Lack of association between serum brain-derived neurotrophic factor levels and improvement of schizophrenia symptoms in a double-blind, randomized, placebo-controlled trial of memantine as adjunctive therapy to clozapine.
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ABSTRACT: It has been postulated that schizophrenia (SZ) is related to a lower expression of brain-derived neurotrophic factor (BDNF). In the past few years, an increasing number of divergent clinical studies assessing BDNF in serum and plasma have been published. It is now possible to verify the relationship between BDNF levels and severity of symptoms in SZ as well as the effects of antipsychotic drugs on BDNF using meta-analysis. The aims of this study were to verify if peripheral BDNF is decreased in SZ, whether its levels are correlated with positive and negative symptomatology and if BDNF levels change after antipsychotic treatment. This report consists of two distinct meta-analyses of peripheral BDNF in SZ including a total of 41 studies and more than 7000 participants: (1) peripheral BDNF levels in serum and plasma were moderately reduced in SZ compared with controls. Notably, this decrease was accentuated with the disease duration. However, the extent of peripheral BDNF level decrease did not correlate with the severity of positive and negative symptoms. (2) In plasma, but not serum, peripheral BDNF levels are consistently increased after antipsychotic treatment irrespective of the patient’s response to medication. In conclusion, there is compelling evidence that there are decreased levels of peripheral BDNF in SZ, in parallel to previously described reduced cerebral BDNF expression. It remains unclear whether these systemic changes are causally related to the development of SZ or if they are merely a pathologic epiphenomenon.Molecular Psychiatry 09/2014; · 15.15 Impact Factor
J Clin Psychiatry 71:1, January 201091
Letters to the editor
Lack of Association Between Serum Brain-Derived
Neurotrophic Factor Levels and Improvement
of Schizophrenia Symptoms in a Double-Blind,
Randomized, Placebo-Controlled Trial of
Memantine as Adjunctive Therapy to Clozapine
To the Editor: We have shown that memantine as adjunctive
therapy to clozapine improves negative and positive symptoms
in patients with refractory schizophrenia.1 However, the biologic
mechanism for this improvement remains unclear. Meisner et
al2 have reported an interaction between memantine and brain-
derived neurotrophic factor (BDNF). An effect of memantine on
nonneuronal BDNF-producing cells may explain this interaction
by activation of extrasynaptic N-methyl-d-aspartate receptors and
promotion of neuronal functioning. BDNF is implicated in many
psychiatric disorders, such as schizophrenia.3–6
We hypothesize that BDNF may play a role in the effect of
memantine in patients with schizophrenia. Some studies have
evaluated BDNF as a predictor of treatment response7,8 and as a
possible diagnosis biomarker.9 The aim of this study is to evaluate
serum BDNF levels in refractory schizophrenia patients before and
after use of memantine as adjunctive therapy to clozapine.
Method. In a double-blind, placebo-controlled trial, 21 outpa-
tients with DSM-IV–defined refractory schizophrenia were ran-
domly assigned, from January 2006 through March 2008, to receive
either 20 mg/d memantine (n = 10) or placebo (n = 11) adjunctive
to clozapine for 12 weeks. Serum BDNF levels were measured at
baseline and after 12 weeks of treatment using an ELISA sandwich
kit. The primary outcome was total score on the Brief Psychiatry
Rating Scale (BPRS)10 and its subscales of positive and negative
symptoms. Response to memantine was defined as a decrease of at
least 50% in BPRS score. Comparisons of serum BDNF levels before
and after memantine or placebo were assessed by paired Student
t test. Unpaired Student t test was used to assess the difference in
serum BDNF levels according to memantine response.
Results. All participants completed the study and were includ-
ed in the analysis. Significant improvement (P < .01) in total BPRS
score and positive (effect size = 1.38) and negative (effect size = 3.33)
subscales was observed in the active treatment group. Five of 10 pa-
tients receiving memantine had a decrease of at least 50% in BPRS
total score and were considered as responders. There was no dif-
ference in mean ± SD serum BDNF levels before and after meman-
tine (0.30 ± 0.08 and 0.30 ± 0.10, respectively; difference = –0.002,
P = .93) or placebo (0.35 ± 0.14 and 0.35 ± 0.17, respectively; dif-
ference = –0.002, P = .91) treatments. In the memantine group, a
statistically nonsignificant decrease of serum BDNF levels in re-
sponders compared to nonresponders (0.28 ± 0.08 and 0.33 ± 0.06,
respectively; P = .41) was seen before treatment.
Adjunctive treatment to clozapine with memantine in this co-
hort was associated with improvement in negative and positive
symptoms. There were no differences in serum BDNF levels after
memantine treatment. BDNF was identified as a predictor of treat-
ment response.7,8 However, a difference in serum BDNF levels be-
tween responders and nonresponders to memantine was not found
in this sample.
There are some limitations in the present study. First, we as-
sessed BDNF in serum. However, a high correlation of serum and
cerebrospinal fluid BDNF levels has been reported.11 Second, the
negative results of our comparisons of BDNF levels between re-
sponders and nonresponders to memantine may be due to the rela-
tively small sample. Third, all patients were on clozapine treatment
before entering the study, and clozapine may increase serum BDNF
levels.4 Therefore, we can hypothesize that an increase in serum
BDNF levels had occurred before randomization.
