Brain-derived neurotrophic factor serum levels before and after treatment for acute mania.
ABSTRACT Accumulating evidence suggests that reduced levels of brain-derived neurotrophic factor (BDNF) in acute mood episodes may play an important role in the pathophysiology of bipolar disorder (BD). In order to assess changes in BDNF serum levels in BD patients before and after treatment for acute mania, ten bipolar patients were prospectively examined at inpatient unit admission and discharge. Diagnoses were made using the Structured Clinical Interview for DSM-IV, SCID-I. Serum BDNF levels were measured by sandwich ELISA. The results showed that BDNF levels were decreased in BD patients during mania when compared to controls (p=0.013) but this difference was no longer significant after treatment (p=0.126). A sharp increase in BDNF levels was found after treatment of the episode of acute mania (p=0.010). These findings suggest that the changes in BDNF serum levels may be associated with treatment response in acute mania. Further studies designed to validate the use of BDNF as a marker of treatment response in bipolar disorder are warranted.
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ABSTRACT: Major psychiatric disorders such as schizophrenia, major depressive and bipolar disorders are severe, chronic and debilitating, and are associated with high disease burden and healthcare costs. Currently, diagnoses of these disorders rely on interview-based assessments of subjective self-reported symptoms. Early diagnosis is difficult, misdiagnosis is a frequent occurrence and there are no objective tests that aid in the prediction of individual responses to treatment. Consequently, validated biomarkers are urgently needed to help address these unmet clinical needs. Historically, psychiatric disorders are viewed as brain disorders and consequently only a few researchers have as yet evaluated systemic changes in psychiatric patients. However, promising research has begun to challenge this concept and there is an increasing awareness that disease-related changes can be traced in the peripheral system which may even be involved in the precipitation of disease onset and course. Converging evidence from molecular profiling analysis of blood serum/plasma have revealed robust molecular changes in psychiatric patients, suggesting that these disorders may be detectable in other systems of the body such as the circulating blood. In this review, we discuss the current clinical needs in psychiatry, highlight the importance of biomarkers in the field, and review a representative selection of biomarker studies to highlight opportunities for the implementation of personalized medicine approaches in the field of psychiatry. It is anticipated that the implementation of validated biomarker tests will not only improve the diagnosis and more effective treatment of psychiatric patients, but also improve prognosis and disease outcome.Progress in Neurobiology 11/2014; · 10.30 Impact Factor
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ABSTRACT: Bipolar disorder (BD) is a complex psychiatric phenotype with a high heritability and a multifactorial etiology. Multisite collaborative efforts using genome-wide association studies (GWAS) have identified only a portion of DNA sequence-based risk factors in BD. In addition to predisposing DNA sequence variants, epigenetic misregulation may play an etiological role in BD and account for monozygotic twin discordance, parental origin effects, and fluctuating course of BD. In this study, we investigated DNA methylation of the brain-derived neurotrophic factor (BDNF) gene in BD. Fifty participants with BD were compared to the same number of age- and sex-matched controls for DNA methylation differences at BDNF promoters 3 and 5. DNA methylation reads were obtained using a mass spectrophotometer for 64 cytosine-guanine (CpG) sites in 36 CpG 'units' across three amplicons of BDNF promoters 3 and 5. Methylation fractions differed between BD participants and controls for 11 of 36 CpG units. Five CpG units, mostly in promoter 5, remained significant after false discovery rate correction (FDR) (p values ≤ 0.004) with medium to large effect sizes (Cohen's d ≥ 0.61). Several of the significant CpGs overlapped with or were immediately adjacent to transcription factor binding sites (TFBSs) - including two of the FDR-significant CpG units in promoter 5. For the CpGs in promoter 3, there was a positive and significant correlation between age at sample collection and DNA methylation fraction (rho = 0.56, p = 2.8 ×10(-5)) in BD cases, but not in controls. Statistically significant differences in mean methylation fraction at 5/36 CpG units (after FDR), some at or immediately adjacent to TFBSs, suggest possible relevance for the current findings to BD etiopathogenesis. The positive correlation between age and methylation seen in promoter 3 is consistent with age-related decline in BDNF expression previously reported. Future studies should provide more exhaustive epigenetic study of the BDNF locus to better characterize the relationship between BDNF methylation differences and BD.International journal of bipolar disorders. 01/2013; 1:28.
