Skip to main content
NCBI home page
Brain and Behavior logoLink to Brain and Behavior
. 2021 Feb 18;11(4):e02075. doi: 10.1002/brb3.2075

Nervonic acid level in cerebrospinal fluid is a candidate biomarker for depressive and manic symptoms: A pilot study

Yuki Kageyama 1,2,3,✉, Yasuhiko Deguchi 2, Kotaro Hattori 4, Sumiko Yoshida 4,5, Yu‐ichi Goto 5, Koki Inoue 2, Tadafumi Kato 3,6
PMCID: PMC8035447  PMID: 33599392

Abstract

Objective

Our previous metabolomics study showed that the plasma nervonic acid levels were higher in patients with major depressive disorder (MDD) than those in healthy controls and patients with bipolar disorder (BD). To examine whether the nervonic acid levels differ in the central nervous system, we investigated the levels in the cerebrospinal fluid (CSF) of patients with MDD, BD, and healthy controls.

Methods

Nervonic acid levels in CSF were measured by gas chromatography time‐of‐flight mass spectrometry. The participants included 30 patients with MDD, 30 patients with BD, and 30 healthy controls.

Results

In contrast to our previous study, no significant differences were found in the nervonic acid level in the CSF among the patients with MDD, BD, and the healthy controls. Though no significant state‐dependent changes were found among the three groups, we did observe a significant negative correlation between the nervonic acid levels and depressive symptoms in the depressive state of patients with MDD and BD (r = −0.38, p = .046). Further, a significant positive correlation was found between the nervonic acid levels and manic symptoms in the manic state of patients with BD (r = 0.79, p = .031).

Conclusion

The nervonic acid levels in the CSF did not differ among the patients with MDD, BD, and the healthy controls; however, a significant negative correlation with depressive symptoms and a positive correlation with manic symptoms was observed. Thus, the nervonic acid levels in the CSF may be a candidate biomarker for mood symptoms.

Keywords: biomarker, bipolar disorder, cerebrospinal fluid, major depressive disorder, nervonic acid

The cerebrospinal fluid (CSF) nervonic acid levels were not different among major depressive disorder patients (MDD), bipolar disorder patients (BD), and healthy controls.CSF nervonic acid levels had significant negative correlation with depressive symptom in MDD and BD, and positive correlation with manic symptom in BD.Further study is needed to understand the biological meaning of CSF nervonic acid level in MDD and BD.

graphic file with name BRB3-11-e02075-g002.jpg

1. INTRODUCTION

Mood disorders are mainly diagnosed by self‐reported symptoms and clinical interviews. Currently, major depressive disorder (MDD) cannot be distinguished from the first depressive episode of bipolar disorder (BD) without a history of (hypo)mania. Previous reports showed that it takes 8–10 years from the onset of BD for the initiation of maintenance treatment (Baldessarini et al., 2003; Drancourt et al., 2013). This leads to worsening of a patient's social prognosis during the undiagnosed period. To solve this problem, a clinically applicable biomarker that distinguishes MDD from BD is required. We previously showed that plasma nervonic acid levels are increased in patients with MDD compared with nervonic acid levels in patients with BD and healthy controls (Kageyama et al., 2018). Therefore, the next step in biomarker research is to elucidate the relationship between depression pathophysiology and individual markers to help refine the current MDD criteria for diagnosis (Young et al., 2016).

Nervonic acid (IUPAC name: (Z)‐Tetracos‐15‐enoic acid) is a long chain of monounsaturated omega‐9 fatty acid. It is essential for the growth and maintenance of the brain and peripheral nervous tissue enriched in sphingomyelin (Martínez & Mougan, 2002). Because sphingomyelin is a key constituent of myelin, nervonic acid is abundant in the white matter of the brain (Li et al., 2019). Further, sphingomyelin is also associated with the regulation of neurogenesis. Previous studies reported that there is an impaired integrity of the white matter in patients with MDD (Li et al., 2007; Nobuhara et al., 2006; Velzen et al., 2020). Thus, a dysregulation of sphingomyelin metabolic pathway and decreased neurogenesis in the hippocampus has been suggested to play a role in depression (Gulbins et al., 2015). Antidepressants enhance the neurogenesis by inhibiting a part of the sphingomyelin metabolic pathway such as the acid sphingomyelinase/ceramide system (Gulbins et al., 2013). Moreover, the effects of lipid rafts on neurotransmitter signaling are also implicated in neurological and psychiatric diseases (Allen et al., 2007). Thus, the increased plasma nervonic acid levels might reflect the dysregulation of oligodendrocytes, sphingomyelin‐rich lipid rafts, and sphingomyelin metabolic pathway in patients with MDD. Although blood fatty acid composition and erythrocyte membrane phospholipids are known accessible indicators of fatty acids in the nervous system, neuronal membranes, and brain phospholipids (Assies et al., 2001; Babin et al., 1993; Song et al., 2018), it is still unclear whether the nervonic acid level in the central nervous system differs among the patients with MDD, BD, and the healthy controls.

