Gender difference in association of cognition with BDNF in chronic schizophrenia

Psychoneuroendocrinology (2014) 48, 136—146

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 (<0.001) 3.51 (0.06) 0.77 (0.38)

1.81 (0.18) 0.63 (0.43) 0.54 (0.46)

0.03 (0.86) 3.53 (0.06) 2.93 (0.09)

73.1 ± 16.2 80.5 ± 15.7 96.4 ± 10.4 87.2 ± 17.9 84.9 ± 14.4 79.6 ± 13.1

73.5 ± 18.8 81.5 ± 14.2 93.5 ± 13.4 86.5 ± 22.1 84.5 ± 16.4 76.9 ± 16.0

17.83 2.32 11.44 3.88 37.43 10.72

3.83 1.94 0.01 0.13 4.38 0.16

0.19 1.22 3.06 1.29 1.80 4.64

11.9 ± 2.3

11.9 ± 253

64.84 (<0.001)

Male

Female

Male

Female

Sample size a, *** Age (years) a, *** Education (years) Body mass index (BMI) Smoker/Non-smoker a, ***

185 51.8 ± 8.6 9.4 ± 2.4 24.5 ± 5.2 143/42b, ***

63 53.0 ± 7.3 9.8 ± 2.6 26.1 ± 4.9 3/59

98 46.8 ± 14.1 9.4 ± 3.4 26.2 ± 4.7 57/39b, ***

RBANS Immediate memory Visuospatial/constructional Language Attention Delayed memory Total score

63.0 ± 18.7c, * 82.2 ± 19.3 86.4 ± 16.1 81.4 ± 15.1 70.4 ± 20.9c, * 71.1 ± 15.2c,#

67.7 ± 20.3 85.2 ± 19.5 86.5 ± 14.0 83.5 ± 16.4 77.3 ± 20.9 75.1 ± 17.1

BDNF (ng/ml)

9.9 ± 1.9c, *

10.9 ± 2.0

a b c d

Sex difference in cognition and BDNF

Table 1

(<0.0001) (0.13) (<0.001) (<0.05) (<0.001) (<0.001)

(0.051) (0.21) (0.93) (0.72) (<0.05) (0.69)

2.23 (0.14)

(0.67) (0.29) (0.08) (0.36) (0.18) (<0.05)

2.95 (0.086)

Indicates significant differences between schizophrenia and healthy controls in gender, age and smoking; ***p < 0.001. There was a significant difference between male and female pairs in each group; ***p < 0.001. Indicates comparison between male and female schizophrenia patients; *p < 0.05; # p = 0.052. The p values for RBANS and BDNF were adjusted for age, education and smoking as covariates.

139

140

X.Y. Zhang et al.

3. Results 3.1. Sample characteristics Table 1 shows significant differences between SZ patients and healthy controls in gender (p < 0.001), and age (p < 0.001), and there was a trend toward a significant difference in education (p = 0.062). Also, there was a significant difference in smoking rates between the patients (59.1%) and normal controls (42.7%) (2 = 11.4, df = 1, p < 0.01). Smoking also was more common in male than female SZ patients and in male than female controls (both p < 0.001). Furthermore, significantly more male chronic SZ patients than male controls smoked (77.3% vs. 59.4%); however, fewer female chronic SZ patients than female controls currently smoked (4.8% vs. 24.7%) (both p values < 0.01). Thus, we controlled for gender, age, education and smoking in the following analyses. Table 2 showed no significant differences between male and female patients in any demographic and clinical parameters (all p > 0.05).

3.2. Cognitive performance in schizophrenia and healthy controls Table 1 showed significantly lower cognitive test scores in SZ patients compared to control subjects on the RBANS total scores and all five indexes, except for the RBANS visuospatial/constructional index (p > 0.05). After controlling for gender, age, education and smoking, there were still statistically significant differences between SZ patients and controls for the RBANS total scores and all index scores (all p < 0.05), except for the RBANS visuospatial/constructional index (p > 0.05). Further multivariate analysis of covariance showed a gender × diagnosis interaction effect on for all cognitive domains (F = 3.36, p < 0.05). In order to decompose the two-way interaction, we examined patients and controls grouped by gender. Male patients performed worse than female patients on delayed memory and immediate memory

Table 2

(both p < 0.05), and had a trend toward a significantly lower RBANS total score (p = 0.052) (Table 1). After controlling for demographic data, clinical symptoms, as well as antipsychotic drugs (dose, type and duration of treatment) and antiparkinsonian drug among the patients, both the delayed and immediate memory remained significant (both p < 0.05). In the control group, the males and females showed no significant differences on any RBANS index or its total score (all p > 0.05) (Table 1).

3.3. Serum BDNF in schizophrenia and healthy controls Serum BDNF levels were significantly lower in patients than in controls (9.9 ± 2.0 ng/ml vs. 11.9 ± 2.4 ng/ml, F = 88.46, df = 1, 434, p < 0.001), which still remained significant after covariance for age, sex, education, smoking, and BMI (F = 18.26, df = 6, 273; p < 0.001) and had an effect size of 0.91 (Table 1). Furthermore, BDNF levels also were significantly lower in male than female patients (F = 4.27, df = 1, 246, p < 0.05), and not attenuated after covariance for age, sex, education, smoking, and BMI (p < 0.05), nor for the clinical parameters including age of onset, hospitalization, antipsychotic drug (type, dose and duration of treatment), antiparkinsonian drug and PANSS scale (p < 0.05). However, we observed no sex difference in BDNF levels for healthy controls (p > 0.05).

