Alterations of eicosanoids and related mediators in patients with schizophrenia

Dongfang Wanga, Xiaoyu Suna, Jingjing Yana, Biao Renb, Bing Caoa, Lailai Yana,c,d,

Qingbin Lua,c,d, Yaqiong Liua,c,d, Jing Zenga,c,d, Ninghua Huanga,c,d, Qing Xiea,c,d, Haiwei

Gue*, and Jingyu Wanga,c,d*

a Department of Laboratorial Science and Technology, School of Public Health,

Peking University, Beijing 100191, P. R. Chinab Shimadzu (China) Co., LTD Beijing Branch, Beijing 100020, P. R. China.c Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food

Safety, Beijing 100191, P.R. Chinad Peking University Medical and Health Analysis Center, Peking University, Beijing

100191, P.R. Chinae Center for Metabolic and Vascular Biology, School of Nutrition and Health

Promotion, College of Health Solutions, Arizona State University, Phoenix, AZ

85004, USA

* Corresponding Authors:Haiwei Gu, Ph.D. Center for Metabolic and Vascular BiologySchool of Nutrition and Health PromotionCollege of Health SolutionsArizona State University13208 E. Shea Blvd, CRB 2-221Scottsdale, AZ 85259Tel: 480-301-6016Fax: 480-301-7017Email: haiweigu@asu.edu Jingyu Wang, Ph.D. School of Public Health, Peking UniversityNo.38 Xueyuan Road, Haidian DistrictBeijing 100191, P.R. ChinaTel/Fax: +86-10-82801107Email: wjy@bjmu.edu.cn

1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

161718192021222324252627282930313233

12

Table S1. The spiked concentrations of 14 internal standards.

A Separate Excel Table: Table S2. The LC-MS/MS parameters of the 158

metabolites and 14 internal standards used in this study.

Table S3. The gradient conditions for reversed phase C8 separation.

Table S4. Demographic and clinical characteristics of first episode and recurrent

patients at baseline.

Table S5. Antipsychotic use for patients during 8-week treatment.

Table S6. The AUROCs of individual significant metabolites for the comparison

between SCZ patients and healthy controls at baseline.

Table S7. The AUROCs of individual significant metabolites for the comparison

between pretreatment and posttreatment patients.

Fig. S1. Distribution of coefficients of variation (CVs) of all measured metabolites in

this study.

Fig. S2. Top 10 metabolites with highest VIP values from OPLS-DA models for

separation between (a) SCZ patients and healthy controls, (b) pretreatment patients

and posttreatment patients.

Fig. S3. Partial correlation coefficients among changes of eicosanoids and related

metabolites, and among changes of eicosanoid metabolites and clinical characteristics,

after adjusting for age, sex, BMI, current smoking, current drinking and

psychiatric family history.

S-2

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

34

Table S1

The spiked concentrations of 14 internal standards.

Group

Internal standardSpiked concentration

(ng/mL)

1 Tetranor-PGEM-d6 1.1252 6-keto-Prostaglandin F1α-d4 1.1253 Thromboxane B2-d4 1.1254 Prostaglandin F2α-d4 2.3755 Prostaglandin E2-d4 2.3756 Prostaglandin D2-d4 1.1257 Leukotriene C4-d5 1.1258 Leukotriene B4-d4 1.1259 15(S) HETE-d8 1.12510 12(S) HETE-d8 1.12511 5(S) HETE-d8 1.12512 PAF C-16-d4 2.00013 Oleoyl Ethanolamide-d4 2.00014 Arachidonic Acid-d8 25.000

S-3

54

55

56

56

Table S3

The gradient conditions for reversed phase C8 separation.

Time(min) A (v%) B (v%)0.0 90 105.0 75 2510.0 65 3520.0 25 7520.1 5 9525.0 5 9525.1 90 1030.0 90 10

S-4

57

58

78

Table S4

Demographic and clinical characteristics of first episode and recurrent patients.

VariableFirst episode patients

(N=27)Recurrent patients

(N=88)p

Age (years); median (IQR) 29.0 (22.0, 34.0) 29.0 (25.0, 33.0) 0.807a

Gender; male n (%) 11 (40.7) 40 (45.5) 0.666b

BMI (kg/m2); median (IQR) 22.8 (20.4, 27.2) 24.0 (20.9, 25.9) 0.838a

Current smoker; n (%) 1 (3.7) 13 (14.8) 0.254b

Current drinker; n (%) 1 (3.7) 7 (8.0) 0.066b

Psychiatric family history; n (%) 7 (25.9) 12 (13.6) 0.146b

FBG (mmol/L); median (IQR) 5.4 (4.8, 5.6) 5.2 (4.7, 5.4) 0.268c

TG (mmol/L); median (IQR) 1.1 (0.6, 1.3) 0.9 (0.7, 1.4) 0.717c

TC (mmol/L); median (IQR) 4.2 (3.7, 5.4) 4.5 (3.9, 5.0) 0.380c

VLDL (mmol/L); median (IQR) 0.5 (0.3, 0.6) 0.4 (0.3, 0.7) 0.680c

Age of onset (years); median (IQR) 21.0 (18.0, 29.0) 21.5 (19.0, 26.0) 0.900a

Duration of illness (years); median (IQR) 4.2 (1.0, 8.3) 6.0 (2.4, 10.1) 0.119a

PANSS scores; median (IQR)Total score 80.0 (72.0, 93.0) 82.5 (73.3, 101.0) 0.273a

