ORIGINAL ARTICLE
Metabolic Syndrome and Its Factors Affect Cognitive Function in Chronic Schizophrenia Complicated by Metabolic Syndrome Chenhu Li, Guilai Zhan, BS, Shunzeng Rao, BS, and Hong Zhang, BS
Abstract: The aim of this study was to investigate the characteristics of cognitive function damage in chronic schizophrenia patients with metabolic syndrome (MS); 388 patients were divided into two groups: MS group (180 people with schizophrenia and MS) and non-MS group (208 people with schizophrenia but without MS). The Positive and Negative Syndrome Scale (PANSS) and the Treatment Emergent Symptom Scale (TESS) were used to evaluate clinical symptoms and drug adverse reaction. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was used to assess cognitive function. There was no significant change in PANSS ( p = 0.53) and TESS score ( p = 0.26) between the MS group and the non-MS group. However, RBANS total scale score as well as attention, immediate memory, and delayed memory scores in the MS group were significantly lower than those in the non-MS group ( p G 0.05). There was no significant change in visuospatial skill ( p = 0.07) and language scores ( p = 0.08) between the two groups. Besides, course of disease, triglyceride, antipsychotic drug type, systolic pressure, negative symptom factor, and education level showed a notable significance for cognitive function damage in turn. MS might aggravate injury of cognitive function in chronic schizophrenia, especially in immediate memory, delayed memory, and attention. Key Words: Schizophrenia, metabolic syndrome, cognitive function (J Nerv Ment Dis 2014;202: 313Y318)
S
chizophrenia, a kind of severe psychiatric disorder, mostly presents with lack of coherence and logicality in thought and associative processes (Dekker et al., 2010). Gallhofer first brought the matter up in 1970, proposing that schizophrenia presented positive symptoms (such as thinking disturbance, affective disorder, delusions, hallucinations) and negative symptoms (poverty of thought, retraction of behavior, abulia, etiquette neglect), as well as cognitive dysfunction (TuulioHenriksson et al., 2011). In recent years, research concerning the cognitive dysfunction of schizophrenia were focused on idiopathic cognitive dysfunction widely occurring in people with schizophrenia, which mainly involved frontal lobe executive function, memory, and attention (Collins et al., 1997; Donders et al., 2010). Atypical antipsychotics were widely applied in therapy, and schizophrenia complicated with metabolic syndrome (MS) received much more attention. MS was formed with a spectrum of medical disorders associated with an increased risk for cardiovascular disease and development of type 2 diabetes mellitus. However, few research studies reported that MS could induce cognitive function lesion. MS was caused by multiple genes and environmental factors, in which insulin resistance (IR) was the common base and core mechanism. IR resulted in hyperinsulinism and cerebrovascular and cardiovascular diseases, including obesity, hypertension, hyperlipidemia, and disorder of coagulation system, which were induced by injuries of Department of Psychiatry, Shanghai Xuhui District Mental Health Center, Shanghai, China. Send reprint requests to Chenhu Li, MM, Department of Psychiatry, Shanghai Xuhui District Mental Health Center, No. 249 Longhua Xi Rd, Shanghai 200232, China. E-mail: [email protected]. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0022-3018/14/20204Y0313 DOI: 10.1097/NMD.0000000000000124
The Journal of Nervous and Mental Disease
endotheliocyte and formation of atherosclerosis. Abnormality of IR or hyperinsulinism and its signal pathways affected brain tissue (especially seahorse, cortex of temporal lobe neurite), which caused injury to cognitive function. Thus, it was important to pay attention to MS problem in schizophrenia patients. The prevalence rate of MS differed from 9% to 68% in schizophrenia, which was more severe among healthy controls and the general population (De Hert et al., 2006). Older age, female sex, more severe illness, and use of antipsychotic drugs seemed to be potential risk factors of developing the syndrome (Lee et al., 2011). Studies showed that the prevalence of MS in patients with schizophrenia has been limited in small samples and/or patients without any comorbidity (Meyer and Stahl, 2009). Thus, our research was proposed to investigate the characteristics of cognitive dysfunction in people with schizophrenia with MS.
METHODS Patients All participants gave their informed consent before their inclusion in the study, and all human studies were approved by China Ethics Committee and performed in accordance with the ethical standards. Patients in their recovery periods were recruited from November 2010 to July 2011 at the Department of Psychiatry, Shanghai Xuhui District Mental Health Center (Shanghai, China). The inclusion criteria were as follows: aged 18 to 60 years (according to diagnostic criteria for chronic schizophrenia of the Chinese Classification and Diagnostic Criteria of Mental Disorders Version 3, stable dose of a single antipsychotic for at least 2 years, Positive and Negative Syndrome Scale (PANSS) total score of lower than 60, inspection items completed, and willingness to give written informed consent. Patients with the following situations were excluded in our research: severe liver, kidney, or nervous system physical diseases; alcohol abuse or psychoactive drug or substance abuse; severe physical disability; other severe mental disorders, mental retardation, dementia, and severe cognitive dysfunction; severe medicine adverse reactions (such as extrapyramidal symptoms) and obvious tardive dyskinesia; pregnant or lactating women; and participating in other researches. The patients were divided into two groups: the MS group including 180 patients with MS and the non-MS group including 208 patients free of MS. The patients were diagnosed according to diagnostic criteria for MS of the Chinese Diabetes Society in 2004 and were assigned to the MS group if they satisfied three or four of the following conditions (Al-Aqeedi et al., 2013; Cavali Mde et al., 2010): obesity, body mass index (BMI) of 25.0 kg/m2 or greater; hyperglycemia or diabetes mellitus, fasting plasma glucose of 6.1 mmol/l or greater or plasma glucose of 7.8 mmol/l or greater; hypertension, systolic/diastolic pressure of 140/90 mm Hg or greater; and dyslipidemia, fasting serum triglycerides (TGs) of 1.7 mmol/l or greater or fasting high-density lipoprotein cholesterol (HDL-C) of less than 0.9 mmol/l for the men and less than 1.0 mmol/l for the women.
Methods Our study is a cross-sectional study. Information about the patients was obtained in our study, such as general demographic
& Volume 202, Number 4, April 2014
www.jonmd.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
313
The Journal of Nervous and Mental Disease
Li et al.
information, the course of disease, first-episode age, frequency of hospitalization, family history of mental illness, currently taking antipsychotic drugs (single medication), history of somatic diseases, diabetes mellitus and hypertension, biological index including BMI, fasting blood glucose and lipid, blood pressure, and waist-hip ratio. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), a brief neurocognitive battery, was used in our research (King et al., 2012; Moore et al., 2013), which contained 12 subtests and 5 alternate forms: immediate memory (vocabulary learning, story rehearsal), visuospatial skills (graphics depiction, line orientation), language (picture naming, semantic fluency), attention (digit span and digit symbol), and delayed memory (vocabulary recall, word recognition, story recall, and figure recall). The PANSS was used to take secondary objective efficacy measures in our study (Cruz et al., 2013; Pilla Reddy et al., 2012), including 33 items and 4 subscales (positive symptoms, negative symptoms, general mental disease pathology symptoms, and accessory symptoms). The Treatment Emergent Symptom Scale (TESS) information included 34 symptoms and general investigations (Cruz et al., 2013; Pilla Reddy et al., 2012) and was scored in four grades to evaluate the status of adverse drug reaction. Moreover, glycometabolism and lipometabolism tests were also taken in our research. Plasma TG was obtained from the ulnar vein at 7 a.m.
Statistical Analysis Data were analyzed using the Statistical Package for the Social Sciences 11.5. The t-test, the chi-square test, covariance analysis, regression analysis, and parameter test were used for statistical analysis. Data were applied using a two-sided test and expressed as mean
& Volume 202, Number 4, April 2014
(standard deviation). A p-value of less than 0.05 was considered as significant.