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ABSTRACT: Peripheral brain-derived neurotrophic factor (BDNF) is decreased in acute major depressive disorder (MDD) and bipolar disorder (BD) and recovered after treatment. Here we validated on a meta-analytical level whether BDNF restores differentially according to treatment response and whose measurements could be used as a biomarker, plasma or serum. Using strict inclusion criteria, we compared BDNF in healthy controls and patients with MDD (38 studies, n=6619), and BD (17 studies, n=1447). Pre- and post-treatment BDNF levels were meta-analyzed according to treatment response in patients from 21 MDD studies (n=735) and 7 BD studies (n=88). Serum and plasma subgroups were analyzed, publication bias was assessed and heterogeneity was investigated. Serum and plasma BDNF were decreased in acute MDD and BD, and did not differ in euthymia in comparison with control subjects. Antidepressive treatment increased serum BDNF levels in MDD in responders (Cohen׳s d (d)=1.27, p=4.4E-07) and remitters (d=0.89, p=0.01), significantly more than in non-responders (d=0.11, p=0.69). For plasma BDNF in MDD and for BD, the evidence was insufficient for a meta-analysis. Although no significant difference was found between serum and plasma ES, variance of plasma ES was higher. Between-study heterogeneity was explained only partially; signs of publication bias in serum studies. Serum BDNF might be regarded as a biomarker for the successful treatment of MDD. Serum measurements seem more reliable than plasma ones. Further research should focus on defining optimal time points for BDNF measurements and increase evidence for the usage of BDNF as a predictive biomarker in BD. Copyright © 2014 Elsevier B.V. All rights reserved.Journal of Affective Disorders 11/2014; 174C:432-440. · 3.76 Impact Factor
Neuroscience Letters 452 (2009) 111–113
Contents lists available at ScienceDirect
journal homepage: www.elsevier.com/locate/neulet
Brain-derived neurotrophic factor serum levels before and after treatment
for acute mania
Juliana Fernandes Tramontinaa,b, Ana Cristina Andreazzaa,b, Marcia Kauer-Sant’Annaa,b,
Laura Stertza,b, Julia Goia,b, Fabria Chiarania,b, Flávio Kapczinskia,b,∗
aMolecular Psychiatry Laboratory, Hospital de Clinicas de Porto Alegre, Brazil
bBipolar Disorders Program, Federal University of Rio Grande do Sul, Brazil
a r t i c l e i n f o
Received 13 November 2008
Received in revised form 9 January 2009
Accepted 10 January 2009
a b s t r a c t
Accumulating evidence suggests that reduced levels of brain-derived neurotrophic factor (BDNF) in acute
mood episodes may play an important role in the pathophysiology of bipolar disorder (BD). In order
to assess changes in BDNF serum levels in BD patients before and after treatment for acute mania, ten
bipolar patients were prospectively examined at inpatient unit admission and discharge. Diagnoses were
made using the Structured Clinical Interview for DSM-IV, SCID-I. Serum BDNF levels were measured by
sandwich ELISA. The results showed that BDNF levels were decreased in BD patients during mania when
compared to controls (p=0.013) but this difference was no longer significant after treatment (p=0.126).
A sharp increase in BDNF levels was found after treatment of the episode of acute mania (p=0.010). These
findings suggest that the changes in BDNF serum levels may be associated with treatment response in
acute mania. Further studies designed to validate the use of BDNF as a marker of treatment response in
bipolar disorder are warranted.
© 2009 Elsevier Ireland Ltd. All rights reserved.
Bipolar disorder (BD) is among the most disabling medical dis-
orders and is associated with high mortality rates due to suicide
and other medical illnesses . Notably, some authors reported
neuroanatomical changes in BD patients that tend to be more
pronounced with repeated episodes and length of illness [15,6].
