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Clinical and Research Reports   |    
BDNF val66met Polymorphism Is Associated With Age at Onset and Intensity of Symptoms of Paranoid Schizophrenia in a Polish Population
Renata Suchanek, Ph.D.; Aleksander Owczarek, Ph.D.; Monika Paul-Samojedny, Ph.D.; Małgorzata Kowalczyk, Ph.D.; Krzysztof Kucia, Ph.D.; Jan Kowalski, Prof.
The Journal of Neuropsychiatry and Clinical Neurosciences 2013;25:88-94. doi:10.1176/appi.neuropsych.11100234
View Author and Article Information

Dept. of Medical Genetics, Medical University of Silesia, Sosnowiec, Poland (RS, MPS, MK, JK); Division of Statistics, Dept. of Instrumental Analysis, Medical University of Silesia, Sosnowiec, Poland (AO); Dept. of Psychiatry and Psychotherapy, Medical University of Silesia, Katowice, Poland (KK).

Send correspondence to Renata Suchanek, Ph.D.; e-mail: rsuchanek@sum.edu.pl

Copyright © 2013 American Psychiatric Association

Received October 05, 2011; Revised December 17, 2011; Accepted May 26, 2012.

Abstract

The brain-derived neurotrophic factor (BDNF) is one of the candidate genes for schizophrenia. There is evidence that val66met polymorphism may be involved in the pathophysiology of schizophrenia. The authors genotyped val66met (rs6265) polymorphism of the BDNF gene in 208 inpatients with paranoid schizophrenia and 254 control subjects in a Polish population. There was no association between val66met polymorphism and development of paranoid schizophrenia in either men or women. However, an association was found between this polymorphism and age at onset and psychopathology of paranoid schizophrenia. Men with the val/met genotype had an earlier age at onset, and the val/val genotype predisposed to more severe symptoms, particularly on the General Psychopathology Scale of the Positive and Negative Symptoms Scale (PANSS-G). The analysis of PANSS single items has shown that patients with the val/met genotype had higher scores on a hallucinatory behavior item than those with other genotypes.

Abstract Teaser
Figures in this Article

Schizophrenia is a disabling mental disorder, occurring relatively early in life, and it carries an increased risk of suicide. The etiology of schizophrenia still remains undetermined. It is well known that both environmental and genetic factors are involved in the development of disease. The participation of genes is significant and is estimated to be approximately 80%.1

Brain-derived neurotrophic factor (BDNF) regulates neuronal function by promoting survival of neurons and enhancing synaptic plasticity via TrkB receptors.2 On the basis of the neurodevelopmental hypothesis, the BDNF gene is a good candidate locus for schizophrenia. Several reports have found alterations of BDNF protein levels in the cortical area and hippocampus of schizophrenic patients.3 Moreover, the first episode of schizophrenia is accompanied by a significant reduction in BDNF serum level.4

The val66met (rs6265) is a functional polymorphism in the coding sequence of the BDNF gene. It has been shown that the met allele affects intracellular trafficking and activity-dependent secretion of BDNF.5,6 There are still some discrepancies among the results of association studies between schizophrenia and BDNF val66met polymorphism in Caucasian populations.79 Despite the fact that schizophrenia is a heterogeneous mental disease characterized by a number of symptoms, surprisingly, there are no papers focusing on a single subtype of schizophrenia.

The present study concentrates on the paranoid subtype of schizophrenia. First, we aimed to determine whether val66met polymorphism of the BDNF gene is a risk factor for the development of this subtype schizophrenia in a Caucasian population. Second, we examined whether val66met polymorphism is associated with age at onset and psychopathology of paranoid schizophrenia. Also, we assessed the associations taking into account gender of patients.

