Reduced erythrocyte membrane polyunsaturated fatty acid levels indicate diminished treatment response in patients with multi- versus first-episode schizophrenia

Abstract

Antipsychotic effects seem to decrease in relapsed schizophrenia patients and the underlying mechanisms remain to be elucidated. Based on the essential role of polyunsaturated fatty acids in brain function and the treatment of schizophrenia, we hypothesize that disordered fatty acid metabolism may contribute to treatment resistance in multi-episode patients. We analyzed the erythrocyte membrane fatty acids in 327 schizophrenia patients under various episodes (numbers of patients: first-episode drug naïve 89; 2-3 episodes 110; 4-6 episodes 80; over 6 episodes 48) and 159 age- and gender-matched healthy controls. Membrane fatty acid levels and PANSS scales were assessed at baseline of antipsychotic-free period and one-month of follow-up after treatment. Totally, both saturated and unsaturated fatty acids were reduced at baseline when compared to healthy controls. Subgroup analyses among different episodes indicated that in response to atypical antipsychotic treatment, the membrane fatty acids were only increased in patients within 3 episodes, and this therapeutic effects on omega-3 index were merely present in the first episode. Results of fatty acid ratios suggested that dysregulations of enzymes such as D6 desaturase, D5 desaturase, and elongases for polyunsaturated fatty acids in patients with multi-episode schizophrenia could account for the differences. Additionally, certain fatty acid level/ratio changes were positively correlated with symptom improvement. The alterations of C22:5n3 and omega-3 index, gender, and the number of episodes were significant risk factors correlated with treatment responsiveness. Using targeted metabolomic approach, we revealed the potential mechanisms underlying abnormal fatty acid metabolism responsible for reduced treatment response in patients with multi-episode schizophrenia.

Fig. 1. Symptom improvement after treatment among patients with different episodes.

a correlation between PANSS total score reduction and number of episodes; proportion of treatment response in patient subgroups of different episodes. b PANSS reduction after treatment among patients with different episodes. First-episode patients showed the largest improvement in PANSS total scores, positive, general psychopathology, paranoid/belligerence, and depression. No significant differences were found in negative symptoms or other cluster scores (anergia, thought disturbance, and activation). FE, first episode; Spearman correlation, Kruskal–Wallis test and a Dunn–Bonferroni post hoc method were used; *p < 0.05, **p < 0.01, ***p < 0.001.

Fig. 2. Differences in membrane fatty acid levels and ratios between patients with schizophrenia at baseline (SZ-0) and healthy controls (HC) as well as changes after antipsychotic treatment (SZ-4).

a Specific fatty acids we measured and summations for SFAs, n-6 PUFAs, n-3 PUFAs, PUFAs, and total FAs; b n-6/n-3 ratio, omega-3 index and unsaturation index; c fatty acid ratios (markers of enzymes). SFAs, saturated fatty acids; PUFAs, polyunsaturated fatty acids; FAs, fatty acids; plots are shown as the means and standard errors; the Mann–Whitney test was used to analyze the variations between HC and SZ-0, and group pairwise differences between SZ-0 and SZ-4 were determined by the Wilcoxon signed rank test. *p < 0.05, **p < 0.01, ***p < 0.001.

Fig. 3. Differences in membrane fatty acid levels and ratios between baseline and after antipsychotic treatment in patient subgroups divided by episodes.

a EPA (C20:5n3), DHA (C22:6n3) and summations for SFAs, MUFAs, PUFAs, n-6 PUFAs, n-3 PUFAs, and total FAs; b n-6/n-3 ratio, omega-3 index and unsaturation index. c Fatty acid ratios that present corresponding enzymes in the fatty acid synthetic pathways; d the synthetic pathways of fatty acids. SCD-1, stearoyl-coenzyme A desaturase-1. The fatty acids in red text indicate the types of specific fatty acids we analyzed in this study. The red dotted line divides the opposing trends of changes among the four subgroups. FE, first-episode; MUFAs, monounsaturated fatty acids; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid. Plots are shown as the means and standard errors. The Wilcoxon signed rank test was used. *p < 0.05, **p < 0.01, ***p < 0.001 for increase; #p < 0.05, ##p < 0.01, ###p < 0.001 for decrease.

Fig. 4. Partial correlation and logistic regression analyses in all the patients with schizophrenia after antipsychotic treatment.

a Significant correlations between fatty acid level changes and PANSS total score improvement. b Significant correlations between fatty acid ratio changes and PANSS total score improvement. c Forest plot of logistic regression of treatment response and fatty acid level changes. Gender, age, chlorpromazine-equivalent dose, number of episodes, and disease course are added to the regression model to control the influence of these confounding factors on antipsychotic responses. Partial Spearman’s rank correlation and binary logistic regression were used.

Fig. 5. Flowchart of the research.

Through eligibility assessment, 327 schizophrenia patients and 159 healthy controls were recruited. The recruited patients were divided into four subgroups according to episodes: first episode (FE), 2–3 episodes, 4–6 episodes, and over 6 episodes. We measured the concentrations of ten fatty acids in the erythrocyte membrane and performed PANSS assessment at baseline (SZ-0) and after four weeks of treatment (SZ-4). Total and subgroup analyses were conducted to identify differential biomarkers between schizophrenia patients and healthy controls. Correlations between fatty acid level changes and symptom improvement were analyzed by partial correlation analysis and logistic regression, to explore potential biomarkers indicative of treatment responsiveness.