Multimodality biopsychosocial evaluation and non-pharmacological interventions for cognitive function decline in patients with treatment-resistant schizophrenia-spectrum disorders

Professor Chan, Kit Wa   (Principal Investigator (PI))

Professor Lim Kelvin O   (Collaborator)

Professor Hui Christy Lai Ming   (Collaborator)

Professor Cao Peng   (Co-principal investigator)

Professor Sham Pak Chung   (Co-principal investigator)

Professor So Hon Cheong   (Co-principal investigator)

Professor Chen Yu Hai Eric   (Collaborator)

36

2025-06-26

4024374

Multimodality biopsychosocial evaluation and non-pharmacological interventions for cognitive function decline in patients with treatment-resistant schizophrenia-spectrum disorders

""Treatment resistance"", ""schizophrenia"", ""Longitudinal Cognition"", ""Microbiome"", ""neurostimulation""

Psychosocial and Behavioural ResearchNeuroscience

Biology and Medicine (M)

C7001-24Y

Collaborative Research Fund (CRF) - Group Research Project 2024/2025

2024

On-going

1. To identify the evidence of accelerated deterioration of cognitive functions and brain aging in patients with treatment-resistant schizophrenia (TRS) compared with treatment-responsive (TResp) schizophrenia, as well as cognitive function deficits compared between patients and age/gender matched healthy controls. Patients with TRS have poorer cognitive functions than TResp patients and may represent a severe end of the neurodegenerative processes of schizophrenia. We hypothesize that patients with TRS have accelerated cognitive function decline compared with TResp patients. There has not been any study examining longer-term cognitive function outcomes of patients with TRS. For this objective, we will conduct a 24 year follow up of the clinical outcomes and cognitive function of our first-episode cohort involved in our previous case-control study (TRS vs TResp) who had comprehensive assessment of premorbid, early illness characteristics at first-episode, clinical and cognitive function assessment at 12 years after their first illness.  We further hypothesis that patients with TRS will have a greater deviation from the normal brain aging trajectories than patients with Tresp, and patients with both schizophrenia will have a greater deviation from the normal brain aging trajectories than healthy controls. 2. To study the effect of aerobic exercise and the benefit of adding tDCS to aerobic exercise on the improvement of cognitive function in patients with TRS and explore the role of microbiome and brain function in mediating the potential effect.  Aerobic exercise has been reported to have a medium-to-large effect on cognitive function in patients with schizophrenia. tDCS is a safe noninvasive neurostimulation intervention shown to enhance neuroplasticity and likely to augment the effect of other cognitive enhancement interventions. Therefore, combined intervention has been suggested. We propose to conduct a randomized control trial to examine the effect of aerobic exercise, tDCS and the possible benefit of tDCS+exercise on improvement of cognitive functions in patients with TRS, as well as exploring the role of microbiome and brain function in mediating the potential effect.  3. To examine the role of the microbiota-gut-brain axis in the cognitive function differences between TRS and TResp schizophrenia, possible accelerated cognitive decline in TRS patients, and the effect of exercise and tDCS+exercise intervention on cognition in TRS patients. Multiple biopsychosocial factors may contribute to cognitive function decline in patients with TRS. The neuroactive metabolites synthesized by the gut microbiota regulates the neurotransmitters such as dopamine, glutamate, GABA and 5-HT, and also contribute to neuroinflammation. This may affect the neurodevelopment and neurodegenerative processes of patients with schizophrenia. We hypothesize that a different microbiota composition may be present between patients with TRS and TResp and contribute to the cognitive decline. Differences in distinct brain structures and functional connectivity have been suggested between TRS and TResp. We further hypothesize that such differences, in particular the network connecting dorsal-lateral prefrontal cortex (DLPFC) and hippocampus, may explain the difference in cognitive function decline between TRS and TResp. The relationship between microbiota composition and cognition may be mediated by the differences in brain functional and structural connectivity, and DLPFC glutamate and GABA levels. A reduction of the pro-inflammatory process as well as enhancement of the functional connectivity of DLPFC with temporal and parietal regions have been suggested as possible mechanisms of exercise in improving cognitive functions. The role of the microbiota-gutbrain axis in the effect of exercise and tDCS+exercise on cognitive function improvement in patients with TRS will also be examined.   4. To explore the contribution of genetic vulnerability and longitudinal illness related psychosocial factors to cognitive deficits in patients with schizophrenia and accelerated cognitive decline in patients with TRS specifically. We hypothesize that genetic vulnerability or predisposition to schizophrenia, Alzheimer’s disease and intelligence measured with polygenic risk scores (PRS), and pathway-specific PRS in relationship to neurotransmitter systems (glutamate, GABA, dopamine, muscarinic and serotonin), immune signaling and inflammatory response may contribute to the variation of the cognitions of patients with schizophrenia and the longitudinal changes of cognition in TRS. This may be considered as a static risk. Role of longitudinal illness related psychosocial factors including employment, social functioning and medication will also be examined.