The patient group consisted of 208 unrelated inpatients (91 women [44%] and 117 men [56%], mean age: 42.3 [SD: 12.7] years) with diagnosis of paranoid schizophrenia according to DMS-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision) criteria. The patients were recruited from inpatients being treated at the Department and Clinic of Psychiatry, Medical University of Silesia in Katowice, and the Psychiatric Hospital in Lubliniec. They were consecutive patients. Psychopathology at the time of admittance was monitored by the structured interview for the Positive and Negative Symptom Scale (PANSS). The diagnosis was assigned by two independent psychiatrists and based on the Structured Clinical Interview for DSM-IV Axis I Disorders–Clinician Version.10 Only the cases meeting diagnostic consensus were included. Patients with diagnosed endocrine disorders, neurological illness, autoimmune diseases, and other Axis I and Axis II diagnosis were excluded from observation. Age at onset of schizophrenia has been identified as the time of the first appearance of positive psychotic symptoms. There was a statistically significant difference in mean age between women and men (46.7 [12.3] versus 38.8 [12.0]; p <0.001).

The control group consisted of 254 unrelated subjects: (98 women [39%] and 156 men [61%], mean age: 41.4 [9.4]) recruited among volunteer blood donors. There was no statistically significant difference in mean age between women (41.6 [9.3]) and men (41.2 [9.5]; NS). There were no statistically significant differences in mean age between patients and controls. The study was approved by the Bioethics Committee of Medical University of Silesia.

Genomic DNA was isolated from peripheral blood samples by phenol-chloroform extraction. The val66met polymorphism of the BDNF gene was determined by the use of the polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) method. An amplification of the region containing the studied single nucleotide polymorphism (SNP) was achieved using the nested PCR strategy. Amplification reactions in the first- and second-step PCR were performed in 25 µl of reaction mixture containing 0.25 mM dNTP, 2.5 µl DreamTaq buffer 10×, 1.25U DreamTaqDNA polymerase (Feremetas), and 0.4 mM specific primers. In the first-step PCR, 300 ng DNA and external primers were used. Cycling parameters were the following: 95°C for 3 min.; 40 cycles at 95°C for 45 sec., 53°C for 35 sec., 72°C for 45 sec., and final elongation at 72°C for 10 min. A 2-µl aliquot of the amplified PCR product was transferred to the new mixture containing internal primers. Cycling parameters of the second-step PCR were: 95°C for 2 min., 35 cycles at 95°C for 35 sec., 51°C for 30 sec., 72°C for 25 sec., and final elongation at 72°C for 10 min. The PCR primers used for amplifications were the following: external [sense 5′-CCCCATGAAAGAAGCAAACA-3′; antisense 5′-TTTGTCTGCTGCCGTTACC-3′; amplicon length 403 bp]; internal (sense 5′-GGACTCTGGAGAGCGTGAATG-3′, antisense 5′-GAGAAGAGGAGGCTCCAAAGG-3′; amplicon length 200 bp]. Internal primers were designed for reference sequence AC087446, Version AC087446.13 (NCBI base). Amplification was performed using G-Storm GS1 thermal cycler (Gene Technologies, LTD, Essex, UK). PCR products were analyzed by agarose electrophoresis in 2% agarose gel stained with ethidium bromide.

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RFLP Analysis

The BDNF val66met genotypes were determined with RFLP analysis. The PCR product was digested with NlaIII (Fermentas). Products of digestion were separated and analyzed in 3% agarose gel stained with ethidium bromide. For the met allele, 123-bp and 77-bp fragments, and, for the val allele, 200-bp (undigested) fragment were observed.

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Statistical Analysis

Descriptive variables are presented as mean (standard deviation [SD]. The distribution of alleles and genotypes frequencies between control and patient groups were compared either by the χ2 test, the maximum-likelihood χ2 test, or Fisher’s exact test. Two-way ANOVA with interaction was used for comparisons of PANSS subscales and age at onset of schizophrenia between groups. The Student t-test was used to compare PANSS items between patients with different genotypes and age of patients and controls. The variables’ distributions were evaluated by the Shapiro-Wilk test. Homogeneity of variance was assessed by the Hartley test. Statistical calculations were performed with Statistica software, Version 8.0 (www.statsoft.com). All p values were two-tailed, and statistical significance was established at p <0.05.

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Case–Control Study

Table 1 shows the genotype and allele distributions of val66met polymorphism of the BDNF gene for patients with paranoid schizophrenia and control subjects. In both groups, the met/met genotype was not detected. There were no statistically significant differences in the incidence of genotypes and alleles between patients and controls. Similarly, the analyses when men and women were analyzed separately have not shown statistically significant differences in genotype and allele layout between patients and controls (Table 1).

 
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TABLE 1.Genotype and Alleles Frequencies of val66met Polymorphism in the BDNF Gene Among Patient and Control Groups
Table Footer Note

BDNF: brain-derived neurotrophic factor.

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Age at Onset and PANSS Subscales

ANOVA results have shown a statistically significant difference in age at onset between sexes (F=17.14; p <0.001). Men generally had a first episode of paranoid schizophrenia earlier (24.1 [5.5]) than women (27.8 [7.7]). The multiple-comparison test indicated that the first episode of paranoid schizophrenia appeared an average of 6.2 years earlier in men with the val/met genotype than in women with the val/met genotype (p <0.01), and also an average of 2.8 years earlier in men with the val/val genotype than in women with the val/val genotype (p <0.05).

PANSS is composed of 7 positive-symptoms items, 7 negative-symptoms items, and 16 general psychopathology symptom items. Each of these 30 items is scored with the same 7-point severity scale. The sum of these three subscales (Positive, Negative, General) comprises the Total score.

PANSS subscale analyses have shown a significant influence of sex and a tendency toward the influence of genotype on symptom intensity. For the P (positive) scale, a post-hoc test has revealed a statistically significant difference for the val/met genotype (p <0.05) and a tendency to statistical significance for the val/val genotype (p=0.074) between women and men. The val/met women had the lowest mean values for the P scale (p <0.05). For the G (general) scale, a post-hoc test has shown that the val/val men had higher mean scores than the val/met men (p <0.01), the val/met women (p <0.05), and the val/val women (p <0.01). There was no statistically significant difference for mean scores on the G scale between women with the val/val and val/met genotypes, respectively. The total score of the PANSS scale was also higher for the val/val men, as compared with the val/val women (p <0.05). There were no significant differences in sex × genotype interaction for any PANSS subscales (Table 2).

 
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TABLE 2.Two-Way ANOVA (Sex, Genotype) Results for Positive and Negative Symptom Scale (PANSS) Subscales and PANSS Total Scale
Table Footer Note

Values represent mean scores of PANSS points (standard deviation); P: positive symptoms; N: negative symptoms; G: general psychopathology; F: female; M: male.

Table Footer Note

aMain effect of sex.

Table Footer Note

bMain effect of genotype.

Table Footer Note

cSex × genotype interaction.

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PANSS Single Items and Suicidal Behavior

We have also estimated all 30 items of the PANSS according to patients’ genotypes. The analyses have revealed statistically significant differences for the following items: P3 (hallucinatory behavior), N4 (passive/apathetic social withdrawal), G1 (somatic concern), and a tendency toward statistical difference for G3 (guilt feelings) and G15 (preoccupation). Patients with the val/val genotype had higher mean scores for these items than patients with the val/met genotype, except for the P3 item (hallucinatory behavior), in which values were inverse (P3: –4.4 [0.85] versus 4.6 [0.75], p <0.05; N4: –3.7 [0.97] versus 3.1 [0.91], p <0.001; G1: –2.1 [1.16] versus 1.7 [0.78], p <0.01; G3: –1.8 [0.95] versus 1.5 [0.81], p=0.06; G15: −3.5 [0.99] versus 3.2 [1.07], p=0.08; respectively; Figure 1).

 
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FIGURE 1.Analysis of Positive and Negative Symptom Scale (PANSS) Items Between Patients With val/val and val/met Genotypes

P1: delusions; P2: conceptual disorganization; P3: hallucinatory behavior; P4: excitement, P5: grandiosity; P6: suspiciousness/persecution; P7: hostility; N1: blunted affect, N2: emotional withdrawal; N3: poor rapport; N4: passive/apathetic social withdrawal; N5: difficulty in abstract thinking; N6: lack of spontaneity and flow of conversation; N7: stereotyped thinking; G1: somatic concern; G2: anxiety; G3: guilt feelings; G4: tension; G5: mannerisms and posturing; G6: depression; G7: motor retardation; G8: uncooperativeness; G9: unusual thought content; G10: disorientation; G11: poor attention; G12: lack of judgment and insight; G13: disturbance of volition; G14: poor impulse control; G15: preoccupation; G16: active social avoidance.