Thus, we examined whether the nervonic acid levels in the cerebrospinal fluid (CSF) differ in patients with MDD, BD, and the healthy controls using gas chromatography time‐of‐flight mass spectrometry (GC‐TOFMS).

2. MATERIALS AND METHODS

2.1. Participants

The CSF samples (30 samples from patients with MDD, 30 from patients with BD, and 30 from healthy controls) were derived from the National Center of Neurology and Psychiatry (NCNP) Biobank (project number: NCNPBB‐0050). The patients and healthy controls were either recruited at the NCNP Hospital or through advertisements on websites and in free local magazines. Trained psychologists and psychiatrists conducted a structured interview for all the participants by using a Japanese version of the Mini‐International Neuropsychiatric Interview (M.I.N.I.) (Sheehan et al., 1998). Then, diagnoses were made according to the criteria in Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM‐IV‐TR) (American Psychiatric Association, 1994). Patients with comorbid axis I disorders, severe head trauma, substance abuse, substance dependence, or a prior history of central nervous system diseases, were excluded. The depressive symptoms were assessed using a Japanese version of the 21‐item Hamilton Depression Rating Scale (HAMD‐21). (Hamilton, 1960) Finally, the Young Mania Rating Scale (YMRS) (Young et al., 1978) was used to measure the severity of the manic episodes in patients with BD.

2.2. Ethics statement

All participants provided their written informed consent after the study procedures had been fully explained. The patient's records and information were anonymized and de‐identified before the analysis. This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Osaka City University (approval number: 3886) and the Ethics Committee of NCNP (approval number: A2018‐007).

2.3. GC‐TOFMS analysis

For the GC‐TOFMS analysis, we followed the method described in our previous publication (Kageyama et al., 2018). In brief, 100 µl of CSF samples was added to 25 µl of 1N HCL, 400 µl of methanol, and 1,000 µl of isooctane. Then, 2.5 ng of oleic acid‐d9 (Avanti Polar Lipids, AL, USA) was added to each CSF sample as an internal standard. The solution was thoroughly mixed and centrifuged at 800 × g for 2 min at room temperature. The supernatant was evaporated and then dissolved in 40 µl of pyridine, 40 µl of N‐(tert‐Butyldimethylsilyl)‐N‐methyltrifluoroacetamide, and 30 µl of acetonitrile for the GC‐TOFMS analysis by using JMS‐T100GCV (JEOL). The absolute concentration was quantified using a standard reference of nervonic acid (Sigma‐Aldrich).

2.4. Statistical analysis

The data are reported as means ± standard deviation (SD). The means were compared using a Welch t test and one‐way analysis of variance with post hoc Tukey's test. The categorical variables were compared using the Chi‐squared test, and the outliers were determined by Smirnov–Grubbs' test. The results for independent variables were typically reported as odds ratios with 95% confidence intervals, and the Spearman's rank correlation coefficient was used for correlation analysis. The threshold for the statistical analyses was set at p < .05, and multiple comparisons were performed by estimating the false discovery rate using q‐values. The statistical power was calculated using G‐Power version 3.1 (Faul et al., 2007) where we regarded the value of power (1 –β) as 0.80. Finally, these statistical analyses were performed using the Graph‐Pad Prism 8.3.1 statistical program (GraphPad Software Inc.) and R version 3.6.3 (http://cran.r‐project.org/).

3. RESULTS

3.1. Characteristics of the participants

The demographic and clinical data of the participants are shown in Table 1. There were no significant differences in the sex ratios and ages among the groups.

TABLE 1.

