Efficacy and safety of the adjunctive Baicalin in schizophrenia patients with negative symptoms and cognitive impairment: a randomized pilot study

doi:10.21203/rs.3.rs-122724/v1

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Research Article

Efficacy and safety of the adjunctive Baicalin in schizophrenia patients with negative symptoms and cognitive impairment: a randomized pilot study

https://doi.org/10.21203/rs.3.rs-122724/v1

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posted 21 Dec, 2020

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Background Negative symptoms and cognitive impairments are severe enough to cause predominant impairment, effective treatment is needed. We examined a new adjunctive therapy Baicalin with olanzapine in schizophrenia.

Methods Eighty-nine schizophrenia patients were treated with either olanzapine and Baicalin (Olan+Baicalin group, n=45) or olanzapine alone (Olan group, n=44) for 24 weeks. We evaluated the Positive and Negative Syndrome Scale (PANSS), cognitive function at baseline, week 12 and week 24. The treatment efficacy was investigated, with particular focus on improvements in predominant negative symptoms.

Results Our results showed significant overall reductions in including positive, negative, general psychopathology and total scores (PANSS-P, PANSS-N, PANSS-G and PANSS-T, respectively) and significantly improved cognition in Olan+Baicalin group compared with that of Olan group after 24 weeks of treatment (p’s<0.001). The observed changes in PANSS-N were independent of changes in PANSS-P and depression. After 24 weeks of treatment, significant reductions in PANSS scores and significant improvements in cognitive skills, including attention/vigilance (AV), working memory (WM), and brief visuospatial memory test (BVMT), were observed in the Olan+Baicalin group compared with the Olan group (p’s<0.05). The oxidative stress and inflammatory responses were significantly attenuated in schizophrenia patients treated with the combination of Olan+Baicalin compared with patients treated with Olan alone (p’s<0.05).

Conclusions The addition of Baicalin was effective for improving the oxidative stress, inflammation, cognition, and PANSS-N, which may provide psychiatrists with a new and safe therapeutic option for the treatment of schizophrenia.

This study is registered with Chictr.org, number ChiCTR1800016727 on 20/06/2018 (http://www.chictr.org.cn/edit.aspx?pid=27895&htm=4).

Psychiatry

Schizophrenia

Baicalin

Olanzapine

Cognitive function

Negative symptoms

The negative symptoms in schizophrenia are the primary contributors to persistent impairment and often respond poorly to antipsychotics [1, 2]. Primary negative symptoms include blunted affect, avolition and alogia and affect a considerable clinical subpopulation[3, 4]. In contrast, secondary negative symptoms are considered to occur because of positive symptoms, depression, or antipsychotic side-effects. Although secondary negative symptoms are only marginally responsive to antipsychotics, their improvement generally coincides with improvements in the positive symptoms, depression, or antipsychotic side-effects. Predominant negative symptoms have been reported to be the primary causes of social disability and recession, and currently, no treatments or drugs have been reported to effectively improve these symptoms[5–7].

The mechanism underlying predominant negative symptoms remains under investigation, and various hypotheses have been suggested. One hypothesis suggests that these symptoms are due to a neuronal metabolism imbalance in the prefrontal cortex[8]. Glutamatergic dysfunction, especially N-methyl-D-aspartate receptor hypofunction, has also been suggested to be associated with negative symptoms, and many drugs have been used to improve negative symptoms based on this mechanism[9, 10]. Studies have suggested a link between negative symptoms and disturbances in the dopamine and reward system functions[11]. Brain network dysfunction and neural asynchrony, induced by the progressive volume loss in temporal and subcortical gray matter structures that has been associated with schizophrenia, may result in long-lasting negative symptoms[12]. In addition, inflammation and oxidative stress have been reported to be involved in the pathogenesis of schizophrenia[13]. Multiple underlying causes may be involved in the occurrence of negative symptoms, and the inflammation pathway may represent a link among multiple factors.