Among 208 patients, 34 (16%) had attempted suicide. There was no statistically significant difference between those patients according to genotype (val/val: 17.0% and val/met: 14.5%; χ2=0.18; NS).

In the present study, we analyzed the val66met polymorphism of the BDNF gene in a Caucasian (Polish) population. Our research was focused on a homogeneous patient group, suffering from the paranoid schizophrenia subtype. Schizophrenia patients with coexisting depressive episodes and schizoaffective disorders were excluded. Our case–control study has not shown an association between val66met polymorphism and paranoid schizophrenia occurrence in either men or women. Numerous case–control studies and metaanalyses conducted in Asian populations have also failed to find an association between BDNF val66met polymorphism and schizophrenia.9,11,12 On the other hand, studies in Caucasians are still ambiguous. In agreement with our results, most of the case–control studies have not revealed an association between the val66met polymorphism and incidence of schizophrenia.7,1315 However, Neves-Pereira et al.8 pointed to a schizophrenia association in the val allele. Discrepancies in the results of meta-analyses are observed, as well. Jönsson et al.14 have revealed an association of homozygous states; Gratacòs et al.16 have found that the met/met genotype is a risk factor for development of schizophrenia, but Xu et al.9 have not found any association.

Some previous studies pointed at a potential connection between the BDNF gene and schizophrenia symptoms. BDNF is an important trophic factor for dopaminergic,17 GABAergic,3,18 serotoninergic, cholinergic, or noradrenergic neurons,19 which are known to be dysregulated in schizophrenia. Alterations of GABA or dopamine neurotransmission may contribute to psychopathological symptoms of schizophrenia.20,21 The PANSS scale is the most widely used to measure severity of symptoms in schizophrenia. The current research has revealed an association between BDNF val66met polymorphism and the PANSS scale. It has been shown that male patients with the val/val genotype have a worse clinical course of disease. Our results are in line with the study performed on a large group of Russians, showing a severe clinical course of schizophrenia in men with the val/val genotype.13 Similar to our findings, Chang et al.22 have found higher mean scores for the G scale and Total PANSS scales in patients with the val/val genotype, as compared with patients with other genotypes, although, in contrast to our results, they have also observed higher mean scores for the N scale and no differences on the P scale between genotypes. Spalletta et al.23 have not shown differences between genotypes and the PANSS scale in schizophrenia outpatients. However, an analysis of the Modified Overt Aggression Scale (MOAS) revealed an association between the met allele and aggressive behavior, especially verbal aggression. It is noteworthy that the family-based study showed a preferential transmission of val allele from heterozygous healthy parents to affected by schizophrenia offspring.24

Our analysis of the association between BDNF genotype and time of the first episode of schizophrenia has revealed that men with the val/met genotype had an earlier age at onset then women with the same genotype. It is in agreement with previous findings, which also showed an earlier age at onset for met allele carriers (those who display met/met or met/val genotypes).25,26 On the other hand, some studies have not confirmed such differences.7,27

Discrepancies between our results and those of other studies can result from the fact that we assessed only patients with the paranoid subtype of schizophrenia. Studies discussed above encompassed different subtypes of schizophrenia,2225 and included patients suffering from schizoaffective disorder.27 It is possible that participation of the BDNF gene may vary in distinct subtypes. It is worth mentioning that serum BDNF protein level is different in the course of various subtypes of schizophrenia.28 It is also possible that single-nucleotide polymorphisms (SNPs) in the BDNF gene affect only some of symptoms of schizophrenia. Schumacher et al.15 revealed differences in the frequency of haplotypes for the set of SNPs in the BDNF gene (also including the val66met SNP) between schizophrenic patients with and without coexisting depressive episodes. Interestingly, haplotypes overrepresented in schizophrenic patients with coexisting episodes of depression were also more frequent in depressed patients.15 Golimbet et al13 have found that the val/val genotype was more frequent in men with continuous schizophrenia than in men with episodic schizophrenia.