3.4. Gender differences in the relationships between BDNF levels and cognitive functioning Using multivariate regression analysis the following variables were independently associated with the RBANS total score: PANSS negative symptom score (beta = −0.32, t = −4.47, p < 0.001), gender (beta = −0.91, t = −3.05, p = 0.003), education (beta = 0.16, t = 2.76, p = 0.006), BDNF (beta = 0.48, t = 2.71, p = 0.007), age (beta = −0.16, t = −2.71, p = 0.0075), as well as gender × BDNF (beta = 1.21, t = 3.31, p = 0.001). Since we found a significant BDNF main effect as well as a significant interaction of BDNF × gender,

Characteristics of male and female patients with schizophrenia. Male

Female

t or 2

p-Value

Age of onset (years) Antipsychotic types (typicals/atypicals) Antipsychotic dose (CPZ equivalents) Duration of current antipsychotic treatment Antiparkinsonian drug (Yes/No) Number of hospitalizations

24.1 ± 6.2 36/86 496.0 ± 572.2 51.8 ± 53.3 59/120 3.7 ± 3.1

26.0 ± 7.3 20/58 548.4 ± 648.2 44.4 ± 64.9 19/42 3.8 ± 2.2

1.93 0.35 −1.01 0.86 0.04 −0.14

0.06 0.55 0.32 0.39 0.85 0.89

PANSS Positive symptom scale Negative symptom scale General psychopathology scale Total score

12.4 ± 5.1 22.2 ± 6.8 26.2 ± 5.4 60.7 ± 13.7

13.1 ± 6.4 20.5 ± 7.5 27.6 ± 6.5 61.2 ± 15.2

−0.91 1.67 −1.77 −0.24

0.36 0.10 0.08 0.81

Note: Mean ± SD. CPZ = chlorpromazine; PANSS = the Positive and Negative Syndrome Scale. The hospitalization is defined as the duration of a stay in the hospital for more than 1 month, and the interval of two hospitalizations should be over 3 months.

Sex difference in cognition and BDNF

141

Age (years) Education (years) Age of onset (years) PANSS Positive Negative General psychopathology Total RBANS Immediate memory Visuospatial/constructional Language Attention Delayed memory Total score a

Female (n = 63)

−0.21 (<0.01) −0.02 (0.75) −0.05 (0.49)

−0.24 (<0.05) −0.11 (0.42) −0.11 (0.41)

−0.14 (0.053) −0.19 (<0.05) −0.18 (<0.05)

0.09 (0.49) 0.08 (0.52) 0.22 (0.08)

−0.23 (<0.01)

0.17 (0.18)

0.11 (0.15) −0.07 (0.36)

0.51 (<0.001) 0.18 (0.15)

0.01 0.03 0.01 0.03

(0.87) (0.68) (0.91) (0.68)

−0.05 0.21 0.23 0.34

(0.69) (0.10) (0.08) (<0.01)

Values are shown as r (p).

further analyses were performed separately for the women and men with schizophrenia to assess gender differences in BDNF associated with cognitive impairment. We hypothesized that the association of BDNF with cognitive function were different in the male and female patients. Table 3 shows the correlations between BDNF and clinical symptoms or cognitive performance measures in male and female patients. For male patients, BDNF was significantly associated with the following parameters: age (r = −0.21, df = 185, p < 0.005), PANSS total score (r = −0.23, df = 183, p < 0.005), the negative symptom subscore (r = −0.19, df = 183, p < 0.05), and the general psychopathology subscore (r = −0.18, df = 183, p < 0.05). However, no significant association was found between BDNF and any cognitive performance measure. For female patients, BDNF was found to be significantly associated with the following parameters: immediate memory (r = 0.51, df = 63, p < 0.0001), RBANS total score (r = 0.34, df = 63, p < 0.01) (Fig. 1) and age (r = −0.24, df = 63, p < 0.05), as well as having a trend toward significant association with delayed memory (r = 0.23, df = 63, p = 0.08). Further multiple regression analysis performed in the female patient subgroup showed that BDNF (beta = 0.54, t = 3.33, p < 0.005) and PANSS total score (beta = −0.38, t = −2.34, p < 0.05) were independent contributors to the RBANS total score, with R2 = 0.37. Moreover, BDNF (beta = 0.44, t = 4.19, p < 0.001), negative symptom (beta = −0.26, t = −2.14, p < 0.05), and age (beta = −0.22, t = −2.07, p < 0.05) were independent contributors to immediate memory, with R2 = 0.42. In addition, for the healthy controls, BDNF was not found to be a contributor to any of the RBANS indices or its total score when the males and females were analyzed separately (all p > 0.05).

BDNF ng/ml

Male (n = 185)

r=0.51 df=63 p<.0001

RBANS Immediate Memory Index BDNF ng/ml

Table 3 Correlations between BDNF and clinical variables or cognitive performance measures in male and female schizophrenia patients.a

r=0.34 df=63 p=.006

RBANS total score

Figure 1 There was a significant positive association between serum BDNF levels and both the RBANS immediate memory index (r = 0.51, df = 63, p < 0.0001) and the RBANS total score (r = 0.34, df = 63, p < 0.01) only in female patient group.