RESULTS Comparison of General Information and MS Index Between MS and Non-MS Schizophrenics We obtained 388 patients in our study (182 male patients, 46.0%; 206 female patients, 53.1%). The patients had a mean (SD) age of 42.3 (9.6). The education level of the patients was as follows: 20 patients had primary school degree (5.2%); 111 patients, junior middle school degree (28.6%); 189 patients, senior middle school or secondary school degree (48.7%); and 68 patients, junior college degree or higher (17.5%). The marital status of the patients was as follows: 270 patients were single (69.6%); 94 patients, married (24.2%); 22 patients, divorced (5.7%); and 2 patients, widowed (0.5%). Sixty-two patients were employed (16.0%), and 326 patients were unemployed (84.0%). As shown in Table 1, there were no significant differences in sex ( p = 0.37), age ( p = 0.25), educational level ( p = 0.20), marital status ( p = 0.06), and employment status ( p = 0.03) between the MS group and the non-MS group. On the other hand, the MS group showed a notable difference in BMI, fasting blood glucose, HDL, and TG compared with the non-MS group ( p G 0.05; Table 1). Briefly, in the MS group, the fasting blood glucose level (5.87 [0.84] mmol/l) was significantly higher than that in the non-MS group (5.54 [0.78] mmol/l; p G 0.05), as well as the TG level (1.77 [0.42] vs. 1.68 [0.27] mmol/l; p = 0.01). However, the level of HDL in the MS group (1.05 [0.39] mmol/l) was significantly lower than that in the non-MS group (1.13 [0.28] mmol/l; p = 0.02).
TABLE 1. Comparison of General Information and MS Index of People with Schizophrenia (Mean [SD]) Sex Male Female Age, yrs Education level Primary school Junior middle school Senior middle school degree or secondary school degree Junior college or higher Marital status Unmarried Married Divorced/widowed Work status Employed Unemployed MS BMI, kg/m2 Fasting blood glucose, mmol/l HDL, mmol/l TG, mmol/l Systolic pressure, mm Hg Diastolic pressure, mm Hg
MS Group (n = 180)
Non-MS Group (n = 208)
80 (44.4%) 100 (55.6%) 42.9 (9.7)
102 (49.0%) 106 (51.0%) 41.8 (9.6)
11 (6.1%) 45 (25.0%) 86 (47.8%) 38 (21.1%)
9 (4.3%) 66 (31.7%) 103 (49.5%) 30 (14.5%)
117 (65.0%) 46 (25.6%) 17 (9.4%)
153 (73.6%) 48 (23.0%) 7 (3.4%)
25 (13.9%) 155 (86.1%)
37 (17.8%) 171 (82.2%)
23.74 (2.88) 5.87 (0.84) 1.05 (0.39) 1.77 (0.42) 136.4 (14.8) 82.8 (12.6)
22.32 (2.72) 5.54 (0.78) 1.13 (0.28) 1.68 (0.27) 133.9 (11.1) 81.4 (10.4)
t/W2
p
0.82
0.37
1.15 4.65
0.25 0.20
7.41
0.06
1.09
0.30
4.99 3.98 j2.32 2.62 1.86 1.12
0.00** 0.00** 0.02* 0.01* 0.06 0.26
p-Value of t-test or chi-square test for data. *Significant at the 0.05 level. **Significant at the 0.01 level.
314
www.jonmd.com
* 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The Journal of Nervous and Mental Disease
& Volume 202, Number 4, April 2014
MS and Cognitive Function
TABLE 2. Comparison of MS Characteristics and Therapy Status Between MS and Non-MS People with Schizophrenia (Mean [SD]) MS Group (n = 180)
First-episode age, yrs Course of disease, yrs No. hospitalizations 0 1 2 3 93 Family history of mental disorders No Yes Currently taking antipsychotic drugs Risperidone Olanzapine Quetiapine Aripiprazole Ziprasidone Clozapine Chlorpromazine Perphenazine
28.7 (7.3) 14.2 (9.5) 4 52 23 30 71
Non-MS Group (n = 208)
29.5 (6.6) 12.3 (8.9)
(2.2%) (28.9%) (12.8%) (16.7%) (39.4%)
4 (1.9%) 85 (40.9%) 38 (18.2%) 22 (10.6%) 59 (28.4%)
160 (88.9%) 20 (11.1%)
195 (93.8%) 13 (6.2%)
51 18 13 11 9 37 28 13
(28.3%) (10.0%) (7.2%) (6.1%) (5.0%) (20.6%) (15.6%) (7.2%)
t/W2
p
j1.10 2.04 29.3
0.27 0.04* 0.01*
2.93
0.09
17.37
0.01*
65 (31.3%) 16 (7.7%) 14 (6.7%) 29 (13.9%) 18 (8.7%) 25 (12.0%) 19 (9.1%) 22 (10.6%)
p-Value of t-test or chi-square test for data. *Significant at the 0.05 level.
Comparison of MS Characteristics and Therapy Status Between MS and Non-MS Schizophrenics
Comparison of Mental Symptoms and Adverse Reaction Between MS and Non-MS Schizophrenics
The first-episode age ranged from 16 to 56 years, with a mean (SD) age of 29.1 (7.0) years. Thirty-three patients (9.9%) had a family history of mental disorders and 355 patients (91.5%) did not. Our results presented that there was no apparent difference in first-episode age (28.7 [7.3] vs. 29.5 [6.6], p = 0.27) and family history of mental disorders in the MS group ( p = 0.09) compared with the non-MS group (Table 2). Besides, the mean (SD) course of disease of all patients was 13.2 (9.2) years. The disease course of the MS group was significantly longer than that of the non-MS group (14.2 [9.5] vs. 12.3 [8.9], p = 0.04). Meanwhile, 8 patients (2.1%) had never been hospitalized, 137 patients (35.3%) had been hospitalized once, 61 patients (15.7%) had been hospitalized twice, 52 patients (13.4%) had been hospitalized three times, and 130 patients (33.5%) had been hospitalized for more than three times. There was a notable change between the MS group and the non-MS group in number of hospitalizations ( p = 0.01) and antipsychotic drug use ( p = 0.01), which indicated that MS might be associated with cognitive function of schizophrenics.
We chose schizophrenics in the recovery stage as our patients, whose PANSS score was lower than 60. As illustrated in Table 3, there was no significant change between the MS and non-MS groups in comparison of total score ( p = 0.53); positive ( p = 0.28), negative ( p = 0.94), cognitive ( p = 0.27), excitatory ( p = 0.69), and anxietydepression factors ( p = 0.83) of the PANSS; and total score of the TESS ( p = 0.26). Thus, MS might have fewer effects on recovery-stage schizophrenics.
Comparison of Cognitive Function Between MS and Non-MS Schizophrenics Considering that there existed a notable change between the MS group and the non-MS group in course of disease, number of hospitalizations, and antipsychotic drug use ( p G 0.05, Table 2), which might potentially affect the cognitive function of schizophrenics, we investigated the cognitive function between the MS and non-MS schizophrenics by the RBANS score system. As shown in Table 4, the MS group presented a significant difference in RBANS total score,
TABLE 3. Comparison of Mental Symptoms and Adverse Reaction Between MS and Non-MS People with Schizophrenia (Mean [SD]) PANSS total score Positive factor Negative factor Cognitive factor Excitatory factor Anxiety-depression factor TESS total score
* 2014 Lippincott Williams & Wilkins
MS Group (n = 180)
Non-MS Group (n = 208)
t
p
45.8 (7.8) 6.8 (1.9) 12.9 (4.8) 9.6 (2.2) 9.2 (1.9) 6.5 (1.9) 18.7 (5.1)
44.9 (9.0) 7.1 (2.0) 12.7 (4.5) 9.3 (2.3) 9.3 (1.6) 6.4 (1.5) 18.1 (5.6)
0.63 j1.09 0.08 1.11 j0.40 0.22 1.15
0.53 0.28 0.94 0.27 0.69 0.83 0.26
www.jonmd.com
315
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The Journal of Nervous and Mental Disease
Li et al.
