Progress in Neuro-Psychopharmacology and Biological Psychiatry
The role of brain-derived neurotrophic factor (BDNF) gene variants in antipsychotic response and antipsychotic-induced weight gain
Highlights
►We analyzed markers across the Brain-derived neurotrophic factor gene. ►We examined antipsychotic response and antipsychotic-induced weight gain. ►We found markers and haplotypes including Val66Met associated with response. ►We found the Val66Met-rs1519480 G-A haplotype associated with weight gain.
Introduction
Schizophrenia is a complex, heterogeneous, and severe neuropsychiatric disorder, affecting approximately 1% of the general population. Twin and family studies have suggested a strong genetic component (McGue and Gottesman, 1991). Treatment of schizophrenia symptoms with antipsychotics has been marred by lack of efficacy and emergence of common side effects. One major side effect with the newer antipsychotic drugs is the occurrence of weight gain, which is probably induced in large parts by up-regulation of appetite circuits (Gebhardt et al., 2010, Kluge et al., 2007). While the underlying mechanisms of antipsychotic response and adverse effects have not yet been fully elucidated, genetic factors appear to play an important role in the variable outcome of these drugs (Arranz and de Leon, 2007, Lett et al., 2012, Muller and Kennedy, 2006, Strange, 2001, Vojvoda et al., 1996).
A growing number of epidemiological, genetic, and clinical neurobiological reports point to neurodevelopmental perturbations in the pathophysiology of schizophrenia (Arnold, 1999, Fatemi and Folsom, 2009). The brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin superfamily of survival-promoting molecules including neurotrophin-3/4/5, and nerve growth factor (NGF), which play an important role in cell survival, differentiation, and cell death (Jones and Reichardt, 1990). Members of this family play a vital role in promoting neuronal growth and maintenance during normal development and differentiation of the vertebrate central nervous system (CNS) (Hofer and Barde, 1988). Specifically, BDNF has trophic effects on neuronal plasticity (Duman, 2002) and learning (Tyler et al., 2002). Reports have shown reduced BDNF levels in drug-naïve first-episode schizophrenia patients (Jindal et al., 2010). Antipsychotics have been reported to increase BDNF levels in these patients and in neuroblastoma cells (Lee et al., 2010, Park et al., 2011a, Park et al., 2011b). These previous observations, together with the described developmental aspects of schizophrenia, make the BDNF gene a compelling candidate to help predict antipsychotic response.
There is also a growing evidence for a role of BDNF in appetite and weight regulation as well as in eating disorders, possibly via its interaction with the serotonin system. BDNF is expressed in brain regions including the hypothalamus, where its infusion in rats has been shown to increase serotonin turnover, and suppress appetite (Pelleymounter et al., 1995). Conversely, mice with only one copy of the BDNF gene displayed increased food intake and weight, with decreased serotonin metabolite to serotonin ratio (Lyons et al., 1999). Conditional ablation of the BDNF gene also leads to similar hyperphagic and obese phenotypes (Rios et al., 2001). In humans, the low-activity Met allele has been associated with higher body mass index (Beckers et al., 2008), and higher risk of eating disorder (Gratacos et al., 2007, Skledar et al., 2012). BDNF may also regulate weight and food intake via its regulation of the dopamine system (Geiger et al., 2009, Johnson and Kenny, 2010). It has important modulatory effects on the differentiation of dopaminergic neurons (Studer et al., 1995, Zhou et al., 1994) and plays a critical role in dopaminergic neuronal establishment (Baquet et al., 2005). It has also been demonstrated to specifically regulate the in vivo expression of the dopamine D3 receptor in the nucleus accumbens both during development and in adulthood (Guillin et al., 2001). D3 antagonism was shown to alter attentional bias to food cues in low-restrained obese or overweight individuals (Nathan et al., 2010). Taken together, previous research findings suggest that BDNF may be a key factor in the regulation of eating behavior upstream of dopamine and serotonin systems and BDNF gene variants may play a role in antipsychotic-induced weight gain.