The demographic and clinical data of the participants

MDD BD Control Statistics
Number (male/female) 30 (15/15) 30 (13/17) 30 (15/15) p =.62 a
Age in years (mean ± SD) 43.8 ± 14.2 43.4 ± 11.8 43.1 ± 11.7 p =.98 b
HAMD−21 score (mean ± SD) 12.3 ± 8.9 10.8 ± 8.4 N.A. p =.52 c
YMRS score (mean ± SD) N.A. 4.1 ± 5.9 N.A. N.A.
Open in a new tab

Abbreviations: BD, bipolar disorder; HAMD‐21, 21‐item Hamilton Depression Rating Scale; MDD, major depressive disorder; N.A., not applicable; SD, standard deviation; YMRS, Young Mania Rating Scale.

a

Chi‐squared test.

b

Analysis of variance.

c

Welch t test.

3.2. GC‐TOFMS analysis

We obtained the absolute levels of nervonic acid in CSF in 88 of 90 samples. The nervonic acid level could not be detected in the remaining two participants (MDD, n = 1; BD, n = 1). There were no significant differences observed among the level of nervonic acid in the CSF of patients with MDD, BD, and the control group (MDD, 0.0020 ± 0.00086 µM; BD, 0.0021 ± 0.00011 µM; control, 0.0023 ± 0.0014 µM; p =.39; Figure 1a). The effect size was f = 0.20.

FIGURE 1.

FIGURE 1

Open in a new tab

The nervonic acid level of cerebrospinal fluid in the three groups. The bars indicate the mean of each group. Abbreviations: BD, bipolar disorder; MDD, major depressive disorder

Since the highest value in the control group was statistically rejected by the Smirnov–Grubbs test (p = 2.2e −16), we omitted that data. After omitting the outlier, there were no significant differences among the levels of nervonic acid in the CSF of patients with MDD, BD, and the control group (MDD, 0.0020 ± 0.00086 µM; BD, 0.0021 ± 0.00011 µM; control, 0.0021 ± 0.00011 µM; p =.36; Figure 1b). The effect size was f = 0.21.

3.3. Comparison of the nervonic acid levels in the CSF in a state‐dependent manner in patients with MDD and BD

To investigate whether the nervonic acid level showed a state‐dependent change in patients with MDD, we categorized them into two groups: depressed MDD (dMDD; n = 20) and remitted MDD (rMDD; n = 7), according to the results of M.I.N.I. (Table S1). The data of two patients with MDD were omitted because they had no M.I.N.I. data. We observed no significant difference in the nervonic acid levels between dMDD and rMDD patients (dMDD, 0.0020 ± 0.00081 µM; rMDD, 0.0021 ± 0.00042 µM; p =.72; Figure 2a). To investigate whether the nervonic acid level showed a state‐dependent change in patients with BD, we categorized them into three groups: depressed BD (dBD; n = 8), remitted BD (rBD; n = 4), and manic BD (mBD; n = 9), according to the results of M.I.N.I. (Table S2). The data of eight patients with BD were omitted because they had no M.I.N.I. data. There was no significant difference in the nervonic acid levels among patients with dBD, rBD, and mBD (dBD, 0.0020 ± 0.00011 µM; rBD, 0.0021 ± 0.00015 µM, mBD, 0.0021 ± 0.00011 µM; p =.55; Figure 2b). Then, we compared the nervonic acid levels in patients with dMDD and dBD (Table S3) and observed no significant difference between the two groups (p =.96). Finally, no significant difference was observed in the nervonic acid levels between the patients with rMDD and rBD as well (p =.71; Table S4).

FIGURE 2.

FIGURE 2

Open in a new tab

State‐dependent nervonic acid level in cerebrospinal fluid of patients with MDD and BD. The bars indicate the mean of each group. (a) Comparison between patients with dMDD and rMDD according to Welch t test. (b) Comparison among patients with dBD, rBD, and mBD according to one‐way ANOVA with post hoc Tukey's test. Abbreviations: MDD, major depressive disorder; BD, bipolar disorder; dMDD, depressive patients with major depressive disorder; rMDD, remitted patients with major depressive disorder; dBD, depressive patients with bipolar disorder; rBD, remitted patients with bipolar disorder; mBD, manic patients with bipolar disorder

3.4. Relationship between the nervonic acid levels in the CSF and the clinical assessments

To investigate the relationship between psychiatric symptoms (HAMD‐21 score for dMDD and dBD; YMRS score for mBD) and the nervonic acid levels in the CSF, we conducted a correlation analysis using Spearman's rank correlation coefficients. There was a significant negative correlation between the nervonic acid levels in patients with dMDD and dBD and their HAMD‐21 score (r = −0.38, p =.046; Figure 3a). The data of one patient out of nine patients with mBD were omitted because they had no YMRS data. There was a significant positive correlation between the nervonic acid levels in patients with mBD and their YMRS scores (r = 0.79, p =.031; Figure 3b).