& Volume 202, Number 4, April 2014
TABLE 4. Comparison of Cognitive Function Between MS and Non-MS People with Schizophrenia in RBANS Score (Mean [SD]) RBANS total score Immediate memory Visuospatial skill Attention Language Delayed memory
MS Group (n = 92)
Non-MS Group (n = 113)
F
p
165.6 (17.0) 27.2 (5.9) 28.7 (4.6) 51.7 (7.6) 24.9 (5.1) 30.9 (6.1)
173.0 (23.1) 31.4 (8.3) 28.2 (5.4) 53.9 (9.2) 24.6 (4.3) 34.9 (6.8)
7.63 10.25 2.22 4.29 2.16 14.57
0.00* 0.00* 0.07 0.00* 0.08 0.00*
p-Value of covariance analysis for data. *Significant at the 0.01 level.
immediate memory, attention, and delayed memory sections compared with the non-MS group ( p G 0.01). There was no apparent change in visuospatial skill ( p = 0.07) and language parts ( p = 0.08) between the two groups.
Factors Affecting the Cognitive Function of MS Schizophrenics To investigate the main factors affecting cognitive function of MS schizophrenics, we used the RBANS total score of the MS schizophrenics as dependent variable. Factors that might affect cognitive function, including sex, age, education level, marital status, and employment status of patients; MS index; first-episode age; course of disease; frequency of hospitalization; family history; drug analogues; and PANSS and TESS analysis, were considered as independent variables to carry out logistic stepwise regression analysis and to take gradual regressive analysis. At the level of > = 0.05, six factors showed a notable significance in turn, including course of disease, TG, drug category, systolic pressure, negative symptom factor, and education level (Table 5).
DISCUSSION In recent years, research concerning neuropsychology, neurobiochemistry, brain iconography, and genetics has figured out that cognitive deficit was the core of schizophrenia and presented a continuous symptom, which was independent of positive symptoms and negative symptoms of schizophrenia. Cognitive deficit involved damages of memory, attention, and executive functions, which deeply affected social function and quality of life of schizophrenics (Guse et al., 2013; Harvey et al., 2009). However, the causes of cognitive dysfunction in schizophrenics were still unclear. The cognitive dysfunction of schizophrenics was also impacted by multiple factors and complications of factors (Collins et al., 1997; Mohamed et al., 1999; Semkovska et al., 2001; Yang and Winkelman, 2006). Studies showed that cognitive function of schizophrenics was affected by many factors, including age, sex, mental symptoms (especially negative symptoms), course of disease, frequency of hospitalization, and drug category. However, researches did not receive the same outcomes in how these factors influence cognitive function, and different health conditions might also affect cognitive function of schizophrenics. MS, including glycolipid dysbolism, a common
complication of schizophrenia, may influence the cognitive function of schizophrenics (Nasrallah, 2010). MS was formed with diabetes mellitus, IR, hyperlipidemia, hypertension, and other cardiovascular risk factors. In addition, the incidence of schizophrenics with MS was apparently higher than that of the general population (De Hert et al., 2010; Mitchell et al., 2013; Nasrallah, 2010). Besides, diabetes mellitus and hypertension were widely proven injuries of cognitive function, whereas low HDL-C concentration and hypertriacylglycerolemia were also important factors (De Hert et al., 2010; Mitchell et al., 2013; Nasrallah, 2010). In our study, there was no significant change in sex, age, education level, first-episode age, mental symptoms, and drug adverse reaction between the MS group and the non-MS group. However, there was a notable difference among course of disease, frequency of hospitalization, and category of currently taking antipsychotics in the MS group compared with the non-MS group. Thus, we used covariance analysis to analyze the course of disease, frequency of hospitalization, and category of currently taking antipsychotics by comparing the cognitive function of the MS and non-MS groups. However, these factors were excluded to affect cognitive function in our results. Meanwhile, our results showed that MS could apparently enhance BMI, fasting blood glucose and TG level, and low HDL-C concentration in schizophrenics, which aggravated cognitive function. The mechanism of MS affecting cognitive function included high BMIinduced IR, microangiopathy, macroangiopathy, and inflammation, and glycolipid dysbolism might become the vital factor that caused cognitive function damage. Thus, we found that RBANS total score, attention score, immediate memory score, and delayed memory score in the MS group were significantly lower than those in the non-MS group, whereas there was no significant change in visuospatial skill and language scores, indicating that MS exacerbated the cognitive function injury of schizophrenics, especially the injured immediate memory and recall function of schizophrenics. Moreover, MS-involved cardiovascular risk factors might result in cerebrovascular pathological changes that caused cerebral blood flow descent extensively, which induced chronic hypoxicischemic damage in the brain. Memory-related structures in the brain, including the thalamus and the hippocampus, received the most serious damage for their sensitivity to hypoxic-ischemic injury. Besides, MS factors might interact to integrate an amplification effect
TABLE 5. Multielement Logistic Stepwise Regression Analysis of Cognitive Function Level of People with MS and Schizophrenia Course of disease TG Antipsychotic Systolic pressure Negative symptom factor Education level
316
www.jonmd.com
Regression Coefficient (B)
Standardized Regression Coefficient (A)
t
P
j0.60 j10.39 j1.75 j0.26 j0.71 4.61
j0.29 j0.28 j0.23 j0.22 j0.18 0.16
4.35 j4.14 j3.41 j3.18 j2.68 2.54
0.000 0.000 0.001 0.002 0.008 0.012
* 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The Journal of Nervous and Mental Disease
& Volume 202, Number 4, April 2014
(Friedman et al., 2010; Panza et al., 2010; Raffaitin et al., 2011). The cognitive function of schizophrenics had a positive correlation with negative symptoms level, course of disease, and frequency of hospitalization. Mainly, negative symptoms of schizophrenia presented significant hypofrontality of lobus frontalis execution function, and the decrease of gray matter of the frontal lobe in the left side might become the basement of execution functional lesion. Thus, free radical scavenging could regulate the cognitive functionYrelated frontal lobe hypofrontality caused by free radical dysbolism in the brain. To analyze the factors affecting cognitive function of MS accompanied by schizophrenia, multielement logistic stepwise regression analysis was used in our study. The results showed that the course of disease had the greatest influence on cognitive function level of schizophrenics, which corresponded with previous studies (Napal et al., 2012; Waddington et al., 1998). Interestingly, the category of current use of antipsychotics was also a significant factor that influenced the cognitive function level of schizophrenics. Typical antipsychotics including chlorpromazine and perphenazine had a bad influence on cognitive function, whereas atypical antipsychotics including clozapine and olanzapine resulted in glycolipid dysbolism (TG and systolic pressure enhancement). Meanwhile, TG level and systolic pressure level also showed a greater influence on cognitive function level than did negative symptom and education level. The incidence of hyperglycemia, high TG, low HDL-C, and obesity in patients with schizophrenia accompanied by MS was higher than that in MS patients without schizophrenia. This might be caused by antipsychotics, which could block 5-HT2C, H1, and M1 receptors, resulting in increased food appetite and excess sedation (Puig et al., 2005). Thus, obesity, IR, and insulin insufficiency seemed to advance blood glucose (Karanauskaite et al., 2009). In addition, antagonism of 5-HT1A could reduce the reaction ability of islet cells to blood sugar level, which decrease insulin secretion (Marcos et al., 2008). Moreover, the decrease in insulin tolerance and sugar variability affected the regulation of insulin toward lipid metabolism, caused lipolysis and lipid metabolism disorder, and resulted in increased TG and decreased HDL-C in schizophrenics. Our research showed that the factor of current use of antipsychotic drugs was one of the vital factors that affected cognitive function of schizophrenics ( p = 0.001) because antipsychotic drugs might block the central and peripheral receptors including D2, 5-HT, H1, and H2 (Marcos et al., 2008; Puig et al., 2005). Our study suggested that MS and its components should be considered in the study of cognitive function in schizophrenia. Besides, many studies confirmed that atypical antipsychotic drugs (such as olanzapine, risperidone, and aripiprazole) might improve the cognitive function of schizophrenics within a short period, whereas they would enhance the risk for experiencing MS after long-term use, especially the drugs that easily caused weight gain due to glycolipid metabolic disorders (such as clozapine, olanzapine, risperidone, and quetiapine). These might injure cognitive function in a long-term implication (Mitchell et al., 2013). Therefore, in the long-term therapy for schizophrenia, we should be careful in choosing drugs to decrease influence of glycolipid metabolism.
