Baseline comparisons of demographic and clinical characteristics between the Olan + Baicalin group and the Olan group
Eighty-nine, drug-naïve, first-episode schizophrenia patients were enrolled in this study. Forty-five patients were treated with Olan and Baicalin, and forty-four patients were treated with Olan alone (Fig. 1). There were no differences in demographic characteristics, serum markers (Hcy, SOD and Hs-CRP), PANSS severity and cognitive function between the two groups (p > 0.05) (Table 1).
Table 1
Demographic and clinical characteristics of the subjects.
Characteristics
|
Olan + Baicalin group
|
Olan group
|
X2/F value
|
p value
|
|
(Mean ± SD, N = 45)
|
(Mean ± SD, N = 44)
|
|
|
Age (years)
|
22.6 ± 6.6
|
22.7 ± 6.3
|
0.059
|
0.081
|
Education level (years)
|
10.4 ± 2.5
|
10.9 ± 2.6
|
1.051
|
0.577
|
Course of disease (months)
|
11.5 ± 8.2
|
11.9 ± 7.7
|
0.223
|
0.375
|
BMI (kg/m2)
|
21.8 ± 2.8
|
21.4 ± 3.9
|
-0.427
|
0.671
|
Serum markers
|
N (%)
|
N (%)
|
X2
|
p
|
hs-CRP (mg/L)
|
1.07 ± 1.42
|
0.73 ± 0.78
|
-1.401
|
0.166
|
Hcy (mmol/L)
|
18.79 ± 9.97
|
18.78 ± 7.99
|
-0.006
|
0.995
|
SOD(U/mL)
|
181.04 ± 22.84
|
179.98 ± 21.32
|
-0.226
|
0.822
|
PANSS severity
|
|
|
|
|
PANSS-T
|
83.22 ± 11.63
|
84.23 ± 9.71
|
0.442
|
0.660
|
PANSS-P
|
23.18 ± 4.02
|
23.93 ± 4.60
|
0.824
|
0.412
|
PANSS-N
|
21.29 ± 3.68
|
21.93 ± 3.71
|
0.821
|
0.414
|
PANSS-G
|
38.76 ± 8.09
|
38.36 ± 6.72
|
-0.248
|
0.804
|
Cognitive function
|
|
|
|
|
SOP
|
34.16 ± 12.25
|
32.63 ± 13.52
|
-0.554
|
0.581
|
AV
|
32.24 ± 10.43
|
32.07 ± 10.46
|
-0.075
|
0.941
|
WM
|
43.02 ± 9.86
|
39.48 ± 12.93
|
-1.425
|
0.158
|
HVLT
|
41.32 ± 8.98
|
41.21 ± 8.78
|
-0.054
|
0.957
|
BVMT
|
42.36 ± 13.36
|
43.91 ± 14.69
|
0.509
|
0.612
|
RPS
|
34.93 ± 10.01
|
38.21 ± 11.20
|
1.434
|
0.155
|
SC
|
40.75 ± 15.82
|
41.60 ± 17.95
|
0.232
|
0.817
|
Gender
|
|
|
|
|
Male
|
21(42)
|
24(55)
|
0.552
|
0.527
|
Female
|
24(48)
|
20(45)
|
|
|
Smoking status
|
|
|
|
|
Yes
|
4(9)
|
7(16)
|
1.012
|
0.353
|
No
|
41(91)
|
37(84)
|
|
|
Note: Body Mass Index, hs-CRP: high-sensitivity C-reactive protein, Hcy: homocysteine, SOD: superoxide dismutase. PANSS: The Positive and Negative Syndrome Scale, including positive, negative and general psychopathology symptoms represented by PANSS-P, PANSS-N and PANSS-G respectively, PANSS-T = PANSS-P + PANSS-N + PANSS-G. SOP: Speed of Processing, AV: Attention/Vigilance, WM: Working Memory, HVLT: Hopkin’s Verbal Learning and Memory Test, BVMT: Brief Visual Memory Test, RPS: Reasoning and Problem Solving, SC: Social Cognitive.
Comparisons of clinical measures between the Olan + Baicalin group and the Olan group during the 24-week treatment period.