FIGURE 3.

FIGURE 3

Open in a new tab

Scatter plots of the nervonic acid level in the cerebrospinal fluid versus the clinical symptoms in patients with MDD and BD. Each dot represents the data of one participant. (a) HAMD‐21 scores and nervonic acid level in patients with dMDD and dBD. (b) YMRS scores and nervonic acid level in patients with mBD. Abbreviations: HAMD‐21, 21‐item Hamilton Depression Rating Scale; dMDD, depressive state of major depressive disorder; dBD, depressive state of bipolar disorder, YMRS, Young Mania Rating Scale; mBD, manic state of bipolar disorder

3.5. Results of medication on the nervonic acid levels

We suspected that an antidepressant or mood stabilizer might affect the nervonic acid levels of CSF. To confirm the effect of medication on nervonic acid levels, we categorized the patients with MDD into two subgroups: patients receiving an antidepressant (medicated patients; n = 25) and drug‐free patients (n = 5). There was no significant difference observed between the two groups (medicated, 0.0020 ± 0.000076 µM; drug‐free, 0.0021 ± 0.0012 µM; p =.32; Figure S1a). We also categorized the patients with BD into two subgroups: patients receiving a mood stabilizer (medicated patients; n = 26) and drug‐free patients (n = 4). There was no significant difference observed between these two groups as well (medicated, 0.0021 ± 0.00011 µM; drug‐free, 0.0020 ± 0.000081 µM; p =.12; Figure S1b).

4. DISCUSSION

To the best of our knowledge, this is the first study to investigate the nervonic acid level in the CSF among patients with MDD, BD, and healthy controls. In contrast to our hypothesis, there was no significant difference in the nervonic acid level in the CSF among these three groups. However, we observed a significant negative correlation of the nervonic acid level with depressive symptoms and a positive correlation with manic symptoms. These results indicate that the nervonic acid level in the CSF may be a candidate biomarker for evaluating depressive and manic symptoms in mood disorders. Yet, the sample size was too small to draw a conclusion.

4.1. A comparison with previous studies related to nervonic acid levels in mood disorders

In peripheral samples, the nervonic acid levels in the plasma and erythrocytes are significantly lower in patients with recurrent depression than in healthy people. (Assies et al., 2010) This was an inconsistent finding when compared to our previous results (Kageyama et al., 2018) and might be attributed to the difference in the type of sample used (erythrocyte versus plasma) or the subtypes of MDD (recurrent versus single episode) that were studied. (Hayashi‐Takagi et al., 2014) In the central nervous system (CNS) samples, a previous study showed that there were no differences in the nervonic acid levels in the prefrontal cortex and corpus callosum of patients with MDD, BD, schizophrenia, and healthy controls (Hamazaki et al., 2015, 2017); this is consistent with our results. Therefore, to compare the nervonic acid levels in the peripheral blood and CNS, we should consider the blood–brain barrier permeability and whether they are regulated by common biological processes. (Hayashi‐Takagi et al., 2014).

The synthesis of nervonic acid is regulated by SCD1, SCD5, ELOVL1, ELOVL2, ELOVL3, ELOVL4, ELOVL5, ELOVL6, and ELOVL7. (Castro et al., 2016; Miyazaki & Ntambi, 2008) According to the Genotype‐Tissue Expression database (Mele et al., 2015) (GTEx Portal v8; dbGaP accession: phs000424.v8.p2), the median expression of SCD1, SCD5, ELOVL2, ELOVL4, ELOVL6, and ELOVL7 is higher in the brain than in the blood (Table S5); the expression of ELOVL5 in the whole body, as per the GTEx project, is shown in the Figure S2. This suggested that the biological processes of the synthesis of nervonic acid may be different in the CNS and peripheral blood.

A sodium‐dependent membrane transporter transports docosahexaenoic acid, an essential omega‐3 fatty acid, into the brain. (Nguyen et al., 2014) Nervonic acid, an omega‐9 fatty acid, is supposedly transported through the blood–brain barrier, particularly in newborns. (Cook et al., 1998) The patients with MDD reportedly lose their blood–brain barrier integrity through the loss of the tight‐junction protein claudin‐5, a major cell adhesion molecule that forms a para‐cellular barrier between the endothelial cells. (Dudek et al., 2020; Kealy et al., 2020) This blood–brain barrier dysfunction leads to the infiltration of peripheral substances. Thus, these two factors may allow nervonic acid to cross the blood–brain barrier; however, the dynamics of nervonic acid transport through the blood–brain barrier is still unclear.