Baicalin, extracted from Scutellaria baicalensis, is listed as an official herbal medicine in China, named Huangqin, and has a 500-year history of uses. In addition to clinical applications for acute and chronic hepatitis, Baicalin has also been shown to benefit ischemia reperfusion injuries during cardiovascular and cerebrovascular diseases, type 2 diabetes, obesity and insulin resistance[14, 15]. Baicalin also has behavioral effects and therapeutic effects during Parkinson's disease by protecting dopaminergic neurons [16, 17]. The anti-inflammatory and anti-apoptotic natures of Baicalin may contribute to the beneficial role of Baicalin because both inflammation and oxidative stress have been reported to be associated with these chronic diseases[18]. Further evidence has shown that Baicalin ameliorates inflammation, oxidative stress, and cell death induced by lipopolysaccharide and other factors, in both in vitro and in vivo studies[19, 20]. In addition, the nuclear factor kappa B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) signaling pathways are likely to be involved in the mechanisms underlying the anti-inflammatory and anti-oxidative effects of Baicalin[21].

This study is the first to explore the efficacy of Baicalin in combination with Olan to improve primary negative symptoms in schizophrenia. We hypothesized that Baicalin would improve the cognitive functions and negative symptoms in schizophrenia by its anti-inflammatory and anti-oxidant roles, as both of which have related to schizophrenia. In this study, we compared the effects of 24-weeks Olan treatments with and without Baicalin on the improvement of negative symptoms in schizophrenia. The primary purpose of the present study was to explore whether the addition of Baicalin could improve the predominant negative symptoms in schizophrenia and to explore the possible underlying mechanisms.

Study design and participants

The present study was a 24-week, randomized, open pilot trial. Participants were recruited from the psychiatric department of the First Affiliated Hospital of Zhengzhou University, between June 2015 and June 2016. This research was approved by the Human Ethics Committee of the First Affiliated Hospital of Zhengzhou University, China. All subjects provided signed informed consent forms. Participation was voluntary, and participants could withdraw at any time from the study.

Patients were eligible for the study if they met the following criteria: (1) diagnosed with first episode schizophrenia, based on the Diagnostic and Statistical Manual of Mental Disorders fourth version (DSM-IV) criteria and confirmed using the Structured Clinical Interview for DSM-IV (SCID) [22]; (2) had never been treated with any antipsychotics; and (3) had a PANSS-T > 70 points[23]. In addition, a psychiatric history for each participant had to be available to ensure that the patients had predominant negative symptoms and low levels of positive symptoms and were therefore suitable for participation in this study. All evaluations were performed by the same trained professional psychiatrist. Patients had to be known to investigators directly, through face to face visits.

The exclusion criteria included the following: (1) any diagnoses of organic disease or psychiatric diseases other than schizophrenia; (2) pregnant or lactating women; (3) a history of using any antibiotic or anti-inflammatory agent in the past month; and (4) overweight or obese (body mass index > 24 kg/m²). To guarantee that any observed improvements in negative symptoms were not secondary to improvements in other psychiatric symptoms (i.e., pseudospecific), patients were excluded for having two or more PANSS-positive (PANSS-P) items with scores > 4 (delusions, hallucinatory behavior, grandiosity, suspiciousness, or unusual thought content) or for experiencing moderate or severe depressive symptoms (Montgomery Asberg Depression Rating Scale [MADRS] total score > 12).

Sample size determination was analyzed using PASS version 15.0.5. Assuming that the sample size and variance of the two groups and was equal, we selected two-sample t-tests. The significance level of the test was set to 0.05 and power set to 0.9. When the negative symptom score of the major outcome measure decreased by 6 points and the standard deviation was 6.5 after treatment, it was expected that 26 people could be included in each group. With a dropout rate of 20 percent, at least 32 people in each group are expected to participate in the experiment.

The olanzapine treatment dosage was gradually titrated from 2.5 mg/day to 20 mg/day as clinically indicated. During the follow up, five patients developed emotional instability and Magnesium Valproate was added to their treatment plan; And, one patient was diagnosed with depression symptoms whom were given additional sertraline treatment.

Randomization and Procedures

We successively distributed a unique randomization code to each patient who consented to participate in this study. Participates were randomized through a computer-generated table conducted by doctor Qiyue Zhu. Patients were enrolled and randomly divided into two groups, the Olan + Baicalin group and the Olan group, using the random number table method in SPSS version 24.0 (Armonk, NY, USA). The detailed information about randomization was shown in Supplementary Note 1.