3.5. Mediation analysis for the relationship across gender, BDNF and cognitive functions As described above, male patients had significantly lower memory function (immediately memory and delayed memory scores) and lower BDNF levels than female patients. In the meantime, we found that BDNF was positively associated with immediately memory among female patients. We thus speculated that the relationship between gender and cognitive function might be mediated by BDNF, and tested this hypothesis by carrying out the mediation analysis as below. We used gender as independent factor, cognitive score (immediate memory) as dependent factor, and BDNF as moderator, with age and education as covariates. A statically significant mediation was observed. The model showed reasonably good fit [R2 = 0.16, F(4,237) = 11.12, p < 0.0001]. As Fig. 2 illustrates, ‘‘a’’ value, a standardized regression coefficients for the relationship between gender and

BDNF

C (total) =4.70 Gender

C’=3.24

Immediate Memory

Figure 2 Standardized regression coefficients for the relationship between gender and immediate memory as mediated by BDNF. The letters a, b and c refer to estimated path coefficients. **p < 0.001. Among them, ‘‘a’’ value is a standardized regression coefficients for the relationship between gender and BDNF, and ‘‘b’’ value is a standardized regression coefficients for the relationship between BDNF and immediate memory. C is the whole effect of gender on immediate memory, and ‘‘c ’’ is the direct effect of gender on immediate memory. C = c + a * b.

142 BDNF was 0.85** (p = 0.004), and ‘‘b’’ value, a standardized regression coefficients for the relationship between BDNF and immediate memory was 1.72** (p = 0.005). Both standardized regression coefficients were statistically significant. The standardized indirect effect was a * b = 1.46. Then we tested the significance of this indirect effect using bootstrapping procedures. Unstandardized indirect effects were computed for each of 10,000 bootstrapped samples, and the 95% CI was computed by determining the indirect effects at the 2.5th and 97.5th percentiles. The bootstrapped unstandardized indirect effect was also 1.46. Most importantly, the 95% CI ranged from 0.26 to 4.03. Thus, the indirect effect was statistically significant, suggesting that the relationship between gender and immediate memory was mediated by BDNF. We also explored the mediation possibility of BDNF on the relationship between gender and RBANS total score (or other index) in healthy controls. However, for all of these analyses, no significant mediation effects were detected.

4. Discussion This study had the following major findings. (1) Immediate memory and delayed memory were worse in male than female SZ patients. (2) BDNF levels were lower in male than female patients. (3) More interestingly, we found gender differences in the relationships between decreased BDNF levels and cognitive impairments in SZ. The associations between BDNF and some cognitive domains, especially immediate memory and RBANS total score were found only in female but not male patients. Further mediation analysis showed that the relationship between gender and immediate memory was mediated by BDNF. To our best knowledge, this is the first report to explore a possible mechanism underlying the gender difference in cognitive impairment in SZ. These findings, if replicated, have numerous implications for the pathogenesis and treatment of SZ. In this study, SZ patients had significant cognitive impairments, which are consistent with the majority of studies assessing cognitive performance in SZ patients (Sharma and Antonova, 2003; Dickerson et al., 2004; Palmer et al., 2009; Condray and Yao, 2011). Furthermore, we found gender differences in the cognitive deficits of SZ, and male patients had more serious cognitive deficits than female patients in immediate and delayed memory, which are consistent with some of the previous studies (Sota and Heinrichs, 2003; Antonova et al., 2004; Halari et al., 2006). However, some studies have reported no gender differences in cognitive deficits in SZ (Goldberg et al., 1995; Hoff et al., 1998), or reported women to be more impaired than men (Lewine et al., 1996; Brébion et al., 2004). We could not provide a reasonable explanation for such a discrepancy. Several factors, such as the interethnic differences in the gene polymorphisms related to cognitive functioning, differences in cognitive testing tools, sampling of patients in different stages of disease progression (acute vs. chronic or active phase vs. remission), different illness duration, exposure to neuroleptic treatment (naive vs. medicated), exposure to different medication types, dosage and length of antipsychotics, and the subtypes of schizophrenic patients

X.Y. Zhang et al. recruited, may be responsible for the discrepancy, which deserves further investigation. Female patients displayed better delayed memory and immediate memory compared to males suggesting that females could be protected from cognitive deterioration related to SZ. This protection from deterioration in women with SZ may be related to gonadal hormone effects on cognitive functioning, since estrogen and testosterone may influence cognitive functioning through dopamine and serotonin effects in specific brain regions (Hafner et al., 1991; Fink et al., 1999; Riecher-Rössler and Häfner, 2000). For example, estrogen can decrease dopamine concentrations and modulate sensitivities and numbers of dopamine receptors in the striatum and hippocampus (Di Paolo, 1994; McEwen and Woolley, 1994; Häfner, 2003; Karakaya et al., 2007). Therefore, females may have better cognitive performance than males. However, we found a better performance only in immediate and delayed memories in female patients, but not the other cognitive domains or the RBANS total score. We could not give a reasonable explanation why only two domains of cognitive performance were better in female patients due to the nature of our cross sectional design. Also, this protection in women with SZ may be related to their fewer negative symptoms. Indeed, we found that the RBANS total score was negatively correlated with PANSS negative symptom scores in patients. In addition, female patients also may show better improvements in cognitive deficits with antipsychotic treatments potentially through normalizing estrogen’s activity in the brain (Grigoriadis and Seeman, 2002; Rubin et al., 2008). The exact mechanisms underlying the female advantage in cognitive performance in chronic SZ warrant further investigation. A further finding of our present study was that there was a sex difference in BDNF levels in the patient group, but not in the normal control group. A recent study in humans highlighted a close relationship between plasma BDNF and hormonal variation during the menstrual cycle, suggesting that BDNF levels are influenced by hormonal status and sex steroids play a key role in the regulation of neurotrophin expression (Begliuomini et al., 2007). It is conceivable that high levels of estrogen can induce an increase of BDNF production and release (Begliuomini et al., 2007). Taken together, the findings of higher BDNF levels in female patients in our present study may be related to sex hormone levels. However, we did not find a sex difference in BDNF levels in the normal control group. At present, it is not clear why there was a significant difference in BDNF levels between males and females only in patients, but not in controls, which deserves further investigation. In addition, it is worthy of mentioning that not controlling the menstrual cycle in the female patients in the present study is a limitation, despite that in the control group a sex difference was not found. This limitation should be remedied in the future investigation. We also found a significant association between BDNF levels and cognitive performance, especially immediate memory in SZ, showing that lower serum BDNF levels were correlated with poor cognitive performance. This result is consistent with the recent studies indicating that serum BDNF levels were positively correlated with cognitive function in aging healthy adults (Gunstad et al., 2008; Komulainen et al., 2008). The exact mechanisms for this

