Intranasal insulin increases brain glutathione (GSH) and enhances antioxidant capacity in healthy participants, but not in those with early psychotic disorders.

Background: We examined the acute effects of intranasal insulin on cognitive function and brain glutathione, a central factor in resistance to oxidative stress, in both participants with early psychosis and healthy participants.

Methods: Twenty-one patients with early-stage psychotic disorders and 18 healthy controls underwent magnetic resonance spectroscopy (MRS) scans and cognitive assessments pre- and post- administration of intranasal insulin 40 IU. We conducted H-magnetic resonance spectroscopy (MRS) in the prefrontal cortex at 4T to measure glutathione (GSH) and glutamate metabolites. We assessed cognition using the Brief Assessment of Cognition in Schizophrenia (BACS) symbol coding, digit sequencing, and verbal fluency tasks, in addition to Stroop Task.

Results: The mean (SD) age of participants was 25.7(4.6); 51.3% were female. There were no significant group differences at baseline in age, sex, body mass index, homeostatic model assessment of insulin resistance (HOMA-IR), or cognition. Patients had higher baseline GSH (p<0.001) and glutamate (p=0.007). After insulin administration, GSH increased in controls (Mean change 0.15;95%CI 0.03, 0.26; p=0.015), but not in patients. Symbol coding improved in both patients (0.74;95%CI 0.37,1.11;p<0.001) and controls (0.83;95%CI 0.58,1.09;p<0.001) and verbal fluency improved in controls (0.43;95%CI 0.14, 0.72; p=0.006). Lower baseline HOMA-IR was associated with greater change in GSH (Coeff -0.22; 95%CI -0.40, -0.04; p=0.017).

Conclusions: Intranasal insulin increases brain GSH in healthy participants, but not in early psychotic disorders. These novel findings demonstrate that intranasal insulin enhances antioxidant capacity and resilience to oxidative stress in healthy individuals, in contrast to an absent antioxidant response in those with early psychotic disorders.