The BDNF gene ([MIM 113505]) is located at 11p14 (Hanson et al., 1992). The single nucleotide polymorphism (SNP) Val66Met (G > A; rs6265) effects a valine-to-methionine substitution at amino acid position 66 of the pre-protein and has been demonstrated to impair protein packaging and activity-dependent BDNF secretion (Chen et al., 2004, Egan et al., 2003). More recently, this polymorphism has also been shown to disrupt dendritic targeting of the BDNF messenger RNA (Chiaruttini et al., 2009). Previously, three pharmacogenetic studies examined the BDNF gene variants in antipsychotic response. Firstly, an association was reported between the (GT)n repeat polymorphism and treatment response (responder: P = 0.01; refractory: P = 0.03) in schizophrenia patients (Krebs et al., 2000). Secondly, an association was found between the Val66Met polymorphism and clozapine response in schizophrenic patients, with the Val/Val genotype over-represented in the clozapine responder group (P = 0.023) (Hong et al., 2003). Thirdly, Anttila et al. reported no association with response to typical neuroleptics in schizophrenia patients (Anttila et al., 2005). Other polymorphisms in BDNF have not been thoroughly investigated in antipsychotic response.
In addition to reports suggesting a role of BDNF genetic variants in antipsychotic response, a study on Chinese inpatients found an association between the BDNF Val66Met (Met allele) genotypes and antipsychotic-induced weight gain in patients with chronic schizophrenia (P = 0.009), especially in the male subgroup (P = 0.004) (Zhang et al., 2008). A more recent study found another marker, rs11030101, but not Val66Met, to be associated with antipsychotic-induced weight gain in their Chinese inpatient sample (Tsai et al., 2011). To the best of our knowledge, the role of the BDNF gene in antipsychotic-induced weight gain has not been examined in patients of European ancestry.
In summary, previous studies have examined the Val66Met polymorphism of the BDNF gene in antipsychotic response and two studies have investigated Val66Met in antipsychotic-induced weight gain. Thus, we tested Val66Met and three additional single-nucleotide polymorphisms (SNPs) across the BDNF gene and examined the role of these genetic variations in these antipsychotic-related phenotypes in a larger and well characterized sample.
Section snippets
Clinical diagnostic criteria
In total, 257 subjects were included in this study. Diagnosis for SCZ was assessed by using the structured diagnostic interviews for DSM-IIIR and/or DSM-IV diagnoses (SCID-I, (American Psychiatric Association, 1994, First et al., 1996)), The SCID interview scoring, the medical records, and the clinical summary were reviewed by two well trained and experienced investigators. A best-estimate consensus diagnosis was reached after reviewing DSM-IIIR/IV criteria (Endicott, 2001). Another
Results
Table 2 presents the results from analyses of the response and weight gain phenotypes in patients of European ancestry. Genotype distributions did not deviate from Hardy–Weinberg Equilibrium for any of the four markers in our patients of European ancestry (P > 0.05). The effective number of independent markers tested in this study was determined to be 3, so the multiple-testing corrected p-value threshold for significance was determined to be 0.017. Our subgroups of 241 patients with response
Discussion
Our results suggest that BDNF genetic variants may play a role in predicting both antipsychotic response and antipsychotic induced weight gain. Our finding of Val/Val being associated with antipsychotic response is in agreement with previous findings (Hong et al., 2003). The observed associations of haplotypes across the BDNF gene suggest that additional BDNF gene variants may be involved. We also report here an association between BDNF haplotypes and antipsychotic-induced weight gain. While
Acknowledgments
CIHR operating grant to JLK (MOP 115097) and DJM (Genetics of antipsychotics induced metabolic syndrome, MOP 89853); NARSAD Young Investigator Award to DJM and AKT, CIHR Michael Smith New Investigator Salary Prize for Research in Schizophrenia to DJM, OMHF New Investigator Fellowship to DJM; fellowship funding from American Foundation for Suicide Prevention and Eli Lilly to CCZ. We are greatly indebted to the patients who agreed to participate.
Role of funding sources
This study is supported by
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