Inflammation and White Matter Microstructure in Treatment-Resistant MDD

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The researchers sought to examine whether inflammation and white matter microstructure play a role in treatment response in major depressive disorder.

A pilot study found evidence that inflammation and white matter microstructure may play a role in treatment response in major depressive disorder (MDD). These findings were published in the Journal of Affective Disorders.

Participants (N=25) were recruited for this study from the University of California, Los Angeles. Patients with treatment-resistant MDD (n=10) and age- and gender-matched control individuals (n=15) underwent diffusion-weighted magnetic resonance imaging (MRI) assessment and gave blood samples. The patient cohort were assessed by MRI and gave blood samples before and 24 hours after receiving 0.5 mg/kg ketamine following a benzodiazepine washout period. Imaging features and inflammatory markers were compared between groups.

The MDD and control cohorts had a man:women ratio of 8:2 and 10:5, respectively and were aged mean 47.70±11.90 and 44.73±12.01 years, respectively.

Among the MDD cohort, the Montgomery-Åsberg Depression Rating Scale (MADRS) was 35.10±3.31 at baseline and 16.00±13.58 after receiving ketamine. Stratified by ketamine response, responders (n=6) had similar MADRS scores at baseline as nonresponders (P =.09) but had significantly improved scores after ketamine treatment (mean, 6.67 vs 30.00; P =.001).

The ratio of interleukin (IL)-8 to IL-10 was greater among the MDD cohort than control patients (mean, 10.94 vs 4.26; P =.040) but did not differ between responders and nonresponders (mean, 7.85 vs 15.59; P =.51), respectively.

At baseline, responders and nonresponders had similar tissue-specific fractional anisotropy (FAT) of the forceps minor (F[1,9], 2.15; P =.19), left cingulum hippocampal portion (F[1,9], 0.99; P =.36), right cingulum cingulate gyrus portion (F[1,9], 0.001; P =.98), and right cingulum hippocampal portion (F[1,9], 0.91; P =.38). Responders had greater FAT in the left cingulum cingulate gyrus portion (mean, 0.69 vs 0.61; P =.023).

Average FAT did not correlate with IL-8/IL-10 among either the control participants (Q, 0.11; P =.71) or patients (Q, -0.27; P =.45). The average free-water across all regions of interest was correlated with IL-8/IL-10 among patients (Q, 0.75; P =.013) but not control individuals (Q, -0.07; P =.82).

After receiving ketamine, IL-8/IL-10 decreased significantly among the MDD group (t, 2.4; P =.043). Stratified by treatment response, the IL-8/IL-10 ratio decreased more in the responders (t, 2.12; P =.088) than the nonresponders (t, 1.80; P =.17).

The major limitation of this study was the small sample size. However, it was designed as a pilot study.

The study authors concluded, “Individuals with MDD presented peripheral inflammatory imbalance, which was associated with elevated extracellular free water and downregulated after ketamine treatment. While ketamine did not influence white matter microstructure, cellular abnormalities were predictive of later treatment response. Our findings prove an essential step towards understanding the antidepressant mechanisms of ketamine. However, future, more extensive, longitudinal studies are needed to establish biomarkers for diagnostic purposes and treatment prediction.”


Langhein M, Seitz-Holland J, Lyall AE, et al. Association between peripheral inflammation and free-water imaging in major depressive disorder before and after ketamine treatment – a pilot study. J Affect Disord. 2022;314:78-85. doi:10.1016/j.jad.2022.06.043

This article originally appeared on Psychiatry Advisor