Psychoneuroendocrinology (2014) 48, 136—146
Available online at www.sciencedirect.com
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Gender difference in association of cognition with BDNF in chronic schizophrenia Xiang Yang Zhang a,b,∗, Da-Chun Chen b, Yun-Long Tan b, Shu-ping Tan b, Zhi-Ren Wang b, Fu-De Yang b, Mei-Hong Xiu b, Li Hui b, Meng-Han Lv b, Giovana B. Zunta-Soares a, Jair C. Soares a,∗∗ a
Department of Psychiatry and Behavioral Sciences, Harris County Psychiatric Center, The University of Texas Health Science Center at Houston, Houston, TX, USA b Beijing HuiLongGuan Hospital, Peking University, Beijing, China Received 26 March 2014; received in revised form 9 June 2014; accepted 9 June 2014
KEYWORDS Schizophrenia; Gender difference; Cognition; BDNF; Association
Summary While numerous studies have reported that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia, very few studies have explored its association with cognitive impairment or gender differences in schizophrenia which we explored. We compared gender differences in 248 chronic schizophrenic patients (male/female = 185/63) to 188 healthy controls (male/female = 98/90) on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and serum BDNF. Schizophrenic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). Our results showed that schizophrenic patients performed worse than normals on most of the cognitive tasks, and male patients had significantly lower immediate memory and delayed memory scores than female patients. BDNF levels were significantly lower in patients than controls, and male patients had significantly lower BDNF levels than female patients. For the patients, BDNF was positively associated with immediate memory and the RBANS total score. Furthermore, these associations were only observed in female not male patients. Among healthy controls, no gender difference was observed in cognitive domains and BDNF levels, or in the association between
∗ Corresponding author at: Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, UT Houston Medical School, 1941 East Road, Houston, TX 77054, USA. Tel.: +1-7136674741. ∗∗ Corresponding author at: Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, UT Houston Medical School, 1941 East Road, Ste. 3219, Houston, TX 77054, USA. Tel.: +1 713 486 2507; fax: +1 713 486 2552. E-mail addresses: [email protected] (X.Y. Zhang), [email protected] (J.C. Soares).
http://dx.doi.org/10.1016/j.psyneuen.2014.06.004 0306-4530/© 2014 Elsevier Ltd. All rights reserved.
Sex difference in cognition and BDNF
137
BDNF and cognition. Our results suggest gender differences in cognitive impairments, BDNF levels and their association in chronic patients with schizophrenia. However, the findings should be regarded as preliminary due to the cross-sectional design and our chronic patients, which need replication in a first-episode and drug naïve patients using a longitudinal study. © 2014 Elsevier Ltd. All rights reserved.
1. Introduction Schizophrenia (SZ) patients show cognitive deficits across a number of domains, including learning, memory, attention, executive functioning and cognitive processing speed (Sharma and Antonova, 2003; Harvey et al., 2004; Palmer et al., 2009; Condray and Yao, 2011). Several studies have focused on gender differences in the cognitive deficits of SZ, and found gender differences in cognitive performances in both SZ and healthy populations (Goldstein et al., 2002; Halari et al., 2006; Wisner et al., 2011). However, gender differences in these cognitive deficits among SZ patients have produced equivocal findings. For example, some studies indicate men to be more impaired than women (Goldstein et al., 1998; Fiszdon et al., 2003) whereas others report the opposite (Lewine et al., 1996; Brébion et al., 2004) or no difference (Gur et al., 2001; Halari et al., 2006). Moreover, the pathophysiological mechanisms underlying these gender differences in cognitive deficits of SZ are still unclear and have previously received little systematic study. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors and is essential in regulating cell survival, proliferation and synaptic growth in the developing central nervous system (Poo, 2001; Egan et al., 2003). Also, in the mature nervous system, BDNF promotes the elaboration and refinement of neuronal circuit structure, modulates synaptic plasticity, dendritic complexity and spine density, and, consequently, regulates cognitive brain function including learning and memory (Pandya et al., 2013; Lu et al., 2014). In laboratory animals, BDNF can induce long-term potentiation (LTP), which is considered to be the neurophysiological basis for learning and memory (Diógenes et al., 2011). Furthermore, inhibition of BDNF signaling by gene knockout or antisense RNA impairs spatial learning and memory (Guzowski et al., 2000). Preclinical evidence shows that BDNF activity or levels may contribute to alterations in hippocampal function and hippocampal dependent learning and memory (Hariri et al., 2003). Recently, many studies have demonstrated that BDNF serum levels are significantly lowered in patients with cognitive decline-associated diseases, such as Huntington’s disease (Ciammola et al., 2007), Alzheimer’s disease (AD) (Gunstad et al., 2008), and mild cognitive impairment (Yu et al., 2008). In contrast, up-regulation of BDNF in the hypothalamus has been related to an improvement of cognitive function, including memory (Adlard et al., 2004; Komulainen et al., 2008). Several studies further suggest that peripheral BDNF levels are biomarkers of cognitive function in healthy older adults (Gunstad et al., 2008; Komulainen et al., 2008), as well as in schizophrenia (Vinogradov et al., 2009; Carlino et al., 2011; Niitsu et al., 2011; Nurjono et al., 2012; Zhang et al., 2012; Asevedo et al., 2013; Goff, 2013; Nieto et al., 2013).
