MAGNETIC SUBCORTICAL SUSCEPTIBILITY IS ASSOCIATED WITH THE TREATMENT OUTCOME OF REPEATED KETAMINE INFUSION FOR PATIENTS WITH TREATMENT-RESISTANT DEPRESSION
Authors: Yonezawa *Kengo , Tani Hideaki , Shibukawa Shuhei , Ohtani Yohei , Nomoto-Takahashi Kie , Yatomi Taisuke , Honda Shiori , Koike Shinsuke , Uchida Hiroyuki , Nakajima Shinichiro 
Published: February 2025

Abstract

Background
Whereas ketamine has displayed robust antidepressant effects in treatment-resistant depression (TRD) (Han et al., 2016), only 30-40% of patients with TRD respond to ketamine therapy (Wilkinson et al., 2018; Sakurai et al., 2020). Several postmortem studies have shown decreased myelination in patients with depression (Hamidi, Drevets and Price, 2004; Altshuler et al., 2010), and an animal study suggested that increased myelination may underlie the antidepressant effects of ketamine for TRD (Huang et al., 2023). Quantitative susceptibility mapping (QSM) is a magnetic resonance imaging technique for assessing magnetic susceptibility in brain tissues, which can examine the degrees of iron deposition and myelination (Harada et al., 2022). Several studies noted increased susceptibility in the subcortical regions of patinets with depression (Yao et al., 2017; Zhang et al., 2019; Duan et al., 2022; Wang et al., 2022). However, no study has examined the relationship between magnetic susceptibility and ketamine treatment efficacy in patients with TRD.

Aims and Objections
To evaluate whether pre-treatment subcortical susceptibility can predict clinical outcomes post-ketamine infusion, we conducted a post-hoc analysis of data from a placebo-controlled, double-blind, randomized clinical trial (DBRCT) followed by an open-label trial, where the efficacy of repeated ketamine infusion was examined in patients with TRD.

Methods
In this DBRCT, 34 patients with TRD were either treated with intravenous ketamine (0.5 mg/kg) or placebo, which were administered over 40 minutes, twice weekly for two weeks. After the DBRCT was completed, those allocated to the placebo group were enrolled in an open-label trial, in which the participants received the same ketamine treatment as in DBRCT. The primary outcome was the Montgomery-Å sberg Depression Rating Scale (MADRS) score difference between pre- and post- treatment. All participants underwent 3T MRI scans using a 32-channel head/neck coil with the following parameters: repetition time/first echo time = 44.0/3.6 ms, echo spacing = 5.91 ms, and number of echoes = 8. We measured magnetic susceptibility in the region of interest (ROI), including 10 subcortical structures defined by the ITK-SNAP software. Univariate regression analyses were performed to examine the association between susceptibility in each ROI before ketamine infusion and the change in MADRS total scores after treatment from baseline.

Results
Among the 34 patients who participated in the original clinical trial, 13 (DBRCT, n=7; open-label phase, n=6) were included in this post-hoc analysis. The mean change in MADRS total score between ketamine treatment was -7.8 ± 6.3. Positive correlations between the baseline susceptibility in the left globus pallidus externa (GPe) (β = 152.8, p = 0.035), left globus pallidus interna (GPi) (β = 153.2, p = 0.042), left substantia nigra (SN) (β = 142.3, p = 0.017) and right SN (β = 131.5, p = 0.031), and the change in MADRS total scores following the treatment.

Discussion and Conclusion
The baseline myelination measured by QSM in the left GPe, left GPi, and bilateral SN may predict a favorable response to ketamine treatment in patients with TRD.

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