Neuroprotective kynurenine metabolite indices are abnormally reduced and positively associated with hippocampal and amygdalar volume in bipolar disorder.

Inflammation-related changes in the concentrations of kynurenine-pathway
metabolites occur in depression secondary to medical conditions but
have not been well characterized in primary bipolar disorder (BD), with
contradictory results potentially attributable to the presence or
absence of psychosis and/or medication effects. In contrast, reductions
in hippocampal and amygdalar volume that theoretically reflect dendritic
atrophy occurring in the context of a neurotoxic process are commonly
reported in unmedicated BD patients. Here we tested whether the
concentrations of putatively neuroprotective (kynurenic acid, KynA) and neurotoxic (3-hydroxy-kynurenine, 3HK and quinolinic acid,
QA) kynurenine-pathway metabolites were altered in primary BD and
whether these metabolites were associated with hippocampal and amygdalar
volume. Twenty-five moderately-to-severely depressed unmedicated
subjects and 38 moderately-to-severely depressed medicated subjects who
met DSM-IV-TR criteria for BD, as well as 48 healthy controls (HCs)
completed a structural MRI scan and provided a blood sample for
kynurenine metabolite analysis, performed using high performance liquid
chromatography with tandem mass spectrometry. Gray matter volumes were
measured with the automated segmentation software, FreeSurfer. A
putative neuroprotective index, KynA/QA, was significantly lower in the
BD subjects relative to the HCs, a finding that was unrelated to current
treatment with medication or a prior history of psychosis. Further,
another putative neuroprotective index, KynA/3HK was positively
associated with hippocampal volume in the BD group after controlling for
age, sex, body mass index (BMI), and intracranial volume (ICV). Kyn/3HK
was significantly associated with total amygdalar volume in the BD
group, but after controlling for age, sex, BMI, but not ICV, this
association was reduced to a trend. In addition, Kyn/3HK was positively
associated with amygdalar volume in the HCs although the association was
no longer significant after accounting for the effects of age, sex, and
BMI. The results raise the possibility that BD-associated abnormalities
in kynurenine metabolism may impact the structure of the hippocampus
and amygdala, highlighting a pathway through which inflammation may
exert neuropathological effects in the context of depression.

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