By taking the biological processes and blood–brain barrier permeability of the nervonic acid into consideration, it may be difficult to compare the nervonic acid levels in the peripheral blood and CSF. Although a significant difference was observed in the plasma nervonic acid level of the patients with MDD and healthy controls, we observed no such significant difference in the nervonic acid levels in the CSF; this might suggest that the biological interpretation of the nervonic acid level is different between the peripheral and CNS samples.

4.2. Nervonic acid level in the CSF and severity of depressive symptoms

The expression levels of SCD and ELOVL5 in the postmortem prefrontal cortex are reportedly lower in patients with MDD than in the healthy controls. (Lalovic et al., 2010; McNamara & Liu, 2011) The ELOVL5 gene is expressed in a region‐specific (Figure S2) (Mele et al., 2015) and a cell type‐specific (Medina & Tabernero, 2002) manner in the CNS. This leads to a region‐specific and cell type‐specific profile of fatty acid synthesis and incorporation into complex lipids, which may be related to depressive symptoms. (Müller et al., 2015) This suggests that the effects of expression change of ELOVL5 may attribute to the negative correlation between the nervonic acid level in the CSF and the severity of the depressive symptoms in mood disorders; therefore, a further understanding of the lipid profiles in the CNS is important. (Deák et al., 2019).

4.3. Nervonic acid level in CSF and the severity of manic symptoms

The severity of manic symptoms is reported to be negatively correlated with the levels of arachidonic acid (20:4n‐6) and eicosapentaenoic acid (20:5n‐3), and positively correlated with the arachidonic acid: eicosapentaenoic acid ratio. (Sublette et al., 2007) Hence, the long‐chain unsaturated fatty acid level in the CNS may play a role in the severity of the manic symptoms; however, the precise mechanism is not known.

In this study, four mBD patients showed a YMRS score of 0, indicating that the manic symptoms had been ameliorated at the time of sampling. However, it is difficult to perform a CSF sampling in excited manic patients. This is a limitation of the study because of which we need to carefully evaluate the meaning of the positive correlation between the nervonic acid level and the severity of the manic symptoms.

This study has several other limitations as well. First, we did not evaluate the effect of the socioeconomic status, BMI levels, and physical illness of the patients on the nervonic acid level in the CSF. Second, the transport system of nervonic acid between the peripheral blood, brain, and CSF remains unclear. Third, the metabolic homeostasis of nervonic acid is not known. Lastly, the sample size was too small. Larger samples are needed to draw a definitive conclusion.

In conclusion, the nervonic acid level did not differ among the patients with MDD, BD, and healthy controls. Moreover, the nervonic acid level in the CSF had a significant negative correlation with depressive symptoms and a positive correlation with manic symptoms. Therefore, further studies are needed to understand the biological meaning of nervonic acid level in the CSF in patients with MDD and BD.

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

AUTHOR CONTRIBUTIONS

YK and YD conceived and designed the study and wrote the manuscript. YK acquired and analyzed the data. KH, SY, and YG collected the samples. TK supervised the project. All authors drafted and approved the final manuscript.

PEER REVIEW

The peer review history for this article is available at https://publons.com/publon/10.1002/brb3.2075.

Supporting information

Supplementary Material

Click here for additional data file. (406KB, docx)

ACKNOWLEDGEMENTS

The authors sincerely thank Dr. Takemichi Nakamura for his technical support with the GC‐TOFMS analysis. We would like to thank the patients and controls who participated in this study. Further, we thank the Genotype‐Tissue Expression (GTEx) Project which is supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS.

Kageyama Y, Deguchi Y, Hattori K, et al. Nervonic acid level in cerebrospinal fluid is a candidate biomarker for depressive and manic symptoms: A pilot study. Brain Behav. 2021;11:e02075. 10.1002/brb3.2075

Yuki Kageyama and Yasuhiko Deguchi contributed equally to this work.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.

