Blood Plasma Lipid Alterations Differentiating Psychotic and Affective Disorder Patients

Abstract

Psychotic and affective disorders, including schizophrenia (SCZ) and depression (MDD), affect millions of people globally. The overlapping symptoms of these diseases and the lack of objective diagnostic tools could lead to misdiagnosis. Recent studies suggest that the analysis of plasma lipid levels may help to develop new diagnostic tools. In this study, we investigated the plasma lipidome of psychiatric patients and healthy controls to identify disease-specific lipid species. Using untargeted mass spectrometry, we profiled blood plasma lipids from 416 patients with common psychotic and affective disorders and 272 healthy individuals from two different cohorts. We observed lipidome alterations in SCZ and MDD consistent with earlier findings. In total, 144 lipids showed significant changes, with 107 of them being concordant across both disorders, and 37 being discordant. Lipids that differentiated SCZ from MDD were mainly triacylglycerols with polyunsaturated fatty acid residues decreased in MDD. In an additional group of 111 patients with bipolar, schizotypal, and schizoaffective disorders, these lipid markers suggested a trend toward separating psychotic and affective disorders. Furthermore, a logistic regression model trained on lipid data distinguished SCZ from MDD with an ROC AUC of 0.83. Taken together, these results suggest that blood lipid profiling may aid in the objective differentiation of psychotic and affective disorders.

Keywords: biomarkers; depression; lipidomics; mass spectrometry; psychiatric disorders; schizophrenia.

Figure 3

(A) K-means clustering analysis of log₂-transformed FC between SCZ or MDD vs. CTR for both cohorts. First two graphs depict smoothed FC of disease vs. CTR for Cohort 1 and Cohort 2 datasets in the order of lipids according to the k-means analysis result, and vertical lines indicate the borders of clusters. The last plot shows smoothed FC of MDD vs. SCZ for cohorts. The left colored part of the plots highlights the clusters different between MDD and SCZ (discordant), and the right part shows similar clusters (concordant). (B) Correlations of FC in lipid abundances for SCZ or MDD vs. CTR for all lipids in the discordant clusters. (C) Correlations of FC in lipid abundances for SCZ or MDD vs. CTR for all lipids in the concordant clusters. For B and C, black lines are the diagonals of I and III quadrants; n stands for the number of lipids in the discordant or concordant clusters; and r stands for the Pearson correlation coefficient for both cohorts (Coh. 1 or Coh. 2). (D) Number of lipids of the discordant clusters distributed by classes. Red asterisk depicts the significance (adj. p < 0.05) of the hypergeometric test for enrichment of a particular lipid class in the discordant clusters among lipids of this class in all clusters. (E) Distribution of the double bonds (DB) among the TG included in the concordant and discordant clusters. Red asterisk depicts the significance (p < 0.05) of the Fisher’s exact test of DB number in TG of discordant vs. concordant lipid groups.

Figure 1

(A) The number of individuals in experimental groups: schizophrenia (SCZ), depression (MDD), and control (CTR) in Cohort 1 and Cohort 2. The percentage of females (F) is shown at each bar. (B) Count of detected lipid species distributed by classes: acylcarnitines (CAR), cholesterol esters (CE), ceramides (Cer), cholesterol (Chol), diacylglycerols (DG), lysophosphatidylcholines (LPC), ether LPC (LPC-O), lysophosphatidylethanolamines (LPE), phosphatidylcholines (PC), ether PC (PC-O), phosphatidylethanolamines (PE), plasmalogen PE (PE-P), sphingomyelins (SM), triacylglycerols (TG).

Figure 2

(A) Volcano plots for SCZ and MDD vs. CTR for Cohorts 1 and 2. Significantly altered lipids are red (for the increased ones) and blue (for the decreased ones), and n stands for the number of significantly altered lipids. The x-axis depicts the difference between each lipid log₂-transformed intensity of SCZ or MDD and CTR (FC), and the y-axis depicts − log₁₀ (adj. p-value) for t-test (lipid intensity of SCZ or MDD vs. CTR). (B) Correlations of log₂-transformed FC in lipid abundances for SCZ or MDD against CTR between Cohort 1 and Cohort 2, where r stands for the Pearson correlation coefficient, and n stands for the number of intersected lipids. Red line depicts the linear regression line. (C) Boxplots showing the log₂-transformed FC in lipid abundances for SCZ or MDD against CTR for the intersected lipids from both cohorts distributed by classes. Red asterisks above depict the pairs of boxplots where FC SCZ or MDD vs. CTR of lipids within a class showed a significant difference from 0 (one-sample Wilcoxon test, adj. p < 0.05).

Figure 4

(A) Volcano plots for MDD vs. SCZ for Cohorts 1 and 2. Significantly altered lipids are red (for the increased ones) and blue (for the decreased ones); n stands for the number of significantly altered lipids; x-axis depicts the difference between each lipid log₂-transformed intensity of MDD and SCZ (fold change, FC); and y-axis depicts −log₁₀ (adj. p-value) for t-test (lipid intensity of MDD vs. SCZ). (B) Boxplots showing the log₂-transformed FC in lipid abundances for MDD against SCZ of all the statistically significant lipids from both cohorts distributed by classes. Red asterisks above depict the pairs of boxplots where FC MDD vs. SCZ of lipids within a class showed a significant difference from 0 (one-sample Wilcoxon test, adj. p < 0.05). (C) Correlations of log₂-transformed FC in lipid abundances for MDD against SCZ between Cohort 1 and Cohort 2. The lipids found to be significant in only one of the cohorts are depicted in light red color, while the intersection of significant lipids is shown in dark red points; r stands for the Pearson correlation coefficients (“union” for the all significant lipids in both cohorts (n = 71); and “inters.” for the intersection of significant lipids (n =14)). Black line depicts the linear regression line. (D) UpSet plot for statistically significant lipids between MDD and SCZ (“Sign_MDD_SCZ_statistics”) and those belonging to “discordant” clusters (“Discordant_clusters”). The intersection is shown in the red square (MDD-SCZ lipid panel). The bottom count plot shows the distribution of this panel by lipid classes.

Figure 5

(A) The number of individuals in the experimental groups: schizoaffective (AFF) and schizotypal (TYP) in Cohort 1 and bipolar (BPD) in Cohort 2. The percentage of females (F) is shown on each bar. (B) Illustration of principal component analysis (PCA) for the species included in MDD-SCZ lipid panel performed on both cohorts together. Points corresponding to the different diseases are outlined in colored ellipses. The borders of the ellipses depict the area inside which the points of that group are found with 95% confidence. On the x-axis, the first principal component (PC1) is plotted, while on the y-axis, the second principal component (PC2) is plotted with the percentage of variation explained by this component in the brackets. (C) Kernel density estimation (KDE) of the first components (PC1) of PCA analysis in each cohort. The scale in the middle with symptom gradient is the modified scale of psychotic and affective disorders taken from [38]. C1 in the legends at (B,C) stands for “Cohort 1”, and C2 stands for “Cohort 2”.