Traditionally, the neurobiology of
major depressive disorder (MDD) has been largely considered from the perspective of the state of major depressive episodes (
MDE) versus being in remission, but the current accumulation of disease markers, largely acquired cross-sectionally, is strongly suggestive of neuroprogressive aspects of MDD. This chapter focuses on the changes in disease markers involved in the reorganization of the nervous system in MDD, including the translocator
protein (TSPO; an index of microglial activation),
glial fibrillary acidic protein (GFAP; an index of astroglial activation), [11C]
harmine (a marker of
monoamine oxidase A;
MAO-A), and several other indices (
metabotropic glutamate receptor 5 [mGluR5],
excitatory amino acid transporters, and magnetic resonance imaging spectroscopy measurements) of
glutamate dysregulation. These are markers of processes involved in immune activation, oxidative stress, and chronic
glucocorticoid exposure. Positron emission tomography studies of the TSPO distribution volume, a marker of microglial activation, provide strong evidence for microglial activation throughout the gray matter of the brain during
MDE of MDD. In postmortem studies, GFAP reductions in the orbitofrontal cortex, anterior cingulate cortex, and hippocampus indicate a deficit in reactive astroglia. Elevated
MAO-A levels are present throughout the gray matter of the brain, including affect-modulating brain regions, starting in high-risk states for
MDE such as the early postpartum period, perimenopause, heavy cigarette smoking, heavy alcohol intake, and prior to
MDE recurrence. Evidence is accumulating for
glutamate dysregulation, with some findings of reduced
glutamate transporter density in the orbitofrontal cortex, and decreased mGluR5 density. Collectively, these changes suggest an imbalance in the immune system with increased microglial activation and decreased astroglial activation, continued elevations of the
MAO-A level, and, likely, the development of extracellular
glutamate dysregulation. Many of these imbalances involve processes implicated in increased oxidative stress, apoptosis, and neurodegeneration. Future studies are required to assess potential
therapeutics targeting these processes to ameliorate progression of MDD.