Numerous studies have reported that altered peripheral levels of BDNF may be involved in the pathophysiology of SZ (Pillai et al., 2010; Buckley et al., 2011; Favalli et al., 2012; Pillai and Buckley, 2012). The majority of studies report decreased serum BDNF levels in treated and first-episode SZ patients (Toyooka et al., 2002; Shimizu et al., 2003; Pirildar et al., 2004; Tan et al., 2005; Palomino et al., 2006; Grillo et al., 2007; Ikeda et al., 2008; Rizos et al., 2008, 2010; Chen et al., 2009; Xiu et al., 2009; Pillai et al., 2010). However, some authors failed to replicate these findings in both medicated and unmedicated SZ patients (Shimizu et al., 2003; Huang and Lee, 2006), or even found increased serum BDNF levels in treated SZ patients (Reis et al., 2008). The most recent systematic review with meta-analysis of studies has showed that blood levels of BDNF are reduced in both medicated and drug-naïve patients with SZ (Green et al., 2011). Interestingly, in one of our recent studies we found sex differences in BDNF levels in SZ, showing lower BDNF levels in male compared to female patients (Xiu et al., 2009). One recent study also reported a significant reduction in plasma BDNF levels in females as compared to males including both depressed and control subjects (Pillai et al., 2012). In the view of gender differences in cognitive deficits and the possible gender differences in alterations of BDNF in SZ and the important implication of BDNF in cognition, we explored gender differences in the association of BDNF with cognitive impairments in SZ, which to our knowledge, has not been examined in patients with SZ. We hypothesized that gender differences may exist in cognitive performance, BDNF levels and their association in SZ.
2. Method 2.1. Subjects Two hundred and forty eight physically healthy patients (male/female = 185/63) who met DSM-IV for SZ were compared with 188 Chinese normal controls (male/ female = 98/90). All SZ patients were inpatients of Beijing Hui-Long-Guan Hospital, a Beijing City owned psychiatric hospital. Diagnoses were made for each patient by two independent experienced psychiatrists based on the Structured Clinical Interview for DSM-IV (SCID). All SZ patients were of the chronic type, with a duration of illness for at least 5 years, aged between 25 and 70 years (mean 52.1 ± 8.3 years). Most of patients (93.5%) were considered refractory to treatment according to these criteria: no response to at least three antipsychotics treated 3 months or over at full dose. All patients had been receiving stable doses of oral neuroleptic medications for at least 12 months prior to entry into the study. Their
138 antipsychotic treatment consisted mainly of monotherapy with clozapine (n = 110), risperidone (n = 64), sulpiride (n = 22), perphenazine (n = 17), haloperidol (n = 16), chlorpromazine (n = 14), and others (n = 5). Among them, 25 patients (10.1%) received 2 (n = 20) or 3 (n = 5) different antipsychotic drugs. The mean antipsychotic dose (as chlorpromazine equivalents) was 509.3 ± 591.5 mg/day. The average duration of the current antipsychotic treatment was 4.8 ± 4.6 years at the time of the investigation. In addition, 78 patients received antiparkinsonian drugs. For comparison, healthy controls were recruited from the community. All subjects were Han Chinese recruited at the same period from the Beijing area. The patients and healthy subjects had a similar socioeconomic status and dietary patterns. We obtained a complete medical history and physical examination from all subjects, and any subjects with serious medical abnormalities were excluded. Neither the SZ patients nor the control subjects suffered from drug abuse or dependence. A psychiatrist ruled out any mental disorders among healthy controls by direct psychiatric interview. All subjects provided signed, informed consent to participate in this study, which was approved by the Institutional Review Board, Beijing Hui-Long-Guan Hospital.
