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Metabolic adverse effects of olanzapine on cognitive dysfunction: A possible relationship between BDNF and TNF-alpha
Accepted Manuscript Title: Metabolic adverse effects of olanzapine on cognitive dysfunction: a possible relationship between BDNF and TNF-alpha Authors: Chen Zhang, Xinyu Fang, Peifen Yao, Yemeng Mao, Jun Cai, Yi Zhang, Meijuan Chen, Weixing Fan, Wei Tang, Lisheng Song PII: DOI: Reference:
S0306-4530(17)30253-6 http://dx.doi.org/doi:10.1016/j.psyneuen.2017.04.014 PNEC 3609
To appear in: Received date: Revised date: Accepted date:
13-3-2017 17-4-2017 21-4-2017
Please cite this article as: Zhang, Chen, Fang, Xinyu, Yao, Peifen, Mao, Yemeng, Cai, Jun, Zhang, Yi, Chen, Meijuan, Fan, Weixing, Tang, Wei, Song, Lisheng, Metabolic adverse effects of olanzapine on cognitive dysfunction: a possible relationship between BDNF and TNF-alpha.Psychoneuroendocrinology http://dx.doi.org/10.1016/j.psyneuen.2017.04.014 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Metabolic adverse effects of olanzapine on cognitive dysfunction: a possible relationship between BDNF and TNF-alpha Chen Zhanga,*, Xinyu Fanga, Peifen Yaoa, Yemeng Maob, Jun Caia, Yi Zhanga, Meijuan Chena, Weixing Fanc, Wei Tangd, Lisheng Songa,* a
Schizophrenia Program, Shanghai Mental Health Center, Shanghai Jiao Tong
University School of Medicine, Shanghai, China b
Department of Pharmacology, Shanghai Mental Health Center, Shanghai Jiao Tong
University School of Medicine, Shanghai, China c
Department of Psychiatry, Jinhua Second Hospital, Jinhua, Zhejiang, China
d
Department of Psychiatry, Wenzhou Kanging Hospital, Wenzhou, Zhejiang, China
* Corresponding authors Chen Zhang, Email: [email protected] (C. Zhang) Lisheng Song, Email: [email protected] (L. Song) Highlights
44% patients receiving long-term olanzapine monotherapy met the diagnosis criteria for metabolic syndrome (MetS).
Patients with MetS had worse attention and memory performance than those without MetS.
Increasing glucose level is an independent risk factor for cognitive dysfunction.
Patients with MetS had lower BDNF and higher TNF-alpha levels than those without MetS.
There is a negative correlation between the BDNF and TNF-alpha levels.
Abstract 1
Objective: There is accumulating evidence indicating that long-term treatment with second-generation antipsychotics (SGAs) results in metabolic syndrome (MetS) and cognitive impairment. This evidence suggests an intrinsic link between antipsychoticinduced MetS and cognitive dysfunction in schizophrenia patients. Olanzapine is a commonly prescribed SGA with a significantly higher MetS risk than that of most antipsychotics. In this study, we hypothesized that olanzapine-induced MetS may exacerbate cognitive dysfunction in patients with schizophrenia. Methods: A sample of 216 schizophrenia patients receiving long-term olanzapine monotherapy were divided into two groups, MetS and non-MetS, based on the diagnostic criteria of the National Cholesterol Education Program's Adult Treatment Panel III. We also recruited 72 healthy individuals for a control group. Cognitive function was evaluated using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Plasma brain-derived neurotrophic factor (BDNF) and tumor necrosis factor-alpha (TNF-alpha) were measured by an enzymelinked immunosorbent assay for 108 patients and 47 controls. Results: Among the 216 schizophrenia patients receiving olanzapine monotherapy, MetS was found in 95/216 (44%). Patients with MetS had more negative symptoms, higher total scores in PANSS (Ps<0.05) and lower immediate memory, attention, delayed memory and total scores in RBANS (Ps<0.01). Stepwise multivariate linear regression analysis revealed that increased glucose was the independent risk factor for cognitive dysfunction (t=-2.57, P=0.01). Patients with MetS had significantly lower BDNF (F=6.49, P=0.012) and higher TNF-alpha (F=5.08, P=0.026) levels than 2
those without MetS. There was a negative correlation between the BDNF and TNFalpha levels in the patients (r=-0.196, P=0.042). Conclusion: Our findings provide evidence suggesting that the metabolic adverse effects of olanzapine may aggravate cognitive dysfunction in patients with schizophrenia through an interaction between BDNF and TNF-alpha. Keywords: Olanzapine; Metabolic syndrome; Cognitive function; Brain-derived neurotrophic factor; Tumor necrosis factor-alpha 1. Introduction Schizophrenia is a debilitating and often lifelong psychiatric disorder that can result in social and occupational disability. Schizophrenia is characterized by typical manifestations, including positive symptoms (hallucination, delusions, and disorganized behavior), negative symptoms (affective blunting, apathy, and social withdrawal) and cognitive dysfunction (attention, learning, and memory impairment) (Kuperberg and Heckers, 2000). Antipsychotic medication has been widely used to treat schizophrenia since first-generation antipsychotics (FGAs) were found to have specific therapeutic action against positive symptoms in the 1950s (Zhang et al., 2011). In recent decades, second-generation antipsychotics (SGAs) have been more frequently prescribed for patients with schizophrenia due to their lower risk of extrapyramidal symptoms and tardive dyskinesia compared with that of FGAs. Unfortunately, the metabolic adverse effects that accompany treatment with SGAs are almost as profound as their superior therapeutic effects (Hu et al., 2013).