All patients were treated with Olan, with the dosages gradually titrated from 5 mg/day to 10–20 mg/day, as clinically necessary. The dosage of Baicalin was 1.5 g/day. Psychiatric symptoms and cognitive functions were evaluated at baseline, weeks 12 and 24 for all schizophrenia patients. Psychiatric symptoms were evaluated using the PANSS, depression was evaluated using the MADRS, and cognitive functions were evaluated using the MATRICS Consensus Cognitive Battery (MCCB) in Chinese [24], see Supplementary Note 2 for details.

Measurement

Venous blood (5 ml) was collected between 06:30 am and 07:00 am. The blood was centrifuged at 3,000 rpm, at 4 °C for 10 min, and the serum was collected and divided into six 500-µl Eppendorf tubes, which were stored at -80 °C for the measurement of various biological parameters. Serum levels of homocysteine (Hcy) were detected using an immune turbidimetric test (Roche Cobas c501, Switzerland). Serum levels of superoxide dismutase (SOD) and high-sensitivity C-reactive protein (Hs-CRP) were measured by a chemical colorimetry assay and a particle-enhanced immunoturbidimetric assay respectively using a Roche automatic biochemical analyzer (Roche Diagnostics, C8000, Germany). All assays were performed according to the manufacturer’s instructions.

The primary efficacy outcome was the changes in PANSS-negative (PANSS-N) scores between baseline and 24 weeks (or early termination). We assessed this outcome using a structured clinical interview for the PANSS, which was performed at baseline, at week 12 and at week 24. The secondary efficacy outcomes were cognitive function and the PANSS-T PANSS-P and PANSS-general psychopathology (PANSS-G) scores, which were measured at weeks 12 and 24; higher cognitive function scores indicate enhanced function, whereas a higher score on the PANSS indicates worse severity. Additional efficacy outcomes, metabolites, and safety parameters were assessed, including adverse event reports and clinical laboratory values. To ensure that any observed changes were specific to PANSS negative symptom improvement and were not pseudospecific, we recruited first-episode, drug-free schizophrenia patients and assessed their PANSS-P score and MARDS total score.

Statistical analysis

The data were analyzed using SPSS version 24.0 (Armonk, NY, USA). Descriptive statistics were used for demographics, clinical measures, and laboratory values. The Kolmogorov-Smirnov (K-S) test was used to check for normality. Two-group comparisons with normal distributions were made using the Student’s t-test, for continuous variables, and the Chi-squared test, for categorical variables, whereas the Mann-Whitney test was used for data that did not pass the K-S test. Correlations between variables were studied using Pearson Product-Moment Correlations. To investigate the effects of Baicalin on improvements in schizophrenia symptoms and cognition, we used a mixed linear model for significant interactions among different treatment groups (Olan + Baicalin vs. Olan), with changes between the baseline and 24-week scores for serum parameters, clinical measurements, including PANSS scores, and cognitive evaluations as the dependent measures (within-subject factors). The covariates were demographic and clinical variables. The contingency table test was used to determine the independence between different treatments and each clinical symptom change. For all statistical analyses, a p value of less than 0.05 (two-tailed) was statistically significant.

