Genetic variation in BDNF is associated with antipsychotic treatment resistance in patients with schizophrenia

Zhang, Jian-Ping; Lencz, Todd; Geisler, Stephan; DeRosse, Pamela; Bromet, Evelyn J.; Malhotra, Anil K.

doi:10.1016/j.schres.2013.01.020

Cited by 58 publications

(47 citation statements)

References 25 publications

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“…TrkB and Src promoted the activity of PLC c 1, via mutual regulation, and mediated the glutamate release from cortical neurons induced by BDNF. Although Erk1/2 and Akt participated in the signal transmission of BDNF/TrkB, they did not participate in the BDNF/TrkB/Src/PLCc1-regulated glutamate release from cortical neurons [64]. This may be one of the reasons for the increase in glutamate receptor level even though there is a decrease in BDNF during PCBs treatment.…”

Section: Discussionmentioning

confidence: 89%

Effect of Melatonin on Glutamate: BDNF Signaling in the Cerebral Cortex of Polychlorinated Biphenyls (PCBs)—Exposed Adult Male Rats

et al. 2015

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Various epidemiological survey suggests that the central nervous system is the target for many environmental contaminants. One among them is Aroclor 1254, a mixture of polychlorinated biphenyls (PCBs) which explore a spectrum of biochemical and neurotoxic responses in humans and laboratory animals. Learning and motor coordination deficits are the profound effects of PCBs which may be related to cerebral dysfunction. The aim of the study is to elicit the protective effect of melatonin (Mel), a potent, blood brain permeable antioxidant against the effect of Aroclor 1254 on the signaling of glutamate-principal excitatory neurotransmitter and brain derived neurotrophic factor (BDNF) in the cerebral cortex of adult rats which plays a key role in brain functions. Adult male Wistar rats were grouped into four and treated intraperitonealy (i.p) Group I with corn oil (Control), Group II with PCBs (2 mg/kg/bwt), Group III with PCBs + Mel (2 mg/kg/bwt + 5 mg/kg/bwt) and Group IV with Mel (5 mg/kg/bwt). The protein expression of glutamate signaling molecules and mRNA expressions of GLAST, BDNF signaling molecules were analyzed. The results suggest that simultaneous melatonin treatment significantly attenuated the NMDA receptor mediated glutamate excitotoxicity and protects the inhibition of BDNF signaling caused by PCBs exposure in cerebral cortex of adult male rats. Schematic pathway illustrating the proposed mechanism by which melatonin protects against A1254 mediated glutamate induced neurodegeneration in the cerebral cortex of adult male rats. PCBs induced neurodegeneration is caused by the overactivation of NMDAR, followed by the activation of voltage dependent calcium channels leading to the increase in intracellular Ca(2+) that stimulates calpain. Calpain inturn inhibits the PKA α and neurtrophin BDNF, its receptor and downstream signaling MAPK pathway leading to neurodegeneration. Melatonin had scavenged the ROS produced by PCBS and decreased the NMDAR expression which inturn protected the cells from neurodegeneration.

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Section: Discussionmentioning

confidence: 89%

Effect of Melatonin on Glutamate: BDNF Signaling in the Cerebral Cortex of Polychlorinated Biphenyls (PCBs)—Exposed Adult Male Rats

et al. 2015

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“…However, this study included only Asian subjects with schizophrenia, which does not allow for a simple comparison with the results in Caucasian populations in our meta-analysis. On the other hand, Met/Met genotype has been associated with antipsychotic treatment resistance (Zhang et al, 2013). Since TD has been associated with treatment refractory schizophrenia (Ascher-Svanum et al, 2008), this finding is consistent with our results of a significant association between the Met genotype and TD severity in Caucasians.…”

Section: Discussionmentioning

confidence: 99%

BDNF Val66Met polymorphism and antipsychotic-induced tardive dyskinesia occurrence and severity: A meta-analysis