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Metabolic syndrome (MetS) identifies a group of obesity-related risk factors for chronic metabolic and cardiovascular diseases. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) for schizophrenia in the US has shown that the prevalence of MetS in patients with schizophrenia is 40.9% based on the National Cholesterol Education Program—Adult Treatment Panel III (NCEP-ATP III) criteria. MetS and its components have been identified as important risk factors for developing cognitive impairment and dementia in the general population (Alfaro et al., 2016; Kaffashian et al., 2013; Raffaitin et al., 2011). There is emerging evidence showing that schizophrenia patients with MetS have significantly worse cognitive functions than those without MetS (Bora et al., 2017; de Nijs and Pet, 2016; Li et al., 2014). This evidence also suggests a link between antipsychotic-induced MetS and cognitive dysfunction in schizophrenia patients (Cai et al., 2013a). Previous work has shown that MetS is associated with a state of chronic and low-grade inflammation (Devaraj et al., 2010), and SGAs also potentiate aberrant peripheral levels of inflammation markers (Beumer et al., 2012). Thus, there may be an association between MetS and inflammation in schizophrenia (Mori et al., 2015). On the other hand, brain-derived neurotrophic factor (BDNF) has emerged as a critical mediator of neuronal plasticity and plays an important role in cognitive processes (Kuipers and Bramham, 2006). Ample literature has documented that serum BDNF levels are significantly decreased in patients with cognitive declinerelated diseases as well as schizophrenia compared with those in healthy individuals (Leyhe et al., 2008; Yu et al., 2008; Zhang et al., 2014c). Another study has noted the 4
involvement of BDNF in cognitive dysfunction rather than other symptomatic dimensions in patients with chronic schizophrenia (Zhang et al., 2012). Therefore, serum BDNF levels may serve as a peripheral biomarker for the evaluation of cognitive function in schizophrenia (Vinogradov et al., 2009). Evidence from in vivo studies has demonstrated that inflammation, especially pro-inflammatory cytokines, clearly affects the expression of BDNF in the brain (Calabrese et al., 2014). A recent study has reported an interaction between tumor necrosis factor-alpha (TNF-alpha) and BDNF that caused cognitive dysfunction in patients with chronic schizophrenia (Zhang et al., 2016b). Olanzapine is a commonly prescribed SGA with a significantly higher MetS risk than that of other antipsychotics, except clozapine (Vancampfort et al., 2015). In light of the abovementioned findings, we hypothesized that the metabolic adverse effects of olanzapine may exacerbate cognitive dysfunction in patients with schizophrenia through an interaction between TNF-alpha and BDNF. Therefore, we examined our hypothesis by investigating whether (1) cognitive function differs between patients with or without MetS; (2) serum TNF-alpha and BDNF levels differ between patients with or without MetS; and (3) serum TNF-alpha is correlated with BDNF levels. 2. Methods 2.1. Participants
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We recruited 216 patients with schizophrenia from three mental hospitals in Eastern China, including Shanghai Mental Health Center, Jinhua Second Hospital and Wenzhou Kangning Hospital. According to our previous publications (Cai et al., 2013b; Zhang et al., 2016a; Zhang et al., 2017; Zhang et al., 2014d; Zhang et al., 2013), the inclusion criteria for patients were as follows: (1) patients had been diagnosed with schizophrenia according to DSM-IV with the diagnoses either made or reviewed by experienced psychiatrists; (2) patients were receiving olanzapine treatment alone; (3) patients had received olanzapine for more than 24 months; (4) patients had maintained a stable condition for more than 6 months before entry into the study; and (5) patients had no other diagnosed psychiatric disorder besides schizophrenia. We also recruited 72 healthy individuals for controls, who were screened by a specialized psychiatrist using the Structured Clinical Interview for DSM-IV-TR Axis I Disorders-Patient Edition. All procedures for this study were reviewed and approved by the Institutional Review Boards of the Shanghai Mental Health Center and other participating institutions. This study was performed in strict accordance with the Declaration of Helsinki and other relevant national and international regulations. Written informed consent was obtained from each participant prior to the performance of any procedures related to this study. 2.2. Biochemical parameters
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A cross-sectional assessment of metabolic parameters was performed to determine the prevalence of MetS based on the definition by the NCEP-ATP III, which is the best MetS criterion for a Chinese population (Zhou et al., 2010). MetS was diagnosed based on the presence of any three of the following criteria: (1) a waist circumference ≥90 cm in Chinese men and ≥80 cm in Chinese women (Bao et al., 2008); (2) triglyceride (TG) ≥1.7 mmol/L; (3) high density lipoprotein cholesterol (HDL) <1.0 mmol/L in men and <1.3 mmol/L in women; (4) blood pressure ≥130/85 mmHg; or (5) fasting glucose (GLU) ≥5.6 mmol/L (Grundy et al., 2005). Waist circumference was measured between the lower rib margin and the iliac crest, after a normal expiratory breath. Overnight fasting blood samples were drawn in ice-cooled ethylenediaminetetraacetic acid tubes between 7:00 and 7:30 a.m. Serum was separated by centrifugation at 5°C and stored at -20C°. Serum fasting GLU, TG, and HDL levels were measured using an automatic Biochemical Analyzer (HITACHI 7170A, Hitachi, Ltd, Tokyo, Japan) (Zhang et al., 2014d; Zhang et al., 2013). 2.3. Plasma level analysis by enzyme-linked immunosorbent assay (ELISA) In total, we collected blood samples from 108 patients with schizophrenia and 47 healthy controls for analysis of the plasma levels of BDNF and TNF-alpha. On admission, 10 ml peripheral blood from fasting patients and healthy controls was collected between 07:00 am and 09:00 am to avoid potential diurnal influence. The blood samples were centrifuged at 3000 g for 15 min at 4°C. The plasma was separated and stored at -70°C until measurement. The plasma levels of BDNF and
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TNF-alpha were measured using ELISA kits (R&D Systems, Minneapolis, Minnesota, USA). The reproducibility of the assay was tested prior to the measurement of the samples, and the inter-assay coefficient of variation was approximately 4.4% for BDNF and 5.4% for TNF-alpha (Li et al., 2016; Zhao et al., 2016). 2.4. Evaluation The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) (Randolph et al., 1998) was the primary outcome instrument for this study. The 12-item RBANS consists of 5 subsets, corresponding to the following 5 domains of neuropsychological process: (a) immediate memory (list learning and story memory), (b) visuospatial/constructional (figure copy and line orientation), (c) language (picture naming and semantic fluency), (d) attention (digit span and coding) and (e) delayed memory (list learning free recall, list learning recognition, story memory free recall and figure free recall). RBANS has good validity and reliability in Chinese people (Cheng et al., 2011) and works well in cognitive evaluations of patients with schizophrenia (Cai et al., 2015; Wang et al., 2016). The severity of psychotic symptoms exhibited by the schizophrenia patients was evaluated using the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987). PANSS evaluations were conducted by two experienced psychiatrists who both attended a PANSS training session. Repeated assessments revealed that a correlation coefficient more than 0.8 was maintained for PANSS total scores (Zhu et al., 2015).