2.2. Clinical assessment Four psychiatrists who were blind to the clinical status assessed the patients’ psychopathology with the PANSS on the day of the blood sampling. To ensure consistency and reliability of rating across the study, these four psychiatrists, who had worked at least 5 years in clinical practice, simultaneously attended a training session in using the PANSS before the start of the study. After training, repeated assessments during the course of the study showed that a correlation coefficient greater than 0.8 was maintained for the PANSS total score.
2.3. Cognitive measures We individually administered The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to measure cognitive function (Randolph et al., 1998; Duff et al., 2008). The RBANS is comprised of 12 subtests that are used to calculate 5 age-adjusted index scores and a total score (Randolph et al., 1998). Test indices are immediate memory (comprised of list learning and story memory tasks); visuospatial/constructional (comprised of figure copy and line orientation tasks); language (comprised of picture naming and semantic fluency tasks); attention (comprised of digit span and coding tasks); and delayed memory (comprised of list recall, story recall, figure recall, and list recognition tasks). Our group previously translated the RBANS into Chinese and established its clinical validity and test—retest reliability among controls and SZ patients (Zhang et al., 2009). To ensure consistency and reliability of rating, the two clinical psychologists simultaneously attended a training session for standardizing their use of the RBANS prior to the start of the study. Thereafter, they maintained an intraclass
X.Y. Zhang et al. correlation coefficient of 0.92 on the RBANS at repeated assessments.
2.4. Blood sampling and serum BDNF measurements Serum samples from healthy controls and patients were collected between 7 and 9 AM following an overnight fast. Serum BDNF levels were measured by sandwich enzyme linked immunosorbent assay using a commercially available kit (R&D systems, Beijing, China). A full description of the assays has been given in our previous report (Chen et al., 2009; Xiu et al., 2009). All samples were assayed by a technician blind to the clinical situation. Each assay was run in duplicate. The identity of all subjects was indicated by a code number maintained by the principal investigator until all biochemical analyses were completed. Inter- and intraassay variation coefficients were 8% and 5%, respectively.
2.5. Statistical analysis Group comparisons on demographic and clinical variables used chi squared or Fisher exact tests for categorical variables and Student’s t-tests or analysis of variance (ANOVA) for continuous variables. For the RBANS comparisons, we also included age, education and smoking as covariates in multivariate analyses of covariance for significant gender differences across the dependent measures from the RBANS total score and its five cognitive domains, with independent predictors being gender (male vs. female), diagnosis (patients vs. healthy controls) and the gender-by diagnosis interaction. Furthermore, among the patient group, analyses of covariance (ANCOVA) was constructed with gender as the independent variable, and the cognitive scores shown by the RBANS total and 5 index scores as dependent variables, with age, education, illness course, age of onset, body mass index (BMI), smoking, antiparkinsonian drug, as well as antipsychotic drug type (atypical vs. typical antipsychotics), dose (chlorpromazine equivalents) and duration of treatment as the covariates. We assessed relationships between variables with Pearson’s product moment correlation coefficients. Multiple regression models were used to quantify the amount of variance in cognitive functioning explained by psychopathological variables, after controlling for several potential confounders, e.g., gender, age, years of education, smoking, and clinical variables including age of onset, antiparkinsonian drug, as well as antipsychotic drug (type, dose and duration of treatment) and clinical symptoms shown on PANSS. In addition, a mediation analysis was performed to understand the relationship across gender, BDNF and cognitive functions, and to examine whether BDNF could mediate the association between gender and cognitive functions. In the mediation analysis, gender was independent factor, cognitive functions were dependent factors and BDNF was moderator, with age and education as covariates. SPSS version 15.0 was used to do all statistical analysis. Data were presented as mean ± SD. All p values were 2 tailed at the significance level of ≤0.05.