The within group analysis showed that significant decreases in Hcy levels and significant increases in SOD levels occurred in both groups after 24 weeks of treatment (p’s < 0.05). The PANSS-T, PANSS-P, PANSS-N and PANSS-G scores were significantly decreased after 24 weeks compared with the baseline, for both groups (p’s < 0.001). Moreover, the cognitive domains, including attention/vigilance (AV), WM, hopkins verbal learning test (HVLT) and social cognition (SC), were significantly increased in both groups after 24 weeks of treatment (Table 2).
Among the groups, the PANSS-T scores in the Olan + Baicalin group (54.26 ± 6.44, 46.67 ± 5.71) at both week 12 and week 24 were significantly lower than that of the Olan alone group (58.13 ± 6.44, 51.81 ± 6.16) (p = 0.010 and p = 0.001, respectively); the PANSS-N scores of the Olan + Baicalin group (13.90 ± 3.19, 10.50 ± 1.46) were significantly lower than those of the Olan alone group (16.58 ± 3.62, 14.82 ± 3.31) at both week 12 and week 24 (p = 0.001 and p < 0.001, respectively) (Table 2).
When comparisons of cognitive function were performed among groups, significant improvements in the cognitive domains of AV and BVMT were observed in the Olan + Baicalin group (44.96 ± 9.95 and 55.59 ± 10.46, respectively) compared with those of the Olan alone group (37.60 ± 11.65 and 48.12 ± 8.49, respectively) after the 24-week treatment period (p = 0.018 and p = 0.007, respectively). The T scores for WM were significantly higher in the Olan + Baicalin group (48.42 ± 12.43, 54.56 ± 11.04) than in the Olan alone group (41.63 ± 11.01, 44.88 ± 9.68) at both week 12 and week 24 (p = 0.015 and p = 0.002, respectively) (Table 2).
For each recorded variable, we used the values at 24 weeks minus the corresponding values at baseline to obtain the difference, i.e., the changes in each index after 24 weeks of treatment. The random-intercept linear mixed-effect models showed that changes in the PANSS-N scores showed significant differences between the Olan alone and the Olan + Baicalin groups (p < 0.001). The changes in PANSS-T (p < 0.001), PANSS-N (p < 0.001), PANSS-G (p < 0.05), AV (p = 0.046) and WM (p < 0.01) were also different between the two groups (Table 2, Fig. 2). These results confirmed that differences between the groups (with vs without Baicalin addition) could affect changes in PANSS negative symptoms and cognition functions after 24 weeks of treatment.
Table 2
Descriptive statistics of outcome measures, compared between the Olan + Baicalin group and the Olan group, at baseline, week 12 and week 24
Baseline
|
Week12
|
|
Week 24
|
Estimates
|
se
|
df
|
t
|
Pr>|t|(P value)
|
|
N
|
Mean ± SD
|
p
|
N
|
Mean ± SD
|
p
|
N
|
Mean ± SD
|
p
|
Hcy(µmol/L)
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Olan + Baicalin group
|
45
|
18.79 ± 9.97
|
0.995
|
44
|
14.42 ± 6.29
|
0.336
|
44
|
17.15 ± 4.77
|
0.257
|
7.1
|
0.30
|
331
|
5.910
|
90.404(0.146)
|
Olan group
|
44
|
18.78 ± 7.99
|
44
|
15.76 ± 6.72
|
44
|
19.42 ± 12.27
|
SOD(u/mL)
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Olan + Baicalin group
|
45
|
181.04 ± 22.84
|
0.822
|
45
|
196.16 ± 16.29
|
0.616
|
45
|
203.10 ± 26.14
|
0.054
|
24
|
0.34
|
412
|
1.852
|
0.451(0.121)
|
Olan group
|
44
|
179.97 ± 21.32
|
44
|
193.94 ± 24.46
|
44
|
194.20 ± 15.64
|
Hs-CRP (mg/L)
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Olan + Baicalin group
|
45
|
1.07 ± 1.42
|
0.166
|
45
|
1.19 ± 1.79
|
0.128
|
45
|
1.06 ± 0.74
|
0.012
|
43.2
|
0.26
|
335
|
0.368
|
7.807(0.371)
|
Olan group
|
44
|
0.73 ± 0.78
|
44
|
1.88 ± 2.40
|
44
|
1.91 ± 2.04