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2.5. Statistical analysis Demographic variables were compared between case and control groups with independent t tests for quantitative variables and Fisher’s exact test for qualitative variables. Analysis of covariance (ANCOVA) was used to compare the RBANS scores between case and control groups, controlling for demographic characteristics. Post hoc multiple comparisons were performed to identify the differences between groups. To compare the BDNF and TNF-alpha levels between MetS and non-MetS groups, ANCOVA was carried out with age, sex and BMI as covariates that were controlled for in the model to minimize the potential effect of these factors on the expression levels of BDNF and TNF-alpha. The correlation between these parameters was calculated by Spearman’s correlation analysis. All statistical tests were twotailed, and the significance level was set at p < 0.05. 3. Results The demographic characteristics for the patients with schizophrenia and healthy controls are summarized in Supplementary Table S1. There were significant differences in terms of age and years of education between the two groups. Consequently, we used these parameters as covariates to compare the scores of RBANS between the groups. The results showed that patients had significantly poorer performance than controls on immediate memory, visuospatial skill, language, attention, delayed memory and total RBANS score.
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We then examined the plasma levels of BDNF and TNF-alpha between the patient and control groups. Supplementary Figure S1 shows significant decreases in BDNF levels (2.55±0.83 ng/ml vs 4.22±1.13 ng/ml; F=103.79, P<0.01) and increases in TNF-alpha levels (65.69±0.83 pg/ml vs 4.22±1.13 pg/ml; F=4.17, P=0.04) in the schizophrenia patients compared with those in healthy controls. Among the 216 schizophrenia patients receiving olanzapine monotherapy, MetS was found in 95/216 (44%). The demographic and clinical features of the MetS and non-MetS groups are presented in Table 1. There were significant differences between the two groups in terms of BMI, waist circumference, fasting GLU, fasting TG, fasting HDL, SBP and DBP (Ps<0.05). Patients with MetS had a notably longer duration of olanzapine treatment (t=6.58, P<0.01) and higher daily dose (t=3.24, P<0.01) than those without MetS. To further explore the relationship between MetS and clinical features, we added the duration of olanzapine treatment and daily dose as covariates. Our results showed that patients with MetS had higher negative symptoms and total scores in PANSS (Ps<0.05) and lower immediate memory, attention, delayed memory and total scores in RBANS (Ps<0.01). Stepwise multivariate linear regression analysis using RBANS total score as the dependent variable and waist circumference, GLU, TG, HDL, SBP and DBP as the independent variables revealed that increasing GLU was the independent risk factor for cognitive dysfunction (t=-2.57, P=0.01, Table 2). Within the schizophrenia patients, plasma BDNF and TNF-alpha levels were measured in 51 individuals with MetS and 57 without MetS. Figure 1 shows that 10
patients with MetS had significantly lower BDNF (F=6.49, P=0.012) and higher TNFalpha (F=5.08, P=0.026) levels than those without MetS, after we controlled for age, sex, olanzapine treatment duration, daily dose and BMI. Next, we aimed to determine whether there was an interaction between BDNF and TNF-alpha levels in the patients. Figure 2 shows a negative correlation between the BDNF and TNF-alpha levels (r=-0.196, P=0.042). 4. Discussion Cognitive dysfunction is increasingly recognized as a central aspect of schizophrenia. Our previous work has demonstrated that a wide range of cognitive functions are substantially impaired among antipsychotic-naïve patients with firstepisode schizophrenia (Lu et al., 2012; Zhang et al., 2014a). A randomized controlled trial has indicated that short-term (12-week) olanzapine treatment can improve cognitive function in patients with first-episode schizophrenia (Wang et al., 2013). Our preclinical study has provided further evidence that the advantageous effects of olanzapine on cognitive functioning may be due to its contribution to synaptic plasticity (Zhang et al., 2014b). A high rate of MetS is a typical side effect of longterm olanzapine treatment in clinical practice. Given the important role of MetS in cognitive dysfunction (Yaffe et al., 2004), we administered cognitive evaluations to schizophrenia patients receiving long-term olanzapine monotherapy. Our results showed that patients with MetS had worse cognitive performance than those without MetS, indicating that olanzapine-induced metabolic
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consequences may be an important contributor to worsening cognitive impairment in schizophrenia, especially attention and memory deficits. This finding agrees with recent studies showing that MetS is implicated in impaired attention and memory performance (Rouch et al., 2014; Rubens et al., 2016). Accumulating clinical studies have reported that BDNF is regarded as a biomarker reflecting memory and general cognitive function in patients with schizophrenia (Zhang et al., 2012). Hence, we measured the plasma BDNF level in schizophrenia patients with or without MetS and observed a close relationship between MetS with reduced levels of BDNF in these patients. Previous literature has indicated that BDNF is associated with antipsychotic-induced metabolic alterations (Tsai et al., 2011; Zai et al., 2012; Zhang et al., 2007; Zhang et al., 2008; Zhang et al., 2013). Preclinical observation has also suggested that consumption of a high-fat diet in mice may decrease BDNF levels and exacerbate cognitive impairment (Pistell et al., 2010). In contrast, the amelioration of cognitive impairment is associated with concurrent elevation of BDNF levels (Neshatdoust et al., 2016). BDNF has an important physiological role in cognitive function, including critical involvement in the induction of long-term potentiation, a synaptic plasticity mechanism underlying learning and memory processes (Lu and Martinowich, 2008; Matynia et al., 2002). Therefore, the decreased BDNF levels may account for the worse cognitive function in schizophrenia patients with MetS compared with that in patients without MetS. To clarify the role of metabolic components in cognitive impairment, we performed a stepwise multivariate linear regression analysis and observed that 12