REFERENCES

  1. Allen, J. A. , Halverson‐Tamboli, R. A. , & Rasenick, M. M. (2007). Lipid raft microdomains and neurotransmitter signalling. Nature Reviews Neuroscience, 8, 128–140. 10.1038/nrn2059 [DOI] [PubMed] [Google Scholar]
  2. American Psychiatric Association . (1994). Diagnostic and Statistical Manual of Mental Disorders, 4th ed. : APA. [Google Scholar]
  3. Assies, J. , Lieverse, R. , Vreken, P. , Wanders, R. J. A. , Dingemans, P. M. J. A. , & Linszen, D. H. (2001). Significantly reduced docosahexaenoic and docosapentaenoic acid concentrations in erythrocyte membranes from schizophrenic patients compared with a carefully matched control group. Biological Psychiatry, 49, 510–522. 10.1016/S0006-3223(00)00986-0 [DOI] [PubMed] [Google Scholar]
  4. Assies, J. , Pouwer, F. , Lok, A. , Mocking, R. J. , Bockting, C. L. , Visser, I. , Abeling, N. G. , Duran, M. , & Schene, A. H. (2010). Plasma and erythrocyte fatty acid patterns in patients with recurrent depression: A matched case‐control study. PLoS One, 5, e10635. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Babin, F. , Sarda, P. , Limasset, B. , Descomps, B. , Rieu, D. , Mendy, F. , & Crastes de Paulet, A. (1993). Nervonic acid in red blood cell sphingomyelin in premature infants: An index of myelin maturation? Lipids, 28, 627–630. 10.1007/BF02536057 [DOI] [PubMed] [Google Scholar]
  6. Baldessarini, R. J. , Tondo, L. , & Hennen, J. (2003). Treatment‐latency and previous episodes: Relationships to pretreatment morbidity and response to maintenance treatment in bipolar I and II disorders. Bipolar Disorders, 5, 169–179. 10.1034/j.1399-5618.2003.00030.x [DOI] [PubMed] [Google Scholar]
  7. Castro, L. F. C. , Tocher, D. R. , & Monroig, O. (2016). Long‐chain polyunsaturated fatty acid biosynthesis in chordates: Insights into the evolution of Fads and Elovl gene repertoire. Progress in Lipid Research, 62, 25–40. [DOI] [PubMed] [Google Scholar]
  8. Cook, C. , Barnett, J. , Coupland, K. , & Sargent, J. (1998). Effects of feeding lunaria oil rich in nervonic and erucic acids on the fatty acid compositions of sphingomyelins from erythrocytes, liver, and brain of the quaking mouse mutant. Lipids, 33, 993–1000. [DOI] [PubMed] [Google Scholar]
  9. Deák, F. , Anderson, R. E. , Fessler, J. L. , & Sherry, D. M. (2019). Novel cellular functions of very long chain‐fatty acids: Insight from ELOVL4 mutations. Front Cell Neurosci, 13, 428. 10.3389/fncel.2019.00428 [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Drancourt, N. , Etain, B. , Lajnef, M. , Henry, C. , Raust, A. , Cochet, B. , Mathieu, F. , Gard, S. , MBailara, K. , Zanouy, L. , Kahn, J. P. , Cohen, R. F. , Wajsbrot‐Elgrabli, O. , Leboyer, M. , Scott, J. , & Bellivier, F. (2013). Duration of untreated bipolar disorder: Missed opportunities on the long road to optimal treatment. Acta Psychiatrica Scand., 127, 136–144. 10.1111/j.1600-0447.2012.01917.x [DOI] [PubMed] [Google Scholar]
  11. Dudek, K. A. , Dion‐Albert, L. , Lebel, M. , LeClair, K. , Labrecque, S. , Tuck, E. , Ferrer Perez, C. , Golden, S. A. , Tamminga, C. , Turecki, G. , Mechawar, N. , Russo, S. J. , & Menard, C. (2020). Molecular adaptations of the blood–brain barrier promote stress resilience vs. depression. Proceedings of the National Academy of Sciences, 117, 3326–3336. 10.1073/pnas.1914655117 [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Faul, F. , Erdfelder, E. , Lang, A.‐G. , & Buchner, A. (2007). G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behavior Research Methods, 39, 175–191. 10.3758/BF03193146 [DOI] [PubMed] [Google Scholar]
