Effects of sex, treatment resistance, and antidepressant treatment on monoamine oxidase B total distribution volume

Monoamine oxidase B (MAO-B) is a high-density protein located mainly in astrocytes that influences mitochondrial function and transition to astrogliosis. MAO-B produces hydrogen peroxide while metabolizing non-serotonergic monoamines. Elevated MAO-B level is implicated in the pathophysiology of several common neuropsychiatric diseases. The aims are to examine the effect of treatment resistant major depressive episodes, sex, and antidepressant treatment on MAO-B total distribution volume ([11C]SL25.1188 VT), index of MAO-B level. [11C]SL25.1188 PET was applied in 95 adults (29 with MDE and no history of treatment-resistance (NTR-MDE), 26 with MDE and history of treatment-resistance (TRD), and 40 healthy control (HC)). A subset of NTR-MDE and TRD (n=13) were scanned before and after treatment with phenelzine, rasagiline, or duloxetine. [11C]SL25.1188 VT was higher in grey matter regions in females (10%, p<.001). [11C]SL25.1188 VT was also higher in prefrontal cortex in TRD compared to HC (23%, p<.001) and TRD compared to NTR-MDE (6%, p=.033). Duloxetine had minimal effect on [11C]SL25.1188 VT, but occupancy of rasagiline and phenelzine was ~94%. This study discovered sex differences in MAO-B level, which may explain sex differences in prevalence or trajectory of illnesses with greater MAO-B level like Alzheimer's disease, traumatic brain injury and major depressive disorder. Given our findings of greater MAO-B level in prefrontal cortex of TRD and its insensitivity to serotonin reuptake inhibition, combined with potential harm of highly elevated MAO-B level, development of MAO-B inhibitors could be considered for a subset of TRD. Rasagiline and phenelzine demonstrate similarly potent occupancy in vivo at clinical dosage.