DISCLOSURES This study was supported by Medical Research Fund of Xuhui District of Shanghai City (SHXH201023). The authors declare no conflict of interest.
MS and Cognitive Function
in combination, in male patients admitted with acute coronary syndrome, without previous diagnosis of diabetes mellitus. Libyan J Med. 8:20185. Cavali Mde L, Escrivao MA, Brasileiro RS, Taddei JA (2010) Metabolic syndrome: Comparison of diagnosis criteria. J Pediatr (Rio J). 86:325Y330. Collins AA, Remington GJ, Coulter K, Birkett K (1997) Insight, neurocognitive function and symptom clusters in chronic schizophrenia. Schizophr Res. 27:37Y44. Cruz BF, Resende CB, Abreu MN, Rocha FL, Teixeira AL, Keefe RS, Salgado JV (2013) How specific are negative symptoms and cognitive impairment in schizophrenia? An analysis of PANSS and SCoRS. Cogn Neuropsychiatry. 18:243Y251. De Hert M, Mauri M, Shaw K, Wetterling T, Doble A, Giudicelli A, Falissard B (2010) The METEOR study of diabetes and other metabolic disorders in patients with schizophrenia treated with antipsychotic drugs. I. Methodology. Int J Methods Psychiatr Res. 19:195Y210. De Hert MA, van Winkel R, Van Eyck D, Hanssens L, Wampers M, Scheen A, Peuskens J (2006) Prevalence of the metabolic syndrome in patients with schizophrenia treated with antipsychotic medication. Schizophr Res. 83:87Y93. Dekker JJ, Theunissen J, Van R, Peen J, Duurkoop P, Kikkert M (2010) Victimization of patients with severe psychiatric disorders: Prevalence, risk factors, protective factors and consequences for mental health. A longitudinal study. BMC Public Health. 10:687. Donders J, DenBraber D, Vos L (2010) Construct and criterion validity of the Behaviour Rating Inventory of Executive Function (BRIEF) in children referred for neuropsychological assessment after paediatric traumatic brain injury. J Neuropsychol. 4:197Y209. Friedman JI, Wallenstein S, Moshier E, Parrella M, White L, Bowler S, Gottlieb S, Harvey PD, McGinn TG, Flanagan L, Davis KL (2010) The effects of hypertension and body mass index on cognition in schizophrenia. Am J Psychiatry. 167:1232Y1239. Guse B, Falkai P, Gruber O, Whalley H, Gibson L, Hasan A, Obst K, Dechent P, McIntosh A, Suchan B, Wobrock T (2013) The effect of long-term high frequency repetitive transcranial magnetic stimulation on working memory in schizophrenia and healthy controlsVA randomized placebo-controlled, doubleblind fMRI study. Behav Brain Res. 237:300Y307. Harvey KE, Galletly CA, Field C, Proeve M (2009) The effects of verbalisation on cognitive performance in schizophrenia: A pilot study using tasks from the Delis Kaplan Executive Function System. Neuropsychol Rehabil. 19:733Y741. Karanauskaite J, Hoppa MB, Braun M, Galvanovskis J, Rorsman P (2009) Quantal ATP release in rat beta-cells by exocytosis of insulin-containing LDCVs. Pflugers Arch. 458:389Y401. King LC, Bailie JM, Kinney DI, Nitch SR (2012) Is the Repeatable Battery for the Assessment of Neuropsychological Status factor structure appropriate for inpatient psychiatry? An exploratory and higher-order analysis. Arch Clin Neuropsychol. 27:756Y765. Lee NY, Kim SH, Jung DC, Kim EY, Yu HY, Sung KH, Kang UG, Ahn YM, Kim YS (2011) The prevalence of metabolic syndrome in Korean patients with schizophrenia receiving a monotherapy with aripiprazole, olanzapine or risperidone. Prog Neuropsychopharmacol Biol Psychiatry. 35:1273Y1278. Marcos B, Aisa B, Ramirez MJ (2008) Functional interaction between 5-HT(6) receptors and hypothalamic-pituitary-adrenal axis: Cognitive implications. Neuropharmacology. 54:708Y714. Meyer JM, Stahl SM (2009) The metabolic syndrome and schizophrenia. Acta Psychiatr Scand. 119:4Y14. Mitchell AJ, Vancampfort D, Sweers K, van Winkel R, Yu W, De Hert M (2013) Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disordersVA systematic review and meta-analysis. Schizophr Bull. 39:306Y318. Mohamed S, Paulsen JS, O’Leary D, Arndt S, Andreasen N (1999) Generalized cognitive deficits in schizophrenia: A study of first-episode patients. Arch Gen Psychiatry. 56:749Y754. Moore RC, Davine T, Harmell AL, Cardenas V, Palmer BW, Mausbach BT (2013) Using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) effort index to predict treatment group attendance in patients with schizophrenia. J Int Neuropsychol Soc. 19:198Y205. Napal O, Ojeda N, Elizagarate E, Pena J, Ezcurra J, Gutierrez M (2012) The course of the schizophrenia and its impact on cognition: A review of literature. Actas Esp Psiquiatr. 40:198Y220. Nasrallah HA (2010) Linkage of cognitive impairments with metabolic disorders in schizophrenia. Am J Psychiatry. 167:1155Y1157.
REFERENCES Al-Aqeedi RF, Abdullatef WK, Dabdoob W, Bener A, Albinali HA, Gehani A (2013) The prevalence of metabolic syndrome components, individually and
* 2014 Lippincott Williams & Wilkins
Panza F, Frisardi V, Capurso C, Imbimbo BP, Vendemiale G, Santamato A, D’Onofrio G, Seripa D, Sancarlo D, Pilotto A, Solfrizzi V (2010) Metabolic syndrome and cognitive impairment: Current epidemiology and possible underlying mechanisms. J Alzheimers Dis. 21:691Y724.
www.jonmd.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
317
The Journal of Nervous and Mental Disease
Li et al.
Pilla Reddy V, Kozielska M, Johnson M, Suleiman AA, Vermeulen A, Liu J, de Greef R, Groothuis GM, Danhof M, Proost JH (2012) Modelling and simulation of the Positive and Negative Syndrome Scale (PANSS) time course and dropout hazard in placebo arms of schizophrenia clinical trials. Clin Pharmacokinet. 51:261Y275. Puig MV, Artigas F, Celada P (2005) Modulation of the activity of pyramidal neurons in rat prefrontal cortex by raphe stimulation in vivo: Involvement of serotonin and GABA. Cereb Cortex. 15:1Y14. Raffaitin C, Feart C, Le Goff M, Amieva H, Helmer C, Akbaraly TN, Tzourio C, Gin H, Barberger-Gateau P (2011) Metabolic syndrome and cognitive decline in French elders: The Three-City Study. Neurology. 76: 518Y525.
318
www.jonmd.com
& Volume 202, Number 4, April 2014
Semkovska M, Bedard MA, Stip E (2001) Hypofrontality and negative symptoms in schizophrenia: Synthesis of anatomic and neuropsychological knowledge and ecological perspectives [in French]. Encephale. 27:405Y415. Tuulio-Henriksson A, Perala J, Saarni SI, Isometsa E, Koskinen S, Lonnqvist J, Suvisaari J (2011) Cognitive functioning in severe psychiatric disorders: A general population study. Eur Arch Psychiatry Clin Neurosci. 261:447Y456. Waddington JL, Buckley PF, Scully PJ, Lane A, O’Callaghan E, Larkin C (1998) Course of psychopathology, cognition and neurobiological abnormality in schizophrenia: Developmental origins and amelioration by antipsychotics? J Psychiatr Res. 32:179Y189. Yang C, Winkelman JW (2006) Clinical significance of sleep EEG abnormalities in chronic schizophrenia. Schizophr Res. 82:251Y260.