  13. Gulbins, E. , Palmada, M. , Reichel, M. , Lüth, A. , Böhmer, C. , Amato, D. , Müller, C. P. , Tischbirek, C. H. , Groemer, T. W. , Tabatabai, G. , Becker, K. A. , Tripal, P. , Staedtler, S. , Ackermann, T. F. , van Brederode, J. , Alzheimer, C. , Weller, M. , Lang, U. E. , Kleuser, B. , … Kornhuber, J. (2013). Acid sphingomyelinase‐ceramide system mediates effects of antidepressant drugs. Nature Medicine, 19, 934–938. 10.1038/nm.3214 [DOI] [PubMed] [Google Scholar]
  14. Gulbins, E. , Walter, S. , Becker, K. A. , Halmer, R. , Liu, Y. , Reichel, M. , Edwards, M. J. , Müller, C. P. , Fassbender, K. , & Kornhuber, J. (2015). A central role for the acid sphingomyelinase/ceramide system in neurogenesis and major depression. Journal of Neurochemistry, 134, 183–192. 10.1111/jnc.13145 [DOI] [PubMed] [Google Scholar]
  15. Hamazaki, K. , Maekawa, M. , Toyota, T. , Dean, B. , Hamazaki, T. , & Yoshikawa, T. (2015). Fatty acid composition of the postmortem prefrontal cortex of patients with schizophrenia, bipolar disorder, and major depressive disorder. Psychiatry Research, 227, 353–359. [DOI] [PubMed] [Google Scholar]
  16. Hamazaki, K. , Maekawa, M. , Toyota, T. , Dean, B. , Hamazaki, T. , & Yoshikawa, T. (2017). Fatty acid composition of the postmortem corpus callosum of patients with schizophrenia, bipolar disorder, or major depressive disorder. European Psychiatry, 39, 51–56. [DOI] [PubMed] [Google Scholar]
  17. Hamilton, M. (1960). A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry, 23, 56–62. 10.1136/jnnp.23.1.56 [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hayashi‐Takagi, A. , Vawter, M. P. , & Iwamoto, K. (2014). Peripheral biomarkers revisited: Integrative profiling of peripheral samples for psychiatric research. Biological Psychiatry, 75, 920–928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kageyama, Y. , Kasahara, T. , Nakamura, T. , Hattori, K. , Deguchi, Y. , Tani, M. , Kuroda, K. , Yoshida, S. , Goto, Y.‐I. , Inoue, K. , & Kato, T. (2018). Plasma nervonic acid is a potential biomarker for major depressive disorder: A pilot study. International Journal of Neuropsychopharmacology, 21, 207–215. 10.1093/ijnp/pyx089 [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kealy, J. , Greene, C. , & Campbell, M. (2020). Blood‐brain barrier regulation in psychiatric disorders. Neuroscience Letters, 726, 133664. [DOI] [PubMed] [Google Scholar]
  21. Lalovic, A. , Klempan, T. , Sequeira, A. , Luheshi, G. , & Turecki, G. (2010). Altered expression of lipid metabolism and immune response genes in the frontal cortex of suicide completers. Journal of Affective Disorders, 120, 24–31. 10.1016/j.jad.2009.04.007 [DOI] [PubMed] [Google Scholar]
  22. Li, L. , Ma, N. , Li, Z. , Tan, L. , Liu, J. , Gong, G. , Shu, N. I. , He, Z. , Jiang, T. , & Xu, L. . (2007). Prefrontal white matter abnormalities in young adult with major depressive disorder: A diffusion tensor imaging study. Brain Research, 1168, 124–128. 10.1016/j.brainres.2007.06.094 [DOI] [PubMed] [Google Scholar]
  23. Li, Q. , Chen, J. , Yu, X. , & Gao, J.‐M. (2019). A mini review of nervonic acid: Source, production, and biological functions. Food Chemistry, 301, 125286. 10.1016/j.foodchem.2019.125286 [DOI] [PubMed] [Google Scholar]
  24. Martínez, M. , & Mougan, I. (2002). Fatty acid composition of human brain phospholipids during normal development. Journal of Neurochemistry, 71, 2528–2533. 10.1046/j.1471-4159.1998.71062528.x [DOI] [PubMed] [Google Scholar]
  25. McNamara, R. K. , & Liu, Y. (2011). Reduced expression of fatty acid biosynthesis genes in the prefrontal cortex of patients with major depressive disorder. Journal of Affective Disorders, 129, 359–363. 10.1016/j.jad.2010.08.021 [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Medina, J. M. , & Tabernero, A. (2002). Astrocyte‐synthesized oleic acid behaves as a neurotrophic factor for neurons. Journal of Physiology, 96, 265–271. [DOI] [PubMed] [Google Scholar]
