A Brain-Derived Neurotrophic Factor Haplotype Is Associated with Therapeutic Response in Obsessive-Compulsive Disorder

OCD Clinical and Research Unit, Instituto de Salud Carlos III, Department of Psychiatry, Bellvitge University Hospital, Barcelona, Spain.
Biological psychiatry (Impact Factor: 10.26). 08/2009; 66(7):674-80. DOI: 10.1016/j.biopsych.2009.05.017
Source: PubMed


Several clinical and genetic studies have focused on the role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of various mental disorders. Recent lines of evidence regarding the network hypothesis of treatment outcome point towards the involvement of BDNF variants in the pharmacologic response in mood disorders (MD). Furthermore, there is strong evidence of a role for the serotonergic system in the pathophysiology and treatment of OCD, and upregulation of BDNF has been observed with various classes of antidepressants, including selective serotonin reuptake inhibitors (SSRI). Thus, we hypothesized that the BDNF gene might also be associated with treatment outcome in OCD.
We performed a single-marker and haplotype association study of eight tag single nucleotide polymorphisms in the BDNF genomic region and related this to pharmacologic response in a sample of 131 OCD patients.
We found an association for a haplotype containing two single nucleotide polymorphisms that have previously been reported to be associated with treatment outcome in MD (rs908867 and rs1491850).
Our results support the hypothesis that the BDNF gene is involved in the response to psychopharmacologic treatment even though these preliminary findings await replication in a follow-up sample.

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Available from: Rafael de Cid, Jul 23, 2015
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    • "As a mature protein, BDNF activates tyrosin kinase receptors (Tkr) promoting cell survival, while the pro-protein activates p75 neurotrophin receptor (p75 NTR ), which leads to apoptosis (Lu et al., 2005). Moreover, serum levels of BDNF in OCD patients have been found lower than those found in control subjects (Dos Santos et al., 2011; Maina et al., 2010) even after a brief period of pharmacological treatment (Fontenelle et al., 2012; Wang et al., 2011) suggesting that may be involved in pharmacological response (Real et al., 2009). It was described a single nucleotide polymorphism (rs6265) at position 196 G/A that results in valine to methionine substitution (Val66Met) (Egan et al. 2003; Sen et al., 2003). "
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    ABSTRACT: Obsessive-compulsive disorder (OCD) is a psychiatric disorder whose etiology is not yet known. We investigate the role of three variants of the BDNF gene (rs6265, rs1519480 and rs7124442) by single SNP and haplotype analysis in OCD Mexican patients using a case-control and family-based association design. BDNF gene variants were genotyped in 283 control subjects, 232 OCD patients and first degree relatives of 111 OCD subjects. Single SNP analysis in case-control study showed an association between rs6265 and OCD with a high frequency of Val/Val genotype and Val allele (p=0.0001 and p=0.0001, respectively). Also, genotype and allele analysis of rs1519480 showed significant differences (p=0.0001, p=0.0001; respectively) between OCD and control groups. Haplotype analysis showed a high frequency of A-T (rs6265-rs1519480) in OCD patients compared with the control group (OR=2.06 [1.18-3.59], p=0.0093) and a low frequency of haplotype A-C in the OCD patients (OR=0.04 [0.01-0.16], p=0.000002). The family-based association study showed no significant differences in the transmission of any variant. Our study replicated the association between BDNF Val66Met gene polymorphism and OCD. Also, we found a significant association of rs1519480 in OCD patients compared with a control group, region that has never been analyzed in OCD. In conclusion, our findings suggest that BDNF gene could be related to the development of OCD.
    Full-text · Article · Aug 2013 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
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    • "Most studies that revealed significant association between the Val66Met polymorphism and antidepressants treatment response were based on Asian populations, whereas Caucasian studies showed no association. Another study showed that two BDNF polymorphisms (rs908867 and rs1491850) with unknown functions were associated with SSRI treatment outcome in obsessive compulsive disorder patients (Real et al., 2009). In depressed patients receiving SSRI treatment the BDNF rs962369 polymorphism was associated with increased suicidal ideation, by interacting with variants in BDNF and NTRK2, the gene encoding the BNDF receptor (Perroud et al., 2009). "
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    ABSTRACT: Selective serotonin reuptake inhibitors (SSRIs) are among the most widely prescribed drugs in psychiatry. Based on the fact that SSRIs increase extracellular monoamine levels in the brain, the monoamine hypothesis of depression was introduced, postulating that depression is associated with too low serotonin, dopamine and noradrenaline levels. However, several lines of evidence indicate that this hypothesis is too simplistic and that depression and the efficacy of SSRIs are dependent on neuroplastic changes mediated by changes in gene expression. Because a coherent view on global gene expression is lacking, we aim to provide an overview of the effects of SSRI treatment on the final targets of 5-HT receptor signal transduction pathways, namely the transcriptional regulation of genes. We address gene polymorphisms in humans that affect SSRI efficacy, as well as in vitro studies employing human-derived cells. We also discuss the molecular targets affected by SSRIs in animal models, both in vivo and in vitro. We conclude that serotonin transporter gene variation in humans affects the efficacy and side-effects of SSRIs, whereas SSRIs generally do not affect serotonin transporter gene expression in animals. Instead, SSRIs alter mRNA levels of genes encoding serotonin receptors, components of non-serotonergic neurotransmitter systems, neurotrophic factors, hypothalamic hormones and inflammatory factors. So far little is known about the epigenetic and age-dependent molecular effects of SSRIs, which might give more insights in the working mechanism(s) of SSRIs.
    Full-text · Article · Aug 2012 · Pharmacology [?] Therapeutics
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    • "Therefore, strictly speaking the possible BDNF effects were on a combined (CBT plus drugs) treatment. Furthermore, although a previous study in an independent sample did not find an association between the BDNF Val66Met and pharmacological response in OCD [25], it is still possible that the results for CBT are contaminated by a gene x drug x CBT interaction. Third, our participants belong to the ''level I'' of non-response, according to the operationalized criteria [22], that is, resistant to one SSRI. "
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    ABSTRACT: Recent research suggests that the brain-derived neurotrophic factor (BDNF) may play a role in extinction learning. The goal of this study was to test whether variation in the BDNF Val66Met polymorphism is related to treatment response to exposure-based cognitive-behavior therapy (CBT), a form of extinction learning, in obsessive-compulsive disorder (OCD). One hundred and six OCD patients from a specialized clinic, who underwent a standardized CBT treatment after partial or non-response to a 12-week pharmacological trial, were genotyped for the BDNF Val66Met and the relationship between genotype and treatment response was analyzed. Among 98 CBT completers, 36% of those carrying the BDNF Met allele were rated as CBT responders compared to 60% of nonMet allele carriers (P=0.027). When analyzing the different obsessive-compulsive symptom dimensions, in patients with contamination/cleaning symptoms, the Met allele was associated with a significantly worse CBT response (P<0.0001) and a lower obsessions severity decrease from pre- to posttreatment (P=0.046). Genetic variation in BDNF may be associated with treatment response in exposure-based CBT in OCD, especially in those patients exhibiting contamination/cleaning symptoms.
    Full-text · Article · Dec 2011 · European Psychiatry
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