Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants

Abstract

Background

Because researchers have reported that antidepressants increase the expression of brain-derived neurotrophic factor (BDNF) in the rat hippocampus, we investigated whether serum BDNF levels may be used as a putative biological marker for major depressive disorders (MDD).

Methods

We measured serum BDNF in the following three groups: antidepressant-naive patients with MDD (n = 16), antidepressant-treated patients with MDD (n = 17), and normal control subjects (n = 50). Patients were evaluated using the Hamilton Rating Scale for Depression (HAM-D). Serum BDNF was assayed with the sandwich ELISA method.

Results

We found that serum BDNF was significantly lower in the antidepressant-naive group (mean, 17.6 ng/mL; SD, 9.6) than in the treated (mean, 30.6 ng/mL; SD, 12.3; p = .001) or in the control group (mean, 27.7 ng/mL; SD, 11.4; p = .002). There was a significant negative correlation (r = −.350, z = −2.003, p = .045) between serum BDNF and HAM-D scores in all patients. In a preliminary examination, reduced BDNF values of three drug-naive patients recovered to basal levels after antidepressant treatment.

Conclusions

Our study suggests that low BDNF levels may play a pivotal role in the pathophysiology of MDD and that antidepressants may increase BDNF in depressed patients.

Introduction

Brain-derived neurotrophic factor (BDNF), the most abundant of the neurotrophins in the brain, enhances the growth and maintenance of several neuronal systems, serves as a neurotransmitter modulator, and participates in plasticity mechanisms such as long-term potentiation (Gartner and Staiger 2002) and learning Lindsay et al 1994, Lindvall et al 1994, Snider 1994, Thoenen 1995. It is a member of the nerve growth factor family, which includes nerve growth factor, neurotrophin-3, and neurotrophin-4/5.

Accumulating evidence suggests BDNF as a candidate molecule involved in the pathophysiology of mental disorders. In particular, the association of low BDNF levels with major depressive disorder (MDD) has been suggested Altar 1999, Duman et al 1997, Nestler et al 2002. In animals subjected to forced swimming (Russo-Neustadt et al 2001) and chronic immobilization stress Smith et al 1995, Xu et al 2002, BDNF mRNA levels were significantly depressed. In addition, chronic antidepressant treatment increases the expression of BDNF and neurogenesis in the adult rat hippocampus Duman and Vaidya 1998, Malberg et al 2000. Infusion of BDNF itself into the brain produces antidepressant effects in behavioral models of depression Shirayama et al 2002, Siuciak et al 1997. From the viewpoint of nonpharmacologic therapy for depression, long-term electroconvulsive seizures (ECS) are known to increase the expression of BDNF and its receptor, TrkB, in limbic brain regions. Chronic ECS is also reported to induce sprouting of hippocampal neurons, and studies of BDNF mutant mice indicated that this sprouting is partially dependent on the upregulation of BDNF (Duman and Vaidya 1998).

Consistent with the animal studies, increased BDNF expression was recently found in hippocampal regions in subjects treated with antidepressant medications at the time of death, compared with untreated subjects (Chen et al 2001). Furthermore, two independent research groups reported the same findings about an association between BDNF gene and bipolar disorder through the different approaches of family-based association test by genotyping single-nucleotide polymorphisms in the gene Neves-Pereira et al 2002, Sklar et al 2002. These studies have shown BDNF as a potential risk allele of mood disorders. Moreover, Karege et al (2002a) reported decreased levels of BDNF in the serum of antidepressant-free patients with MDD. They recruited only patients who were antidepressant-free for 3 or more weeks or who had stopped their medication 3–10 days before blood sample collection. Neither antidepressant-naive nor treated patients were included in their study. Although antidepressants increase BDNF levels in rat and human brains, it is still unclear how discontinuation of antidepressant treatment affects BDNF levels. To the best of our knowledge, no reports have been published regarding either altered BDNF levels in antidepressant-naive patients with depression who had never received medication or regarding BDNF levels in a matched group of antidepressant-treated patients. To perform a study of BDNF levels in association with depression, it was necessary to exclude the possibility that discontinuation of antidepressants exerted an effect on BDNF levels. Therefore, we sought to determine whether serum levels of BDNF in antidepressant-naive and antidepressant-treated patients with depression would be different from those of healthy control subjects.