The International Journal of Neuropsychopharmacology

Research Article

Number of manic episodes is associated with elevated DNA oxidation in bipolar I disorder

Márcio Gerhardt Soeiro-de-Souzaa1 c1, Ana C. Andreazzaa2a3a4, Andre F. Carvalhoa5, Rodrigo Machado-Vieiraa6a7, L. Trevor Younga2a3a4 and Ricardo Alberto Morenoa1

a1 Mood Disorders Unit (GRUDA), Department and Institute of Psychiatry, School of Medicine, University of Sao Paulo, Brazil

a2 Department of Psychiatry, University of Toronto, ON, Canada

a3 Centre for Addiction and Mental Health, Toronto, ON, Canada

a4 Mental Health Research Institute, Melbourne, Australia

a5 Department of Clinical Medicine, Federal University of Ceará, Brazil

a6 Department and Institute of Psychiatry, Laboratory of Neuroscience, School of Medicine, University of Sao Paulo, Brazil

a7 Center for Interdisciplinary Research in Applied Neurosciences, University of São Paulo, Brazil


Bipolar disorder (BD) is a major public health problem characterized by progressive functional impairment. A number of clinical variables have been associated with progression of the disease, most notably number of affective episodes and presence of psychotic symptoms, both of which correlate with greater cognitive impairment, lower response rates for lithium, and possibly lower levels of neurotrophic factors. Oxidative damage to cytosine and guanosine (8-OHdG) has been described as a modulator of DNA methylation, but the extent of DNA oxidative damage involvement in BD remains unclear. The aim of this study was to evaluate the extent of DNA oxidative damage to 8-OHdG and 5-methylcytosine (5-HMec), as well as global methylation (5-Mec), in BD patients and healthy controls. Potential association with clinical variables was also investigated. DNA levels of 8-OHdG, 5-HMec and 5-Mec were measured in 50 BD type I patients and 50 healthy controls. DNA 8-OHdG levels were higher in BD patients compared to healthy controls and found to be positively influenced by number of previous manic episodes. BD subjects had lower levels of 5-HMec compared to controls, whereas this measure was not influenced by the clinical features of BD. Number of manic episodes was correlated with higher levels of 8-OHdG, but not of 5-Mec or 5-HMec. Lower demethylation activity (5-HMec) but no difference in global 5-Mec levels was observed in BD. This finding suggests that oxidative damage to 8-OHdG might be a potential marker of disease progression, although further prospective cross-sectional studies to confirm neuroprogression in BD are warranted.

(Received August 10 2012)

(Reviewed October 11 2012)

(Revised November 27 2012)

(Accepted January 11 2013)

(Online publication March 01 2013)

Key words

  • Bipolar disorder;
  • 8-hydroxy-2-deoxyguanosine;
  • 5-hydroxymethylcystosine;
  • 5-methylcytosine;
  • oxidative stress


c1 Address for correspondence: Dr M. G. Soeiro-de-Souza, Ovidio Pires de Campos, 785, Instituto de Psiquiatria, 3° andar norte, CEAPESQ sala 12. CEP 05403-010, São Paulo, Brazil. Tel.: 55 11 26616648 Fax: 55 11 26617894 Email: