Prevention and treatment in schizophrenia

Summary

This research program investigates the neuropathology and side-effects of antipsychotic drugs in schizophrenia. Current treatment largely relies on pharmacotherapy, which does not directly address the fundamental neuropathology and can cause severe metabolic side effects (e.g. obesity) and cortical thinning. Metabolic related side-effects are responsible for more than 50% of mortality in schizophrenia patients. My research program aims to identify new therapeutic solutions to address the neuropathology of schizophrenia and reduce treatment side effects.

The first research program aims to prevent and treat neurite and synaptic spine pathology. We have demonstrated that imbalanced D2R and NMDAR regulation contribute to this pathology. By modifying this imbalance, we have demonstrated reduced neurite and synaptic spine deficits, and improved behaviour in rodent models relevant to schizophrenia. We will further validate these targets to develop new treatment strategies through the following objectives:

  1. Decrease neurite lesion caused by D2R hyperactivity
  2. Correct the imbalance of D2R and NMDAR regulation
  3. Reduce NR2B internalisation/endocytosis to correct NMDR hypofunction

The second research program aims to prevent and treat antipsychotic drug-induced obesity and cortical thinning. Using medicinal chemistry, we have reduced H1R binding affinity and maintained therapeutic binding sites of olanzapine (E-Olan and H-Olan). We will:

  1. Further validate these drug leads as potential new therapeutics.

We have demonstrated that propionate and butyrate robustly protect neurite lesions induced by antipsycotic drug treatment. We will:

  1. Reveal the mechanism and proof of concept for clinical translation of the efficacy of the application of propionate and butyrate in a clinical setting for the prevention and treatment of antipsychotic drug-induced cortical thinning.

My overall goal is to improve patient treatment outcomes.

Funding body

National Health and Medical Research Institute

Scheme name

Investigator Grant (Leadership 2)

Years funded

2019 – 2024

Lead institution

University of Wollongong