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	Estimates	se	df	t	Pr>\|t\|(P value)
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	0.995	44	15.76 ± 6.72	0.336	44	19.42 ± 12.27	0.257	7.1	0.30	331	5.910	90.404(0.146)
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	0.822	44	193.94 ± 24.46	0.616	44	194.20 ± 15.64	0.054	24	0.34	412	1.852	0.451(0.121)
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	0.166	44	1.88 ± 2.40	0.128	44	1.91 ± 2.04	0.012	43.2	0.26	335	0.368	7.807(0.371)
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	0.66	39	58.13 ± 6.44	0.010	27	51.82 ± 6.16	0.001	335.6	0.15	313	1.700	19.304(0.003)
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	0.412	39	12.80 ± 2.39	0.203	27	10.30 ± 1.66	0.785	431	0.37	539	3.000	1.052(0.247)
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	0.414	40	16.58 ± 3.62	0.001	27	14.82 ± 3.31	< 0.001	15	0.83	490	16.000	9.215(< 0.001)
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	0.804	40	28.60 ± 3.43	0.750	27	26.70 ± 4.62	0.421	42.6	0.73	332	0.520	10.190(0.011)
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	0.581	38	35.63 ± 11.78	0.879	25	36.72 ± 10.93	0.261	35.6	0.42	580	2.500	0.802(0.373)
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	0.941	38	35.18 ± 11.02	0.441	25	37.60 ± 11.65	0.018	14	0.18	239	7.600	5.107(0.046)
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	0.158	38	41.63 ± 11.01	0.015	25	44.88 ± 9.68	0.002	343	0.47	415	4.600	13.000(< 0.001)
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	0.957	38	40.18 ± 7.47	0.821	25	47.6 ± 8.67	0.852	2.64	0.12	457	0.020	0.700(0.791)
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	0.612	38	42.76 ± 11.38	0.08	25	48.12 ± 8.49	0.007	6	0.57	218	7.230	3.305(0.730)
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	0.155	38	39.26 ± 8.74	0.796	25	42.56 ± 8.81	0.139	15	0.63	109	3.240	22.730(0.120)
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	0.817	38	45.58 ± 17.31	0.228	25	51.88 ± 14.83	0.922	3.43	0.43	114	1.990	20.340(0.520)
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

Baicalin, administered at 1.5 g/d, over a 24-week treatment period, was considerable safe and well-tolerated when added to Olan. Surprisingly, the addition of Baicalin had a beneficial effect on the dyslipidemia induced by Olan (Supplementary Table 2). There were no significant differences in the frequencies and types of adverse events between the two treatment groups (Supplementary Table 3). All adverse events are depicted in the Supplementary information. Liver function tests showed no significant differences in transaminase levels between the two treatment groups (Supplementary Table 3).

In our study, patients treated with the combination of Olan and Baicalin experienced greater improvements in both primary and secondary negative symptoms than those treated with Olan alone. Also, patients treated with Olan and Baicalin showed greater improvements in cognitive function than those treated with Olan alone. To our knowledge, this is the first study to provide clinical evidence that negative symptoms can be improved by using Baicalin in combination with Olan to treat first-episode schizophrenia patients with predominant negative symptoms; additionally, this study provides a basis for new prescribing instructions for psychiatrists by demonstrating an advantage for the combination of Olan + Baicalin compared with Olan alone.

The treatment of primary negative symptoms is not currently promising, and traditional medicines with limited side effects are being considered as potential treatments for schizophrenia with predominant negative symptoms and cognitive impairment. Differences in PANSS-T, PANSS-P and PANSS-G scores between the two treatment groups indicated that the observed improvements in negative symptoms were not attributable to improvements in positive or overall symptoms. Additionally, pseudospecificity measurements supported the finding that the improvements in predominant negative symptoms observed in the Olan + Baicalin group occurred independently of changes in other symptoms (i.e., positive, depressive, and extrapyramidal symptoms) that are known to impact negative symptoms. In our study, patients with positive scores > 15 or with depression scores > 20 at baseline were excluded to eliminate the potential influences of positive symptoms and depression. The present study found that the improvements in predominant negative symptoms observed when Baicalin was added to Olan treatments were statistically significant.

Few studies have investigated the efficacy of antipsychotics primarily on negative symptoms in patients with schizophrenia; most studies have been derived from post-hoc analyses of large studies that were not specifically designed to evaluate primary negative symptoms in schizophrenia patients. György Németh reported the improved efficacy of cariprazine on predominant negative symptoms compared with risperidone in patients with schizophrenia[25]. Amisulpride has been reported to be efficacious versus placebo in improving predominant negative symptoms in several European countries[26]. However, the findings reported by Lecrubier et al. using amisulpride showed equivocal efficacy for the treatment of predominant negative symptoms[27]. A 12-week trial found equivalent improvements in negative symptoms and overall psychopathology when comparing amisulpride and ziprasidone treatments[28].