In conclusion, our results do not support the hypothesis that im-
provement in positive and negative symptoms with adjunctive treat-
ment to clozapine with memantine in patients who have refractory
schizophrenia is associated with serum BDNF level variances.
Trial registration: clinicaltrials.gov Identifier: NCT00757978
1. de Lucena D, Fernandes BS, Berk M, et al. Improvement of negative and
positive symptoms in treatment-refractory schizophrenia: a double-blind,
randomized, placebo-controlled trial with memantine as add-on therapy
to clozapine. J Clin Psychiatry. 2009;70(10):1416–1423.
2. Meisner F, Scheller C, Kneitz S, et al, German Competence Network
HIV/AIDS. Memantine upregulates BDNF and prevents dopamine defi-
cits in SIV-infected macaques: a novel pharmacological action of
memantine. Neuropsychopharmacology. 2008;33(9):2228–2236. PubMed doi:10.1038/sj.npp.1301615
3. de Oliveira GS, Ceresér KM, Fernandes BS, et al. Decreased brain-
92 J Clin Psychiatry 71:1, January 2010
Letters to the editor
derived neurotrophic factor in medicated and drug-free bipolar patients.
J Psychiatr Res. 2009;43(14):1171–1174. PubMed doi:10.1016/j.jpsychires.2009.04.002
4. Gama CS, Andreazza AC, Kunz M, et al. Serum levels of brain-derived
neurotrophic factor in patients with schizophrenia and bipolar disorder.
Neurosci Lett. 2007;420(1):45–48. PubMed doi:10.1016/j.neulet.2007.04.001
5. Gama CS, Berk M, Andreazza AC, et al. Serum levels of brain-derived
neurotrophic factor and thiobarbituric acid reactive substances in chroni-
cally medicated schizophrenic patients: a positive correlation. Rev Bras
Psiquiatr. 2008;30(4):337–340. PubMed
6. Jacka FN, Gama CS, Berk M. Brain-derived neurotrophic factor:
a modifiable common mediator in both the pathophysiology of
psychiatric illness and in successful pharmacological treatments.
Acta Neuropsychiatr. 2008;20(4):223–225. doi:10.1111/j.1601-5215.2008.00323.x
7. Marano CM, Phatak P, Vemulapalli UR, et al. Increased plasma con-
centration of brain-derived neurotrophic factor with electroconvulsive
therapy: a pilot study in patients with major depression. J Clin Psychiatry.
8. Fernandes B, Gama CS, Massuda R, et al. Serum brain-derived
neurotrophic factor (BDNF) is not associated with response to electro-
convulsive therapy (ECT): a pilot study in drug resistant depressed
patients. Neurosci Lett. 2009;453(3):195–198. PubMed doi:10.1016/j.neulet.2009.02.032
9. Fernandes BS, Gama CS, Kauer-Sant’Anna M, et al. Serum brain-
derived neurotrophic factor in bipolar and unipolar depression: a
potential adjunctive tool for differential diagnosis. J Psychiatr Res.
10. Romano F, Elkis H. Tradução e Adaptação de um Instrumento de
Avaliação Psicopatológica das Psicoses: a Escala Breve de Avaliação
Psiquiátrica. Versão Ancorada (BPRS-A). J Bras Psiquiatr. 1996;45:43–49.
11. Pan W, Banks WA, Fasold MB, et al. Transport of brain-derived neu-
rotrophic factor across the blood-brain barrier. Neuropharmacology.
1998;37(12):1553–1561. PubMed doi:10.1016/S0028-3908(98)00141-5
David de Lucena, MD
Brisa Simões Fernandes, MD
Mauricio Kunz, MD, MSc
Gabriel Rodrigo Fries, BSc
Laura Stertz, BSc
Bianca Aguiar, BSc
Bianca Pfaffenseller, BSc
Clarissa Severino Gama, MD, PhD
Author affiliations: Postgraduate Program in Psychiatry, Universidade Federal do
Rio Grande do Sul (Drs de Lucena, Fernandes, Kunz, and Gama); the Laboratory of
Molecular Psychiatry, Research Center (all authors), Schizophrenia Program (Drs de
Lucena, Fernandes, and Gama), and Bipolar Disorders Program (Drs Fernandes, Kunz,
and Gama; Mr Fries; and Mss Stertz, Aguiar, and Pfaffenseller), Hospital de Clínicas
de Porto Alegre; and INCT (Instituto Nacional de Ciência e Tecnologia [National In-
stitute for Science and Technology]) for Translational Medicine (Drs Fernandes, Kunz,
and Gama; Mr Fries; and Mss Stertz, Aguiar, and Pfaffenseller), Porto Alegre/RS, Brazil.
Financial disclosure: Dr Gama has received grant/research support from Conselho
Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundo de Incentivo
a Pesquisa do Hospital de Clínicas de Porto Alegre (FIPE–HCPA), and Endeavour
and has been a paid speaker for AstraZeneca. Drs de Lucena, Fernandes, and Kunz;
Mr Fries; and Mss Stertz, Aguiar, and Pfaffenseller have declared no conflict of inter-
est. Funding/support: The study was supported by grants from FIPE-HCPA (#05-406)
to Dr Gama. Dr Fernandes is supported by a scholarship from CNPq, Brazil. Role of
sponsor: The above agencies had no role in study design, acquisition, or interpretation
of data or writing the report.
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