increased GLU level is a pronounced risk factor for cognitive dysfunction in schizophrenia patients receiving long-term olanzapine treatment. There is a clear link between the use of olanzapine and the risk of developing type 2 diabetes mellitus (Galling et al., 2016). Previous research has shown that olanzapine induces weight gain and causes alterations in glucose metabolism and insulin resistance (Fountaine et al., 2010; Newcomer, 2004) that could lead to the cognitive impairment observed in either clinical or preclinical studies (Ma and Li, 2017; Xia et al., 2016). Regarding BDNF levels, there is accumulating data suggesting that plasma BDNF levels are reduced in patients with diabetes and negatively correlated with plasma glucose and insulin resistance (Murillo Ortiz et al., 2016). Elevated blood glucose levels can trigger subclinical chronic inflammation and activation of the immune system (Rodrigues et al., 2017). Elevated levels of cytokines, such as TNF-alpha, are frequently reported in patients with diabetes (Hu et al., 2004; Lechleitner et al., 2002). BDNF is well known to be regulated by cytokines (Calabrese et al., 2014). Our present results indicate a negative interaction between BDNF and TNF-alpha in patients with schizophrenia, suggesting that BDNF may be inversely modulated by TNF-alpha. In this study, the main cognitive impairment associated with MetS was attention and memory deficits. Changes in the hippocampus have been implicated in the attention and memory deficits in schizophrenia (McGarrity et al., 2016). Previous research has established that TNF-alpha is critically involved in hippocampaldependent cognitive deficits (Rowan et al., 2007). A recent work has indicated that 13
TNF-alpha negatively regulates BDNF expression in the hippocampus and affects the synaptic connectivity in hippocampal CA1 pyramidal neurons (Liu et al., 2017). Previously, we revealed that the PI3K/AKT signaling pathway may participate in the development of metabolic syndrome and cognitive impairment (Cai et al., 2013a). Experimental data have shown that the PI3K/AKT signaling pathway is activated by TNF-alpha (Li et al., 2017). As such, further investigations to determine whether long-term olanzapine application stimulates metabolic and cognitive activities through the PI3K/AKT signaling pathway activated by TNF-alpha will be of considerable interest. The strength of this study is that the patients recruited for this study were all subjected to long-term olanzapine monotherapy. Alongside the strength, however, we would be remiss in not noting some marked limitations of this study. First, our sample size is small, especially the sample size for the ELISA measurement, and accordingly, our findings should be viewed as preliminary until replicated and independently verified. Second, our subjects are chronic patients, and whether other antipsychotic treatments prior to this study may have already influenced the risk for MetS is unknown, which lessens the effects attributable to olanzapine that the patients are currently taking. Third, the patients’ baseline metabolic parameters prior to olanzapine treatment and their previous antipsychotic agents were unknown, which may potentially confound the results obtained in this study. Lastly, the ideal study design for observing the trajectory of olanzapine-induced MetS and cognitive dysfunction is a longitudinal, prospective, randomized and parallel-control 14
clinical trial. However, our study was cross-sectional rather than longitudinal; therefore, we cannot affirm that some subjects in the non-MetS group did not develop MetS after the investigation. To avoid the negative consequences of this potential bias, it is important to replicate these data using larger studies that are better designed to find conclusive and not simply suggestive evidence of the associations that we noted in the present study. 5. Conclusion We performed a clinical study to examine the association between MetS and cognitive impairment in schizophrenia patients receiving long-term olanzapine monotherapy. Our findings provide evidence suggesting that the metabolic adverse effects of olanzapine may aggravate cognitive dysfunction in patients with schizophrenia through an interaction between BDNF and TNF-alpha. Large-scale longitudinal studies should be conducted to replicate these findings and offer more conclusive evidence. Acknowledgements We are deeply grateful to all participants. This work was supported by the National Natural Science Foundation of China (81471358), the Shanghai Science and Technology Commission Foundation (14411969000), the Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (20152530), the Shanghai Municipal Commission of Health and Family Planning Foundation (201540029) and the Shanghai Mental Health Center Foundation (2014-FX-03).
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Figure Legends Figure 1 Serum levels of BDNF and TNF-alpha in MetS and non-MetS groups. A. BDNF; B. TNF-alpha. Scatter plots for the comparison between the MetS and nonMetS groups. Horizontal lines represent the mean BDNF or TNF-alpha levels. MetS, patients with metabolic syndrome (n=51); non-MetS, patients without metabolic syndrome (n=57). Figure 2 Correlation between serum BDNF and TNF-alpha levels in the patients. 21
22
Figr-1
23
Figr-2
24
Table 1 Demographics and clinical features between MetS and non-MetS groups MetS (n=95)
non-MetS (n=121)
χ2
P
52/43
63/58
0.15
0.78
t
P
Gender (Male/Female)
Age (year) a
28.65±3.52
28.75±3.89
-0.19
0.85
Education (year) a
9.81±1.86
9.84±2.05
-0.12
0.90
Duration of olanzapine treatment (month)
35.09±6.47
30.25±3.49
6.58
＜0.01
Daily olanzapine dose (mg) a
13.32±4.32
11.24±4.92
3.24
＜0.01
BMI (kg/m2) a
27.03±1.47
23.06±1.97
16.96
＜0.01
Waist circumference (cm) a
89.64±6.10
84.94±5.75
5.81
＜0.01
Fasting GLU (mmol/l) a
6.75±1.56
5.78±0.75
5.59
＜0.01
Fasting TG (mmol/l) a
1.83±0.70
1.58±0.95
2.11
0.03
Fasting HDL (mmol/l) a
0.91±0.35
1.42±0.43
-9.44
＜0.01
SBP (mm Hg) a
125.81±20.99
117.45±20.60
2.94
＜0.01
DBP (mm Hg) a
88.76±9.90
79.03±7.84
7.84
＜0.01
F
P
a
PANSS Positive symptoma
10.48±2.94
10.02±3.14
1.32
0.25
Negative symptoma