* 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Metabolic Syndrome and Its Factors Affect Cognitive Function in Chronic Schizophrenia Complicated by Metabolic Syndrome Chenhu Li, Guilai Zhan, BS, Shunzeng Rao, BS, and Hong Zhang, BS
Abstract: The aim of this study was to investigate the characteristics of cognitive function damage in chronic schizophrenia patients with metabolic syndrome (MS); 388 patients were divided into two groups: MS group (180 people with schizophrenia and MS) and non-MS group (208 people with schizophrenia but without MS). The Positive and Negative Syndrome Scale (PANSS) and the Treatment Emergent Symptom Scale (TESS) were used to evaluate clinical symptoms and drug adverse reaction. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was used to assess cognitive function. There was no significant change in PANSS ( p = 0.53) and TESS score ( p = 0.26) between the MS group and the non-MS group. However, RBANS total scale score as well as attention, immediate memory, and delayed memory scores in the MS group were significantly lower than those in the non-MS group ( p G 0.05). There was no significant change in visuospatial skill ( p = 0.07) and language scores ( p = 0.08) between the two groups. Besides, course of disease, triglyceride, antipsychotic drug type, systolic pressure, negative symptom factor, and education level showed a notable significance for cognitive function damage in turn. MS might aggravate injury of cognitive function in chronic schizophrenia, especially in immediate memory, delayed memory, and attention. Key Words: Schizophrenia, metabolic syndrome, cognitive function (J Nerv Ment Dis 2014;202: 313Y318)
S
chizophrenia, a kind of severe psychiatric disorder, mostly presents with lack of coherence and logicality in thought and associative processes (Dekker et al., 2010). Gallhofer first brought the matter up in 1970, proposing that schizophrenia presented positive symptoms (such as thinking disturbance, affective disorder, delusions, hallucinations) and negative symptoms (poverty of thought, retraction of behavior, abulia, etiquette neglect), as well as cognitive dysfunction (TuulioHenriksson et al., 2011). In recent years, research concerning the cognitive dysfunction of schizophrenia were focused on idiopathic cognitive dysfunction widely occurring in people with schizophrenia, which mainly involved frontal lobe executive function, memory, and attention (Collins et al., 1997; Donders et al., 2010). Atypical antipsychotics were widely applied in therapy, and schizophrenia complicated with metabolic syndrome (MS) received much more attention. MS was formed with a spectrum of medical disorders associated with an increased risk for cardiovascular disease and development of type 2 diabetes mellitus. However, few research studies reported that MS could induce cognitive function lesion. MS was caused by multiple genes and environmental factors, in which insulin resistance (IR) was the common base and core mechanism. IR resulted in hyperinsulinism and cerebrovascular and cardiovascular diseases, including obesity, hypertension, hyperlipidemia, and disorder of coagulation system, which were induced by injuries of Department of Psychiatry, Shanghai Xuhui District Mental Health Center, Shanghai, China. Send reprint requests to Chenhu Li, MM, Department of Psychiatry, Shanghai Xuhui District Mental Health Center, No. 249 Longhua Xi Rd, Shanghai 200232, China. E-mail: [email protected]. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0022-3018/14/20204Y0313 DOI: 10.1097/NMD.0000000000000124
The Journal of Nervous and Mental Disease
endotheliocyte and formation of atherosclerosis. Abnormality of IR or hyperinsulinism and its signal pathways affected brain tissue (especially seahorse, cortex of temporal lobe neurite), which caused injury to cognitive function. Thus, it was important to pay attention to MS problem in schizophrenia patients. The prevalence rate of MS differed from 9% to 68% in schizophrenia, which was more severe among healthy controls and the general population (De Hert et al., 2006). Older age, female sex, more severe illness, and use of antipsychotic drugs seemed to be potential risk factors of developing the syndrome (Lee et al., 2011). Studies showed that the prevalence of MS in patients with schizophrenia has been limited in small samples and/or patients without any comorbidity (Meyer and Stahl, 2009). Thus, our research was proposed to investigate the characteristics of cognitive dysfunction in people with schizophrenia with MS.
METHODS Patients All participants gave their informed consent before their inclusion in the study, and all human studies were approved by China Ethics Committee and performed in accordance with the ethical standards. Patients in their recovery periods were recruited from November 2010 to July 2011 at the Department of Psychiatry, Shanghai Xuhui District Mental Health Center (Shanghai, China). The inclusion criteria were as follows: aged 18 to 60 years (according to diagnostic criteria for chronic schizophrenia of the Chinese Classification and Diagnostic Criteria of Mental Disorders Version 3, stable dose of a single antipsychotic for at least 2 years, Positive and Negative Syndrome Scale (PANSS) total score of lower than 60, inspection items completed, and willingness to give written informed consent. Patients with the following situations were excluded in our research: severe liver, kidney, or nervous system physical diseases; alcohol abuse or psychoactive drug or substance abuse; severe physical disability; other severe mental disorders, mental retardation, dementia, and severe cognitive dysfunction; severe medicine adverse reactions (such as extrapyramidal symptoms) and obvious tardive dyskinesia; pregnant or lactating women; and participating in other researches. The patients were divided into two groups: the MS group including 180 patients with MS and the non-MS group including 208 patients free of MS. The patients were diagnosed according to diagnostic criteria for MS of the Chinese Diabetes Society in 2004 and were assigned to the MS group if they satisfied three or four of the following conditions (Al-Aqeedi et al., 2013; Cavali Mde et al., 2010): obesity, body mass index (BMI) of 25.0 kg/m2 or greater; hyperglycemia or diabetes mellitus, fasting plasma glucose of 6.1 mmol/l or greater or plasma glucose of 7.8 mmol/l or greater; hypertension, systolic/diastolic pressure of 140/90 mm Hg or greater; and dyslipidemia, fasting serum triglycerides (TGs) of 1.7 mmol/l or greater or fasting high-density lipoprotein cholesterol (HDL-C) of less than 0.9 mmol/l for the men and less than 1.0 mmol/l for the women.
Methods Our study is a cross-sectional study. Information about the patients was obtained in our study, such as general demographic
& Volume 202, Number 4, April 2014
www.jonmd.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
313
The Journal of Nervous and Mental Disease
Li et al.
information, the course of disease, first-episode age, frequency of hospitalization, family history of mental illness, currently taking antipsychotic drugs (single medication), history of somatic diseases, diabetes mellitus and hypertension, biological index including BMI, fasting blood glucose and lipid, blood pressure, and waist-hip ratio. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), a brief neurocognitive battery, was used in our research (King et al., 2012; Moore et al., 2013), which contained 12 subtests and 5 alternate forms: immediate memory (vocabulary learning, story rehearsal), visuospatial skills (graphics depiction, line orientation), language (picture naming, semantic fluency), attention (digit span and digit symbol), and delayed memory (vocabulary recall, word recognition, story recall, and figure recall). The PANSS was used to take secondary objective efficacy measures in our study (Cruz et al., 2013; Pilla Reddy et al., 2012), including 33 items and 4 subscales (positive symptoms, negative symptoms, general mental disease pathology symptoms, and accessory symptoms). The Treatment Emergent Symptom Scale (TESS) information included 34 symptoms and general investigations (Cruz et al., 2013; Pilla Reddy et al., 2012) and was scored in four grades to evaluate the status of adverse drug reaction. Moreover, glycometabolism and lipometabolism tests were also taken in our research. Plasma TG was obtained from the ulnar vein at 7 a.m.
Statistical Analysis Data were analyzed using the Statistical Package for the Social Sciences 11.5. The t-test, the chi-square test, covariance analysis, regression analysis, and parameter test were used for statistical analysis. Data were applied using a two-sided test and expressed as mean
& Volume 202, Number 4, April 2014
(standard deviation). A p-value of less than 0.05 was considered as significant.
