Effects of antipsychotics on brain insulin action in females: Study protocol for a placebo-controlled, crossover neuroimaging study

Antipsychotic medications can cause serious metabolic adverse effects, including type 2 diabetes, with females disproportionally more affected than males. Recently, brain insulin resistance (IR) has been posited as a potential determinant of these effects. Currently there are no direct methods to investigate brain IR, but physiological response to intranasal insulin (INI) can be used as a surrogate marker. INI reliably suppresses endogenous glucose production and modulates resting-state brain activity in humans; however, the current literature has been heavily focused on males. Recently, it has been reported that hormonal fluctuations throughout the menstrual cycle may influence brain insulin sensitivity. Brain insulin sensitivity is greatest in lean females during the follicular phase, matching that of lean males, but decreases during the luteal phase. This study aims to investigate brain insulin action in females across different phases of the menstrual cycle, and to determine how a metabolically high-risk antipsychotic medication, olanzapine, may disrupt these effects. In a single-blind, crossover design, fifteen female participants aged 18-35 years will undergo a neuroimaging-based assay of brain insulin action with oral olanzapine (or placebo) and intranasal insulin (or placebo) as pharmacological challenges. All treatment conditions will be administered once in each menstrual phase, meaning that each participant receives every condition twice over the course of the study. Two visits will take place during the follicular phase of the menstrual cycle (i.e., cycle days 3-11), and another two visits during the luteal phase (i.e., cycle days 18-25). During each study period, participants will receive either oral olanzapine (OLA) or oral placebo (PL) at doses of 5 mg on Day 0 and 10 mg on Day 1. On Day 2, participants will undergo two MRI scans, the first following intranasal placebo (INP) administration and the second following intranasal insulin (INI). It is hypothesized that INI, but not INP, will modulate resting state brain activity during the follicular menstrual cycle phase but not luteal phase. Oral OLA will subsequently inhibit all INI-induced effects, relative to oral PL, during the follicular phase; OLA will have no apparent effect in the luteal phase given pre-existing brain IR. This is the first study to explore the effect of menstrual cycle phases on the anti-insulin action of antipsychotics. This investigation is necessary for the development of suitable treatment options to minimize the metabolic impact of antipsychotics in females. TRIAL REGISTRATION: ClinicalTrials.gov Registration: NCT06251635.