Miura

Zhang

Nitta

et al. 2014

Schizophrenia Research

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Background Tardive dyskinesia (TD) is a serious long-term consequence of antipsychotic treatment. Since brain-derived neurotrophic factor (BDNF) has potent neurotrophic activity, genetic alterations in the BDNF gene may affect antipsychotic-induced TD. Methods Searching PubMed and Web of Science until 05/31/13, we conducted a systematic review and a meta-analysis of the effects of BDNF Val66Met polymorphism on antipsychotic-induced TD. Pooled odds ratio was calculated to assess the effects of BDNF Val66Met polymorphism on TD occurrence. Additionally, pooled standardized mean differences (Hedges' g) were calculated to assess the effects on Abnormal Involuntary Movement Scale (AIMS) total score. Results Out of 699 potentially eligible hits, 6 studies (N = 1740, mean age = 46.0 ± 10.4 years; males = 73.1%; Asians = 80.5%, Caucasians = 19.5%; schizophrenia = 96.2%) were included in this meta-analysis. Pooling data from all studies, no significant associations were found between BDNF Val66Met polymorphism and TD (p = 0.82) or AIMS total scores (p = 0.11). However, in studies including only Caucasians (n = 339), Met allele carriers had significantly higher AIMS total scores (Hedges' g = 0.253, 95% confidence interval = 0.030 to 0.476, p = 0.026) and non-significantly higher TD occurrence (p = 0.127). Conversely, there was no association between BDNF and AIMS scores (p = 0.57) or TD (p=0.65) in Asians. Conclusion Although there was no significant association between BDNF Val66Met polymorphism and TD or AIMS scores across all patients, our results suggest that BDNF Val66Met polymorphism affects severity and, possibly, TD development in Caucasians. Since the number of studies and patients was still small, additional data are needed to confirm genotype-racial interactions. Furthermore, BDNF enhancing treatments for TD may require further study, especially in Caucasians.

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“…18 In large population-based genetic studies of schizophrenia, ascertainment of such high-dimensional clinical data has proven difficult. Despite its proven efficacy, 19 clozapine is usually reserved as a second-line or third-line therapy in schizophrenia because of side-effects. However, it is the only approved medication for treatment-resistant schizophrenia and as a result, a history of having been prescribed clozapine has been used as a proxy for treatment resistance.…”

Section: Methodsmentioning

confidence: 99%

Polygenic overlap between schizophrenia risk and antipsychotic response: a genomic medicine approach

Ruderfer¹,

Charney²,

Readhead

et al. 2016

The Lancet Psychiatry

117

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Summary Background Therapeutic treatments for schizophrenia do not alleviate symptoms for all patients and efficacy is limited by common, often severe, side-effects. Genetic studies of disease can identify novel drug targets, and drugs for which the mechanism has direct genetic support have increased likelihood of clinical success. Large-scale genetic studies of schizophrenia have increased the number of genes and gene sets associated with risk. We aimed to examine the overlap between schizophrenia risk loci and gene targets of a comprehensive set of medications to potentially inform and improve treatment of schizophrenia. Methods We defined schizophrenia risk loci as genomic regions reaching genome-wide significance in the latest Psychiatric Genomics Consortium schizophrenia genome-wide association study (GWAS) of 36 989 cases and 113 075 controls and loss of function variants observed only once among 5079 individuals in an exome-sequencing study of 2536 schizophrenia cases and 2543 controls (Swedish Schizophrenia Study). Using two large and orthogonally created databases, we collated drug targets into 167 gene sets targeted by pharmacologically similar drugs and examined enrichment of schizophrenia risk loci in these sets. We further linked the exome-sequenced data with a national drug registry (the Swedish Prescribed Drug Register) to assess the contribution of rare variants to treatment response, using clozapine prescription as a proxy for treatment resistance. Findings We combined results from testing rare and common variation and, after correction for multiple testing, two gene sets were associated with schizophrenia risk: agents against amoebiasis and other protozoal diseases (106 genes, p=0·00046, pcorrected =0·024) and antipsychotics (347 genes, p=0·00078, pcorrected=0·046). Further analysis pointed to antipsychotics as having independent enrichment after removing genes that overlapped these two target sets. We noted significant enrichment both in known targets of antipsychotics (70 genes, p=0·0078) and novel predicted targets (277 genes, p=0·019). Patients with treatment-resistant schizophrenia had an excess of rare disruptive variants in gene targets of antipsychotics (347 genes, p=0·0067) and in genes with evidence for a role in antipsychotic efficacy (91 genes, p=0·0029). Interpretation Our results support genetic overlap between schizophrenia pathogenesis and antipsychotic mechanism of action. This finding is consistent with treatment efficacy being polygenic and suggests that single-target therapeutics might be insufficient. We provide evidence of a role for rare functional variants in antipsychotic treatment response, pointing to a subset of patients where their genetic information could inform treatment. Finally, we present a novel framework for identifying treatments from genetic data and improving our understanding of therapeutic mechanism.

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Genetic variation in BDNF is associated with antipsychotic treatment resistance in patients with schizophrenia

Cited by 58 publications

References 25 publications

Effect of Melatonin on Glutamate: BDNF Signaling in the Cerebral Cortex of Polychlorinated Biphenyls (PCBs)—Exposed Adult Male Rats

Effect of Melatonin on Glutamate: BDNF Signaling in the Cerebral Cortex of Polychlorinated Biphenyls (PCBs)—Exposed Adult Male Rats

BDNF Val66Met polymorphism and antipsychotic-induced tardive dyskinesia occurrence and severity: A meta-analysis

Polygenic overlap between schizophrenia risk and antipsychotic response: a genomic medicine approach

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