RESULTS Comparison of General Information and MS Index Between MS and Non-MS Schizophrenics We obtained 388 patients in our study (182 male patients, 46.0%; 206 female patients, 53.1%). The patients had a mean (SD) age of 42.3 (9.6). The education level of the patients was as follows: 20 patients had primary school degree (5.2%); 111 patients, junior middle school degree (28.6%); 189 patients, senior middle school or secondary school degree (48.7%); and 68 patients, junior college degree or higher (17.5%). The marital status of the patients was as follows: 270 patients were single (69.6%); 94 patients, married (24.2%); 22 patients, divorced (5.7%); and 2 patients, widowed (0.5%). Sixty-two patients were employed (16.0%), and 326 patients were unemployed (84.0%). As shown in Table 1, there were no significant differences in sex ( p = 0.37), age ( p = 0.25), educational level ( p = 0.20), marital status ( p = 0.06), and employment status ( p = 0.03) between the MS group and the non-MS group. On the other hand, the MS group showed a notable difference in BMI, fasting blood glucose, HDL, and TG compared with the non-MS group ( p G 0.05; Table 1). Briefly, in the MS group, the fasting blood glucose level (5.87 [0.84] mmol/l) was significantly higher than that in the non-MS group (5.54 [0.78] mmol/l; p G 0.05), as well as the TG level (1.77 [0.42] vs. 1.68 [0.27] mmol/l; p = 0.01). However, the level of HDL in the MS group (1.05 [0.39] mmol/l) was significantly lower than that in the non-MS group (1.13 [0.28] mmol/l; p = 0.02).
TABLE 1. Comparison of General Information and MS Index of People with Schizophrenia (Mean [SD]) Sex Male Female Age, yrs Education level Primary school Junior middle school Senior middle school degree or secondary school degree Junior college or higher Marital status Unmarried Married Divorced/widowed Work status Employed Unemployed MS BMI, kg/m2 Fasting blood glucose, mmol/l HDL, mmol/l TG, mmol/l Systolic pressure, mm Hg Diastolic pressure, mm Hg
MS Group (n = 180)
Non-MS Group (n = 208)
80 (44.4%) 100 (55.6%) 42.9 (9.7)
102 (49.0%) 106 (51.0%) 41.8 (9.6)
11 (6.1%) 45 (25.0%) 86 (47.8%) 38 (21.1%)
9 (4.3%) 66 (31.7%) 103 (49.5%) 30 (14.5%)
117 (65.0%) 46 (25.6%) 17 (9.4%)
153 (73.6%) 48 (23.0%) 7 (3.4%)
25 (13.9%) 155 (86.1%)
37 (17.8%) 171 (82.2%)
23.74 (2.88) 5.87 (0.84) 1.05 (0.39) 1.77 (0.42) 136.4 (14.8) 82.8 (12.6)
22.32 (2.72) 5.54 (0.78) 1.13 (0.28) 1.68 (0.27) 133.9 (11.1) 81.4 (10.4)
t/W2
p
0.82
0.37
1.15 4.65
0.25 0.20
7.41
0.06
1.09
0.30
4.99 3.98 j2.32 2.62 1.86 1.12
0.00** 0.00** 0.02* 0.01* 0.06 0.26
p-Value of t-test or chi-square test for data. *Significant at the 0.05 level. **Significant at the 0.01 level.
314
www.jonmd.com
* 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The Journal of Nervous and Mental Disease
& Volume 202, Number 4, April 2014
MS and Cognitive Function
TABLE 2. Comparison of MS Characteristics and Therapy Status Between MS and Non-MS People with Schizophrenia (Mean [SD]) MS Group (n = 180)
First-episode age, yrs Course of disease, yrs No. hospitalizations 0 1 2 3 93 Family history of mental disorders No Yes Currently taking antipsychotic drugs Risperidone Olanzapine Quetiapine Aripiprazole Ziprasidone Clozapine Chlorpromazine Perphenazine
28.7 (7.3) 14.2 (9.5) 4 52 23 30 71
Non-MS Group (n = 208)
29.5 (6.6) 12.3 (8.9)
(2.2%) (28.9%) (12.8%) (16.7%) (39.4%)
4 (1.9%) 85 (40.9%) 38 (18.2%) 22 (10.6%) 59 (28.4%)
160 (88.9%) 20 (11.1%)
195 (93.8%) 13 (6.2%)
51 18 13 11 9 37 28 13
(28.3%) (10.0%) (7.2%) (6.1%) (5.0%) (20.6%) (15.6%) (7.2%)
t/W2
p
j1.10 2.04 29.3
0.27 0.04* 0.01*
2.93
0.09
17.37
0.01*
65 (31.3%) 16 (7.7%) 14 (6.7%) 29 (13.9%) 18 (8.7%) 25 (12.0%) 19 (9.1%) 22 (10.6%)
p-Value of t-test or chi-square test for data. *Significant at the 0.05 level.
Comparison of MS Characteristics and Therapy Status Between MS and Non-MS Schizophrenics
Comparison of Mental Symptoms and Adverse Reaction Between MS and Non-MS Schizophrenics
The first-episode age ranged from 16 to 56 years, with a mean (SD) age of 29.1 (7.0) years. Thirty-three patients (9.9%) had a family history of mental disorders and 355 patients (91.5%) did not. Our results presented that there was no apparent difference in first-episode age (28.7 [7.3] vs. 29.5 [6.6], p = 0.27) and family history of mental disorders in the MS group ( p = 0.09) compared with the non-MS group (Table 2). Besides, the mean (SD) course of disease of all patients was 13.2 (9.2) years. The disease course of the MS group was significantly longer than that of the non-MS group (14.2 [9.5] vs. 12.3 [8.9], p = 0.04). Meanwhile, 8 patients (2.1%) had never been hospitalized, 137 patients (35.3%) had been hospitalized once, 61 patients (15.7%) had been hospitalized twice, 52 patients (13.4%) had been hospitalized three times, and 130 patients (33.5%) had been hospitalized for more than three times. There was a notable change between the MS group and the non-MS group in number of hospitalizations ( p = 0.01) and antipsychotic drug use ( p = 0.01), which indicated that MS might be associated with cognitive function of schizophrenics.
We chose schizophrenics in the recovery stage as our patients, whose PANSS score was lower than 60. As illustrated in Table 3, there was no significant change between the MS and non-MS groups in comparison of total score ( p = 0.53); positive ( p = 0.28), negative ( p = 0.94), cognitive ( p = 0.27), excitatory ( p = 0.69), and anxietydepression factors ( p = 0.83) of the PANSS; and total score of the TESS ( p = 0.26). Thus, MS might have fewer effects on recovery-stage schizophrenics.
Comparison of Cognitive Function Between MS and Non-MS Schizophrenics Considering that there existed a notable change between the MS group and the non-MS group in course of disease, number of hospitalizations, and antipsychotic drug use ( p G 0.05, Table 2), which might potentially affect the cognitive function of schizophrenics, we investigated the cognitive function between the MS and non-MS schizophrenics by the RBANS score system. As shown in Table 4, the MS group presented a significant difference in RBANS total score,
TABLE 3. Comparison of Mental Symptoms and Adverse Reaction Between MS and Non-MS People with Schizophrenia (Mean [SD]) PANSS total score Positive factor Negative factor Cognitive factor Excitatory factor Anxiety-depression factor TESS total score
* 2014 Lippincott Williams & Wilkins
MS Group (n = 180)
Non-MS Group (n = 208)
t
p
45.8 (7.8) 6.8 (1.9) 12.9 (4.8) 9.6 (2.2) 9.2 (1.9) 6.5 (1.9) 18.7 (5.1)
44.9 (9.0) 7.1 (2.0) 12.7 (4.5) 9.3 (2.3) 9.3 (1.6) 6.4 (1.5) 18.1 (5.6)
0.63 j1.09 0.08 1.11 j0.40 0.22 1.15
0.53 0.28 0.94 0.27 0.69 0.83 0.26
www.jonmd.com
315
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The Journal of Nervous and Mental Disease
Li et al.