Demographics, cognitive function and BDNF levels in schizophrenia and healthy controls. Schizophrenia
Healthy control Diagnose F (p value)d
Gender F (p value)d
Diagnose × gender F (p value)d
90 48.4 ± 11.0 8.6 ± 3.9 25.6 ± 4.3 22/67
19.92 (
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/psyneuen
Gender difference in association of cognition with BDNF in chronic schizophrenia Xiang Yang Zhang a,b,∗, Da-Chun Chen b, Yun-Long Tan b, Shu-ping Tan b, Zhi-Ren Wang b, Fu-De Yang b, Mei-Hong Xiu b, Li Hui b, Meng-Han Lv b, Giovana B. Zunta-Soares a, Jair C. Soares a,∗∗ a
Department of Psychiatry and Behavioral Sciences, Harris County Psychiatric Center, The University of Texas Health Science Center at Houston, Houston, TX, USA b Beijing HuiLongGuan Hospital, Peking University, Beijing, China Received 26 March 2014; received in revised form 9 June 2014; accepted 9 June 2014
KEYWORDS Schizophrenia; Gender difference; Cognition; BDNF; Association
Summary While numerous studies have reported that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia, very few studies have explored its association with cognitive impairment or gender differences in schizophrenia which we explored. We compared gender differences in 248 chronic schizophrenic patients (male/female = 185/63) to 188 healthy controls (male/female = 98/90) on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and serum BDNF. Schizophrenic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). Our results showed that schizophrenic patients performed worse than normals on most of the cognitive tasks, and male patients had significantly lower immediate memory and delayed memory scores than female patients. BDNF levels were significantly lower in patients than controls, and male patients had significantly lower BDNF levels than female patients. For the patients, BDNF was positively associated with immediate memory and the RBANS total score. Furthermore, these associations were only observed in female not male patients. Among healthy controls, no gender difference was observed in cognitive domains and BDNF levels, or in the association between
∗ Corresponding author at: Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, UT Houston Medical School, 1941 East Road, Houston, TX 77054, USA. Tel.: +1-7136674741. ∗∗ Corresponding author at: Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, UT Houston Medical School, 1941 East Road, Ste. 3219, Houston, TX 77054, USA. Tel.: +1 713 486 2507; fax: +1 713 486 2552. E-mail addresses: [email protected] (X.Y. Zhang), [email protected] (J.C. Soares).
http://dx.doi.org/10.1016/j.psyneuen.2014.06.004 0306-4530/© 2014 Elsevier Ltd. All rights reserved.
Sex difference in cognition and BDNF
137
BDNF and cognition. Our results suggest gender differences in cognitive impairments, BDNF levels and their association in chronic patients with schizophrenia. However, the findings should be regarded as preliminary due to the cross-sectional design and our chronic patients, which need replication in a first-episode and drug naïve patients using a longitudinal study. © 2014 Elsevier Ltd. All rights reserved.
1. Introduction Schizophrenia (SZ) patients show cognitive deficits across a number of domains, including learning, memory, attention, executive functioning and cognitive processing speed (Sharma and Antonova, 2003; Harvey et al., 2004; Palmer et al., 2009; Condray and Yao, 2011). Several studies have focused on gender differences in the cognitive deficits of SZ, and found gender differences in cognitive performances in both SZ and healthy populations (Goldstein et al., 2002; Halari et al., 2006; Wisner et al., 2011). However, gender differences in these cognitive deficits among SZ patients have produced equivocal findings. For example, some studies indicate men to be more impaired than women (Goldstein et al., 1998; Fiszdon et al., 2003) whereas others report the opposite (Lewine et al., 1996; Brébion et al., 2004) or no difference (Gur et al., 2001; Halari et al., 2006). Moreover, the pathophysiological mechanisms underlying these gender differences in cognitive deficits of SZ are still unclear and have previously received little systematic study. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors and is essential in regulating cell survival, proliferation and synaptic growth in the developing central nervous system (Poo, 2001; Egan et al., 2003). Also, in the mature nervous system, BDNF promotes the elaboration and refinement of neuronal circuit structure, modulates synaptic plasticity, dendritic complexity and spine density, and, consequently, regulates cognitive brain function including learning and memory (Pandya et al., 2013; Lu et al., 2014). In laboratory animals, BDNF can induce long-term potentiation (LTP), which is considered to be the neurophysiological basis for learning and memory (Diógenes et al., 2011). Furthermore, inhibition of BDNF signaling by gene knockout or antisense RNA impairs spatial learning and memory (Guzowski et al., 2000). Preclinical evidence shows that BDNF activity or levels may contribute to alterations in hippocampal function and hippocampal dependent learning and memory (Hariri et al., 2003). Recently, many studies have demonstrated that BDNF serum levels are significantly lowered in patients with cognitive decline-associated diseases, such as Huntington’s disease (Ciammola et al., 2007), Alzheimer’s disease (AD) (Gunstad et al., 2008), and mild cognitive impairment (Yu et al., 2008). In contrast, up-regulation of BDNF in the hypothalamus has been related to an improvement of cognitive function, including memory (Adlard et al., 2004; Komulainen et al., 2008). Several studies further suggest that peripheral BDNF levels are biomarkers of cognitive function in healthy older adults (Gunstad et al., 2008; Komulainen et al., 2008), as well as in schizophrenia (Vinogradov et al., 2009; Carlino et al., 2011; Niitsu et al., 2011; Nurjono et al., 2012; Zhang et al., 2012; Asevedo et al., 2013; Goff, 2013; Nieto et al., 2013).
