Symposium
Session Room: Alsh
Session Room: Alsh
Monday, June 29, 10:50 AM – 12:05 PM
SCNP-Selected Symposium 22:
Neurobiological signatures of antipsychotic response and resistance in schizophrenia: from multimodal neuroimaging to transcranial magnetic stimulation as a dynamic probe
Neurobiological signatures of antipsychotic response and resistance in schizophrenia: from multimodal neuroimaging to transcranial magnetic stimulation as a dynamic probe
Treatment resistance schizophrenia is a severe condition affecting approximately one-third of patients and significantly impairing social and occupational functioning1. Clozapine is the only approved and effective drug for treatment-resistant schizophrenia (TRS), its prescription is often delayed due to the lack of early predictors of treatment response/resistance2,3. Importantly, treatment resistance may already be present from the first episode of schizophrenia4.
The first talk (Dr. Kirsten Borup Bojesen, Denmark) will present findings on cerebral glutamate, GABA, and dopamine levels in antipsychotic-naïve patients with first-episode psychosis (FEP), and their relationships with short- and long-term clinical outcomes. Using a multimodal approach, magnetic resonance spectroscopy (1H-MRS) was combined with 18F-DOPA-PET imaging in patients followed up at 6 weeks, 6 months, and 2 years. FEP patients showed increased glutamate levels in the thalamus and reduced GABA and glutamate levels in the anterior cingulate cortex (ACC)5,6, whereas striatal dopamine synthesis did not differ from controls7. A favorable short-term response to antipsychotics was observed in FEP patients with higher striatal dopaminergic activity7. Conversely, higher glutamate levels in the thalamus and lower GABA levels in the ACC were associated with poor clinical outcomes6,8,9. In addition, the prefrontal GABAergic regulation of striatal dopaminergic activity was abnormal in the antipsychotic-naïve state and the degree of abnormality was related to poor short-term outcomes10. These results suggest non-dopaminergic and combined neurotransmitter disturbances as novel treatment targets in FEP with poor treatment response to dopamine-blocking antipsychotics.
The second talk (Dr. Giuseppe De Simone,Spain), will present recent findings from neuroimaging studies, including 18F-FDG PET, which allows the detection of brain glucose uptake. Glucose signal revealed regional metabolic abnormalities in schizophrenia and TRS patients compared to controls, especially in frontal areas11. Further, metabolic connectivity studies, supported by machine-learning applications, showed different network-level configurations that stratified patients according to their clinical outcomes and treatment response, with ACC, frontal and temporal areas, and hippocampus as key nodes involved12. These neuroimaging findings will be integrated with preclinical and clinical evidence indicating that metabolic disturbances represent a core feature and a potential neurobiological substrate of treatment resistance in schizophrenia13. Lastly, novel applications of whole-brain modeling have translated the chemical information provided by FDG-PET in physical terms, allowing the quantification of the energetic cost of cognition exerted by each brain region14. We will present results from the application of this novel framework in schizophrenia patients.
The final presentation (Dr. Annarita Barone, Italy) will explore how alterations in cortical excitability and plasticity may represent a neurophysiological fingerprint of TRS. Using transcranial magnetic stimulation (TMS), cortical inhibition and facilitation were assessed in patients with TRS, non-TRS schizophrenia, and healthy controls. TRS patients exhibited significantly higher motor thresholds, impaired short-interval intracortical inhibition (SICI), and an elevated excitation index (EI) in the motor cortex, suggesting pronounced GABAergic dysfunction and cortical hyperexcitability15. Moreover, both TRS and non-TRS groups showed impaired neuronal plasticity following intermittent theta burst stimulation (iTBS), consistent with glutamatergic dysregulation15. These neurophysiological markers, especially SICI, correlated with negative and autistic symptom dimensions, supporting a continuum model of cortical dysfunction in schizophrenia15.
The first talk (Dr. Kirsten Borup Bojesen, Denmark) will present findings on cerebral glutamate, GABA, and dopamine levels in antipsychotic-naïve patients with first-episode psychosis (FEP), and their relationships with short- and long-term clinical outcomes. Using a multimodal approach, magnetic resonance spectroscopy (1H-MRS) was combined with 18F-DOPA-PET imaging in patients followed up at 6 weeks, 6 months, and 2 years. FEP patients showed increased glutamate levels in the thalamus and reduced GABA and glutamate levels in the anterior cingulate cortex (ACC)5,6, whereas striatal dopamine synthesis did not differ from controls7. A favorable short-term response to antipsychotics was observed in FEP patients with higher striatal dopaminergic activity7. Conversely, higher glutamate levels in the thalamus and lower GABA levels in the ACC were associated with poor clinical outcomes6,8,9. In addition, the prefrontal GABAergic regulation of striatal dopaminergic activity was abnormal in the antipsychotic-naïve state and the degree of abnormality was related to poor short-term outcomes10. These results suggest non-dopaminergic and combined neurotransmitter disturbances as novel treatment targets in FEP with poor treatment response to dopamine-blocking antipsychotics.
The second talk (Dr. Giuseppe De Simone,Spain), will present recent findings from neuroimaging studies, including 18F-FDG PET, which allows the detection of brain glucose uptake. Glucose signal revealed regional metabolic abnormalities in schizophrenia and TRS patients compared to controls, especially in frontal areas11. Further, metabolic connectivity studies, supported by machine-learning applications, showed different network-level configurations that stratified patients according to their clinical outcomes and treatment response, with ACC, frontal and temporal areas, and hippocampus as key nodes involved12. These neuroimaging findings will be integrated with preclinical and clinical evidence indicating that metabolic disturbances represent a core feature and a potential neurobiological substrate of treatment resistance in schizophrenia13. Lastly, novel applications of whole-brain modeling have translated the chemical information provided by FDG-PET in physical terms, allowing the quantification of the energetic cost of cognition exerted by each brain region14. We will present results from the application of this novel framework in schizophrenia patients.
The final presentation (Dr. Annarita Barone, Italy) will explore how alterations in cortical excitability and plasticity may represent a neurophysiological fingerprint of TRS. Using transcranial magnetic stimulation (TMS), cortical inhibition and facilitation were assessed in patients with TRS, non-TRS schizophrenia, and healthy controls. TRS patients exhibited significantly higher motor thresholds, impaired short-interval intracortical inhibition (SICI), and an elevated excitation index (EI) in the motor cortex, suggesting pronounced GABAergic dysfunction and cortical hyperexcitability15. Moreover, both TRS and non-TRS groups showed impaired neuronal plasticity following intermittent theta burst stimulation (iTBS), consistent with glutamatergic dysregulation15. These neurophysiological markers, especially SICI, correlated with negative and autistic symptom dimensions, supporting a continuum model of cortical dysfunction in schizophrenia15.