Importance
The neuroinflammatory hypothesis of major depressive disorder
is supported by several main findings. First, in humans and animals,
activation of the immune system causes sickness behaviors that present
during a major depressive episode (MDE), such as low mood, anhedonia,
anorexia, and weight loss. Second, peripheral markers of inflammation
are frequently reported in major depressive disorder. Third,
neuroinflammatory illnesses are associated with high rates of MDEs.
However, a fundamental limitation of the neuroinflammatory hypothesis is
a paucity of evidence of brain inflammation during MDE. Translocator
protein density measured by distribution volume (TSPO VT) is increased in activated microglia, an important aspect of neuroinflammation.
Objective
To determine whether TSPO VT is elevated in the
prefrontal cortex, anterior cingulate cortex (ACC), and insula in
patients with MDE secondary to major depressive disorder.
Design, Setting, and Participants
Case-control study in a tertiary care psychiatric hospital
from May 1, 2010, through February 1, 2014. Twenty patients with MDE
secondary to major depressive disorder and 20 healthy control
participants underwent positron emission tomography with fluorine F
18–labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([18F]FEPPA). Patients with MDE were medication free for at least 6 weeks. All participants were otherwise healthy and nonsmokers.
Main Outcomes and Measures
Values of TSPO VT in the prefrontal cortex, ACC, and insula.
Results
In MDE, TSPO VT was significantly elevated in all brain regions examined (multivariate analysis of variance, F15,23 = 4.5 [P = .001]). The magnitude of TSPO VT elevation was 26% in the prefrontal cortex (mean [SD] TSPO VT, 12.5 [3.6] in patients with MDE and 10.0 [2.4] in controls), 32% in the ACC (mean [SD] TSPO VT, 12.3 [3.5] in patients with MDE and 9.3 [2.2] in controls), and 33% in the insula (mean [SD] TSPO VT, 12.9 [3.7] in patients with MDE and 9.7 [2.3] in controls). In MDE, greater TSPO VT in the ACC correlated with greater depression severity (r = 0.63 [P = .005]).
Conclusions and Relevance
This finding provides the most compelling evidence to date of
brain inflammation, and more specifically microglial activation, in MDE.
This finding is important for improving treatment because it implies
that therapeutics that reduce microglial activation should be promising
for MDE. The correlation between higher ACC TSPO VT and the
severity of MDE is consistent with the concept that neuroinflammation in
specific regions may contribute to sickness behaviors that overlap with
the symptoms of MDE.