Effect of Oxcarbazepine on Serum Brain Derived Neurotrophic Factor (BDNF) in Bipolar Disorder

The present study has been designed to evaluate the change in serum BDNF level with oxcarbazepine monotherapy in bipolar disorder and to explore the possibility of its neuroprotective effect.

Bipolar disorder (BD) is a chronic psychiatric illness of partially unknown pathophysiology. BD likely involves, at a molecular and cellular level, dysfunctions of critical neurotrophic, cellular plasticity and resilience pathways and neuroprotective processes. Abnormalities of neurotrophins (NTs) and other trophic factors orchestrate important alterations which could be implicated in the etiology of BD. As consistently reported in post-mortem studies, these modifications are generally associated with the disruption of distinct subregions and functions of the brain, one of which is the deregulation of neurotrophins. NTs are capable of signaling neurons, glial cells and other cellular systems to enable survival, differentiation and growth. BDNF is one of the most studied and abundant NTs in the brain, which plays an important role in a variety of neural processes during the development of both animals and humans. Initially, BDNF is important for neurogenesis, neuronal survival, and normal maturation of neural development pathways. In the adult, BDNF is not only important for synaptic plasticity and dendritic growth, but also for long-term memory consolidation. Several studies have proved that BDNF is significantly reduced in manic, hypomanic or depressive stages of BD, whereas euthymic patients exhibit BDNF levels similar to healthy controls. Rafael T. de Sousa et al have observed a significant increase in serum BDNF levels after 28 days of lithium monotherapy in patients with BD and suggested neuroprotective role of lithium due to its direct regulatory effect on BDNF. Oxcarbazepine is a commonly used mood stabilizer which has demonstrated comparable efficacy to divalproate sodium and better tolerability profile but till date there is no study on its effect on BDNF. The aim of the present study is to evaluate the change in serum BDNF level with oxcarbazepine monotherapy in bipolar disorder and to explore the possibility of its neuroprotective effect.

Twenty five (25) age and sex matched healthy individuals will serve as the control group. Control subjects will be evaluated at baseline only.

After baseline assessments, patients in test group will be prescribed Tab. Oxcarbazepine (600mg/daily in two divided dose for 1 week followed by 900mg/daily in two divided dose for next 3 weeks).

Serum BDNF was estimated by ELISA using human BDNF ELISA kit from Boster Biological Technology Co. Ltd., Pleasanton, CA.

Correlation Between Young Mania Rating Scale (YMRS) and Serum Brain Derived Neurotrophic Factor (BDNF)

The YMRS total score ranges from 0 to 60 where higher scores indicate more severe mania. Spearman's rank correlation coefficient (Spearman's ρ) was calculated for measuring correlation between YMRS score and serum BDNF.

Inclusion Criteria: All patients with the diagnosis of bipolar affective disorder (by ICD-10 DCR) current episode mania without psychotic symptoms Patients aged 18-45 years, of either sex. Patients with baseline score > 20 on the Young Mania Rating Scale (YMRS). Patients who had not taken any treatment for at least 4 weeks before inclusion. Exclusion Criteria: Patients with bipolar disorder (by ICD-10 DCR) presenting during depressive/euthymic/mixed episode. Patients who are already under treatment for the presenting conditions. Rapid cycling in the past 12 months. Previous history of refractoriness to carbazepine or oxcarbazepine. Patients with comorbid substance abuse or history of organicity Pregnant and nursing women, patients with history of major medical or neurological illness.

Frey BN, Andreazza AC, Houenou J, Jamain S, Goldstein BI, Frye MA, Leboyer M, Berk M, Malhi GS, Lopez-Jaramillo C, Taylor VH, Dodd S, Frangou S, Hall GB, Fernandes BS, Kauer-Sant'Anna M, Yatham LN, Kapczinski F, Young LT. Biomarkers in bipolar disorder: a positional paper from the International Society for Bipolar Disorders Biomarkers Task Force. Aust N Z J Psychiatry. 2013 Apr;47(4):321-32. doi: 10.1177/0004867413478217. Epub 2013 Feb 14.

Mufson EJ, Kroin JS, Sendera TJ, Sobreviela T. Distribution and retrograde transport of trophic factors in the central nervous system: functional implications for the treatment of neurodegenerative diseases. Prog Neurobiol. 1999 Feb;57(4):451-84. doi: 10.1016/s0301-0082(98)00059-8.

Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci. 2001;24:677-736. doi: 10.1146/annurev.neuro.24.1.677.

Kaplan DR, Miller FD. Neurotrophin signal transduction in the nervous system. Curr Opin Neurobiol. 2000 Jun;10(3):381-91. doi: 10.1016/s0959-4388(00)00092-1.

Post RM. Role of BDNF in bipolar and unipolar disorder: clinical and theoretical implications. J Psychiatr Res. 2007 Dec;41(12):979-90. doi: 10.1016/j.jpsychires.2006.09.009. Epub 2007 Jan 18.

Cunha AB, Frey BN, Andreazza AC, Goi JD, Rosa AR, Goncalves CA, Santin A, Kapczinski F. Serum brain-derived neurotrophic factor is decreased in bipolar disorder during depressive and manic episodes. Neurosci Lett. 2006 May 8;398(3):215-9. doi: 10.1016/j.neulet.2005.12.085. Epub 2006 Feb 9.

Fernandes BS, Gama CS, Cereser KM, Yatham LN, Fries GR, Colpo G, de Lucena D, Kunz M, Gomes FA, Kapczinski F. Brain-derived neurotrophic factor as a state-marker of mood episodes in bipolar disorders: a systematic review and meta-regression analysis. J Psychiatr Res. 2011 Aug;45(8):995-1004. doi: 10.1016/j.jpsychires.2011.03.002. Epub 2011 May 6.

de Sousa RT, van de Bilt MT, Diniz BS, Ladeira RB, Portela LV, Souza DO, Forlenza OV, Gattaz WF, Machado-Vieira R. Lithium increases plasma brain-derived neurotrophic factor in acute bipolar mania: a preliminary 4-week study. Neurosci Lett. 2011 Apr 20;494(1):54-6. doi: 10.1016/j.neulet.2011.02.054. Epub 2011 Mar 6.

Kakkar AK, Rehan HS, Unni KE, Gupta NK, Chopra D, Kataria D. Comparative efficacy and safety of oxcarbazepine versus divalproex sodium in the treatment of acute mania: a pilot study. Eur Psychiatry. 2009 Apr;24(3):178-82. doi: 10.1016/j.eurpsy.2008.12.014. Epub 2009 Mar 25.