Grant: CIHR Fellowship

Schizophrenia is a chronic, progressive mental illness that affects up to 1% of the population. The current treatment for schizophrenia includes medications named antipsychotics. Unfortunately, antipsychotics do not improve symptoms in 30% of patients; these cases are known as treatment-resistant schizophrenia (TRS). Clozapine (CLZ) is one antipsychotics that is actually effective for TRS; however, its mechanism of action remains unclear. Still, 30% of patients with TRS do not respond even to CLZ. Thus, it is important to elucidate the differences in underlying pathophysiology between CLZ responders and non-responders. Recent studies have reported that patients with TRS have elevated glutamate (Glu) levels in the brain. Notably, animal studies have suggested that CLZ has modulatory effects on glutamatergic system. Taken together, the beneficial effects of CLZ may be associated with the glutamatergic system. To date, no study has examined the relationship between Glu levels and CLZ response in patients with TRS using a longitudinal study design. Thus, the aim of this study is to examine Glu levels in patients with TRS before and after CLZ treatment. This study will measure Glu levels in two brain regions called the anterior cingulate cortex and caudate, in which have disruptions of Glu have been previously shown in patients with schizophrenia. Glu will be measured using a non-invasive MRI method called proton magnetic resonance spectroscopy (1H-MRS). Patients will undergo two 1H-MRS scans before and after 12 weeks of CLZ treatment. We will include 83 patients with TRS who initialize CLZ treatment (25 responder and 58 non-responder [Response ratio to CLZ is 70% in our institution]). We hypothesize that non-responders will show lower Glu levels and responders will show higher Glu levels than HCs prior to starting CLZ. The results will provide insight towards the biological predictors of CLZ response and direct new strategies for the treatment of patients with TRS.