12.71±3.23
11.47±4.06
6.46
0.01
General psychopathologya
22.78±3.67
22.28±4.42
1.44
0.23
Total scorea
45.97±7.53
43.77±8.36
4.97
0.03
F
P
RBANS Immediate memorya
62.58±12.90
67.29±11.12
8.87
＜0.01
Visuospatial skilla
63.78±7.23
64.08±9.92
1.56
0.21
Languagea
60.29±8.04
61.98±14.62
3.02
0.08
Attentiona
72.18±143.50
79.74±17.18
18.13
＜0.01
Delayed memorya
71.39±10.21
74.00±11.37
9.01
＜0.01
Total scorea
330.22±34.29
347.10±50.54
16.45
＜0.01
Note: aData presented asx±s; BMI: body mass index; GLU: glucose; TG: triacylglyceride; HDL: high density lipoprotein; SBP: systolic pressure; DBP: diastolic pressure
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Table 2 Multivariate linear regression analysis with RBANS total score as the dependent variable in patient with schizophrenia receiving long-term olanzapine monotherapy B SE β t Waist circumference 0.06 0.53 0.01 0.11 Fasting GLU -6.72 2.61 -0.19 -2.57 Fasting TG 2.14 3.69 0.04 0.58 Fasting HDL -0.08 7.60 -0.001 -0.01 SBP 0.13 0.15 0.06 0.89 DBP -0.16 0.32 -0.04 -0.51 Note: B: unstandardized coefficients; SE: standard error; β: standardized coefficients; GLU: glucose; TG: triacylglyceride; HDL: high density lipoprotein; SBP: systolic pressure; DBP: diastolic pressure
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P 0.92 0.01 0.56 0.99 0.38 0.61
S0306-4530(17)30253-6 http://dx.doi.org/doi:10.1016/j.psyneuen.2017.04.014 PNEC 3609
To appear in: Received date: Revised date: Accepted date:
13-3-2017 17-4-2017 21-4-2017
Please cite this article as: Zhang, Chen, Fang, Xinyu, Yao, Peifen, Mao, Yemeng, Cai, Jun, Zhang, Yi, Chen, Meijuan, Fan, Weixing, Tang, Wei, Song, Lisheng, Metabolic adverse effects of olanzapine on cognitive dysfunction: a possible relationship between BDNF and TNF-alpha.Psychoneuroendocrinology http://dx.doi.org/10.1016/j.psyneuen.2017.04.014 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Metabolic adverse effects of olanzapine on cognitive dysfunction: a possible relationship between BDNF and TNF-alpha Chen Zhanga,*, Xinyu Fanga, Peifen Yaoa, Yemeng Maob, Jun Caia, Yi Zhanga, Meijuan Chena, Weixing Fanc, Wei Tangd, Lisheng Songa,* a
Schizophrenia Program, Shanghai Mental Health Center, Shanghai Jiao Tong
University School of Medicine, Shanghai, China b
Department of Pharmacology, Shanghai Mental Health Center, Shanghai Jiao Tong
University School of Medicine, Shanghai, China c
Department of Psychiatry, Jinhua Second Hospital, Jinhua, Zhejiang, China
d
Department of Psychiatry, Wenzhou Kanging Hospital, Wenzhou, Zhejiang, China
* Corresponding authors Chen Zhang, Email: [email protected] (C. Zhang) Lisheng Song, Email: [email protected] (L. Song) Highlights
44% patients receiving long-term olanzapine monotherapy met the diagnosis criteria for metabolic syndrome (MetS).
Patients with MetS had worse attention and memory performance than those without MetS.
Increasing glucose level is an independent risk factor for cognitive dysfunction.
Patients with MetS had lower BDNF and higher TNF-alpha levels than those without MetS.
There is a negative correlation between the BDNF and TNF-alpha levels.
Abstract 1
Objective: There is accumulating evidence indicating that long-term treatment with second-generation antipsychotics (SGAs) results in metabolic syndrome (MetS) and cognitive impairment. This evidence suggests an intrinsic link between antipsychoticinduced MetS and cognitive dysfunction in schizophrenia patients. Olanzapine is a commonly prescribed SGA with a significantly higher MetS risk than that of most antipsychotics. In this study, we hypothesized that olanzapine-induced MetS may exacerbate cognitive dysfunction in patients with schizophrenia. Methods: A sample of 216 schizophrenia patients receiving long-term olanzapine monotherapy were divided into two groups, MetS and non-MetS, based on the diagnostic criteria of the National Cholesterol Education Program's Adult Treatment Panel III. We also recruited 72 healthy individuals for a control group. Cognitive function was evaluated using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Plasma brain-derived neurotrophic factor (BDNF) and tumor necrosis factor-alpha (TNF-alpha) were measured by an enzymelinked immunosorbent assay for 108 patients and 47 controls. Results: Among the 216 schizophrenia patients receiving olanzapine monotherapy, MetS was found in 95/216 (44%). Patients with MetS had more negative symptoms, higher total scores in PANSS (Ps<0.05) and lower immediate memory, attention, delayed memory and total scores in RBANS (Ps<0.01). Stepwise multivariate linear regression analysis revealed that increased glucose was the independent risk factor for cognitive dysfunction (t=-2.57, P=0.01). Patients with MetS had significantly lower BDNF (F=6.49, P=0.012) and higher TNF-alpha (F=5.08, P=0.026) levels than 2
those without MetS. There was a negative correlation between the BDNF and TNFalpha levels in the patients (r=-0.196, P=0.042). Conclusion: Our findings provide evidence suggesting that the metabolic adverse effects of olanzapine may aggravate cognitive dysfunction in patients with schizophrenia through an interaction between BDNF and TNF-alpha. Keywords: Olanzapine; Metabolic syndrome; Cognitive function; Brain-derived neurotrophic factor; Tumor necrosis factor-alpha 1. Introduction Schizophrenia is a debilitating and often lifelong psychiatric disorder that can result in social and occupational disability. Schizophrenia is characterized by typical manifestations, including positive symptoms (hallucination, delusions, and disorganized behavior), negative symptoms (affective blunting, apathy, and social withdrawal) and cognitive dysfunction (attention, learning, and memory impairment) (Kuperberg and Heckers, 2000). Antipsychotic medication has been widely used to treat schizophrenia since first-generation antipsychotics (FGAs) were found to have specific therapeutic action against positive symptoms in the 1950s (Zhang et al., 2011). In recent decades, second-generation antipsychotics (SGAs) have been more frequently prescribed for patients with schizophrenia due to their lower risk of extrapyramidal symptoms and tardive dyskinesia compared with that of FGAs. Unfortunately, the metabolic adverse effects that accompany treatment with SGAs are almost as profound as their superior therapeutic effects (Hu et al., 2013).