We also conducted an evaluation of the val66met polymorphism in relation to PANSS single-item scores. As far as we know, this is the first work in which such analysis has been performed. We have noted that patients with the val/val genotype scored higher on the following items: passive/apathetic social withdrawal, somatic concern, guilt feelings, and preoccupation. However, hallucinatory behavior was connected with the val/met genotype.

Some authors have suggested the possibility that BDNF participates in the pathophysiology of suicidal behavior. Both the mRNA and protein levels of BDNF and its receptor TrkB have been significantly decreased in the brain of suicide subjects.29 The alterations in epigenetic modifications of the BDNF gene have been revealed in suicidal behavior. DNA methylation levels at the BDNF promoter were increased in suicide subjects. Moreover, this hypermethylation was connected with a lower amount of BDNF transcript IV.30 Unfortunately, we have not found any association between the BDNF val66met genotypes and suicide attempts; this may be due to the small number of subjects. Other researchers have shown that the val/met and the met/met genotypes could be a risk factor for a suicide in women, but not in men. Moreover, these genotypes were frequently found in female suicide victims who used violent methods of suicide and in victims exposed to childhood trauma.31 The val/met and met/met variants were also found to increase the risk of suicidal behavior among depressed patients.32

Summarizing, in this report we have conducted an analysis of BDNF val66met functional polymorphism in a homogeneous group of patients with the paranoid subtype of schizophrenia and without coexisting depressive episodes or schizoaffective disorders. There was no association between the BDNF val66met polymorphism and schizophrenia occurrence, but an association was found with regard to the clinical course of disease. In men, but not in women, the val/met genotype was connected with earlier age at onset, whereas val/val genotype was associated with more severe symptoms, particularly general symptoms (PANSS-G scale). However, PANSS single-item score analysis has shown that hallucinatory behavior was more intense among the val/met patients. The main limitation of our study is its relatively small sample size. Therefore, larger studies should be performed to confirm these findings.

We thank Pawel Raif, Ph.D. Eng., from Silesian University of Technology, for help in interpreting the statistical analyses.

Craddock  N;  O’Donovan  MC;  Owen  MJ:  The genetics of schizophrenia and bipolar disorder: dissecting psychosis.  J Med Genet 2005; 42:193–204
[CrossRef] | [PubMed]
 
Chao  MV;  Rajagopal  R;  Lee  FS:  Neurotrophin signalling in health and disease.  Clin Sci (Lond) 2006; 110:167–173
[CrossRef] | [PubMed]
 
Hashimoto  T;  Bergen  SE;  Nguye  QL  et al:  Relationship of brain-derived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia.  J Neurosci 2005; 25:372–383
[CrossRef] | [PubMed]
 
Chen  C;  Wang  J;  Wang  B  et al:  Decreased levels of serum brain-derived neurotrophic factor in drug-naïve first-episode schizophrenia: relationship to clinical phenotypes.  Psychopharmacology (Berl) 2009; 207:375–380
[CrossRef] | [PubMed]
 
Egan  MF;  Kojima  M;  Callicott  JH  et al:  The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function.  Cell 2003; 112:257–269
[CrossRef] | [PubMed]
 
Chen  ZY;  Patel  PD;  Sant  G  et al:  Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons.  J Neurosci 2004; 24:4401–4411
[CrossRef] | [PubMed]
 