Beyond monotherapy, other medicines have been prescribed adjunctively in combination with antipsychotic drugs for the treatment of negative symptoms in patients with schizophrenia. One approach that is commonly used in clinic is adjunctive therapy with antidepressants. Limited evidence exists to support this strategy for the improvement of negative symptoms and cognitive impairment[29]. Some beneficial effects of aspirin and estrogens have been observed; however, the use of aspirin risks the induction of gastrointestinal bleeding, and estrogens are not suitable for men, which should be considered[30–32]. Other drugs with different mechanisms of action (e.g., cholinergic, glutamatergic and glycine transport inhibitors) are currently being evaluated as adjunctive therapies or are in development; presently, clinical trial evidence has been modest and has been limited by heterogeneous patient populations and disparate negative symptom criteria. The use of adjunctive treatments to improve predominant negative symptoms and cognitive impairment in schizophrenia patients remains under investigation.

As expected, we showed that the addition of Baicalin helped increase the amelioration of psychiatric symptoms, especially for predominant negative symptoms and cognitive function. This beneficial effect may be due to the anti-inflammatory and anti-oxidant effects of Baicalin. Baicalin likely inhibits inflammation and ROS production by significantly increasing the expression levels of the antioxidant enzyme SOD, in a dose-dependent manner, which has been demonstrated by both in vitro and in vivo studies[33, 34]. In addition, Baicalin can be decomposed to baicalein by β-glucuronidase in the intestines, and baicalein can cross the blood brain barrier into the central nervous system (CNS) [35, 36]. Further evidence has shown that Baicalin can act as an effective adjunctive therapy in the treatment of neurodegenerative diseases, atherosclerosis, and other diseases[16, 37, 38]. The beneficial effects of Baicalin on negative symptoms and cognitive functions in schizophrenia may be largely due to its ability to improve neuroinflammation, which has been reported to be associated with schizophrenia[39, 40]. In summary, Baicalin protects the body from ROS injuries through its anti-oxidant and anti-inflammatory actions, both of which are altered in schizophrenia[33, 34, 41–43].

This study has some limitations: (1) small sample size; (2) a pharmacokinetic study remains necessary to investigate the possible interactions between Olan and Baicalin, as well as drug clearance. Despite these limitations, our study is the first to investigate efficacy of adjunctive Baicalin in schizophrenia and provide evidence for superior efficacy of adjunctive Baicalin over Olan alone in schizophrenia. It was safe and harmless as has been reported previously regarding the beneficial effects of Baicalin on liver and kidney function[44].

Our study showed increased levels of Hcy and Hs-CRP but decreased levels of SOD in schizophrenia before treatment. After treatment, a significantly reduced level of Hs-CRP, a trend for decreased Hcy levels and increased SOD levels in the Olan + Baicalin group compared with the Olan group, which further supports the anti-inflammatory and anti-oxidation effects of Baicalin. These findings have added to the evidence for the adjuvant treatment of schizophrenia with Baicalin.

Olanzapine (Olan); the Positive and Negative Syndrome Scale (PANSS); Speed of Processing (SOP); Working Memory (WM); Brief Visuospatial Memory Test (BVMT); Nuclear Factor kappa B (NF-κB); Mitogen-Activated Protein Kinase (MAPK); the Diagnostic and Statistical Manual of Mental Disorders fourth version (DSM-IV); the Structured Clinical Interview for DSM-IV (SCID); Montgomery Asberg Depression Rating Scale (MADRS); the MATRICS Consensus Cognitive Battery (MCCB); Homocysteine (Hcy); Superoxide dismutase (SOD); High-sensitivity C-Reactive Protein (Hs-CRP); the Kolmogorov-Smirnov (K-S) test; Attention/Vigilance (AV); Hopkins Verbal Learning test (HVLT) ; Social Cognition (SC); the difference-value (D-value); Reasoning and Problem Solving (RPS); Central Nervous System (CNS)

Ethics approval and consent to participate

This research was approved by the Human Ethics Committee of the First Affiliated Hospital of Zhengzhou University, China (Ethics ID SS-2019-025). All methods were performed in accordance with the relevant guidelines and regulations and all patients were provided with written informed consent.

Consent for publication

Not applicable

Availability of data and materials

Data supporting the results reported in the article were generated during the study.

Competing interests

The authors declare that they have no competing interests.

Funding

This study was funded by the National Natural Science Foundation of China (No. 81971253 to X-QS), Zhong yuan Innovation Leading Talents of the Thousand Talents Plan (204200510019), Medical science and technology foundation of health and family planning commission of Henan province (SBGJ201808 to X-QS), School and Hospital Co-incubation Funds of Zhengzhou University (No. 2017-BSTDJJ-04 to X-QS), and UiO: Lifesciences Convergence Environment, Oslo University, Norway (project 4MENT to YW).