Sex difference in cognition and BDNF relationship are unknown. One possible reason is the neuroprotective function of BDNF. BDNF plays an essential role in regulating synaptic plasticity (Lu et al., 2008), which is thought to be the cellular mechanism for learning and memory in adult brains (Diógenes et al., 2011). Moreover, long-term potentiation (LTP), including early and late phase LTP, which is considered as the neurophysiological basis for learning and memory, is evoked by BDNF (Lu and Gottschalk, 2000; Poo, 2001; Diógenes et al., 2011). Animal experiments demonstrate that hippocampal LTP is significantly impaired in BDNF knockout mice (Tyler et al., 2002), and this impairment can be ameliorated by up-regulation of BDNF (Korte et al., 1996) or by treating with recombinant BDNF (Patterson et al., 1996). Those studies indicate that BDNF is important in the process of learning and improvement in cognitive function, and thus provides a biological basis for our finding. More interestingly, we found that only female patients showed a positive association between BDNF and some cognitive domains, especially immediate memory and RBANS total score, while male patients showed significant associations of BDNF with the clinical symptoms, including negative symptoms, and general psychopathology. Further mediation analysis also showed a significant relationship between gender and immediate memory mediated by BDNF. Consistent with this sex difference, a recent study in an elderly general population showed that decreased plasma BDNF level is a biomarker of cognitive impairment in aging women, but not in men (Komulainen et al., 2008). The gender difference for the association between decreased BDNF serum levels and cognitive impairment in SZ may be explained by sex hormones. For example, estradiol has been found to induce BDNF expression and the effects of estradiol in hippocampus may be mediated by BDNF (Scharfman and Maclusky, 2005). In some animal experiments, estrogen treatment has increased BDNF expression in the hippocampus (Frye et al., 2005; Sohrabji and Lewis, 2006). Also, progesterone can be neuroprotective by increasing the expression of BDNF mRNA and protein (Kaur et al., 2007). In addition, low testosterone levels were detected in patients with mild cognitive impairment or Alzheimer’s disease (Beauchet, 2006); furthermore, testosterone may have neurotrophic and neuroprotective effects (Beauchet, 2006). Androgen receptors are also found in brain regions that are important for learning and memory (Janowsky, 2006). Also, a recent study showed that female SZ patients with higher levels of oxytocin perceived faces as happier on emotional processing test, suggesting that oxytocin might enhance mood states and social interaction in female SZ patients (Rubin et al., 2011). Taken together, there are close relationships between sex hormones and cognitive function, maybe via the BDNF system. Thus, our finding a positive association between BDNF and immediate memory only in female patients may be related to high sex hormone levels, which can induce an increase of BDNF production and release. However, it is worthy noting that we did not find sex differences in the association between BDNF and cognition in our normal control group, which was somewhat younger, however. These sexually differential alterations in association between BDNF and cognition among SZ patients and normal controls may be related to different biological bases. At present, it is not clear why there was a significant difference in association between BDNF and cognition

143 between males and females only in patients, but not in controls, but age must be considered as important for showing such effects among normals based on the Komulainen study (2008). In summary, among patients with SZ, compared to females, males have more cognitive impairments than females in immediate memory and delayed memory, as well as lower BDNF serum levels. Moreover, we found that the associations between BDNF and some cognitive domains, especially immediate memory and RBANS total score were found only in female patients. No gender difference was observed in cognitive domains and BDNF levels, or in the association between BDNF and cognition in healthy controls. However, it is worthy of mentioning that the different gender composition in the patient group (75% male) and in the healthy control group (52% male) is considered a main limitation for our present study that aims to focus on gender differences, despite the appropriate management of the statistical analysis controlling for this variables. Therefore, the findings in our present study remain preliminary due to the imbalance in the gender composition in the patient and control groups, and not controlling for the menstrual cycle in the female patients. Furthermore, the cross-sectional design we used prevented asserting valid conclusions whether the gender difference for the relationship between BDNF and cognitive functions may exist through the results that female patients showed a positive correlation between BDNF and cognitive function. A future longitudinal study using the first-episode and drug naïve patients with SZ and directly exploring possible reasons why this gender imbalance occurred in the relationships between BDNF and cognitive function in our chronic SZ patients would help clarify this important issue.

