BDNF protein levels are decreased in transformed lymphoblasts from lithium-responsive patients with bipolar disorder

Department of Psychiatry, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canda.
Journal of psychiatry & neuroscience: JPN (Impact Factor: 5.86). 10/2008; 33(5):449-53.
Source: PubMed


Brain-derived neurotrophic factor (BDNF) is a key factor in neuroplasticity and has been implicated in the affective disorders; studies have demonstrated elevated BDNF in patients taking lithium and other mood stabilizers. The objective of our study was to analyze BDNF in lithium-responsive patients with bipolar disorder (BD) to further understand the role of BDNF in the pathophysiology of BD.
Using enzyme-linked immunosorbent assay, we measured transformed B lymphocytes for BDNF protein.
BDNF levels were 36% lower in lymphoblasts from patients with BD (n = 12), compared with matched control participants (n = 13), and 55% lower when compared with their unaffected relatives (n = 14). Lithium significantly decreased BDNF levels in patients with BD and healthy control participants, although BDNF levels remained lower (33%) in the BD group posttreatment.
Decreased BDNF may constitute part of the pathophysiologic process of BD in a lithium-responsive subgroup of individuals with this disease. A compensatory mechanism protecting the genetically predisposed unaffected relatives from phenotypic expression of BD is suggested.

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    • "The present study was performed on transformed lymphoblasts collected from subjects with BD and an excellent response to lithium in addition to relatives and healthy controls (CTL). The details of this sample are described in detail elsewhere (Tseng et al., 2008; Mamdani et al., 2008). There was a total of sixty subjects in four groups: (1) CTL (n = 16) with no personal or family history of psychiatric illness among 1st and 2nd degree relatives; (2) subjects with BD and an excellent response to lithium monotherapy (n = 14); (3) unaffected relatives (UR) of the BD subject group (n = 16); and, (4) affected relatives (AR, n = 14) who met diagnostic criteria for either BD or major depressive disorder (MDD). "
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    ABSTRACT: Mitochondrial dysfunction, oxidative stress, and alterations in DNA methylation, are all associated with the pathophysiology of bipolar disorder (BD). We therefore studied the relationship between oxidative stress and DNA methylation in patients with BD with an excellent response to lithium treatment, their affected and unaffected relatives and healthy controls. Transformed lymphoblasts were cultured in the presence or absence of lithium chloride (0.75 mm). DNA and proteins were extracted from the cells to determine levels of 8-hydroxy-2-deoxyguanosine (8-OHdG), 5-methylcytosine (5-mc), mitochondrial complex I and glutathione peroxidase (GPx) activities. Methylation was decreased in BD subjects and their relatives compared to controls and remained so after lithium treatment in BD subjects but not in their relatives. 8-OHdG levels and complex I activity did not differ between groups before and after lithium treatment. Finally, relatives of patients showed increased GPx activity before and after lithium treatment, which negatively correlated with 5-mc levels. Changes in global methylation may be specific for BD and lithium may be involved in glutathione regulation. The present study supports the importance of DNA methylation to the pathophysiology of BD and the therapeutic potential of antioxidants in this illness.
    Full-text · Article · Dec 2013 · The International Journal of Neuropsychopharmacology
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    • "Other studies have focused on gene and protein expression measurements in peripheral tissues such as fresh blood or lymphoblastoid cell lines (LCLs) sampled from BD patients characterized for lithium response. Evidence from these studies suggested that altered protein levels of brain derived neurotrophic factor (BDNF) [13] and expression of Synapsin II (SYN2) gene [14] [15] may be involved in lithium response or serve as peripheral markers. "
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    ABSTRACT: Bipolar disorder (BD) is a debilitating psychiatric disease characterized by alternating episodes of mania and depression. Among mood stabilizers, lithium is the mainstay for the treatment of BD, with approximately one-third of patients showing remission from episode recurrence. While there is evidence suggesting genetic load for lithium response in BD, its molecular underpinnings are still not completely understood. To identify genes potentially involved in (or correlated with) lithium response, we carried out a genome-wide expression analysis on lymphoblastoid cell lines (LCLs) from 10 BD patients responders (R) and 10 non-responders (NR) to lithium. We compared expression levels of the two groups and tested whether in vitro lithium treatment had different effects in LCLs of R compared to NR. At basal, 2060 genes were differentially expressed between R and NR while no genes were differentially regulated by lithium in the two groups. After pathway analysis based on the 2060 genes, 9 genes were selected for validation with qRT-PCR. Eight genes were validated in the same sample of LCLs while only Insulin-like Growth Factor 1 (IGF-1) was significantly over-expressed in R compared to NR in the same sample as well as in an independent sample comprised of 6 R and 6 NR (sample 1, fold change=1.94; p=0.005; sample 2, fold change=2.21; p=0.005). IGF-1 was also significantly over-expressed in R but not in NR when compared to a sample of non-psychiatric controls. Our findings suggest that IGF-1 may be involved in lithium response, supporting further investigation on its potential as a biomarker.
    Full-text · Article · Apr 2013 · Pharmacological Research
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    • "In humans, Leyhe et al. [9] found a similar increase in serum BDNF in subjects with Alzheimer's disease after 10 weeks of therapy with lithium. In contrast, lithium showed to decrease BDNF in lymphoblastoid cells [25]. Previous studies describe an increase in BDNF levels after diverse combined treatments in mania [19] [24]. "
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    ABSTRACT: Several studies have suggested an important role for brain-derived neurotrophic factor (BDNF) in the pathophysiology and therapeutics of bipolar disorder (BPD). The mechanisms underlying the therapeutic effects of lithium in BPD seem to involve a direct regulation of neurotrophic cascades. However, no clinical study evaluated the specific effects of lithium on BDNF levels in subjects with BPD. This study aims to investigate the effects of lithium monotherapy on BDNF levels in acute mania. Ten subjects with bipolar I disorder in a manic episode were evaluated at baseline and after 28 days of lithium therapy. Changes in plasma BDNF levels and Young Mania Rating Scale (YMRS) scores were analyzed. A significant increase in plasma BDNF levels was observed after 28 days of therapy with lithium monotherapy (510.9±127.1pg/mL) compared to pre-treatment (406.3±69.5pg/mL) (p=0.03). Although it was not found a significant association between BDNF levels and clinical improvement (YMRS), 87% of responders presented an increase in BDNF levels after treatment with lithium. These preliminary data showed lithium's direct effects on BDNF levels in bipolar mania, suggesting that short-term lithium treatment may activate neurotrophic cascades. Further studies with larger samples and longer period may confirm whether this biological effect is involved in the therapeutic efficacy of lithium in BPD.
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