Authors' contributions

Authors Xin Tian and Xueqin Song designed the study. Authors Qiyue Zhu and Xiuxia Yuan were responsible for recruiting the patients, performing the clinical rating, collecting all samples, and helping with statistical analyses. Authors Yu Miao and Yulin Kang managed the literature searches and manuscript preparation. Additionally, author Xue Li and Shuying Wang undertook the statistical analyses. Authors Zuhong Lu, Luxian Lv, Xu-Feng Huang, Yunpeng Wang and Xueqin Song were responsible for supervision and reviewing all aspects of the research. All authors have read and approved the manuscript.

Acknowledgements

The authors thank all the patients and their families, the healthy volunteers for their participation, and the psychiatrist who helped us take clinical data and blood samples. We thank the Biological Sample Bank of The First Affiliated Hospital of Zhengzhou University for helping us store the samples. We thank the Academy of Medical Science, Zhengzhou University for providing us with a perfect experimental platform.

Muscatello MR, Bruno A, De Fazio P, Segura-Garcia C, Pandolfo G, Zoccali R: Augmentation strategies in partial responder and/or treatment-resistant schizophrenia patients treated with clozapine. Expert Opin Pharmacother 2014, 15(16):2329-2345.
Strassnig MT, Harvey PD: Treatment resistance and other complicating factors in the management of schizophrenia. CNS Spectr 2014, 19 Suppl 1:16-23; quiz 13-15, 24.
Gault JM, Davis R, Cascella NG, Saks ER, Corripio-Collado I, Anderson WS, Olincy A, Thompson JA, Pomarol-Clotet E, Sawa A et al: Approaches to neuromodulation for schizophrenia. Journal of neurology, neurosurgery, and psychiatry 2018, 89(7):777-787.
Buchanan RW: Persistent negative symptoms in schizophrenia: an overview. Schizophrenia bulletin 2007, 33(4):1013-1022.
Cruz BF, Resende CB, Carvalhaes CF, Cardoso CS, Teixeira AL, Keefe RS, Rocha FL, Salgado JV: Interview-based assessment of cognition is a strong predictor of quality of life in patients with schizophrenia and severe negative symptoms. Rev Bras Psiquiatr 2016, 38(3):216-221.
Savilla K, Kettler L, Galletly C: Relationships between cognitive deficits, symptoms and quality of life in schizophrenia. Aust N Z J Psychiatry 2008, 42(6):496-504.
Lee B, Sur B, Shim I, Lee H, Hahm DH: Baicalin improves chronic corticosterone-induced learning and memory deficits via the enhancement of impaired hippocampal brain-derived neurotrophic factor and cAMP response element-binding protein expression in the rat. J Nat Med 2014, 68(1):132-143.
Dlabac-de Lange JJ, Liemburg EJ, Bais L, van de Poel-Mustafayeva AT, de Lange-de Klerk ESM, Knegtering H, Aleman A: Effect of Bilateral Prefrontal rTMS on Left Prefrontal NAA and Glx Levels in Schizophrenia Patients with Predominant Negative Symptoms: An Exploratory Study. Brain stimulation 2017, 10(1):59-64.
Davidson M, Saoud J, Staner C, Noel N, Luthringer E, Werner S, Reilly J, Schaffhauser JY, Rabinowitz J, Weiser M et al: Efficacy and Safety of MIN-101: A 12-Week Randomized, Double-Blind, Placebo-Controlled Trial of a New Drug in Development for the Treatment of Negative Symptoms in Schizophrenia. Am J Psychiatry 2017, 174(12):1195-1202.
Umbricht D, Alberati D, Martin-Facklam M, Borroni E, Youssef EA, Ostland M, Wallace TL, Knoflach F, Dorflinger E, Wettstein JG et al: Effect of bitopertin, a glycine reuptake inhibitor, on negative symptoms of schizophrenia: a randomized, double-blind, proof-of-concept study. JAMA Psychiatry 2014, 71(6):637-646.
Maia TV, Frank MJ: An Integrative Perspective on the Role of Dopamine in Schizophrenia. Biol Psychiatry 2017, 81(1):52-66.