Role of the funding sources Funding for this study was provided by grants from the National Natural Science Foundation of China (81371477), the Beijing Municipal Natural Science Foundation (7132063 and 7072035), the NARSAD Independent Investigator Grant (20314), and the Stanley Medical Research Institute (03T459 and 05T-726). These sources had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Conflict of interest None declared.

Acknowledgements The authors would like to thank Wu Fang Zhang, Song Chen, Bao Hua Zhang, and Gui Gang Yang for all of their hard work and significant contributions toward the study.

References Adlard, P.A., Perreau, V.M., Engesser-Cesar, C., Cotman, C.W., 2004. The timecourse of induction of brain-derived neurotrophic

144 factor mRNA and protein in the rat hippocampus following voluntary exercise. Neurosci. Lett. 363 (1), 43—48. Antonova, E., Sharma, T., Morris, R., Kumari, V., 2004. The relationship between brain structure and neurocognition in schizophrenia: a selective review. Schizophr. Res. 70 (2—3), 117—145. Asevedo, E., Gadelha, A., Noto, C., Mansur, R.B., Zugman, A., Belangero, S.I., Berberian, A.A., Scarpato, B.S., Leclerc, E., Teixeira, A.L., Gama, C.S., Bressan, R.A., Brietzke, E., 2013. Impact of peripheral levels of chemokines BDNF and oxidative markers on cognition in individuals with schizophrenia. J. Psychiatr. Res. 47 (10), 1376—1382. Beauchet, O., 2006. Testosterone and cognitive function: current clinical evidence of a relationship. Eur. J. Endocrinol. 155 (6), 773—781. Begliuomini, S., Casarosa, E., Pluchino, N., Lenzi, E., Centofanti, M., Freschi, L., Pieri, M., Genazzani, A.D., Luisi, S., Genazzani, A.R., 2007. Influence of endogenous and exogenous sex hormones on plasma brain-derived neurotrophic factor. Hum. Reprod. 22 (4), 995—1002. Brébion, G., David, A.S., Jones, H., Pilowsky, L.S., 2004. Semantic organization and verbal memory efficiency in patients with schizophrenia. Neuropsychology 18 (2), 378—383. Buckley, P.F., Pillai, A., Howell, K.R., 2011. Brain-derived neurotrophic factor: findings in schizophrenia. Curr. Opin. Psychiatry 24 (2), 122—127. Carlino, D., Leone, E., Di Cola, F., Baj, G., Marin, R., Dinelli, G., Tongiorgi, E., De Vanna, M., 2011. Low serum truncatedBDNF isoform correlates with higher cognitive impairment in schizophrenia. J. Psychiatr. Res. 45 (2), 273—279. Chen, D.C., Wang, J., Wang, B., Yang, S.C., Zhang, C.X., Zheng, Y.L., Li, Y.L., Wang, N., Yang, K.B., Xiu, M.H., Kosten, T.R., Zhang, X.Y., 2009. Decreased levels of serum brain-derived neurotrophic factor in drug-naïve first-episode schizophrenia: relationship to clinical phenotypes. Psychopharmacology (Berl.) 207 (3), 375—380. Ciammola, A., Sassone, J., Cannella, M., Calza, S., Poletti, B., Frati, L., Squitieri, F., Silani, V., 2007. Low brain-derived neurotrophic factor (BDNF) levels in serum of Huntington’s disease patients. Am. J. Med. Genet. B: Neuropsychiatr. Genet. 144B (4), 574—577. Condray, R., Yao, J.K., 2011. Cognition, dopamine and bioactive lipids in schizophrenia. Front. Biosci. 3, 298—330. Dickerson, F., Boronow, J.J., Stallings, C., Origoni, A.E., Cole, S.K., Yolken, R.H., 2004. Cognitive functioning in schizophrenia and bipolar disorder: comparison of performance on the Repeatable Battery for the Assessment of Neuropsychological Status. Psychiatry Res. 129 (1), 45—53. Diógenes, M.J., Costenla, A.R., Lopes, L.V., Jerónimo-Santos, A., Sousa, V.C., Fontinha, B.M., Ribeiro, J.A., Sebastião, A.M., 2011. Enhancement of LTP in aged rats is dependent on endogenous BDNF. Neuropsychopharmacology 36 (9), 1823—1836. Di Paolo, T., 1994. Modulation of brain dopamine transmission by sex steroids. Rev. Neurosci. 5, 27—41. Duff, K., Humphreys Clark, J.D., O’Bryant, S.E., Mold, J.W., Schiffer, R.B., Sutker, P.B., 2008. Utility of the RBANS in detecting cognitive impairment associated with Alzheimer’s disease: sensitivity, specificity, and positive and negative predictive powers. Arch. Clin. Neuropsychol. 23, 603—612. Egan, M.F., Kojima, M., Callicott, J.H., Goldberg, T.E., Kolachana, B.S., Bertolino, A., Zaitsev, E., Gold, B., Goldman, D., Dean, M., Lu, B., Weinberger, D.R., 2003. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112, 257—269. Favalli, G., Li, J., Belmonte-de-Abreu, P., Wong, A.H., Daskalakis, Z.J., 2012. The role of BDNF in the pathophysiology and treatment of schizophrenia. J. Psychiatr. Res. 46 (1), 1—11.

