Omega-3 polyunsaturated fatty acid supplementation and white matter changes in major depression
Graphical abstract
Introduction
Major Depressive Disorder (MDD) is one of the top five causes of disability worldwide (Ustun et al., 2004), with a lifetime prevalence of approximately 10–18% (Williams et al., 2007, Kessler et al., 2003). The cause of MDD is not known, although aberrant neurocircuitry and factors affecting brain health are active areas of research. Linking a causal mechanism to a treatment may help improve prognosis.
Abnormalities in white matter observed in MDD include hyperintensities seen on structural magnetic resonance imaging (MRI) (Coffey et al., 1990, Coffey et al., 1993) and reduced myelin integrity as measured using magnetization transfer imaging (Gunning-Dixon et al., 2008). Similarly, post-mortem histopathologic studies have found altered deep white matter staining in MDD (Thomas et al., 2002, Thomas et al., 2003, Regenold et al., 2007). White matter abnormalities could lead to diminished functional connections between brain regions and thereby contribute to depression symptomatology.
Microstructural changes of white matter within neural networks can be detected using diffusion tensor imaging (DTI) to quantify fractional anisotropy (FA), a measure of the directionality of water diffusion (Basser, 1995, Le Bihan et al., 2001). Healthy white matter generally has high anisotropy, because water movement in myelinated nerve fibers is primarily in the direction of the axon fiber bundles (Le Bihan et al., 2001).
Abnormalities in FA of prefrontal (Shimony et al., 2009, Yang et al., 2007, Zou et al., 2008), temporal (Yang et al., 2007, Nobuhara et al., 2006), and parietal (Zou et al., 2008) cortex and in anterior cingulate (Bae et al., 2006) are reported in MDD compared with healthy volunteers (HV). One large DTI study (n = 132) that found differences between MDD and HV in regions including splenium, genu and body of the corpus callosum, superior longitudinal fasciculus, and anterior corona radiata, also found a negative correlation between depression severity and white matter integrity (Cole et al., 2012). In elderly depressed patients, FA impairment is associated with executive dysfunction (Murphy et al., 2007). First-episode, medication-naïve (Ma et al., 2007, Li et al., 2007, Wu et al., 2011) adults demonstrate similar deficits in frontal and parietal white matter, which negatively correlate with severity of the depressive symptoms (Zou et al., 2008). Adolescent MDD patients likewise exhibit white matter abnormalities and low FA in subgenual anterior cingulate cortex and amygdala (Cullen et al., 2010).
One determinant of white matter health is the balance of lipids in the brain. For example, polyunsaturated fatty acids (PUFAs), key components of phospholipids in cell membranes, comprise 35% of lipids in the brain (Benatti et al., 2004) and are critical for nervous system development and functioning (Luchtman and Song, 2013, Lauritzen et al., 2001, Gerster, 1998, Singh, 2005, Spector, 1999). Highly unsaturated long-chain PUFAs arachidonic acid (AA, 20:4n-6) and docosahexaenoic acid (DHA, 22:6n-3), are the major constituents of brain PUFAs, and have been implicated in psychiatric illness, including major depression (Lin et al., 2010), bipolar disorder (Rapoport, 2014, Sublette et al., 2004) and suicide risk (Huan et al., 2004, Lewis et al., 2011, Sublette et al., 2006). Eicosapentaenoic acid (EPA, 20:5n-3), although present in considerably lower quantities in brain as a result of its rapid β-oxidation and metabolism (Chen et al., 2009, Chen et al., 2011, Chen and Bazinet, 2015), also is reported to have specific effects related to neuropsychiatric conditions (Beier et al., 2014, Martins, 2009, Martins et al., 2012, Sublette et al., 2011a, Lin et al., 2012, Ross et al., 2007).
Given that both reduced white matter integrity and lower omega-3 PUFAs are seen in MDD, we hypothesized that supplementation with omega-3 PUFAs would cause increased FA in MDD greater than HV, and that increased FA would correlate with improvement in depression symptoms. We used DTI in a prospective study to test effects of fish oil supplementation for 6 weeks on white matter integrity in MDD compared with HV, and to generate brain maps of correlations of FA with 1) plasma phospholipid PUFAs and 2) depression severity.
Section snippets
Sample
This study was approved by the Institutional Review Board of the New York State Psychiatric Institute in accordance with the latest version of the Declaration of Helsinki. After the procedures were fully explained, all subjects (n = 28) gave written informed consent to participate in this research study, which included a positron emission tomography (PET) scan component (not discussed here). At study entry, 16 depressed adults, ages 22–50, met DSM-IV criteria (American Psychiatric Association,
Sample
As detailed in Table 1, MDD and HV groups did not differ with respect to sex, age, or other demographic characteristics examined, although the MDD group trended toward a higher percentage of white participants. Participants were adults ages 22–50. Depressed participants had not taken psychotropic medications for at least 14 days prior to PET studies with the exception of three participants (one on sertraline, one on duloxetine, and one on mirtazapine plus clonazepam). MDD participants were
Discussion
This is the first reported DTI study of PUFA supplementation effects on white matter in MDD. We found that white matter deficits in MDD, relative to HV, improved after six weeks of fish oil supplementation, as defined by increased FA in a single voxel cluster. Moreover, although changes were seen in plasma phospholipid levels of all three PUFAs, only the DHA% increases correlated with brain FA increases, and only in the MDD group, with a trend toward greatest FA increases in clinical
Conclusions
Our observations replicate previous findings that corpus callosum and anterior corona radiata are regions of vulnerability in MDD (Cole et al., 2012), and suggest that omega-3 PUFA supplements have restorative effects on white matter integrity that may relate to antidepressant efficacy in some patients. Additional, larger placebo-controlled studies are needed to replicate these findings and test whether omega-3 PUFA-induced enhancement of white matter integrity can cause improvements in
Conflicts of interest
Drs. Mann and Oquendo receive royalties for commercial use of the C-SSRS from the Research foundation for Mental Hygiene. Dr. Mann received past unrelated grants from Novartis and GSK. Dr. Oquendo received unrestricted educational grants and/or lecture fees from Astra-Zeneca, Bristol-Meyers Squibb, Eli Lilly, Janssen, Otsuka, Pfizer, Sanofi-Aventis, and Shire as well as financial compensation from Pfizer for the safety evaluation of a clinical facility, unrelated to the current manuscript. In
Contributors
Mr. Chhetry and Ms. Hezghia contributed equally. Mr. Chhetry performed the image analyses and wrote the methods and results sections. Ms. Hezghia performed the literature search and wrote the first draft. Dr. Miller oversaw the image analysis and participated in interpretation of results. Dr. Lee was the statistician. Mr. Rubin-Falcone performed portions of the image analysis and wrote portions of the methods text. Mr. Cooper performed the biochemical analyses. Research participants were
Role of funding source
This work was funded by K-08 MH079033 (PI:Sublette) and R01 MH48514 (PI:Oquendo). Omega-3 PUFA supplements were donated by Unicity, International, Inc. (Orem, UT, USA). The funding sources had no involvement in the study design, data collection and analysis, or interpretation of results.
Acknowledgments
These data were presented previously as a poster at the 2014 Society for Biological Psychiatry Conference. Dr. Dongrong Xu performed a much-appreciated critical reading of the manuscript.
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