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

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 outpatients with DSM-IV-defined refractory schizophrenia were randomly 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 included 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 patients receiving memantine had a decrease of at least 50% in BPRS total score and were considered as responders. There was no difference in mean ± SD serum BDNF levels before and after memantine (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; difference = -0.002, P = .91) treatments. In the memantine group, a statistically nonsignificant decrease of serum BDNF levels in responders 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 cohort 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 treatment response.7,8 However, a difference in serum BDNF levels between responders and nonresponders to memantine was not found in this sample.

There are some limitations in the present study. First, we assessed 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 responders and nonresponders to memantine may be due to the relatively 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 improvement in positive and negative symptoms with adjunctive treatment to clozapine with memantine in patients who have refractory schizophrenia is associated with serum BDNF level variances.

Trial registration: clinicaltrials.gov Identifier: NCT00757978

References

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 deficits 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-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 chronically 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 concentration of brain-derived neurotrophic factor with electroconvulsive therapy: a pilot study in patients with major depression. J Clin Psychiatry. 2007;68(4):512-517. PubMed

8. Fernandes B, Gama CS, Massuda R, et al. Serum brain-derived neurotrophic factor (BDNF) is not associated with response to electroconvulsive 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. 2009;43(15):1200-1204.doi:10.1016/j.jpsychires.2009.04.010

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 neurotrophic 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

[email protected]

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 Institute 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 interest. 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.

doi:10.4088/JCP.09l05388

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