Brain-derived neurotrophic factor in generalized anxiety disorder: Results from a duloxetine clinical trial

Abstract

Background

Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of depression and anxiety, but has not been examined systematically in generalized anxiety disorder (GAD). The objective of this study was to examine the relationship between baseline BDNF level and treatment response in patients with GAD.

Methods

Patients (N = 168) were from China, met criteria for DSM-IV GAD, had a Hospital Anxiety and Depression Rating Anxiety (HADS-A) subscale score ≥ 10, and a Sheehan Disability Scale (SDS) global functioning total score ≥ 12 at baseline. Study design was double-blind therapy for 15 weeks with duloxetine 60–120 mg or placebo. Efficacy measures included the HADS-A and Hamilton Anxiety Rating Scale (HAMA) total score. Change from baseline to endpoint for BDNF by treatment group was analyzed using ANCOVA models with baseline BDNF level as a covariate.

Results

No significant association was found between baseline plasma BDNF levels and anxiety illness severity. Patients who received duloxetine (n = 88) had a significantly greater mean increase in plasma BDNF level (957.80 picograms/ml) compared with patients who received placebo (n = 80; 469.93 pg/mL) (P = .007). Patients who met response and remission criteria (with either treatment) had greater mean increases in BDNF at endpoint from baseline (P ≤ .05) but when compared with nonresponders and nonremitters, respectively, the differences in mean increase were not statistically significant between groups.

Conclusions

BDNF levels significantly increased with duloxetine treatment for GAD, but response and remission outcomes were not clearly related to an increase in plasma BDNF level.

Introduction

With a greater understanding of the pathophysiology underlying depression and anxiety, attention has shifted from effects of treatment not only on monoamine neurotransmitters, but also on other neurochemistries. In particular, growth factors, such as brain-derived neurotrophic factor (BDNF) have been observed to play an important role in neurogenesis, neuroplasticity, and resilience of neurons (as reviewed by Krystal et al., 2009, Lu et al., 2005). Preclinical animal models have suggested that under conditions of chronic stress, BDNF signaling may become dysregulated, resulting in neuronal atrophy and cellular loss as well as the behavioral manifestations of stress (Duman and Monteggia, 2006). Clinically, serum BDNF level has been studied in patients with major depressive disorder (MDD) to determine if there is any relationship between the growth factor and illness severity. A meta-analysis of 11 clinical studies concluded that patients with MDD have lower levels of serum BDNF at baseline compared with healthy controls, and that BDNF levels increase following antidepressant therapy (Sen et al., 2008). Furthermore, meta-analyses of 20 studies suggested that the increases in BDNF following antidepressant therapy are also significantly associated with improvement in depressive illness (Brunoni et al., 2008). Additionally, the clinical relevance of BDNF level has been supported by an association between lower BDNF levels and recurrent episodes of MDD as well as with suicidal behavior in patients with MDD (Lee et al., 2007).

Similar to depression, BDNF signaling has also been implicated in the expression of anxiety using preclinical models but the association of BDNF and clinical outcomes has been less well studied in anxiety disorders. In a recent study, the mean baseline serum BDNF level of 393 patients with social phobia, panic disorder, agoraphobia, and generalized anxiety disorder (GAD) were compared with mean baseline serum BDNF values from 382 healthy comparison subjects. Patients with anxiety disorders did not differ in baseline BDNF by anxiety diagnosis or by anxiety severity. The mean serum BDNF value of patients did not differ significantly from controls. While this is the largest published study of BDNF levels in patients with anxiety disorders, the authors did not examine response to treatment (Molendijk et al., 2012). In an open-label study of panic disorder (N = 42), patients who achieved a treatment response (≥ 40% from baseline to endpoint) had a significantly higher serum BDNF level at baseline compared with patients who had a poor outcome, but change in serum BDNF levels from pre- to post-treatment was not examined (Kobayashi et al., 2005).

Given the shared diathesis between major depression and GAD (e.g., Kendler et al., 1992) understanding whether BDNF has a similar response to treatment could help to further elucidate the role of BDNF in depression and anxiety. Therefore, the present study was undertaken to examine whether plasma BDNF levels in patients with GAD change significantly in response to active treatment (duloxetine) compared with placebo treatment. An additional objective was to examine whether changes in plasma BDNF level were associated with response or remission status at endpoint of treatment. These biochemical objectives were secondary outcomes within a double-blind, placebo-controlled clinical trial of duloxetine, a selective serotonergic noradrenergic reuptake inhibitor, for the treatment of GAD that was conducted for regulatory purposes in the Republic of China. The primary outcome from this trial has been reported elsewhere (Wu et al., 2011).