|
PANSS-T
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Olan + Baicalin group
|
45
|
83.22 ± 11.63
|
0.66
|
39
|
54.26 ± 6.44
|
0.010
|
33
|
46.67 ± 5.71
|
0.001
|
335.6
|
0.15
|
313
|
1.700
|
19.304(0.003)
|
Olan group
|
44
|
84.23 ± 9.71
|
39
|
58.13 ± 6.44
|
27
|
51.82 ± 6.16
|
PANSS-P
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Olan + Baicalin group
|
45
|
23.18 ± 4.02
|
0.412
|
39
|
12.03 ± 2.88
|
0.203
|
34
|
10.41 ± 1.62
|
0.785
|
431
|
0.37
|
539
|
3.000
|
1.052(0.247)
|
Olan group
|
44
|
23.93 ± 4.60
|
39
|
12.80 ± 2.39
|
27
|
10.30 ± 1.66
|
PANSS-N
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Olan + Baicalin group
|
45
|
21.29 ± 3.68
|
0.414
|
39
|
13.90 ± 3.19
|
0.001
|
34
|
10.50 ± 1.46
|
< 0.001
|
15
|
0.83
|
490
|
16.000
|
9.215(< 0.001)
|
Olan group
|
44
|
21.93 ± 3.71
|
40
|
16.58 ± 3.62
|
27
|
14.82 ± 3.31
|
PANSS-G
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Olan + Baicalin group
|
45
|
38.76 ± 8.09
|
0.804
|
39
|
28.33 ± 3.96
|
0.750
|
33
|
25.76 ± 4.40
|
0.421
|
42.6
|
0.73
|
332
|
0.520
|
10.190(0.011)
|
Olan group
|
44
|
38.36 ± 6.72
|
40
|
28.60 ± 3.43
|
27
|
26.70 ± 4.62
|
SOP
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Olan + Baicalin group
|
44
|
34.16 ± 12.25
|
0.581
|
36
|
36.00 ± 8.85
|
0.879
|
27
|
39.78 ± 8.38
|
0.261
|
35.6
|
0.42
|
580
|
2.500
|
0.802(0.373)
|
Olan group
|
42
|
32.63 ± 13.52
|
38
|
35.63 ± 11.78
|
25
|
36.72 ± 10.93
|
AV
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Olan + Baicalin group
|
44
|
32.24 ± 10.43
|
0.941
|
36
|
36.97 ± 8.63
|
0.441
|
27
|
44.96 ± 9.95
|
0.018
|
14
|
0.18
|
239
|
7.600
|
5.107(0.046)
|
Olan group
|
41
|
32.07 ± 10.46
|
38
|
35.18 ± 11.02
|
25
|
37.60 ± 11.65
|
WM
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Olan + Baicalin group
|
44
|
43.02 ± 9.86
|
0.158
|
36
|
48.42 ± 12.43
|
0.015
|
27
|
54.56 ± 11.04
|
0.002
|
343
|
0.47
|
415
|
4.600
|
13.000(< 0.001)
|
Olan group
|
42
|
39.48 ± 12.93
|
38
|
41.63 ± 11.01
|
25
|
44.88 ± 9.68
|
HVLT
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Olan + Baicalin group
|
44
|
41.32 ± 8.98
|
0.957
|
36
|
40.58 ± 7.61
|
0.821
|
27
|
48.11 ± 10.79
|
0.852
|
2.64
|
0.12
|
457
|
0.020
|
0.700(0.791)
|
Olan group
|
42
|
41.21 ± 8.78
|
38
|
40.18 ± 7.47
|
25
|
47.6 ± 8.67
|
BVMT
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Olan + Baicalin group
|
44
|
42.36 ± 13.36
|
0.612
|
36
|
47.50 ± 11.59
|
0.08
|
27
|
55.59 ± 10.46
|
0.007
|
6
|
0.57
|
218
|
7.230
|
3.305(0.730)
|
Olan group
|
42
|
43.91 ± 14.69
|
38
|
42.76 ± 11.38
|
25
|
48.12 ± 8.49
|
RPS
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Olan + Baicalin group
|
44
|
34.93 ± 10.01
|
0.155
|
36
|
38.68 ± 10.92
|
0.796
|
27
|
38.56 ± 10.29
|
0.139
|
15
|
0.63
|
109
|
3.240
|
22.730(0.120)
|
Olan group
|
42
|
38.21 ± 11.20
|
38
|
39.26 ± 8.74
|
25
|
42.56 ± 8.81
|
SC
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Olan + Baicalin group
|
44
|
40.75 ± 15.82
|
0.817
|
36
|
50.94 ± 20.61
|
0.228
|
27
|
52.37 ± 20.29
|
0.922
|
3.43
|
0.43
|
114
|
1.990
|
20.340(0.520)
|
Olan group
|
42
|
41.60 ± 17.95
|
38
|
45.58 ± 17.31
|
25
|
51.88 ± 14.83
|
Note: Hcy: homocysteine, SOD: superoxide dismutase, Hs-CRP: high-sensitivity C-reactive protein; PANSS: The Positive and Negative Syndrome Scale, including positive, negative and general psychopathology symptoms represented by PANSS-P, PANSS-N and PANSS-G respectively, PANSS-T = PANSS-P + PANSS-N + PANSS-G; SOP: Speed of Processing, AV: Attention/Vigilance, WM: Working Memory, HVLT: Hopkins Verbal Learning Test, BVMT: Brief Visual Memory Test, RPS: Reasoning and Problem Solving, SC: Social Cognitive. |
