For Doctors in a Hurry
- Clinicians lack clarity on whether synaptic excitation or inhibition deficits drive psychosis risk in high-risk individuals.
- The study analyzed auditory brain wave data from 583 individuals at clinical high risk for developing psychosis.
- Reduced pyramidal cell excitability best explained amplitude deficits in converters, with a posterior probability exceeding 0.95.
- The researchers concluded that reduced pyramidal cell function is a primary pathology rather than a chronic illness effect.
- These findings suggest that targeting excitatory synaptic pathways may offer a potential therapeutic strategy for early intervention.
Predicting the Transition to Psychosis in High Risk Populations
The clinical high risk syndrome represents a critical developmental window where early intervention may fundamentally alter the trajectory of schizophrenia spectrum disorders [1, 2]. While approximately 20 percent to 30 percent of these individuals transition to full psychosis within two years, current clinical assessments often struggle to provide precise individual prognoses [3]. Electrophysiological markers, specifically those measuring how the brain processes unexpected auditory stimuli, have emerged as low cost tools with significant potential for risk stratification [4]. However, the utility of these biomarkers in routine practice remains limited because their underlying cellular mechanisms have long been unclear [3, 5]. A new study now utilizes biophysical modeling (a computational method that uses mathematical equations to simulate the electrical activity of specific neuron types) to clarify the specific synaptic failures that precede the first psychotic episode.
Mapping Synaptic Function Through Auditory Biomarkers
The researchers focused on two well established electrophysiological markers: mismatch negativity (MMN), which is an automatic brain response to a change in a repetitive sequence of sounds, and the P300 event-related potential (ERP), a wave associated with the cognitive processing of infrequent or target stimuli. Reductions in the amplitudes of both MMN and P300 are widely replicated in patients with schizophrenia and are also observed in individuals at clinical high risk for psychosis (CHR-P) who eventually convert to the full disorder. While these excitatory and inhibitory synaptic functions are both implicated in the pathophysiology of schizophrenia and are considered potential drug targets, it has remained unknown whether the observed signal reductions reflect failures in excitation, inhibition, or a combination of both. To resolve this mechanistic uncertainty, the study analyzed baseline MMN and P300 ERPs from the North American Prodrome Longitudinal Study 2 (NAPLS2), investigating a large cohort of 583 individuals at clinical high risk for psychosis. The researchers utilized specific auditory paradigms to elicit these signals, including pitch plus duration double-deviant tones to evoke MMN and target tones from both passive and active auditory oddball paradigms to elicit the P300. By applying biophysical modeling, the team sought to determine if altered synaptic excitation or inhibition could explain the specific amplitude reductions seen in the 77 participants who converted to psychosis compared to the 94 participants who remitted by the 24 month follow up.
Pyramidal Cell Excitability as a Primary Driver of Conversion
To pinpoint the cellular mechanisms underlying the observed signal loss, the researchers employed biophysical modeling, which is a computational method used to infer cellular-level synaptic activity from macro-scale brain signals like those captured on an electroencephalogram. This approach allowed the team to distinguish between the activity of (excitatory) pyramidal cells, which are the primary output neurons of the cortex, and (inhibitory) interneuron function, which regulates the firing of those pyramidal cells. The analysis specifically compared the baseline electrophysiological data of 77 individuals at clinical high risk who converted to psychosis (CHR-Converters) against 94 individuals who remitted (CHR-Remitters) by the 24 month follow up. The results indicated that the characteristic reductions in mismatch negativity and P300 amplitudes observed in the converter group were not driven by inhibitory deficits. Instead, the MMN and P300 amplitude reductions in future CHR-Converters relative to CHR-Remitters were best explained by reduced pyramidal cell excitability. This finding was supported by a high statistical threshold, with a posterior probability of a group-by-condition interaction effect for reduced pyramidal cell excitability of P > .95. This suggests that the primary physiological driver of the transition to psychosis is a failure in the intrinsic excitability of excitatory neurons rather than a breakdown in the inhibitory interneuron system. To validate these findings, the researchers conducted computer simulations to observe how specific cellular changes affected the resulting brain waves. These simulations demonstrated that reduced pyramidal cell excitability suppressed deviant and target event-related potentials, mirroring the exact signal patterns seen in the clinical data from the converter group. For the practicing clinician, these findings suggest that the neurobiological foundation of psychosis transition may be rooted in excitatory hypofunction, providing a specific cellular target for future pharmacological interventions aimed at stabilizing cortical excitability before the onset of full-scale symptoms.
Clinical Implications for Symptom Severity and Early Pathology
The identification of excitatory deficits in the clinical high risk phase provides a critical link to the established neurobiology of chronic schizophrenia. These results mirror previous findings in schizophrenia, suggesting that the physiological signatures of the disorder are present long before the first psychotic break. Specifically, the data indicate that reduced pyramidal cell excitability is present at baseline in future converters, which supports the hypothesis that hypofunction of pyramidal cells is a primary pathology in schizophrenia, rather than a consequence of chronic illness or the secondary effects of long term antipsychotic medication. For the clinician, this shifts the understanding of the prodromal phase from a period of vague risk to one characterized by specific, measurable cellular dysfunction. The study also clarifies the relationship between these cellular deficits and the clinical presentation of the disorder. Among the 77 individuals at clinical high risk who converted to psychosis, more severe positive symptoms were associated with disinhibition of pyramidal cells (P > .99). This statistical relationship suggests that while the underlying disease process is driven by a loss of excitatory function, the overt symptoms of psychosis, such as hallucinations or delusions, may emerge from the brain's attempt to compensate. The researchers propose that positive symptoms among converters may reflect compensatory downregulation of inhibition, where the brain reduces inhibitory signaling to counteract the primary loss of pyramidal cell excitability. This finding provides a nuanced view of symptom progression, suggesting that the clinical manifestations of psychosis are the result of a complex interplay between primary excitatory deficits and secondary inhibitory adjustments, raising the prospect that future diagnostic tools could match patients to targeted interventions based on their neurobiological profile.
References
1. Solmi M, Raduà J, Olivola M, et al. Age at onset of mental disorders worldwide: large-scale meta-analysis of 192 epidemiological studies. Molecular Psychiatry. 2021. doi:10.1038/s41380-021-01161-7
2. Pedruzo B, Aymerich C, Pacho M, et al. Longitudinal change in neurocognitive functioning in children and adolescents at clinical high risk for psychosis: a systematic review.. European child & adolescent psychiatry. 2024. doi:10.1007/s00787-023-02221-9
3. Ricci V, Martinotti G, Mosca A, Maina G. Biomarkers for predicting transition from at-risk mental state to psychosis: A systematic review.. Neuroscience and biobehavioral reviews. 2026. doi:10.1016/j.neubiorev.2026.106612
4. Wei A, Gao R, Fan M, Luan P, Kong L, He X. Investigating event-related potential (ERP) deviations in clinical high-risk populations for psychosis: a systematic review and meta-analysis.. BMC psychiatry. 2026. doi:10.1186/s12888-026-07786-8
5. Tiffin PA, Kelleher I. Commentary: Time to abandon the 'clinical high risk state for psychosis' (CHR-P) concept in adolescence? Commentary on Frearson et al. 'Efficacy of preventative interventions for children and adolescents at clinical high risk of psychosis: A systematic review and meta-analysis of intervention studies'.. Child and adolescent mental health. 2025. doi:10.1111/camh.12776
