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Oxidatively-induced DNA damage has previously been associated with bipolar disorder. More recently, impairments in DNA repair mechanisms have also been reported. We aimed to investigate oxidatively-induced DNA lesions and expression of DNA glycosylases involved in base excision repair in euthymic patients with bipolar disorder compared to healthy individuals. DNA base lesions including both base and nucleoside modifications were measured using gas chromatography-tandem mass spectrometry and liquid chromatography-tandem mass spectrometry with isotope-dilution in DNA samples isolated from leukocytes of euthymic patients with bipolar disorder (n = 32) and healthy individuals (n = 51). The expression of DNA repair enzymes OGG1 and NEIL1 were measured using quantitative real-time polymerase chain reaction. The levels of malondialdehyde were measured using high performance liquid chromatography. Seven DNA base lesions in DNA of leukocytes of patients and healthy individuals were identified and quantified. Three of them had significantly elevated levels in bipolar patients when compared to healthy individuals. No elevation of lipid peroxidation marker malondialdehyde was observed. The level of OGG1 expression was significantly reduced in bipolar patients compared to healthy individuals, whereas the two groups exhibited similar levels of NEIL1 expression. Our results suggest that oxidatively-induced DNA damage occurs and base excision repair capacity may be decreased in bipolar patients when compared to healthy individuals. Measurement of oxidatively-induced DNA base lesions and the expression of DNA repair enzymes may be of great importance for large scale basic research and clinical studies of bipolar disorder.

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Opinion statementBipolar disorder (BD) is a chronic mental illness which follows a relapsing and remitting course and requires lifetime treatment. The lack of biological markers for BD is a major difficulty in clinical practice. Exploring multiple endophenotypes to fit in multivariate genetic models for BD is an important element in the process of finding tools to facilitate early diagnosis, early intervention, prevention of new episodes, and follow-up of treatment response in BD. Reviewing of studies on neuroimaging, neurocognition, and biochemical parameters in populations with high genetic risk for the illness can yield an integrative perspective on the neurobiology of risk for BD. The most up-to-date data reveals consistent deficits in executive function, response inhibition, verbal memory/learning, verbal fluency, and processing speed in risk groups for BD. Functional magnetic resonance imaging (fMRI) studies report alterations in the activity of the inferior frontal gyrus, medial prefrontal cortex, and limbic areas, particularly in the amygdala in unaffected first-degree relatives (FDR) of BD compared to healthy controls. Risk groups for BD also present altered immune and neurochemical modulation. Despite inconsistencies, accumulating data reveals cognitive and imaging markers for risk and to a less extent resilience of BD. Findings on neural modulation markers are preliminary and require further studies. Although the knowledge on the neurobiology of risk for BD has been inadequate to provide benefits for clinical practice, further studies on structural and functional changes in the brain, neurocognitive functioning, and neurochemical modulation have a potential to reveal biomarkers for risk and resilience for BD. Multimodal, multicenter, population-based studies with large sample size allowing for homogeneous subgroup analyses will immensely contribute to the elucidation of biological markers for risk for BD in an integrative model.

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Objective: Glutamatergic/GABAergic imbalance due to autoimmune antibodies targeting N-methyl-D-aspartate receptors (NMDA-R) is considered to be one of the shared pathways between bipolar disorder (BD) and autoimmune diseases. Evidence shows female vulnerability to autoimmune disorders, and suggests a sex-specific approach in autoimmunity research in BD. We aimed to assess serum concentrations of NMDA-R antibodies and density of NMDA and GABA receptors on platelets in euthymic patients with BD in comparison to healthy individuals; and to determine the impact of sex on serum concentrations of NMDA-R antibodies and the density of NMDA and GABA receptors on platelets. Method: NMDA antibody IgG were detected in serum samples of 27 DSM IV euthymic patients with bipolar disorder (16 females, 11 males) and 33 healthy individuals (17 females, 16 males), using ELISA method. The densities of NMDA and GABA receptors on platelets were investigated using immunocytochemical methods. Results: Patients with BD presented higher serum levels of NMDA-R antibodies in comparison to healthy individuals (p<0.001). The densities of NMDA and GABA receptor on platelets were similar in both groups. The NMDA-R antibody levels were influenced by both diagnosis and sex (F=5.813, df=1, p =0.020). Tserum lithium levels showed a significant linear association with the serum NMDA-R antibody levels even adjusting for age, sex, body mass index (F=-56.26, t=-2.52, p = 0.015, CI: -101.12/-11.40). Discussion: Our findings support a potential role of NMDA-R antibodies in the underlying pathophysiology of BD, particularly for females.