Consistently, recent studies suggest that those patients who had
tures . Furthermore, there is evidence that patients with BD
ment is greater in those with multiple episodes as compared with
those who presented their first manic episode .
It has been suggested that reduced levels of neurotrophins
described in acute episodes may play an important role in the brain
cient expression of BDNF may contribute to, or be a consequence
of, the pathophysiology of BD. In addition, Sen et al.  in a recent
meta-analyses examined the difference in serum BDNF of unipo-
lar depressed patients and suggested a potential utility of serum
BDNF levels as a biomarker for illness and antidepressant efficacy.
In bipolar disorder, serum studies have shown decreased serum
Corresponding author at: Laboratório de Psiquiatria Molecular, Centro de
Pesquisas, Hospital de Clínicas de Porto Alegre, Ramiro Barcelos 2350, 90035-000,
Porto Alegre, RS, Brazil.
E-mail address: firstname.lastname@example.org (F. Kapczinski).
BDNF levels in BD patients in manic as well as in those with depres-
sive symptoms, being normalized in euthymia [17,18]. In a study of
patient assessed during a first episode of psychosis (including BD)
plasma levels of BDNF increased about two-fold after 6 months of
treatment among BD patients . The present study was designed
to assess changes in BDNF serum levels of BD patients during acute
mania and after treatment of acute episode.
Ten patients with BD I in acute mania and 10 healthy con-
trols, matched for age and gender, were recruited. We compared
BDNF serum levels of BDNF of the same group of manic patients
during acute mania and after treatment of acute episode. An addi-
tional comparison group of ten non-bipolar healthy subjects was
cas de Porto Alegre (HCPA), Porto Alegre, Brazil. All subjects had
a comprehensive clinical interview by a board-certified psychia-
trist. The diagnosis of BD was established based on all the available
clinical information and confirmed with a Structured Clinical Inter-
view for DSM-IV – Axis I (SCID-I) and a standard protocol to assess
psychopathology and clinical features. Subjects enrolled received
open-label treatment for BD according to available clinical guide-
lines [8,16]. Patients did not have significant comorbid medical
conditions and they were not on medication other than those pre-
scribed to treat acute mania. Psychiatric status was assessed during
and after treatment for acute mania using the Young Mania Rating
0304-3940/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved.
J.F. Tramontina et al. / Neuroscience Letters 452 (2009) 111–113
Controls, matched for age and gender, were screened to rule out
current use of clinical and psychiatric medication, any history of
psychiatric disorder, neurodegenerative disorder, mental retarda-
tion, cancer or chronic/acute infection. All procedures described in
this study received approval from the local ethics committee. Writ-
ten informed consent was obtained from all patients and healthy
subjects prior to conducting any study procedures.
Five milliliters of blood were withdrawn from each subject by
immediately centrifuged at 3000×g for 5min, and serum was kept
frozen at −80◦C until assayed. BDNF serum levels were measured
ufacturer’s instructions (Chemicon, USA). Briefly, microtiter plates
of BNDF. Plates were then washed four times with wash buffer,
monoclonal anti-BNDF rabbit antibody was added (diluted 1:1000
with sample diluents), and incubated for 3h at room temperature.
After washing, a second incubation with anti-rabbit antibody per-
oxidase conjugated (diluted 1:1000) for 1h at room temperature
was carried out. After addition of streptavidin-enzyme, substrate
set in 450nm). The standard curve demonstrates a direct relation-
ship between optical density (OD) and BDNF concentration. The
intra-assay and inter-assay variations were 3.7% and 8.5%, respec-
tively. Total protein was measured by Lowry’s method using bovine
serum albumin as a standard.
16.0 (SPSS Inc., Chicago, IL, USA). Descriptive statistics are used to
report sociodemographic and clinical characteristics of the sam-
ple. Association between dichotomous variables was assessed with
variables were compared between patients and their respective
controls using paired sample t test, as indicated. All statistical tests
were two-tailed and were performed using a significance level of
a=0.05. Data are presented as means and standard deviation (S.D.),
or percentage, as indicated.