van Erp TG, Hibar DP, Rasmussen JM, Glahn DC, Pearlson GD, Andreassen OA, Agartz I, Westlye LT, Haukvik UK, Dale AM et al: Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium. Mol Psychiatry 2016, 21(4):547-553.
Upthegrove R, Manzanares-Teson N, Barnes NM: Cytokine function in medication-naive first episode psychosis: a systematic review and meta-analysis. Schizophrenia research 2014, 155(1-3):101-108.
Yan M, Wen Y, Yang L, Wu X, Lu X, Zhang B, Huang W, Li P: Chinese herbal medicine Tangshen Formula treatment of patients with type 2 diabetic kidney disease with macroalbuminuria: study protocol for a randomized controlled trial. Trials 2016, 17(1):259.
Xie W, Du L: Diabetes is an inflammatory disease: evidence from traditional Chinese medicines. Diabetes Obes Metab 2011, 13(4):289-301.
Xiong P, Chen X, Guo C, Zhang N, Ma B: Baicalin and deferoxamine alleviate iron accumulation in different brain regions of Parkinson's disease rats. Neural regeneration research 2012, 7(27):2092-2098.
Guo C, Chen X, Xiong P: Baicalin suppresses iron accumulation after substantia nigra injury: relationship between iron concentration and transferrin expression. Neural regeneration research 2014, 9(6):630-636.
Goldfine AB, Shoelson SE: Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk. J Clin Invest 2017, 127(1):83-93.
Ye C, Li S, Yao W, Xu L, Qiu Y, Liu Y, Wu Z, Hou Y: The anti-inflammatory effects of baicalin through suppression of NLRP3 inflammasome pathway in LPS-challenged piglet mononuclear phagocytes. Innate Immun 2016, 22(3):196-204.
Ding H, Wang H, Zhao Y, Sun D, Zhai X: Protective Effects of Baicalin on Abeta(1)(-)(4)(2)-Induced Learning and Memory Deficit, Oxidative Stress, and Apoptosis in Rat. Cellular and molecular neurobiology 2015, 35(5):623-632.
Wu Y, Wang F, Fan L, Zhang W, Wang T, Du Y, Bai X: Baicalin alleviates atherosclerosis by relieving oxidative stress and inflammatory responses via inactivating the NF-kappaB and p38 MAPK signaling pathways. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2018, 97:1673-1679.
Runeson BS, Rich CL: Diagnostic and statistical manual of mental disorders, 3rd ed. (DSM-III), adaptive functioning in young Swedish suicides. Annals of clinical psychiatry : official journal of the American Academy of Clinical Psychiatrists 1994, 6(3):181-183.
Kay SR, Fiszbein A, Opler LA: The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia bulletin 1987, 13(2):261-276.
Nuechterlein KH, Green MF, Kern RS, Baade LE, Barch DM, Cohen JD, Essock S, Fenton WS, Frese FJ, 3rd, Gold JM et al: The MATRICS Consensus Cognitive Battery, part 1: test selection, reliability, and validity. The American journal of psychiatry 2008, 165(2):203-213.
Nemeth G, Laszlovszky I, Czobor P, Szalai E, Szatmari B, Harsanyi J, Barabassy A, Debelle M, Durgam S, Bitter I et al: Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet (London, England) 2017, 389(10074):1103-1113.
Danion JM, Rein W, Fleurot O: Improvement of schizophrenic patients with primary negative symptoms treated with amisulpride. Amisulpride Study Group. Am J Psychiatry 1999, 156(4):610-616.
Lecrubier Y, Quintin P, Bouhassira M, Perrin E, Lancrenon S: The treatment of negative symptoms and deficit states of chronic schizophrenia: olanzapine compared to amisulpride and placebo in a 6-month double-blind controlled clinical trial. Acta psychiatrica Scandinavica 2006, 114(5):319-327.
Olie JP, Spina E, Murray S, Yang R: Ziprasidone and amisulpride effectively treat negative symptoms of schizophrenia: results of a 12-week, double-blind study. International clinical psychopharmacology 2006, 21(3):143-151.
