCell's EEG Biomarker for the Yohimbine Model
Higher frequency ranges are often related to locomotor activity and higher-level processes in both humans and rodents. Particularly in rodents, the Epsilon frequency band is associated with an active state (including locomotor activities). Moreover, pharmacological modulations of locomotor activity also increase high-frequency oscillations.
Hansen et al. 2019.
Locomotor Activity
Using a telemetric receiver, animals can be recorded in their home cage, to monitor their locomotor activity without additional stress. Since the animals are recorded in a familiar environment, any increase in locomotor activity can be attributed directly to the injection of yohimbine rather than to environmental exploration. Similarly, reduced locomotor activity following treatment with a candidate compound may serve as an indirect marker of sedation. In this assay, sedation is an undesirable effect.
Locomotor activity and EEG are recorded in parallel 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.
News & Events