& Volume 202, Number 4, April 2014
TABLE 4. Comparison of Cognitive Function Between MS and Non-MS People with Schizophrenia in RBANS Score (Mean [SD]) RBANS total score Immediate memory Visuospatial skill Attention Language Delayed memory
MS Group (n = 92)
Non-MS Group (n = 113)
F
p
165.6 (17.0) 27.2 (5.9) 28.7 (4.6) 51.7 (7.6) 24.9 (5.1) 30.9 (6.1)
173.0 (23.1) 31.4 (8.3) 28.2 (5.4) 53.9 (9.2) 24.6 (4.3) 34.9 (6.8)
7.63 10.25 2.22 4.29 2.16 14.57
0.00* 0.00* 0.07 0.00* 0.08 0.00*
p-Value of covariance analysis for data. *Significant at the 0.01 level.
immediate memory, attention, and delayed memory sections compared with the non-MS group ( p G 0.01). There was no apparent change in visuospatial skill ( p = 0.07) and language parts ( p = 0.08) between the two groups.
Factors Affecting the Cognitive Function of MS Schizophrenics To investigate the main factors affecting cognitive function of MS schizophrenics, we used the RBANS total score of the MS schizophrenics as dependent variable. Factors that might affect cognitive function, including sex, age, education level, marital status, and employment status of patients; MS index; first-episode age; course of disease; frequency of hospitalization; family history; drug analogues; and PANSS and TESS analysis, were considered as independent variables to carry out logistic stepwise regression analysis and to take gradual regressive analysis. At the level of > = 0.05, six factors showed a notable significance in turn, including course of disease, TG, drug category, systolic pressure, negative symptom factor, and education level (Table 5).
DISCUSSION In recent years, research concerning neuropsychology, neurobiochemistry, brain iconography, and genetics has figured out that cognitive deficit was the core of schizophrenia and presented a continuous symptom, which was independent of positive symptoms and negative symptoms of schizophrenia. Cognitive deficit involved damages of memory, attention, and executive functions, which deeply affected social function and quality of life of schizophrenics (Guse et al., 2013; Harvey et al., 2009). However, the causes of cognitive dysfunction in schizophrenics were still unclear. The cognitive dysfunction of schizophrenics was also impacted by multiple factors and complications of factors (Collins et al., 1997; Mohamed et al., 1999; Semkovska et al., 2001; Yang and Winkelman, 2006). Studies showed that cognitive function of schizophrenics was affected by many factors, including age, sex, mental symptoms (especially negative symptoms), course of disease, frequency of hospitalization, and drug category. However, researches did not receive the same outcomes in how these factors influence cognitive function, and different health conditions might also affect cognitive function of schizophrenics. MS, including glycolipid dysbolism, a common
complication of schizophrenia, may influence the cognitive function of schizophrenics (Nasrallah, 2010). MS was formed with diabetes mellitus, IR, hyperlipidemia, hypertension, and other cardiovascular risk factors. In addition, the incidence of schizophrenics with MS was apparently higher than that of the general population (De Hert et al., 2010; Mitchell et al., 2013; Nasrallah, 2010). Besides, diabetes mellitus and hypertension were widely proven injuries of cognitive function, whereas low HDL-C concentration and hypertriacylglycerolemia were also important factors (De Hert et al., 2010; Mitchell et al., 2013; Nasrallah, 2010). In our study, there was no significant change in sex, age, education level, first-episode age, mental symptoms, and drug adverse reaction between the MS group and the non-MS group. However, there was a notable difference among course of disease, frequency of hospitalization, and category of currently taking antipsychotics in the MS group compared with the non-MS group. Thus, we used covariance analysis to analyze the course of disease, frequency of hospitalization, and category of currently taking antipsychotics by comparing the cognitive function of the MS and non-MS groups. However, these factors were excluded to affect cognitive function in our results. Meanwhile, our results showed that MS could apparently enhance BMI, fasting blood glucose and TG level, and low HDL-C concentration in schizophrenics, which aggravated cognitive function. The mechanism of MS affecting cognitive function included high BMIinduced IR, microangiopathy, macroangiopathy, and inflammation, and glycolipid dysbolism might become the vital factor that caused cognitive function damage. Thus, we found that RBANS total score, attention score, immediate memory score, and delayed memory score in the MS group were significantly lower than those in the non-MS group, whereas there was no significant change in visuospatial skill and language scores, indicating that MS exacerbated the cognitive function injury of schizophrenics, especially the injured immediate memory and recall function of schizophrenics. Moreover, MS-involved cardiovascular risk factors might result in cerebrovascular pathological changes that caused cerebral blood flow descent extensively, which induced chronic hypoxicischemic damage in the brain. Memory-related structures in the brain, including the thalamus and the hippocampus, received the most serious damage for their sensitivity to hypoxic-ischemic injury. Besides, MS factors might interact to integrate an amplification effect
TABLE 5. Multielement Logistic Stepwise Regression Analysis of Cognitive Function Level of People with MS and Schizophrenia Course of disease TG Antipsychotic Systolic pressure Negative symptom factor Education level
316
www.jonmd.com
Regression Coefficient (B)
Standardized Regression Coefficient (A)
t
P
j0.60 j10.39 j1.75 j0.26 j0.71 4.61
j0.29 j0.28 j0.23 j0.22 j0.18 0.16
4.35 j4.14 j3.41 j3.18 j2.68 2.54
0.000 0.000 0.001 0.002 0.008 0.012
* 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The Journal of Nervous and Mental Disease
& Volume 202, Number 4, April 2014
(Friedman et al., 2010; Panza et al., 2010; Raffaitin et al., 2011). The cognitive function of schizophrenics had a positive correlation with negative symptoms level, course of disease, and frequency of hospitalization. Mainly, negative symptoms of schizophrenia presented significant hypofrontality of lobus frontalis execution function, and the decrease of gray matter of the frontal lobe in the left side might become the basement of execution functional lesion. Thus, free radical scavenging could regulate the cognitive functionYrelated frontal lobe hypofrontality caused by free radical dysbolism in the brain. To analyze the factors affecting cognitive function of MS accompanied by schizophrenia, multielement logistic stepwise regression analysis was used in our study. The results showed that the course of disease had the greatest influence on cognitive function level of schizophrenics, which corresponded with previous studies (Napal et al., 2012; Waddington et al., 1998). Interestingly, the category of current use of antipsychotics was also a significant factor that influenced the cognitive function level of schizophrenics. Typical antipsychotics including chlorpromazine and perphenazine had a bad influence on cognitive function, whereas atypical antipsychotics including clozapine and olanzapine resulted in glycolipid dysbolism (TG and systolic pressure enhancement). Meanwhile, TG level and systolic pressure level also showed a greater influence on cognitive function level than did negative symptom and education level. The incidence of hyperglycemia, high TG, low HDL-C, and obesity in patients with schizophrenia accompanied by MS was higher than that in MS patients without schizophrenia. This might be caused by antipsychotics, which could block 5-HT2C, H1, and M1 receptors, resulting in increased food appetite and excess sedation (Puig et al., 2005). Thus, obesity, IR, and insulin insufficiency seemed to advance blood glucose (Karanauskaite et al., 2009). In addition, antagonism of 5-HT1A could reduce the reaction ability of islet cells to blood sugar level, which decrease insulin secretion (Marcos et al., 2008). Moreover, the decrease in insulin tolerance and sugar variability affected the regulation of insulin toward lipid metabolism, caused lipolysis and lipid metabolism disorder, and resulted in increased TG and decreased HDL-C in schizophrenics. Our research showed that the factor of current use of antipsychotic drugs was one of the vital factors that affected cognitive function of schizophrenics ( p = 0.001) because antipsychotic drugs might block the central and peripheral receptors including D2, 5-HT, H1, and H2 (Marcos et al., 2008; Puig et al., 2005). Our study suggested that MS and its components should be considered in the study of cognitive function in schizophrenia. Besides, many studies confirmed that atypical antipsychotic drugs (such as olanzapine, risperidone, and aripiprazole) might improve the cognitive function of schizophrenics within a short period, whereas they would enhance the risk for experiencing MS after long-term use, especially the drugs that easily caused weight gain due to glycolipid metabolic disorders (such as clozapine, olanzapine, risperidone, and quetiapine). These might injure cognitive function in a long-term implication (Mitchell et al., 2013). Therefore, in the long-term therapy for schizophrenia, we should be careful in choosing drugs to decrease influence of glycolipid metabolism.