Skibinska  M;  Hauser  J;  Czerski  PM  et al:  Association analysis of brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism in schizophrenia and bipolar affective disorder.  World J Biol Psychiatry 2004; 5:215–220
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Neves-Pereira  M;  Cheung  JK;  Pasdar  A  et al:  BDNF gene is a risk factor for schizophrenia in a Scottish population.  Mol Psychiatry 2005; 10:208–212
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Xu  MQ;  St Clair  D;  Ott  J  et al:  Brain-derived neurotrophic factor gene C-270T and Val66Met functional polymorphisms and risk of schizophrenia: a moderate-scale population-based study and meta-analysis.  Schizophr Res 2007; 91:6–13
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Tochigi  M;  Otowa  T;  Suga  M  et al:  No evidence for an association between the BDNF Val66Met polymorphism and schizophrenia or personality traits.  Schizophr Res 2006; 87:45–47
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Naoe  Y;  Shinkai  T;  Hori  H  et al:  No association between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and schizophrenia in Asian populations: evidence from a case–control study and meta-analysis.  Neurosci Lett 2007; 415:108–112
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Golimbet  VE;  Korovaĭtseva  GI;  Abramova  LI  et al:  [Association between the Val66Met polymorphism of brain-derived neurotrophic factor gene and schizophrenia in Russians].  Mol Biol (Moscow) 2008; 42:599–603
 
Jönsson  EG;  Edman-Ahlbom  B;  Sillén  A  et al:  Brain-derived neurotrophic factor gene (BDNF) variants and schizophrenia: an association study.  Prog Neuropsychopharmacol Biol Psychiatry 2006; 30:924–933
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References Container

FIGURE 1. Analysis of Positive and Negative Symptom Scale (PANSS) Items Between Patients With val/val and val/met Genotypes

P1: delusions; P2: conceptual disorganization; P3: hallucinatory behavior; P4: excitement, P5: grandiosity; P6: suspiciousness/persecution; P7: hostility; N1: blunted affect, N2: emotional withdrawal; N3: poor rapport; N4: passive/apathetic social withdrawal; N5: difficulty in abstract thinking; N6: lack of spontaneity and flow of conversation; N7: stereotyped thinking; G1: somatic concern; G2: anxiety; G3: guilt feelings; G4: tension; G5: mannerisms and posturing; G6: depression; G7: motor retardation; G8: uncooperativeness; G9: unusual thought content; G10: disorientation; G11: poor attention; G12: lack of judgment and insight; G13: disturbance of volition; G14: poor impulse control; G15: preoccupation; G16: active social avoidance.

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TABLE 1.Genotype and Alleles Frequencies of val66met Polymorphism in the BDNF Gene Among Patient and Control Groups
Table Footer Note

BDNF: brain-derived neurotrophic factor.

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TABLE 2.Two-Way ANOVA (Sex, Genotype) Results for Positive and Negative Symptom Scale (PANSS) Subscales and PANSS Total Scale
Table Footer Note

Values represent mean scores of PANSS points (standard deviation); P: positive symptoms; N: negative symptoms; G: general psychopathology; F: female; M: male.

Table Footer Note

aMain effect of sex.

Table Footer Note

bMain effect of genotype.

Table Footer Note

cSex × genotype interaction.

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References

Craddock  N;  O’Donovan  MC;  Owen  MJ:  The genetics of schizophrenia and bipolar disorder: dissecting psychosis.  J Med Genet 2005; 42:193–204
[CrossRef] | [PubMed]
 
Chao  MV;  Rajagopal  R;  Lee  FS:  Neurotrophin signalling in health and disease.  Clin Sci (Lond) 2006; 110:167–173
[CrossRef] | [PubMed]
 
Hashimoto  T;  Bergen  SE;  Nguye  QL  et al:  Relationship of brain-derived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia.  J Neurosci 2005; 25:372–383
[CrossRef] | [PubMed]
 
Chen  C;  Wang  J;  Wang  B  et al:  Decreased levels of serum brain-derived neurotrophic factor in drug-naïve first-episode schizophrenia: relationship to clinical phenotypes.  Psychopharmacology (Berl) 2009; 207:375–380
[CrossRef] | [PubMed]
 
Egan  MF;  Kojima  M;  Callicott  JH  et al:  The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function.  Cell 2003; 112:257–269
[CrossRef] | [PubMed]
 
Chen  ZY;  Patel  PD;  Sant  G  et al:  Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons.  J Neurosci 2004; 24:4401–4411
[CrossRef] | [PubMed]
 
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