Poster No:
372
Submission Type:
Abstract Submission
Authors:
Ben Moloney1, Jonathon Zong1, Anna Forsyth1, Catherine Morgan1, Flavio Dell'Acqua2, Rachael Sumner1, Nicholas Hoeh1, Frederick Sundram1, Suresh Muthukumaraswamy1, Joanne Lin1
Institutions:
1University of Auckland, Auckland, New Zealand, 2Kings College London, London, United Kingdom
First Author:
Ben Moloney
University of Auckland
Auckland, New Zealand
Co-Author(s):
Joanne Lin
University of Auckland
Auckland, New Zealand
Introduction:
Current treatments for major depressive disorder (MDD) are ineffective in approximately one-third of patients (Warden et al, 2007). Increased inflammation is increasingly recognized as a factor that can inform MDD subtyping and treatment, and drugs that have purported anti-inflammatory actions in the brain, like low-dose naltrexone (LDN), may have beneficial effects for alleviating depressive symptoms (Miller et al., 2009; Mischoulon et al., 2017). However a lack of validated tools for assessing treatment effects for neuroinflammation limits our understanding of the action of these drugs in MDD. Blood-based biomarkers of peripheral inflammation like C-reaction protein (CRP) are highly unspecific in MDD and current methods for measuring neuroinflammation in vivo are invasive and not clinically feasible. There is a growing body of evidence suggesting that diffusion-weighted imaging (DWI) techniques like diffusion kurtosis imaging (DKI) and neurite orientation dispersion and density index imaging (NODDI) are sensitive to neuroinflammation and may be clinically useful in monitoring it in MDD (Oestreich & O'Sullivan, 2022). This preliminary study aims to determine the effect of LDN in MDD using DKI and NODDI markers.
Methods:
We recruited 30 participants with MDD who were moderately depressed and receiving pharmacological antidepressant therapy to participate in a double-blind randomized control trial of 12 weeks of low-dose naltrexone vs. inactive placebo. Participants underwent DWI at baseline and 12 weeks. Mean DKI and NODDI metrics were extracted from 25 mid-sagittal and bilateral regions of interest that have previously shown significant DWI and structural alterations in MDD (Schmaal et al., 2017; Schmaal et al., 2016; Van Velzen et al., 2020). These regional averages were analyzed for treatment effect using a linear mixed effects model with a significance threshold of false-discovery rate (FDR) adjusted p < 0.05. Our primary analysis examined the overall effects of LDN vs. placebo on these regional averages, while a secondary analysis assessed this within baseline stratified low (CRP ≤ 1 mg/L; n = 24) and high (CRP ≥ 3mg/L; n = 6) inflammatory subgroups.
Results:
23 participants completed both baseline and 12 week scans and were included in analyses. We found no significant difference between LDN (n = 10) and placebo (n = 13) groups in mean NODDI metrics in the regions of interest. Several differences in DKI metrics were observed between LDN and placebo groups in the sagittal stratum, temporal occipital fusiform cortex and external capsule, however, these did not survive correction for multiple comparisons. Furthermore, no group differences in DKI or NODDI metrics survived FDR correction when analyzed within the inflammatory subgroups.
Conclusions:
These preliminary results indicate that LDN does not have a discernable effect from placebo on neuroinflammation when measured with DKI or NODDI. This may be due to the absence of an anti-inflammatory effect of LDN in the brain or insensitivity of DKI and NODDI to a subtle effect of LDN on neuroinflammation. This study was preliminary and limited by a small sample size, particularly in the high-inflammation subgroup, where a greater effect of LDN was hypothesized to occur. Further analysis within a larger sample will be necessary to adequately characterize the effect of LDN on NODDI and DKI markers in MDD.
Disorders of the Nervous System:
Psychiatric (eg. Depression, Anxiety, Schizophrenia) 1
Novel Imaging Acquisition Methods:
Diffusion MRI 2
Physiology, Metabolism and Neurotransmission:
Pharmacology and Neurotransmission
Keywords:
MRI
Psychiatric
Psychiatric Disorders
STRUCTURAL MRI
Treatment
White Matter
WHITE MATTER IMAGING - DTI, HARDI, DSI, ETC
1|2Indicates the priority used for review
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Healthy subjects only or patients (note that patient studies may also involve healthy subjects):
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Was this research conducted in the United States?
No
Were any human subjects research approved by the relevant Institutional Review Board or ethics panel?
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Were any animal research approved by the relevant IACUC or other animal research panel?
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Please indicate which methods were used in your research:
Diffusion MRI
For human MRI, what field strength scanner do you use?
3.0T
Which processing packages did you use for your study?
FSL
Provide references using APA citation style.
Miller, A. H. (2009). Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biological Psychiatry, 65(9), 732-741.
Mischoulon, D. (2017). Randomized, proof-of-concept trial of low dose naltrexone for patients with breakthrough symptoms of major depressive disorder on antidepressants. Journal of Affective Disorders, 208, 6-14.
Oestreich, L. K. L. (2022). Transdiagnostic In Vivo Magnetic Resonance Imaging Markers of Neuroinflammation. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging.
Schmaal, L. (2017). Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group. Molecular Psychiatry, 22(6), 900-909.
Schmaal, L. (2016). Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group. Molecular Psychiatry, 21(6), 806-812.
Van Velzen, L. S. (2020). White matter disturbances in major depressive disorder: a coordinated analysis across 20 international cohorts in the ENIGMA MDD working group. Molecular Psychiatry, 25(7), 1511-1525.
Warden, D. (2007). The STAR*D Project results: a comprehensive review of findings. Current Psychiatry Reports, 9(6), 449-459.
No