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: Based on the glutamatergic NMDA receptor hypofunction theory of schizophrenia, NMDA receptor modulators (NMDARMs) may have therapeutic potential in the treatment of schizophrenia. This meta-analysis aimed to evaluate the potential of modulators of the NMDA receptor as adjunctive therapy for schizophrenia, using the results from published trials. A primary electronic search for controlled clinical trials using NMDARMs in schizophrenia was conducted on the PubMed, Cochrane Library, EMBASE, CINAHL® and PsycINFO databases. A secondary manual search of references from primary publications was also performed. Inclusion criteria were the application of an established method of diagnosis, randomized case assignment, comparison of NMDARM add-on therapy with placebo, and double-blind assessment of symptoms in chronic schizophrenia using standardized rating scales. Results were based on a total sample size of 1253 cases from 29 trials that fulfilled the specified criteria. Scores on rating scales or on their relevant subscales were obtained for all selected studies from published results for the minimum dataset to compute the difference between post- and pre-trial scores and their pooled standard deviation for NMDARM add-on therapy and placebo groups for negative, positive and total symptoms. A negative standardized mean difference (SMD) indicates therapeutic benefit in favour of NMDARM add-on therapy and all SMD results mentioned here are statistically significant. The overall effect size for NMDARMs as a group was small for negative (SMD -0.27) and medium for total (SMD -0.40) symptoms of chronic schizophrenia. Subgroup analysis revealed medium effect sizes for D-serine and N-acetyl-cysteine (NAC) for negative (SMD -0.53 and -0.45, respectively) and total (SMD -0.40 and -0.64, respectively) symptoms, and for glycine (SMD -0.66) and sarcosine (SMD -0.41) for total symptoms. As adjuvants to non-clozapine antipsychotics, additional therapeutic benefits were observed for NMDARM as a group (SMD -0.14) and glycine (SMD -0.54) for positive symptoms; D-serine (SMD -0.54), NAC (SMD -0.45) and sarcosine (SMD -0.39) for negative symptoms; and NMDARM as a group (SMD -0.38), D-serine (SMD -0.40), glycine (SMD -1.12), NAC (SMD -0.64) and sarcosine (SMD -0.53) for total symptoms. When added to clozapine, none of the drugs demonstrated therapeutic potential, while addition of glycine (SMD +0.56) worsened positive symptoms. Taking into consideration the number of trials and sample size in subgroup analyses, D-serine, NAC and sarcosine as adjuncts to non-clozapine antipsychotics have therapeutic benefit in the treatment of negative and total symptoms of chronic schizophrenia. While glycine improves positive and total symptoms as an adjuvant to non-clozapine antipsychotics, it worsens them when added to clozapine.CNS Drugs 10/2011; 25(10):859-85. · 4.38 Impact Factor
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ABSTRACT: Brain-derived neurotrophic factor (BDNF) plays a central role in synaptic plasticity and neurogenesis. Bipolar disorder (BD) is among the most disabling of all psychiatric disorders and is associated with poor outcomes. Some studies suggest that BDNF levels decrease during mood states and remain normal during euthymia, but other studies have contradicted this paradigm. Therefore, the aim of this study was to perform a meta-analysis of all studies that measured peripheral BDNF levels in adults with BD. We conducted a systematic review using electronic databases. Inclusion criteria were studies that measured BDNF in plasma or serum in vivo in adult patients with BD. The resulting studies were compiled to measure the effect sizes (ESs) of the differences in BDNF levels between BD patients in different mood states and controls. Thirteen studies were included with a total of 1113 subjects. The BDNF levels were decreased in both mania and depression when compared to controls (ES -0.81, 95% CI -1.11 to -0.52, p < 0.0001 and ES -0.97, 95% CI -1.79 to -0.51, p = 0.02, respectively). The BDNF levels were not different in euthymia when compared to controls (ES -0.20, 95% CI -0.61 to 0.21, p = 0.33). Meta-regression analyses in euthymia showed that age (p < 0.0001) and length of illness (p = 0.04) influenced the variation in ES. There was also an increase in BDNF levels following the treatment for acute mania (ES -0.63, 95% CI -1.11 to -0.15, p = 0.01). In conclusion, BDNF levels are consistently reduced during manic and depressive episodes and recover after treatment for acute mania. In euthymia, BDNF decreases with age and length of illness. These data suggest that peripheral BDNF could be used as a biomarker of mood states and disease progression for BD.Journal of Psychiatric Research 05/2011; 45(8):995-1004. · 4.09 Impact Factor
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ABSTRACT: Memantine, a non-competitive NMDA receptor antagonist approved for Alzheimer's disease with a good safety profile, is increasingly being studied in a variety of non-dementia psychiatric disorders. We aimed to critically review relevant literature on the use of the drug in such disorders. We performed a PubMed search of the effects of memantine in animal models of psychiatric disorders and its effects in human studies of specific psychiatric disorders. The bulk of the data relates to the effects of memantine in major depressive disorder and schizophrenia, although more recent studies have provided data on the use of the drug in bipolar disorder as an add-on. Despite interesting preclinical data, results in major depression are not encouraging. Animal studies investigating the possible usefulness of memantine in schizophrenia are controversial; however, interesting findings were obtained in open studies of schizophrenia, but negative placebo-controlled, double-blind studies cast doubt on their validity. The effects of memantine in anxiety disorders have been poorly investigated, but data indicate that the use of the drug in obsessive-compulsive disorder and post-traumatic stress disorder holds promise, while findings relating to generalized anxiety disorder are rather disappointing. Results in eating disorders, catatonia, impulse control disorders (pathological gambling), substance and alcohol abuse/dependence, and attention-deficit hyperactivity disorder are inconclusive. In most psychiatric non-Alzheimer's disease conditions, the clinical data fail to support the usefulness of memantine as monotherapy or add-on treatment However, recent preclinical and clinical findings suggest that add-on memantine may show antimanic and mood-stabilizing effects in treatment-resistant bipolar disorder.CNS Drugs 08/2012; 26(8):663-90. · 4.38 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.
© Copyright 2010 Physicians Postgraduate Press, Inc.