In our last post, we discussed how precision psychiatry is transforming neuroscience drug development by aligning treatments with the biological mechanisms that drive symptoms. This week, we turn our focus to a key population in that paradigm: people at clinical high risk (CHR) for psychosis.
Understanding CHR: The Window of Opportunity
Psychotic disorders such as schizophrenia typically emerge in late adolescence or early adulthood, but the biological and cognitive changes begin well before the first onset of illness. Individuals at CHR often experience cognitive impairments, attenuated psychotic symptoms, and functional decline, with around 20–30% developing a full psychotic disorder within two to three years.
The CHR phase is a critical window for intervention and for studying early cognitive, clinical, neurophysiological, and molecular disruptions that can mark disease trajectory and reveal potential biological markers that a treatment can target. For example:
- Cognition: Cognitive dysfunction is an independent predictor of conversion to schizophrenia, underscoring the value of tracking cognitive change in CHR cohorts (e.g., Seidman et al., 2016).
- Neurophysiology: EEG abnormalities point to early circuit-level disruption and may serve as sensitive markers of neurobiological change relevant to progression (e.g., Wang et al., 2022).
- Inflammation: Dysregulated immune/inflammatory pathways have been implicated in CHR, with inflammatory markers linked to cognitive dysfunction and risk trajectories (e.g., Kogan et al., 2020).
Understanding how such mechanisms respond to pharmacological intervention – and establishing reliable pharmacodynamic biomarkers – is essential to identify and assess drug mechanisms, inform development of treatments targeting symptoms and impairments in the CHR population, and ultimately optimize early intervention strategies to prevent or delay the onset of psychosis.
Lessons from Cognitive Impairment in Schizophrenia
Efforts to develop treatments for cognitive impairment associated with schizophrenia (CIAS) have faced high failure rates, even when mechanisms are compelling. However, post hoc analyses often uncover positive signals — suggesting that meaningful treatment effects exist within biologically defined or cognitively homogeneous subgroups, underscoring the importance of precision psychiatry. (e.g., Granger et al., 2023).
Looking Ahead: A Big Milestone for the Field
In our upcoming proof-of-principle clinical trial of MT1988, a nicotinic agonist designed to enhance cognitive function, we are integrating a suite of biomarkers — spanning clinical, cognitive (including Monument’s proprietary biomarker), neurophysiological, biofluid, and momentary assessments. This placebo-controlled study will evaluate 150 individuals at CHR for psychosis over an 8-week period to assess the potential of these biomarkers to predict treatment effects and monitor treatment response. This trial marks major step forward in developing meaningful treatment options for people at risk for schizophrenia.
In our next blog, we’ll introduce the team behind this milestone that are driving this effort to change the odds for at risk patients.
Next release date: 3rd November 2025.
#FromSymptomstoSignals #PrecisionPsychiatry #Biomarkers #DrugDevelopment