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Metabolic syndrome (MetS) identifies a group of obesity-related risk factors for chronic metabolic and cardiovascular diseases. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) for schizophrenia in the US has shown that the prevalence of MetS in patients with schizophrenia is 40.9% based on the National Cholesterol Education Program—Adult Treatment Panel III (NCEP-ATP III) criteria. MetS and its components have been identified as important risk factors for developing cognitive impairment and dementia in the general population (Alfaro et al., 2016; Kaffashian et al., 2013; Raffaitin et al., 2011). There is emerging evidence showing that schizophrenia patients with MetS have significantly worse cognitive functions than those without MetS (Bora et al., 2017; de Nijs and Pet, 2016; Li et al., 2014). This evidence also suggests a link between antipsychotic-induced MetS and cognitive dysfunction in schizophrenia patients (Cai et al., 2013a). Previous work has shown that MetS is associated with a state of chronic and low-grade inflammation (Devaraj et al., 2010), and SGAs also potentiate aberrant peripheral levels of inflammation markers (Beumer et al., 2012). Thus, there may be an association between MetS and inflammation in schizophrenia (Mori et al., 2015). On the other hand, brain-derived neurotrophic factor (BDNF) has emerged as a critical mediator of neuronal plasticity and plays an important role in cognitive processes (Kuipers and Bramham, 2006). Ample literature has documented that serum BDNF levels are significantly decreased in patients with cognitive declinerelated diseases as well as schizophrenia compared with those in healthy individuals (Leyhe et al., 2008; Yu et al., 2008; Zhang et al., 2014c). Another study has noted the 4
involvement of BDNF in cognitive dysfunction rather than other symptomatic dimensions in patients with chronic schizophrenia (Zhang et al., 2012). Therefore, serum BDNF levels may serve as a peripheral biomarker for the evaluation of cognitive function in schizophrenia (Vinogradov et al., 2009). Evidence from in vivo studies has demonstrated that inflammation, especially pro-inflammatory cytokines, clearly affects the expression of BDNF in the brain (Calabrese et al., 2014). A recent study has reported an interaction between tumor necrosis factor-alpha (TNF-alpha) and BDNF that caused cognitive dysfunction in patients with chronic schizophrenia (Zhang et al., 2016b). Olanzapine is a commonly prescribed SGA with a significantly higher MetS risk than that of other antipsychotics, except clozapine (Vancampfort et al., 2015). In light of the abovementioned findings, we hypothesized that the metabolic adverse effects of olanzapine may exacerbate cognitive dysfunction in patients with schizophrenia through an interaction between TNF-alpha and BDNF. Therefore, we examined our hypothesis by investigating whether (1) cognitive function differs between patients with or without MetS; (2) serum TNF-alpha and BDNF levels differ between patients with or without MetS; and (3) serum TNF-alpha is correlated with BDNF levels. 2. Methods 2.1. Participants
5
We recruited 216 patients with schizophrenia from three mental hospitals in Eastern China, including Shanghai Mental Health Center, Jinhua Second Hospital and Wenzhou Kangning Hospital. According to our previous publications (Cai et al., 2013b; Zhang et al., 2016a; Zhang et al., 2017; Zhang et al., 2014d; Zhang et al., 2013), the inclusion criteria for patients were as follows: (1) patients had been diagnosed with schizophrenia according to DSM-IV with the diagnoses either made or reviewed by experienced psychiatrists; (2) patients were receiving olanzapine treatment alone; (3) patients had received olanzapine for more than 24 months; (4) patients had maintained a stable condition for more than 6 months before entry into the study; and (5) patients had no other diagnosed psychiatric disorder besides schizophrenia. We also recruited 72 healthy individuals for controls, who were screened by a specialized psychiatrist using the Structured Clinical Interview for DSM-IV-TR Axis I Disorders-Patient Edition. All procedures for this study were reviewed and approved by the Institutional Review Boards of the Shanghai Mental Health Center and other participating institutions. This study was performed in strict accordance with the Declaration of Helsinki and other relevant national and international regulations. Written informed consent was obtained from each participant prior to the performance of any procedures related to this study. 2.2. Biochemical parameters
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A cross-sectional assessment of metabolic parameters was performed to determine the prevalence of MetS based on the definition by the NCEP-ATP III, which is the best MetS criterion for a Chinese population (Zhou et al., 2010). MetS was diagnosed based on the presence of any three of the following criteria: (1) a waist circumference ≥90 cm in Chinese men and ≥80 cm in Chinese women (Bao et al., 2008); (2) triglyceride (TG) ≥1.7 mmol/L; (3) high density lipoprotein cholesterol (HDL) <1.0 mmol/L in men and <1.3 mmol/L in women; (4) blood pressure ≥130/85 mmHg; or (5) fasting glucose (GLU) ≥5.6 mmol/L (Grundy et al., 2005). Waist circumference was measured between the lower rib margin and the iliac crest, after a normal expiratory breath. Overnight fasting blood samples were drawn in ice-cooled ethylenediaminetetraacetic acid tubes between 7:00 and 7:30 a.m. Serum was separated by centrifugation at 5°C and stored at -20C°. Serum fasting GLU, TG, and HDL levels were measured using an automatic Biochemical Analyzer (HITACHI 7170A, Hitachi, Ltd, Tokyo, Japan) (Zhang et al., 2014d; Zhang et al., 2013). 2.3. Plasma level analysis by enzyme-linked immunosorbent assay (ELISA) In total, we collected blood samples from 108 patients with schizophrenia and 47 healthy controls for analysis of the plasma levels of BDNF and TNF-alpha. On admission, 10 ml peripheral blood from fasting patients and healthy controls was collected between 07:00 am and 09:00 am to avoid potential diurnal influence. The blood samples were centrifuged at 3000 g for 15 min at 4°C. The plasma was separated and stored at -70°C until measurement. The plasma levels of BDNF and
7
TNF-alpha were measured using ELISA kits (R&D Systems, Minneapolis, Minnesota, USA). The reproducibility of the assay was tested prior to the measurement of the samples, and the inter-assay coefficient of variation was approximately 4.4% for BDNF and 5.4% for TNF-alpha (Li et al., 2016; Zhao et al., 2016). 2.4. Evaluation The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) (Randolph et al., 1998) was the primary outcome instrument for this study. The 12-item RBANS consists of 5 subsets, corresponding to the following 5 domains of neuropsychological process: (a) immediate memory (list learning and story memory), (b) visuospatial/constructional (figure copy and line orientation), (c) language (picture naming and semantic fluency), (d) attention (digit span and coding) and (e) delayed memory (list learning free recall, list learning recognition, story memory free recall and figure free recall). RBANS has good validity and reliability in Chinese people (Cheng et al., 2011) and works well in cognitive evaluations of patients with schizophrenia (Cai et al., 2015; Wang et al., 2016). The severity of psychotic symptoms exhibited by the schizophrenia patients was evaluated using the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987). PANSS evaluations were conducted by two experienced psychiatrists who both attended a PANSS training session. Repeated assessments revealed that a correlation coefficient more than 0.8 was maintained for PANSS total scores (Zhu et al., 2015).