Perry LA, Ramson D, Stricklin S: Mirtazapine adjunct for people with schizophrenia. The Cochrane database of systematic reviews 2018, 5:Cd011943.
Sommer IE, van Westrhenen R, Begemann MJ, de Witte LD, Leucht S, Kahn RS: Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: an update. Schizophrenia bulletin 2014, 40(1):181-191.
Kindler J, Weickert CS, Skilleter AJ, Catts SV, Lenroot R, Weickert TW: Selective Estrogen Receptor Modulation Increases Hippocampal Activity during Probabilistic Association Learning in Schizophrenia. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2015, 40(10):2388-2397.
Nitta M, Kishimoto T, Muller N, Weiser M, Davidson M, Kane JM, Correll CU: Adjunctive use of nonsteroidal anti-inflammatory drugs for schizophrenia: a meta-analytic investigation of randomized controlled trials. Schizophrenia bulletin 2013, 39(6):1230-1241.
Wang H, Zhang Y, Bai R, Wang M, Du S: Baicalin Attenuates Alcoholic Liver Injury through Modulation of Hepatic Oxidative Stress, Inflammation and Sonic Hedgehog Pathway in Rats. Cell Physiol Biochem 2016, 39(3):1129-1140.
Yao J, Cao X, Zhang R, Li YX, Xu ZL, Zhang DG, Wang LS, Wang JY: Protective Effect of Baicalin Against Experimental Colitis via Suppression of Oxidant Stress and Apoptosis. Pharmacogn Mag 2016, 12(47):225-234.
Tarrago T, Kichik N, Claasen B, Prades R, Teixido M, Giralt E: Baicalin, a prodrug able to reach the CNS, is a prolyl oligopeptidase inhibitor. Bioorganic & medicinal chemistry 2008, 16(15):7516-7524.
Teixido M, Giralt E: The role of peptides in blood-brain barrier nanotechnology. Journal of peptide science : an official publication of the European Peptide Society 2008, 14(2):163-173.
Chen C, Li X, Gao P, Tu Y, Zhao M, Li J, Zhang S, Liang H: Baicalin attenuates alzheimer-like pathological changes and memory deficits induced by amyloid beta1-42 protein. Metabolic brain disease 2015, 30(2):537-544.
Wang SF, Wu MY, Cai CZ, Li M, Lu JH: Autophagy modulators from traditional Chinese medicine: Mechanisms and therapeutic potentials for cancer and neurodegenerative diseases. Journal of ethnopharmacology 2016, 194:861-876.
Moller M, Swanepoel T, Harvey BH: Neurodevelopmental Animal Models Reveal the Convergent Role of Neurotransmitter Systems, Inflammation, and Oxidative Stress as Biomarkers of Schizophrenia: Implications for Novel Drug Development. ACS chemical neuroscience 2015, 6(7):987-1016.
Sawa A, Sedlak TW: Oxidative stress and inflammation in schizophrenia. Schizophrenia research 2016, 176(1):1-2.
Wang G, Liang J, Gao LR, Si ZP, Zhang XT, Liang G, Yan Y, Li K, Cheng X, Bao Y et al: Baicalin administration attenuates hyperglycemia-induced malformation of cardiovascular system. Cell Death Dis 2018, 9(2):234.
Wen YF, Zhao JQ, Bhadauria M, Nirala SK: Baicalin prevents cadmium induced hepatic cytotoxicity, oxidative stress and histomorphometric alterations. Exp Toxicol Pathol 2013, 65(1-2):189-196.
Li CG, Yan L, Mai FY, Shi ZJ, Xu LH, Jing YY, Zha QB, Ouyang DY, He XH: Baicalin Inhibits NOD-Like Receptor Family, Pyrin Containing Domain 3 Inflammasome Activation in Murine Macrophages by Augmenting Protein Kinase A Signaling. Front Immunol 2017, 8:1409.
Pang H, Xue W, Shi A, Li M, Li Y, Cao G, Yan B, Dong F, Xiao W, He G et al: Multiple-Ascending-Dose Pharmacokinetics and Safety Evaluation of Baicalein Chewable Tablets in Healthy Chinese Volunteers. Clinical drug investigation 2016, 36(9):713-724.

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Efficacy and safety of the adjunctive Baicalin in schizophrenia patients with negative symptoms and cognitive impairment: a randomized pilot study

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