There is no difference between patients and their respective
control groups regarding gender (50% Female, 50% Male, in both
group) and age (Controls 34.41±3.97; Patients 34.9±13.85; paired
t=−0.655; p=0.529). The clinical characteristics of the patients are
presented in Table 1. BDNF levels were decreased in BD patients
paired t=3.092; p=0.013) but this difference was no longer sig-
nificant after treatment (0.38±0.14; paired t=−1.682; p=0.126)
(Fig. 1). There was a sharp increase in BDNF levels after effec-
tive treatment of acute manic episode (paired t=−3.230; p=0.010)
(Fig. 1). The BDNF levels either in acute episode or after treatment
did not presented correlation with the clinical scales (GAF, YMRS
As far as we know, this is the first study designed to exam-
ine BDNF levels during acute mania and after treatment of the
episode. Results suggest that BDNF levels may be associated with
improvement of acute symptoms and may offer a biological marker
of clinical response to treatment in acute mania. These results were
obtained using a small sample size and replication is warranted.
However, given that the present results are inline with previous
studies [17,18,7] it is unlikely that a larger sample would change
the direction of the results.
BDNF is a member of the neurotrophin family, and plays an
important role in neuroplasticity and neuroprotection . In BD
patients, serum BDNF is decreased in both manic and depressive
episodes  and has been negatively correlated with sever-
ity of episodes [17,18]. In addition, three independent studies
reported that serum BDNF levels were reduced in unipolar depres-
sive patients and were negatively correlated with the severity of
Clinical characteristic of patients with BD at baseline (before treatment) and follow-up (after treatment).
Time of illness
Age of onset
Lithium, olanzapine, haloperidol,
Electroconvulsive therapy (ECT)
Lithium, haloperidol, clonazepam
†Patients 7 and 10 were medication-free (at least 14 days without medication) and the remaining patients were at described treatment for no longer than 10 days at blood draw.
‡Number of days from admission until discharge.
*Paired samples T-test.
J.F. Tramontina et al. / Neuroscience Letters 452 (2009) 111–113
Fig. 1. BDNF levels in patients. Nine out of ten patients assessed at admission were
discharged after resolution of the manic episode. One patient (patient five) was a
charged still within a manic episode and BDNF levels of this patient were decreased.
Patient seven also presented a decrease in BDNF levels but was not manic at dis-
charge. Overall out of nine responders BDNF levels were sharply increased in six
patients. BDNF 1: before treatment BDNF 2: after treatment.
reflects brain changes remains a topic of debate. Although it is pos-
sible that peripheral BDNF levels may not reflect brain changes,
BDNF has been shown to cross the blood–brain-barrier  and
has been associated with many of the crucial pharmacotherapeutic
quetiapine, and ECT) .
Some limitations should be considered when interpreting the
results of this study. First, our findings might have been strength-
ened with a larger number of study participants, particularly in
regard to increasing the power of statistical analyses. Second, the
patient received open-label maintenance treatment, which does
not permit to analyze the specific treatment effect on BDNF lev-
els. In conclusion our findings suggest that the changes in BDNF
serum levels may be associated with treatment response in acute
mania. Further studies designed to validate the use of BDNF as a
marker of treatment response in bipolar disorder are warranted.
Juliana Tramontina and Ana Cristina Andreazza receive research
support from CAPES (Coordenac ¸ão de Aperfeic ¸oamento de Pessoal
The Stanley Medical Research Institute, NARSAD (National Alliance
for Research on Schizophrenia and Depression), CNPq (Conselho
Nacional de Desenvolvimento Científico e Tecnológico), CAPES,
INCT-TM (Instituto Nacional de Ciência e Tecnologia Translacional
em Medicina) and AstraZeneca. He is a speaker and/or consultant
of Janssen, Lilly, AstraZeneca and Servier. Marcia Kauer-Sant’Anna
receives research support from NARSAD, CNPq, CAPES, FIPE-HCPA
(Fundo de Incentivo a Pesquisa do Hospital de Clínicas de Porto
Alegre) and AstraZeneca.
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