Changes in PANSS negative symptoms and cognition functions in the Olan + Baicalin and Olan alone groups
The PANSS change rates, including those for PANSS-T, PANSS-P, PANSS-N, and PANSS-G, were calculated using the following formula: Change rate (%) = [(the baseline score - the corresponding score after 24 weeks of treatment)/the baseline score] × 100. Based on this calculation, change rates were categorized as high response if the value was ≥ 50%, as clinical response if the value was ≥ 25% and ≤ 50%, and as low response if the value was ≤ 25%.
The Olan + Baicalin group showed much better response rates than the Olan alone group for PANSS-T, PANSS-N and PANSS-G. In the Olan alone group for PANSS-P, only 2% of patients were categorized as high response. In contrast, in the Olan + Baicalin group for PANSS-N, the percentage of high response patients was 57%, which was much higher than that of the Olan alone group (Fig. 3). Similarly, the percentage of high response patients for PANSS-T and PANSS-G were significantly higher in the Olan + Baicalin group than in the Olan alone group. Conversely, the percentage of low response patients was significantly lower in the Olan + Baicalin group than in the Olan alone group. The contingency cross-table test showed that PANSS-T (contingency coefficient = 0.329, p = 0.005) and PANSS-N (contingency coefficient = 0.531, p’s < 0.001) were significant correlated with the different treatments (i.e., Olan + Baicalin vs Olan alone) (Supplementary Table 1). Our results demonstrated that using Olan in combination with Baicalin resulted in improved responses to treatment in patients compared with using Olan alone.
To further identify whether the observed improvements in PANSS negative symptoms were primary or secondary, those patients whose positive scores > 15 at baseline or who had depression scores > 20 were excluded from the analysis to eliminate the influences of positive symptoms and depression. The results showed that the Olan + Baicalin group had a better performance in the PANSS negative symptoms compared with the Olan group (> 50%).
All the MCCB scores showed great time effects (p’s < 0.001 for all parameters) for both groups (Table 2), which indicated that cognition was improved in both groups after 12 weeks and after 24 weeks. To compare the effects of Baicalin addition on cognitive functions, the difference-value (D-value) of each patient for each score (reasoning and problem solving, RPS) (SOP, AV, WM, BVMT, HVLT, RPS, and SC) was calculated using the following formula: D-value = the value after 24 weeks-the corresponding value at baseline. Patients with a D-value in any score of at least 10 were greatly improved. Patients with D-values lower than 10 were poorly improved. For all the MCCB scores, the Olan + Baicalin group had a greater percentage of greatly improved patients than the Olan alone group (Fig. 4). For AV, WM and HVLT, the percentages of greatly improved patients in the Olan + Baicalin group were almost double those of the Olan alone group. In addition, the contingency table test showed that the AV (contingency coefficient = 0.230, p = 0.026), WM (contingency coefficient = 0.316, p = 0.002) and BVMT (contingency coefficient = 0.271, p = 0.008) scores were strongly correlated with the different treatments (Supplementary Table 1). Our results showed that the addition of Baicalin could significantly improve cognitive function after 24 weeks in schizophrenia patients treated with Olan.
Adverse events