X.Y. Zhang et al. Fink, G., Sumner, B., Rosie, R., Wilson, H., McQueen, J., 1999. Androgen actions on central serotonin neurotransmission: relevance for mood, mental state and memory. Behav. Brain Res. 105, 53—68. Fiszdon, J.M., Silverstein, S.M., Buchwald, J., Hull, J.W., Smith, T.E., 2003. Verbal memory in schizophrenia: sex differences over repeated assessments. Schizophr. Res. 61 (2—3), 235—243. Frye, C.A., Rhodes, M.E., Dudek, B., 2005. Estradiol to aged female or male mice improves learning in inhibitory avoidance and water maze tasks. Brain Res. 1036 (1—2), 101—108. Goff, D.C., 2013. Future perspectives on the treatment of cognitive deficits and negative symptoms in schizophrenia. World Psychiatry 12 (2), 99—107. Goldberg, T.E., Gold, J.M., Torrey, E.F., Weinberger, D.R., 1995. Lack of sex differences in the neuropsychological performance of patients with schizophrenia. Am. J. Psychiatry 152 (6), 883—888. Goldstein, J.M., Seidman, L.J., Goodman, J.M., Koren, D., Lee, H., Weintraub, S., Tsuang, M.T., 1998. Are there sex differences in neuropsychological functions among patients with schizophrenia? Am. J. Psychiatry 155 (10), 1358—1364. Goldstein, J.M., Seidman, L.J., O’Brien, L.M., Horton, N.J., Kennedy, D.N., Makris, N., Caviness Jr., V.S., Faraone, S.V., Tsuang, M.T., 2002. Impact of normal sexual dimorphisms on sex differences in structural brain abnormalities in schizophrenia assessed by magnetic resonance imaging. Arch. Gen. Psychiatry 59 (2), 154—164. Green, M.J., Matheson, S.L., Shepherd, A., Weickert, C.S., Carr, V.J., 2011. Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis. Mol. Psychiatry 16 (9), 960—972. Grigoriadis, S., Seeman, M.V., 2002. The role of estrogen in schizophrenia: implications for schizophrenia practice guidelines for women. Can. J. Psychiatry 47, 437—442. Grillo, R.W., Ottoni, G.L., Leke, R., Souza, D.O., Portela, L.V., Lara, D.R., 2007. Reduced serum BDNF levels in schizophrenic patients on clozapine or typical antipsychotics. J. Psychiatr. Res. 41, 31—35. Gunstad, J., Benitez, A., Smith, J., Glickman, E., Spitznagel, M.B., Alexander, T., Juvancic-Heltzel, J., Murray, L., 2008. Serum brain-derived neurotrophic factor is associated with cognitive function in healthy older adults. J. Geriatr. Psychiatry Neurol. 21 (3), 166—170. Gur, R.C., Ragland, J.D., Moberg, P.J., Turner, T.H., Bilker, W.B., Kohler, C., Siegel, S.J., Gur, R.E., 2001. Computerized neurocognitive scanning: I. Methodology and validation in healthy people. Neuropsychopharmacology 25 (5), 766—776. Guzowski, J.F., Lyford, G.L., Stevenson, G.D., Houston, F.P., McGaugh, J.L., Worley, P.F., Barnes, C., 2000. Inhibition of activity-dependent arc protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long term memory. J. Neurosci. 20 (11), 3993—4001. Hafner, H., Behrens, S., De Vry, J., Gattaz, W.F., 1991. An animal model for the effects of estradiol on dopamine-mediated behavior: implications for sex differences in schizophrenia. Psychiatry Res. 38, 125—134. Häfner, H., 2003. Gender differences in schizophrenia. Psychoneuroendocrinology 28 (Suppl. 2), 17—54. Halari, R., Mehrotra, R., Sharma, T., Ng, V., Kumari, V., 2006. Cognitive impairment but preservation of sexual dimorphism in cognitive abilities in chronic schizophrenia. Psychiatry Res. 141 (2), 129—139. Hariri, A.R., Goldberg, T.E., Mattay, V.S., Kolachana, B.S., Callicott, J.H., Egan, M.F., Weinberger, D.R., 2003. Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J. Neurosci. 23 (17), 6690—6694.

