Biomarkers in bipolar

Doctor Bergink, Netherlands started proceedings by discussing inflammatory markers in bipolar spectrum disorders. She focussed on the post-partum onset of psychosis and the links between autoimmune diseases, such as inflammatory bowel disease and multiple sclerosis, and bipolar disorder. There is a high risk of bipolar disorder onset or exacerbation immediately following birth, and Dr Bergink postured as to whether there could really be immunological dysfunction underlying these mood disorders.

A FACS analysis found that women with post-partum psychosis have more monocytes in their blood compared with controls. The same women also had higher expression of pro-inflammatory monocyte genes such as IL1, IL6 and TNF. Healthy postpartum mothers have elevated T-cell counts but in these patients with psychosis, the T-cells were suppressed. Dr Bergink concluded that while there are clearly immune-related biomarkers, the clinical significance is still unclear.

A vicious cycle

Doctor Grande, Spain went on to consider neurotrophins, brain interconnectivity and neuronal survival in bipolar disorder. She reminded us of the Kindling hypothesis; systemic toxicity such as oxidative stress and inflammation affects all cells, leading to cell damage, pathological reorganisation, stress, mania and then back to further cell damage in a repeating cycle. Impairment in neuroplasticity and cellular resilience may play an important role in the pathophysiology of bipolar disorder.

The influence of neurotrophins on bipolar disorder

Dr Grande also found that neurotrophins decrease during an acute episode. Therefore, if we can find a way to improve neuronal survival then we can improve treatment for patients and their functional daily life. However, the polarity of the episode could influence trajectory levels of brain-derived neurotrophic factor (BDNF). For example, depressed patients had an increase in BDNF over time whereas patients with a manic or mixed episode had decreased BDNF over time.

Dr Grande seemed optimistic that further investigations into the BDNF pathway could lead to clinical predictors or effective treatments that prevent the progression of bipolar disorder.

GSK3β as a mood regulator

Doctor Bendetti, Italy focused on the role of GSK3β in his talk on the effect of stress and lithium on both GSK inhibition and white matter integrity in bipolar disorder.

GSK3β is at the crossroad of signalling pathways linking monoaminergic neurotransmission, neurotrophins, neuroinflammation and the biological clock. He suggested that GSK3β could be a central modulator in mood regulation as GSK3 is hyperactivated in mood disorders, downstream of monoaminergic signalling, BNDF, Akt and/or DISC1. However, substrates of GSK3 that mediate its functions in these conditions have not yet been established and require further research.

Changes in white matter volume

White matter integrity is disrupted in bipolar disorder, as can be seen with diffusion tensor imaging, and appears to be influenced by genes, stress and lithium in bipolar disorder. Lithium protects white matter integrity, which suggests the clinical effects of lithium are associated with a neurotrophic effect on the whole brain, probably mediated by GSK3β inhibition. This inhibition, which is a protective factor alone, is consistent with perspectives which emphasise the effects of neurotransmitters and other substances on many cellular lineages via volume transmission through a global molecular network in the whole brain. Further prospective research will clarify if these changes in genetic machinery could influence brain development and wiring cased by exposure to stress and epigenetics, and if interventions targeting these mechanisms will prevent the detrimental effects of stress and bipolar disorder on the brain and restore its function.

Professor McDonald, Ireland brought the session to a close with his talk on neuroimaging deviations in bipolar disorder: genetic liability and structural disconnectivity. Professor McDonald found reduced global white matter in bipolar patients and a reduction in hippocampal volume. However there was excess lateral temporal grey matter in patients taking lithium. White matter disorganisation of longitudinal, commissural and anterior limbic system tracts are trait abnormalities of bipolar disorder.

Clearly progress is being made in the development of biomarkers, and hopefully further research will yield biomarkers that can be used reliably in clinical practice.

Continue the conversation on Twitter #ECNP2014