Among the studies on the causes of bipolar disorder we report one (Frey BN et al., 2013) with some interesting considerations useful for specialists. The considerations expressed by this “Network” of the International Society on Bipolar Disorder on the possible biomarkers involved in its etiopathogenesis, opens the doors to new scenarios and new diagnostic possibilities of manic-depressive illness.
Although the causes of bipolar depression remain uncertain and yet to be deciphered , studies of Neuroimaging, Peripheral Markers and Genetics have brought important new knowledge about the pathophysiological processes that underlie bipolar disorder.

Bipolar Disorders: Imaging Neuroimaging studies (
Structural , Functional and Spectroscopy) consistently demonstrated gray matter loss and impaired activation of the ventral prefrontal and anterior temporal regions in response to emotional stimuli in bipolar disorder. Structural Imaging
The most common structural alteration reported in bipolar disorder is the increased volume of the lateral ventricle and higher rates of white matter hyperintensity :

  • lithium appears to lead to an increase in the volume of gray matter in the prefrontal cortex, amygdala and hippocampus;
  • studies on bipolar disorder in childhood highlight the involvement of fronto-limbic structures;
  • microstructural alterations of the myelinated tracts of the prefrontal cortex were observed (connectivity between the limbic and striatal subcortical regions with the prefrontal cortex);
  • the decrease in the fronto-temporal white matter anisostropy would make it possible to distinguish bipolar disorder from major depression.

Functional Imaging
It would identify patterns of brain activation or connectivity that could potentially predict the consequent transformation of high-risk individuals towards bipolar disorder, helping in the differential diagnosis of mood disorders (unipolar vs bipolar) and / or in the orientation of therapeutic choice.

It would allow to highlight the alterations in brain biochemistry in the context of a normal anatomy (n-acetyl-aspartate, glutamate, glutamine, myo-inositol studied in bipolar disorder).

Bipolar Disorders: Markers
Studies on Peripheral Markers(BDNF, Inflamation, Oxidative Stress) found a reduction in the levels of some neurotrophic factors and an increase in proinflammatory cytokines and markers of oxidative stress. Since 1970 there has been a strong interest in researching peripheral markers in patients with mood disorders, and scientific research has focused on the hypothalamus-pituitary-adrenal gland axis and on monoaminergic brain neurotransmitters.

Subsequently, studies on the reduction of peripheral BDNF levels in mania have also been reported.

IL-2, IL-6, IL-8, TNF-alpha are the inflammatory cytokines that would be increased in the depressive and manic phases. TNF-alpha, IL-13 and apolipoprotein A1 appear to be associated with bipolar disorder.

Oxidative Stress
TBARS (substance reactive to thiobarbituric acid) and NO (nitric oxide) would be increased in all phases of bipolar disorder. Several studies would suggest a connection between inflammation, oxidative stress and neuroplasticity.

Genetics Studies Genetics
Studies (Genome-wide association studies, Polygenic exploration, Transcriptomic and convergent functional genomic approaches) have identified several potential candidate genes associated with an increased risk of developing bipolar disorder involving circadian rhythm, neuronal development and calcium metabolism. The identifications of bipolar disorder biomarkers

Together, these findings provide the basis for the identification of potential biomarkers of disease expression and vulnerability and could be useful in helping understand the course of bipolar disease and response to treatment. This information can be further elaborated as in other areas of medicine, where validated biomarkers guide the decision and clinical action.

  • Biomarkers Network from International Society for Bipolar Disorder (ISBD-BIONET)
  • Frey BN, Andreazza ACX, Houenou J, Jamain S, Goldstein BI, Frye MA, Leboyer M, Berk M, Mahli 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.

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