  27. Mele, M. , Ferreira, P. G. , Reverter, F. , DeLuca, D. S. , Monlong, J. , Sammeth, M. , Young, T. R. , Goldmann, J. M. , Pervouchine, D. D. , Sullivan, T. J. , & Johnson, R. (2015). The human transcriptome across tissues and individuals. Science, 348, 660–665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Miyazaki, M. , & Ntambi, J. M. (2008). Fatty acid desaturation and chain elongation in mammals. In: Biochemistry of Lipids, Lipoproteins and Membrane. Elsevier, 191–211. [Google Scholar]
  29. Müller, C. P. , Reichel, M. , Mühle, C. , Rhein, C. , Gulbins, E. , & Kornhuber, J. (2015). Brain membrane lipids in major depression and anxiety disorders. Biochimica et Biophysica Acta (BBA) ‐ Molecular and Cell Biology of Lipids, 1851, 1052–1065. 10.1016/j.bbalip.2014.12.014 [DOI] [PubMed] [Google Scholar]
  30. Nguyen, L. N. , Ma, D. , Shui, G. , Wong, P. , Cazenave‐Gassiot, A. , Zhang, X. , Wenk, M. R. , Goh, E. L. , & Silver, D. L. (2014). Mfsd2a is a transporter for the essential omega‐3 fatty acid docosahexaenoic acid. Nature, 509, 503–506. [DOI] [PubMed] [Google Scholar]
  31. Nobuhara, K. , Okugawa, G. , Sugimoto, T. , Minami, T. , Tamagaki, C. , Takase, K. , Saito, Y. , Sawada, S. , & Kinoshita, T. (2006). Frontal white matter anisotropy and symptom severity of late‐life depression: A magnetic resonance diffusion tensor imaging study. Journal of Neurology, Neurosurgery and Psychiatry, 77, 120–122. 10.1136/jnnp.2004.055129 [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sheehan, D. V. , Lecrubier, Y. , Sheehan, K. H. , Amorim, P. , Janavs, J. , Weiller, E. , Hergueta, T. , Baker, R. , & Dunbar, G. C. (1998). The Mini‐International Neuropsychiatric Interview (M.I.N.I.): The development and validation of a structured diagnostic psychiatric interview for DSM‐IV and ICD‐10. Journal of Clinical Psychiatry, 59, 22–33. [PubMed] [Google Scholar]
  33. Song, S. , Wang, H. , Jia, S. S. , Man, Q. Q. , Qin, B. , & Zhang, J. (2018). Analysis of correlation between serum fatty acid profile and cognitive impairment in the elderly. Chinese J Prev Med, 52, 636–641. [DOI] [PubMed] [Google Scholar]
  34. Sublette, M. E. , Bosetti, F. , DeMar, J. C. , Ma, K. , Bell, J. M. , Fagin‐Jones, S. , Russ, M. J. , & Rapoport, S. I. (2007). Plasma free polyunsaturated fatty acid levels are associated with symptom severity in acute mania. Bipolar Disorders, 9, 759–765. 10.1111/j.1399-5618.2007.00387.x [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. van Velzen, L. S. , Kelly, S. , Isaev, D. , Aleman, A. , Aftanas, L. I. , Bauer, J. , Baune, B. T. , Brak, I. V. , Carballedo, A. , Connolly, C. G. , Couvy‐Duchesne, B. , Cullen, K. R. , Danilenko, K. V. , Dannlowski, U. , Enneking, V. , Filimonova, E. , Förster, K. , Frodl, T. , Gotlib, I. H. , … Schmaal, L. (2020). White matter disturbances in major depressive disorder: A coordinated analysis across 20 international cohorts in the ENIGMA MDD working group. Molecular Psychiatry, 25, 1511–1525. 10.1038/s41380-019-0477-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Young, J. J. , Silber, T. , Bruno, D. , Galatzer‐Levy, I. R. , Pomara, N. , & Marmar, C. R. (2016). Is there progress? An overview of selecting biomarker candidates for major depressive disorder. Frontiers in Psychiatry, 7, 72. 10.3389/fpsyt.2016.00072 [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Young, R. C. , Biggs, J. T. , Ziegler, V. E. , & Meyer, D. A. (1978). A rating scale for mania: Reliability, validity and sensitivity. British Journal of Psychiatry, 133, 429–435. 10.1192/bjp.133.5.429 [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Material

Click here for additional data file. (406KB, docx)

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Articles from Brain and Behavior are provided here courtesy of Wiley

RESOURCES