Numerous studies have reported that altered peripheral levels of BDNF may be involved in the pathophysiology of SZ (Pillai et al., 2010; Buckley et al., 2011; Favalli et al., 2012; Pillai and Buckley, 2012). The majority of studies report decreased serum BDNF levels in treated and first-episode SZ patients (Toyooka et al., 2002; Shimizu et al., 2003; Pirildar et al., 2004; Tan et al., 2005; Palomino et al., 2006; Grillo et al., 2007; Ikeda et al., 2008; Rizos et al., 2008, 2010; Chen et al., 2009; Xiu et al., 2009; Pillai et al., 2010). However, some authors failed to replicate these findings in both medicated and unmedicated SZ patients (Shimizu et al., 2003; Huang and Lee, 2006), or even found increased serum BDNF levels in treated SZ patients (Reis et al., 2008). The most recent systematic review with meta-analysis of studies has showed that blood levels of BDNF are reduced in both medicated and drug-naïve patients with SZ (Green et al., 2011). Interestingly, in one of our recent studies we found sex differences in BDNF levels in SZ, showing lower BDNF levels in male compared to female patients (Xiu et al., 2009). One recent study also reported a significant reduction in plasma BDNF levels in females as compared to males including both depressed and control subjects (Pillai et al., 2012). In the view of gender differences in cognitive deficits and the possible gender differences in alterations of BDNF in SZ and the important implication of BDNF in cognition, we explored gender differences in the association of BDNF with cognitive impairments in SZ, which to our knowledge, has not been examined in patients with SZ. We hypothesized that gender differences may exist in cognitive performance, BDNF levels and their association in SZ.
2. Method 2.1. Subjects Two hundred and forty eight physically healthy patients (male/female = 185/63) who met DSM-IV for SZ were compared with 188 Chinese normal controls (male/ female = 98/90). All SZ patients were inpatients of Beijing Hui-Long-Guan Hospital, a Beijing City owned psychiatric hospital. Diagnoses were made for each patient by two independent experienced psychiatrists based on the Structured Clinical Interview for DSM-IV (SCID). All SZ patients were of the chronic type, with a duration of illness for at least 5 years, aged between 25 and 70 years (mean 52.1 ± 8.3 years). Most of patients (93.5%) were considered refractory to treatment according to these criteria: no response to at least three antipsychotics treated 3 months or over at full dose. All patients had been receiving stable doses of oral neuroleptic medications for at least 12 months prior to entry into the study. Their
138 antipsychotic treatment consisted mainly of monotherapy with clozapine (n = 110), risperidone (n = 64), sulpiride (n = 22), perphenazine (n = 17), haloperidol (n = 16), chlorpromazine (n = 14), and others (n = 5). Among them, 25 patients (10.1%) received 2 (n = 20) or 3 (n = 5) different antipsychotic drugs. The mean antipsychotic dose (as chlorpromazine equivalents) was 509.3 ± 591.5 mg/day. The average duration of the current antipsychotic treatment was 4.8 ± 4.6 years at the time of the investigation. In addition, 78 patients received antiparkinsonian drugs. For comparison, healthy controls were recruited from the community. All subjects were Han Chinese recruited at the same period from the Beijing area. The patients and healthy subjects had a similar socioeconomic status and dietary patterns. We obtained a complete medical history and physical examination from all subjects, and any subjects with serious medical abnormalities were excluded. Neither the SZ patients nor the control subjects suffered from drug abuse or dependence. A psychiatrist ruled out any mental disorders among healthy controls by direct psychiatric interview. All subjects provided signed, informed consent to participate in this study, which was approved by the Institutional Review Board, Beijing Hui-Long-Guan Hospital.