8
2.5. Statistical analysis Demographic variables were compared between case and control groups with independent t tests for quantitative variables and Fisher’s exact test for qualitative variables. Analysis of covariance (ANCOVA) was used to compare the RBANS scores between case and control groups, controlling for demographic characteristics. Post hoc multiple comparisons were performed to identify the differences between groups. To compare the BDNF and TNF-alpha levels between MetS and non-MetS groups, ANCOVA was carried out with age, sex and BMI as covariates that were controlled for in the model to minimize the potential effect of these factors on the expression levels of BDNF and TNF-alpha. The correlation between these parameters was calculated by Spearman’s correlation analysis. All statistical tests were twotailed, and the significance level was set at p < 0.05. 3. Results The demographic characteristics for the patients with schizophrenia and healthy controls are summarized in Supplementary Table S1. There were significant differences in terms of age and years of education between the two groups. Consequently, we used these parameters as covariates to compare the scores of RBANS between the groups. The results showed that patients had significantly poorer performance than controls on immediate memory, visuospatial skill, language, attention, delayed memory and total RBANS score.
9
We then examined the plasma levels of BDNF and TNF-alpha between the patient and control groups. Supplementary Figure S1 shows significant decreases in BDNF levels (2.55±0.83 ng/ml vs 4.22±1.13 ng/ml; F=103.79, P<0.01) and increases in TNF-alpha levels (65.69±0.83 pg/ml vs 4.22±1.13 pg/ml; F=4.17, P=0.04) in the schizophrenia patients compared with those in healthy controls. Among the 216 schizophrenia patients receiving olanzapine monotherapy, MetS was found in 95/216 (44%). The demographic and clinical features of the MetS and non-MetS groups are presented in Table 1. There were significant differences between the two groups in terms of BMI, waist circumference, fasting GLU, fasting TG, fasting HDL, SBP and DBP (Ps<0.05). Patients with MetS had a notably longer duration of olanzapine treatment (t=6.58, P<0.01) and higher daily dose (t=3.24, P<0.01) than those without MetS. To further explore the relationship between MetS and clinical features, we added the duration of olanzapine treatment and daily dose as covariates. Our results showed that patients with MetS had higher negative symptoms and total scores in PANSS (Ps<0.05) and lower immediate memory, attention, delayed memory and total scores in RBANS (Ps<0.01). Stepwise multivariate linear regression analysis using RBANS total score as the dependent variable and waist circumference, GLU, TG, HDL, SBP and DBP as the independent variables revealed that increasing GLU was the independent risk factor for cognitive dysfunction (t=-2.57, P=0.01, Table 2). Within the schizophrenia patients, plasma BDNF and TNF-alpha levels were measured in 51 individuals with MetS and 57 without MetS. Figure 1 shows that 10
patients with MetS had significantly lower BDNF (F=6.49, P=0.012) and higher TNFalpha (F=5.08, P=0.026) levels than those without MetS, after we controlled for age, sex, olanzapine treatment duration, daily dose and BMI. Next, we aimed to determine whether there was an interaction between BDNF and TNF-alpha levels in the patients. Figure 2 shows a negative correlation between the BDNF and TNF-alpha levels (r=-0.196, P=0.042). 4. Discussion Cognitive dysfunction is increasingly recognized as a central aspect of schizophrenia. Our previous work has demonstrated that a wide range of cognitive functions are substantially impaired among antipsychotic-naïve patients with firstepisode schizophrenia (Lu et al., 2012; Zhang et al., 2014a). A randomized controlled trial has indicated that short-term (12-week) olanzapine treatment can improve cognitive function in patients with first-episode schizophrenia (Wang et al., 2013). Our preclinical study has provided further evidence that the advantageous effects of olanzapine on cognitive functioning may be due to its contribution to synaptic plasticity (Zhang et al., 2014b). A high rate of MetS is a typical side effect of longterm olanzapine treatment in clinical practice. Given the important role of MetS in cognitive dysfunction (Yaffe et al., 2004), we administered cognitive evaluations to schizophrenia patients receiving long-term olanzapine monotherapy. Our results showed that patients with MetS had worse cognitive performance than those without MetS, indicating that olanzapine-induced metabolic
11
consequences may be an important contributor to worsening cognitive impairment in schizophrenia, especially attention and memory deficits. This finding agrees with recent studies showing that MetS is implicated in impaired attention and memory performance (Rouch et al., 2014; Rubens et al., 2016). Accumulating clinical studies have reported that BDNF is regarded as a biomarker reflecting memory and general cognitive function in patients with schizophrenia (Zhang et al., 2012). Hence, we measured the plasma BDNF level in schizophrenia patients with or without MetS and observed a close relationship between MetS with reduced levels of BDNF in these patients. Previous literature has indicated that BDNF is associated with antipsychotic-induced metabolic alterations (Tsai et al., 2011; Zai et al., 2012; Zhang et al., 2007; Zhang et al., 2008; Zhang et al., 2013). Preclinical observation has also suggested that consumption of a high-fat diet in mice may decrease BDNF levels and exacerbate cognitive impairment (Pistell et al., 2010). In contrast, the amelioration of cognitive impairment is associated with concurrent elevation of BDNF levels (Neshatdoust et al., 2016). BDNF has an important physiological role in cognitive function, including critical involvement in the induction of long-term potentiation, a synaptic plasticity mechanism underlying learning and memory processes (Lu and Martinowich, 2008; Matynia et al., 2002). Therefore, the decreased BDNF levels may account for the worse cognitive function in schizophrenia patients with MetS compared with that in patients without MetS. To clarify the role of metabolic components in cognitive impairment, we performed a stepwise multivariate linear regression analysis and observed that 12