Sex difference in cognition and BDNF Harvey, P.D., Green, M.F., Keefe, R.S., Velligan, D.I., 2004. Cognitive functioning in schizophrenia: a consensus statement on its role in the definition and evaluation of effective treatments for the illness. J. Clin. Psychiatry 65 (3), 361—372. Hoff, A.L., Wieneke, M., Faustman, W.O., Horon, R., Sakuma, M., Blankfeld, H., Espinoza, S., DeLisi, L.E., 1998. Sex differences in neuropsychological functioning of first-episode and chronically ill schizophrenic patients. Am. J. Psychiatry 155 (10), 1437—1439. Huang, T.L., Lee, C.T., 2006. Associations between serum brainderived neurotrophic factor levels and clinical phenotypes in schizophrenia patients. J. Psychiatr. Res. 10, 664—668. Ikeda, Y., Yahata, N., Ito, I., Nagano, M., Toyota, T., Yoshikawa, T., Okubo, Y., Suzuki, H., 2008. Low serum levels of brain-derived neurotrophic factor and epidermal growth factor in patients with chronic schizophrenia. Schizophr. Res. 101, 58—66. Janowsky, J.S., 2006. The role of androgens in cognition and brain aging in men. Neuroscience 138 (3), 1015—1020. Karakaya, S., Kipp, M., Beyer, C., 2007. Oestrogen regulates the expression and function of dopamine transporters in astrocytes of the nigrostriatal system. J. Neuroendocrinol. 19, 682—690. Kaur, P., Jodhka, P.K., Underwood, W.A., Bowles, C.A., de Fiebre, N.C., de Fiebre, C.M., Singh, M., 2007. Progesterone increases brain-derived neuroptrophic factor expression and protects against glutamate toxicity in a mitogen-activated protein kinaseand phosphoinositide-3 kinase-dependent manner in cerebral cortical explants. Neurosci. Res. 85 (11), 2441—2449. Komulainen, P., Pedersen, M., H¨ anninen, T., Bruunsgaard, H., Lakka, T.A., Kivipelto, M., Hassinen, M., Rauramaa, T.H., Pedersen, B.K., Rauramaa, R., 2008. BDNF is a novel marker of cognitive function in ageing women: the DR’s EXTRA Study. Neurobiol. Learn. Mem. 90 (4), 596—603. Korte, M., Griesbeck, O., Gravel, C., Carroll, P., Staiger, V., Thoenen, H., Bonhoeffer, T., 1996. Virus-mediated gene transfer into hippocampal CA1 region restores long-term potentiation in brain-derived neurotrophic factor mutant mice. Proc. Natl. Acad. Sci. U. S. A. 93 (22), 12547—12552. Lewine, R.R., Walker, E.F., Shurett, R., Caudle, J., Haden, C., 1996. Sex differences in neuropsychological functioning among schizophrenic patients. Am. J. Psychiatry 153 (9), 1178—1184. Lu, B., Gottschalk, W., 2000. Modulation of hippocampal synaptic transmission and plasticity by neurotrophins. Prog. Brain Res. 128, 231—241. Lu, B., Nagappan, G., Lu, Y., 2014. BDNF and synaptic plasticity, cognitive function, and dysfunction. Handb. Exp. Pharmacol. 220, 223—250. Lu, Y., Christian, K., Lu, B., 2008. BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory? Neurobiol. Learn. Mem. 89 (3), 312—323. McEwen, B.S., Woolley, C.S., 1994. Estradiol and progesterone regulate neuronal structure and synaptic connectivity in adult as well as developing brain. Exp. Gerontol. 29, 431—436. Nieto, R., Kukuljan, M., Silva, H., 2013. BDNF and schizophrenia: from neurodevelopment to neuronal plasticity, learning, and memory. Front. Psychiatry 4, 45. Niitsu, T., Shirayama, Y., Matsuzawa, D., Hasegawa, T., Kanahara, N., Hashimoto, T., Shiraishi, T., Shiina, A., Fukami, G., Fujisaki, M., Watanabe, H., Nakazato, M., Asano, M., Kimura, S., Hashimoto, K., Iyo, M., 2011. Associations of serum brainderived neurotrophic factor with cognitive impairments and negative symptoms in schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 35 (8), 1836—1840. Nurjono, M., Lee, J., Chong, S.A., 2012. A review of brain-derived neurotrophic factor as a candidate biomarker in schizophrenia. Clin. Psychopharmacol. Neurosci. 10 (2), 61—70. Palmer, B.W., Dawes, S.E., Heaton, R.K., 2009. What do we know about neuropsychological aspects of schizophrenia? Neuropsychol. Rev. 19 (3), 365—384.

145 Palomino, A.G., Pinto, A.A., Gomez, C., Mosquera, F., Garcia, G., 2006. Decreased levels of plasma BDNF levels in first-episode schizophrenia and bipolar disorder patients. Schizophr. Res. 86, 321—322. Pandya, C.D., Kutiyanawalla, A., Pillai, A., 2013. BDNF-TrkB signaling and neuroprotection in schizophrenia. Asian J. Psychiatry 6 (1), 22—28. Patterson, S.L., Abel, T., Deuel, T.A., Martin, K.C., Rose, J.C., Kandel, E.R., 1996. Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron 16 (6), 1137—1145. Pirildar, S., Gönül, A.S., Taneli, F., Akdeniz, F., 2004. Low serum levels of brain-derived neurotrophic factor in patients with schizophrenia do not elevate after antipsychotic treatment. Prog. Neuropsychopharmacol. Biol. Psychiatry 28, 709—713. Pillai, A., Kale, A., Joshi, S., Naphade, N., Raju, M.S., Nasrallah, H., Mahadik, S.P., 2010. Decreased BDNF levels in CSF of drugnaive first episode psychotic subjects: correlation with plasma BDNF and psychopathology. Int. J. Neuropsychopharmacol. 13 (4), 535—553. Pillai, A., Bruno, D., Sarreal, A.S., Hernando, R.T., Saint-Louis, L.A., Nierenberg, J., Ginsberg, S.D., Pomara, N., Mehta, P.D., Zetterberg, H., Blennow, K., Buckley, P.F., 2012. Plasma BDNF levels vary in relation to body weight in females. PLoS ONE 7 (7), e39358. Pillai, A., Buckley, P.F., 2012. Reliable biomarkers and predictors of schizophrenia and its treatment. Psychiatr. Clin. N. Am. 35 (3), 645—659. Poo, M.M., 2001. Neurotrophins as synaptic modulators. Nat. Rev. Neurosci. 2, 24—32. Randolph, C., Tierney, M.C., Mohr, E., Chase, T.N., 1998. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): preliminary clinical validity. J. Clin. Exp. Neuropsychol. 20, 310—319. Reis, H.J., Nicolato, R., Barbosa, I.G., Teixeira do Prado, P.H., Romano-Silva, M.A., Teixeira, A.L., 2008. Increased serum levels of brain derived neurotrophic factor in chronic institutionalized patients with schizophrenia. Neurosci. Lett. 439, 157—159. Riecher-Rössler, A., Häfner, H., 2000. Gender aspects in schizophrenia: bridging the border between social and biological psychiatry. Acta Psychiatr. Scand. 407 (Suppl.), 58—62. Rizos, E.N., Rontos, I., Laskos, E., Arsenis, G., Michalopoulou, P.G., Vasilopoulos, D., Gournellis, R., Lykouras, L., 2008. Investigation of serum BDNF levels in drug-naive patients with schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 32, 1308—1311. Rizos, E.N., Papadopoulou, A., Laskos, E., Michalopoulou, P.G., Kastania, A., Vasilopoulos, D., Katsafouros, K., Lykouras, L., 2010. Reduced serum BDNF levels in patients with chronic schizophrenic disorder in relapse, who were treated with typical or atypical antipsychotics. World J. Biol. Psychiatry 11, 251—255. Rubin, L.H., Haas, G.L., Keshavan, M.S., Sweeney, J.A., Maki, P.M., 2008. Sex difference in cognitive response to antipsychotic treatment in first episode schizophrenia. Neuropsychopharmacology 33, 290—297. Rubin, L.H., Carter, C.S., Drogos, L., Jamadar, R., PournajafiNazarloo, H., Sweeney, J.A., Maki, P.M., 2011. Sex-specific associations between peripheral oxytocin and emotion perception in schizophrenia. Schizophr. Res. 130 (1—3), 266—270. Scharfman, H.E., Maclusky, N.J., 2005. Similarities between actions of estrogen and BDNF in the hippocampus: coincidence or clue? Trends Neurosci. 28 (2), 79—85. Sharma, T., Antonova, L., 2003. Cognitive function in schizophrenia. Deficits, functional consequences, and future treatment. Psychiatr. Clin. N. Am. 26 (1), 25—40. Shimizu, E., Hashimoto, K., Watanabe, H., Komatsu, N., Okamura, N., Koike, K., Shinoda, N., Nakazato, M., Kumakiri, C., Okada, S., Iyo, M., 2003. Serum brain-derived neurotrophic