DISCLOSURES This study was supported by Medical Research Fund of Xuhui District of Shanghai City (SHXH201023). The authors declare no conflict of interest.
MS and Cognitive Function
in combination, in male patients admitted with acute coronary syndrome, without previous diagnosis of diabetes mellitus. Libyan J Med. 8:20185. Cavali Mde L, Escrivao MA, Brasileiro RS, Taddei JA (2010) Metabolic syndrome: Comparison of diagnosis criteria. J Pediatr (Rio J). 86:325Y330. Collins AA, Remington GJ, Coulter K, Birkett K (1997) Insight, neurocognitive function and symptom clusters in chronic schizophrenia. Schizophr Res. 27:37Y44. Cruz BF, Resende CB, Abreu MN, Rocha FL, Teixeira AL, Keefe RS, Salgado JV (2013) How specific are negative symptoms and cognitive impairment in schizophrenia? An analysis of PANSS and SCoRS. Cogn Neuropsychiatry. 18:243Y251. De Hert M, Mauri M, Shaw K, Wetterling T, Doble A, Giudicelli A, Falissard B (2010) The METEOR study of diabetes and other metabolic disorders in patients with schizophrenia treated with antipsychotic drugs. I. Methodology. Int J Methods Psychiatr Res. 19:195Y210. De Hert MA, van Winkel R, Van Eyck D, Hanssens L, Wampers M, Scheen A, Peuskens J (2006) Prevalence of the metabolic syndrome in patients with schizophrenia treated with antipsychotic medication. Schizophr Res. 83:87Y93. Dekker JJ, Theunissen J, Van R, Peen J, Duurkoop P, Kikkert M (2010) Victimization of patients with severe psychiatric disorders: Prevalence, risk factors, protective factors and consequences for mental health. A longitudinal study. BMC Public Health. 10:687. Donders J, DenBraber D, Vos L (2010) Construct and criterion validity of the Behaviour Rating Inventory of Executive Function (BRIEF) in children referred for neuropsychological assessment after paediatric traumatic brain injury. J Neuropsychol. 4:197Y209. Friedman JI, Wallenstein S, Moshier E, Parrella M, White L, Bowler S, Gottlieb S, Harvey PD, McGinn TG, Flanagan L, Davis KL (2010) The effects of hypertension and body mass index on cognition in schizophrenia. Am J Psychiatry. 167:1232Y1239. Guse B, Falkai P, Gruber O, Whalley H, Gibson L, Hasan A, Obst K, Dechent P, McIntosh A, Suchan B, Wobrock T (2013) The effect of long-term high frequency repetitive transcranial magnetic stimulation on working memory in schizophrenia and healthy controlsVA randomized placebo-controlled, doubleblind fMRI study. Behav Brain Res. 237:300Y307. Harvey KE, Galletly CA, Field C, Proeve M (2009) The effects of verbalisation on cognitive performance in schizophrenia: A pilot study using tasks from the Delis Kaplan Executive Function System. Neuropsychol Rehabil. 19:733Y741. Karanauskaite J, Hoppa MB, Braun M, Galvanovskis J, Rorsman P (2009) Quantal ATP release in rat beta-cells by exocytosis of insulin-containing LDCVs. Pflugers Arch. 458:389Y401. King LC, Bailie JM, Kinney DI, Nitch SR (2012) Is the Repeatable Battery for the Assessment of Neuropsychological Status factor structure appropriate for inpatient psychiatry? An exploratory and higher-order analysis. Arch Clin Neuropsychol. 27:756Y765. Lee NY, Kim SH, Jung DC, Kim EY, Yu HY, Sung KH, Kang UG, Ahn YM, Kim YS (2011) The prevalence of metabolic syndrome in Korean patients with schizophrenia receiving a monotherapy with aripiprazole, olanzapine or risperidone. Prog Neuropsychopharmacol Biol Psychiatry. 35:1273Y1278. Marcos B, Aisa B, Ramirez MJ (2008) Functional interaction between 5-HT(6) receptors and hypothalamic-pituitary-adrenal axis: Cognitive implications. Neuropharmacology. 54:708Y714. Meyer JM, Stahl SM (2009) The metabolic syndrome and schizophrenia. Acta Psychiatr Scand. 119:4Y14. Mitchell AJ, Vancampfort D, Sweers K, van Winkel R, Yu W, De Hert M (2013) Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disordersVA systematic review and meta-analysis. Schizophr Bull. 39:306Y318. Mohamed S, Paulsen JS, O’Leary D, Arndt S, Andreasen N (1999) Generalized cognitive deficits in schizophrenia: A study of first-episode patients. Arch Gen Psychiatry. 56:749Y754. Moore RC, Davine T, Harmell AL, Cardenas V, Palmer BW, Mausbach BT (2013) Using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) effort index to predict treatment group attendance in patients with schizophrenia. J Int Neuropsychol Soc. 19:198Y205. Napal O, Ojeda N, Elizagarate E, Pena J, Ezcurra J, Gutierrez M (2012) The course of the schizophrenia and its impact on cognition: A review of literature. Actas Esp Psiquiatr. 40:198Y220. Nasrallah HA (2010) Linkage of cognitive impairments with metabolic disorders in schizophrenia. Am J Psychiatry. 167:1155Y1157.
REFERENCES Al-Aqeedi RF, Abdullatef WK, Dabdoob W, Bener A, Albinali HA, Gehani A (2013) The prevalence of metabolic syndrome components, individually and
* 2014 Lippincott Williams & Wilkins
Panza F, Frisardi V, Capurso C, Imbimbo BP, Vendemiale G, Santamato A, D’Onofrio G, Seripa D, Sancarlo D, Pilotto A, Solfrizzi V (2010) Metabolic syndrome and cognitive impairment: Current epidemiology and possible underlying mechanisms. J Alzheimers Dis. 21:691Y724.
www.jonmd.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
317
The Journal of Nervous and Mental Disease
Li et al.
Pilla Reddy V, Kozielska M, Johnson M, Suleiman AA, Vermeulen A, Liu J, de Greef R, Groothuis GM, Danhof M, Proost JH (2012) Modelling and simulation of the Positive and Negative Syndrome Scale (PANSS) time course and dropout hazard in placebo arms of schizophrenia clinical trials. Clin Pharmacokinet. 51:261Y275. Puig MV, Artigas F, Celada P (2005) Modulation of the activity of pyramidal neurons in rat prefrontal cortex by raphe stimulation in vivo: Involvement of serotonin and GABA. Cereb Cortex. 15:1Y14. Raffaitin C, Feart C, Le Goff M, Amieva H, Helmer C, Akbaraly TN, Tzourio C, Gin H, Barberger-Gateau P (2011) Metabolic syndrome and cognitive decline in French elders: The Three-City Study. Neurology. 76: 518Y525.
318
www.jonmd.com
& Volume 202, Number 4, April 2014
Semkovska M, Bedard MA, Stip E (2001) Hypofrontality and negative symptoms in schizophrenia: Synthesis of anatomic and neuropsychological knowledge and ecological perspectives [in French]. Encephale. 27:405Y415. Tuulio-Henriksson A, Perala J, Saarni SI, Isometsa E, Koskinen S, Lonnqvist J, Suvisaari J (2011) Cognitive functioning in severe psychiatric disorders: A general population study. Eur Arch Psychiatry Clin Neurosci. 261:447Y456. Waddington JL, Buckley PF, Scully PJ, Lane A, O’Callaghan E, Larkin C (1998) Course of psychopathology, cognition and neurobiological abnormality in schizophrenia: Developmental origins and amelioration by antipsychotics? J Psychiatr Res. 32:179Y189. Yang C, Winkelman JW (2006) Clinical significance of sleep EEG abnormalities in chronic schizophrenia. Schizophr Res. 82:251Y260.
* 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