increased GLU level is a pronounced risk factor for cognitive dysfunction in schizophrenia patients receiving long-term olanzapine treatment. There is a clear link between the use of olanzapine and the risk of developing type 2 diabetes mellitus (Galling et al., 2016). Previous research has shown that olanzapine induces weight gain and causes alterations in glucose metabolism and insulin resistance (Fountaine et al., 2010; Newcomer, 2004) that could lead to the cognitive impairment observed in either clinical or preclinical studies (Ma and Li, 2017; Xia et al., 2016). Regarding BDNF levels, there is accumulating data suggesting that plasma BDNF levels are reduced in patients with diabetes and negatively correlated with plasma glucose and insulin resistance (Murillo Ortiz et al., 2016). Elevated blood glucose levels can trigger subclinical chronic inflammation and activation of the immune system (Rodrigues et al., 2017). Elevated levels of cytokines, such as TNF-alpha, are frequently reported in patients with diabetes (Hu et al., 2004; Lechleitner et al., 2002). BDNF is well known to be regulated by cytokines (Calabrese et al., 2014). Our present results indicate a negative interaction between BDNF and TNF-alpha in patients with schizophrenia, suggesting that BDNF may be inversely modulated by TNF-alpha. In this study, the main cognitive impairment associated with MetS was attention and memory deficits. Changes in the hippocampus have been implicated in the attention and memory deficits in schizophrenia (McGarrity et al., 2016). Previous research has established that TNF-alpha is critically involved in hippocampaldependent cognitive deficits (Rowan et al., 2007). A recent work has indicated that 13
TNF-alpha negatively regulates BDNF expression in the hippocampus and affects the synaptic connectivity in hippocampal CA1 pyramidal neurons (Liu et al., 2017). Previously, we revealed that the PI3K/AKT signaling pathway may participate in the development of metabolic syndrome and cognitive impairment (Cai et al., 2013a). Experimental data have shown that the PI3K/AKT signaling pathway is activated by TNF-alpha (Li et al., 2017). As such, further investigations to determine whether long-term olanzapine application stimulates metabolic and cognitive activities through the PI3K/AKT signaling pathway activated by TNF-alpha will be of considerable interest. The strength of this study is that the patients recruited for this study were all subjected to long-term olanzapine monotherapy. Alongside the strength, however, we would be remiss in not noting some marked limitations of this study. First, our sample size is small, especially the sample size for the ELISA measurement, and accordingly, our findings should be viewed as preliminary until replicated and independently verified. Second, our subjects are chronic patients, and whether other antipsychotic treatments prior to this study may have already influenced the risk for MetS is unknown, which lessens the effects attributable to olanzapine that the patients are currently taking. Third, the patients’ baseline metabolic parameters prior to olanzapine treatment and their previous antipsychotic agents were unknown, which may potentially confound the results obtained in this study. Lastly, the ideal study design for observing the trajectory of olanzapine-induced MetS and cognitive dysfunction is a longitudinal, prospective, randomized and parallel-control 14
clinical trial. However, our study was cross-sectional rather than longitudinal; therefore, we cannot affirm that some subjects in the non-MetS group did not develop MetS after the investigation. To avoid the negative consequences of this potential bias, it is important to replicate these data using larger studies that are better designed to find conclusive and not simply suggestive evidence of the associations that we noted in the present study. 5. Conclusion We performed a clinical study to examine the association between MetS and cognitive impairment in schizophrenia patients receiving long-term olanzapine monotherapy. Our findings provide evidence suggesting that the metabolic adverse effects of olanzapine may aggravate cognitive dysfunction in patients with schizophrenia through an interaction between BDNF and TNF-alpha. Large-scale longitudinal studies should be conducted to replicate these findings and offer more conclusive evidence. Acknowledgements We are deeply grateful to all participants. This work was supported by the National Natural Science Foundation of China (81471358), the Shanghai Science and Technology Commission Foundation (14411969000), the Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (20152530), the Shanghai Municipal Commission of Health and Family Planning Foundation (201540029) and the Shanghai Mental Health Center Foundation (2014-FX-03).
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Figure Legends Figure 1 Serum levels of BDNF and TNF-alpha in MetS and non-MetS groups. A. BDNF; B. TNF-alpha. Scatter plots for the comparison between the MetS and nonMetS groups. Horizontal lines represent the mean BDNF or TNF-alpha levels. MetS, patients with metabolic syndrome (n=51); non-MetS, patients without metabolic syndrome (n=57). Figure 2 Correlation between serum BDNF and TNF-alpha levels in the patients. 21
22
Figr-1
23
Figr-2
24
Table 1 Demographics and clinical features between MetS and non-MetS groups MetS (n=95)
non-MetS (n=121)
χ2
P
52/43
63/58
0.15
0.78
t
P
Gender (Male/Female)
Age (year) a
28.65±3.52
28.75±3.89
-0.19
0.85
Education (year) a
9.81±1.86
9.84±2.05
-0.12
0.90
Duration of olanzapine treatment (month)
35.09±6.47
30.25±3.49
6.58
＜0.01
Daily olanzapine dose (mg) a
13.32±4.32
11.24±4.92
3.24
＜0.01
BMI (kg/m2) a
27.03±1.47
23.06±1.97
16.96
＜0.01
Waist circumference (cm) a
89.64±6.10
84.94±5.75
5.81
＜0.01
Fasting GLU (mmol/l) a
6.75±1.56
5.78±0.75
5.59
＜0.01
Fasting TG (mmol/l) a
1.83±0.70
1.58±0.95
2.11
0.03
Fasting HDL (mmol/l) a
0.91±0.35
1.42±0.43
-9.44
＜0.01
SBP (mm Hg) a
125.81±20.99
117.45±20.60
2.94
＜0.01
DBP (mm Hg) a
88.76±9.90
79.03±7.84
7.84
＜0.01
F
P
a
PANSS Positive symptoma
10.48±2.94
10.02±3.14
1.32
0.25
Negative symptoma
12.71±3.23
11.47±4.06
6.46
0.01
General psychopathologya
22.78±3.67
22.28±4.42
1.44
0.23
Total scorea
45.97±7.53
43.77±8.36
4.97
0.03
F
P
RBANS Immediate memorya
62.58±12.90
67.29±11.12
8.87
＜0.01
Visuospatial skilla
63.78±7.23
64.08±9.92
1.56
0.21
Languagea
60.29±8.04
61.98±14.62
3.02
0.08
Attentiona
72.18±143.50
79.74±17.18
18.13
＜0.01
Delayed memorya
71.39±10.21
74.00±11.37
9.01
＜0.01
Total scorea
330.22±34.29
347.10±50.54
16.45
＜0.01
Note: aData presented asx±s; BMI: body mass index; GLU: glucose; TG: triacylglyceride; HDL: high density lipoprotein; SBP: systolic pressure; DBP: diastolic pressure
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Table 2 Multivariate linear regression analysis with RBANS total score as the dependent variable in patient with schizophrenia receiving long-term olanzapine monotherapy B SE β t Waist circumference 0.06 0.53 0.01 0.11 Fasting GLU -6.72 2.61 -0.19 -2.57 Fasting TG 2.14 3.69 0.04 0.58 Fasting HDL -0.08 7.60 -0.001 -0.01 SBP 0.13 0.15 0.06 0.89 DBP -0.16 0.32 -0.04 -0.51 Note: B: unstandardized coefficients; SE: standard error; β: standardized coefficients; GLU: glucose; TG: triacylglyceride; HDL: high density lipoprotein; SBP: systolic pressure; DBP: diastolic pressure
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P 0.92 0.01 0.56 0.99 0.38 0.61