146 factor (BDNF) levels in schizophrenia are indistinguishable from controls. Neurosci. Lett. 351, 111—114. Sohrabji, F., Lewis, D.K., 2006. Estrogen-BDNF interactions: implications for neurodegenerative diseases. Front. Neuroendocrinol. 27 (4), 404—414. Sota, T.L., Heinrichs, R.W., 2003. Sex differences in verbal memory in schizophrenia patients treated with ‘‘typical’’ neuroleptics. Schizophr. Res. 62, 175—182. Tan, Y.L., Zhou, D.F., Cao, L.Y., Zou, Y.Z., Zhang, X.Y., 2005. Decreased BDNF in serum of patients with chronic schizophrenia on long term treatment with antipsychotics. Neurosci. Lett. 382, 27—32. Toyooka, K., Asama, K., Watanabea, Y., Muratakeb, T., Takahashib, M., Someyab, T., Nawaa, H., 2002. Decreased levels of brainderived neurotrophic factor in serum of chronic schizophrenic patients. Psychiatry Res. 110, 249—257. Tyler, W.J., Alonso, M., Bramham, C.R., Pozzo-Miller, L.D., 2002. From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn. Mem. 9 (5), 224—237. Vinogradov, S., Fisher, M., Holland, C., Shelly, W., Wolkowitz, O., Mellon, S.H., 2009. Is serum brain-derived neurotrophic factor a biomarker for cognitive enhancement in schizophrenia? Biol. Psychiatry 66 (6), 549—553.

X.Y. Zhang et al. Wisner, K.M., Elvevåg, B., Gold, J.M., Weinberger, D.R., Dickinson, D., 2011. A closer look at siblings of patients with schizophrenia: the association of depression history and sex with cognitive phenotypes. Schizophr. Res. 126 (1—3), 164—173. Xiu, M.H., Hui, L., Dang, Y.F., Hou, T.D., Zhang, C.X., Zheng, Y.L., da Chen, C., Kosten, T.R., Zhang, X.Y., 2009. Decreased serum BDNF levels in chronic institutionalized schizophrenia on longterm treatment with typical and atypical antipsychotics. Prog. Neuropsychopharmacol. Biol. Psychiatry 33 (8), 1508—1512. Yu, H., Zhang, Z., Shi, Y., Bai, F., Xie, C., Qian, Y., Yuan, Y., Deng, L., 2008. Association study of the decreased serum BDNF concentrations in amnestic mild cognitive impairment and the Val66Met polymorphism in Chinese Han. J. Clin. Psychiatry 69 (7), 1104—1111. Zhang, B.H., Tan, Y.L., Zhang, W.F., Wang, Z.R., Yang, G.G., Shi, C., Zhang, X.Y., Zhou, D.F., 2009. Repeatable battery for the assessment of neuropsychological status (RBANS) as a screening test in Chinese: reliability and validity. Chin. Ment. Health J. 28, 865—869. Zhang, X.Y., Chen da, C., Xiu, M.H., Haile, C.N., Luo, X., Xu, K., Zhang, H.P., Zuo, L., Zhang, Z., Zhang, X., Kosten, T.A., Kosten, T.R., 2012. Cognitive and serum BDNF correlates of BDNF Val66Met gene polymorphism in patients with schizophrenia and normal controls. Hum. Genet. 131 (7), 1187—1195.