Positive symptoms 22.0 (16.0, 28.0) 21.0 (16.0, 25.0) 0.548a

Negative symptoms 20.0 (11.0, 23.0) 20.5 (15.0, 24.8) 0.249a

General psychopathology 42.0 (34.0, 54.0) 42.0 (37.0, 50.0) 0.995a

ap values were calculated by two-tailed Mann-Whitney U-tests. bp values were calculated by

chi-square tests. cP values were calculated by general linear models (GLM) after adjustment

for age, sex, BMI, smoking, drinking, and psychiatric family history. BMI, body mass

index; FBG, fasting blood glucose; TG, triglyceride; TC, total cholesterol; VLDL, very low

density lipoprotein; IQR, interquartile range.

S-5

59

60

61

62

63

64

65

910

Table S5

Clinical treatment therapies of Study Participants.

Categories DrugsNo. of Patients (n, %)

First generation antipsychotics Haloperidol 9 (8.26)Chlorpromazine 1 (0.92)Promethazine 4 (3.67)

Second generation antipsychotics

Olanzapine 20 (18.35)Risperidone 34 (31.19)Clozapine 30 (27.52)Quetiapine 42 (38.53)Ziprasidone 25 (22.94)Aripiprazole 17 (15.60)Perphenazine 4 (3.67)Sulpiride 2 (1.83)

AnxiolyticsLorazepam 31 (28.44)Clonazepam 6 (5.50)Alprazolam 8 (7.34)

Anticonvulsants Magnesium valproate

20 (18.35)

Sodium valproate 18 (16.51)Anti-Tremor Medications Benzhexol 30 (27.52)

S-6

66

67

1112

Table S6

The AUROCs of individual significant metabolites for the comparison between SCZ

patients and healthy controls at baseline.

Metabolites AUROC 95% CIAA 0.682 0.612-0.751PGE2 0.537 0.458-0.615PGA2 0.539 0.461-0.616PGF2α 0.541 0.462-0.620PGJ2 0.548 0.471-0.625TXB2 0.585 0.508-0.66211-dehydro-TXB2 0.550 0.473-0.62711,12-DHET 0.604 0.528-0.67914,15-DHET 0.632 0.559-0.70520-carboxy-AA 0.643 0.571-0.716LTB4 0.543 0.466-0.62012-HpETE 0.604 0.529-0.67912-HETE 0.534 0.455-0.61315-HETE 0.512 0.432-0.5928-HETE 0.518 0.440-0.59611-HETE 0.544 0.466-0.622DHA 0.622 0.548-0.69513-HDoHE 0.587 0.512-0.662EPA 0.625 0.552-0.69812-HEPE 0.510 0.432-0.587AEA 0.810 0.754-0.867OEA 0.834 0.780-0.88915-KEDE 0.629 0.556-0.702

AUROC, area under the receiver-operating characteristic curve; CI, confidence interval.

S-7

68

69

70

71

1314

Table S7

The AUROCs of individual significant metabolites for the comparison between

pretreatment and posttreatment patients.

Metabolites AUROC 95% CIPGE2 0.585 0.509-0.660PGF2α 0.624 0.550-0.698TXB2 0.639 0.566-0.71211-dehydro-TXB2 0.615 0.540-0.68911,12-DHET 0.721 0.655-0.78814,15-DHET 0.662 0.591-0.73420-carboxy-AA 0.711 0.643-0.7795-KETE 0.577 0.501-0.65212-HETE 0.595 0.520-0.6704-HDoHE 0.636 0.563-0.7097-HDoHE 0.654 0.582-0.72612-HEPE 0.573 0.497-0.649AEA 0.699 0.630-0.769OEA 0.716 0.647-0.78415-KEDE 0.642 0.569-0.71513-HpODE 0.611 0.537-0.68613-KODE 0.633 0.560-0.7079,10-DiHOME 0.635 0.561-0.7089-HpODE 0.609 0.534-0.68313-HODE 0.622 0.548-0.6969-HODE 0.626 0.552-0.6999-KODE 0.638 0.565-0.711

AUROC, area under the receiver-operating characteristic curve; CI, confidence interval.

S-8

72

73

74

75

1516

<5% 5-10% 10-15% 15-20% 20-25%0

5

10

15

20

25

30

35

40

CV distribution

% o

f met

abol

ites

Fig. S1

S-9

76

77

1718

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0

PGE2

12-HpETE

15-KEDE

AA

12-HETE

EPA

11-dehydro-TXB2

AEA

OEA

TXB2

VIP values

Lipi

d m

etab

olite

s

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8

13-HODE

9-HODE

9-HpODE

13-KODE

AEA

14,15-DHET

15-KEDE

11,12-DHET

20-carboxy-AA

OEA

VIP values

Lipi

d m

etab

olite

s

a b

Fig. S2

S-10

78

79

1920

Fig. S3

S-11

8081

2122