2.2. Clinical assessment Four psychiatrists who were blind to the clinical status assessed the patients’ psychopathology with the PANSS on the day of the blood sampling. To ensure consistency and reliability of rating across the study, these four psychiatrists, who had worked at least 5 years in clinical practice, simultaneously attended a training session in using the PANSS before the start of the study. After training, repeated assessments during the course of the study showed that a correlation coefficient greater than 0.8 was maintained for the PANSS total score.
2.3. Cognitive measures We individually administered The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to measure cognitive function (Randolph et al., 1998; Duff et al., 2008). The RBANS is comprised of 12 subtests that are used to calculate 5 age-adjusted index scores and a total score (Randolph et al., 1998). Test indices are immediate memory (comprised of list learning and story memory tasks); visuospatial/constructional (comprised of figure copy and line orientation tasks); language (comprised of picture naming and semantic fluency tasks); attention (comprised of digit span and coding tasks); and delayed memory (comprised of list recall, story recall, figure recall, and list recognition tasks). Our group previously translated the RBANS into Chinese and established its clinical validity and test—retest reliability among controls and SZ patients (Zhang et al., 2009). To ensure consistency and reliability of rating, the two clinical psychologists simultaneously attended a training session for standardizing their use of the RBANS prior to the start of the study. Thereafter, they maintained an intraclass
X.Y. Zhang et al. correlation coefficient of 0.92 on the RBANS at repeated assessments.
2.4. Blood sampling and serum BDNF measurements Serum samples from healthy controls and patients were collected between 7 and 9 AM following an overnight fast. Serum BDNF levels were measured by sandwich enzyme linked immunosorbent assay using a commercially available kit (R&D systems, Beijing, China). A full description of the assays has been given in our previous report (Chen et al., 2009; Xiu et al., 2009). All samples were assayed by a technician blind to the clinical situation. Each assay was run in duplicate. The identity of all subjects was indicated by a code number maintained by the principal investigator until all biochemical analyses were completed. Inter- and intraassay variation coefficients were 8% and 5%, respectively.
2.5. Statistical analysis Group comparisons on demographic and clinical variables used chi squared or Fisher exact tests for categorical variables and Student’s t-tests or analysis of variance (ANOVA) for continuous variables. For the RBANS comparisons, we also included age, education and smoking as covariates in multivariate analyses of covariance for significant gender differences across the dependent measures from the RBANS total score and its five cognitive domains, with independent predictors being gender (male vs. female), diagnosis (patients vs. healthy controls) and the gender-by diagnosis interaction. Furthermore, among the patient group, analyses of covariance (ANCOVA) was constructed with gender as the independent variable, and the cognitive scores shown by the RBANS total and 5 index scores as dependent variables, with age, education, illness course, age of onset, body mass index (BMI), smoking, antiparkinsonian drug, as well as antipsychotic drug type (atypical vs. typical antipsychotics), dose (chlorpromazine equivalents) and duration of treatment as the covariates. We assessed relationships between variables with Pearson’s product moment correlation coefficients. Multiple regression models were used to quantify the amount of variance in cognitive functioning explained by psychopathological variables, after controlling for several potential confounders, e.g., gender, age, years of education, smoking, and clinical variables including age of onset, antiparkinsonian drug, as well as antipsychotic drug (type, dose and duration of treatment) and clinical symptoms shown on PANSS. In addition, a mediation analysis was performed to understand the relationship across gender, BDNF and cognitive functions, and to examine whether BDNF could mediate the association between gender and cognitive functions. In the mediation analysis, gender was independent factor, cognitive functions were dependent factors and BDNF was moderator, with age and education as covariates. SPSS version 15.0 was used to do all statistical analysis. Data were presented as mean ± SD. All p values were 2 tailed at the significance level of ≤0.05.
Demographics, cognitive function and BDNF levels in schizophrenia and healthy controls. Schizophrenia
Healthy control Diagnose F (p value)d
Gender F (p value)d
Diagnose × gender F (p value)d
90 48.4 ± 11.0 8.6 ± 3.9 25.6 ± 4.3 22/67
19.92 (
