Curious contradictions keep inflammation in the spotlight

Speaker is presenting insights on MDD.

Interest in the role of the immune system in patients with MDD has been piqued in recent years by insights from study of the effects of inflammation on brain and neural function. Our correspondent provides highlights from an ECNP Award lecture and symposium on inflammation in the pathophysiology of depression.

Professor Pariante said that research has shown that two of the reasons why cortisol may not be able to exert its anti-inflammatory effects in MDD is that glucocorticoid receptors on lymphocytes are altered and their expression down-regulated. This means that the expected restraining effects of cortisol on immune activation are lost, and instead there is further activation of the immune system.

How do neuroendocrine and immune abnormalities observed in patients with MDD inter-relate and what role does inflammation play? These are the types of questions that have kept researchers like Professor Carmine Pariante of the Institute of Psychiatry, London, UK intrigued in recent decades.

Professor Pariante delivered his Anna Monkia Award lecture to the ECNP during a symposium on “Understanding the role of inflammation in the pathophysiology of depression” and shared his career-long passion for this topic with the audience.

His curiosity stems from wanting to understand a seemingly peculiar contradiction in MDD. Depression is characterized by hypothalamic-pituitary-adrenal (HPA) overactivity, which in turn leads to hypersecretion of cortisol. Cortisol has anti-inflammatory properties, yet there is evidence that patients with depression have high levels of inflammatory biomarkers.

Professor Pariante said that research has shown that two of the reasons why cortisol may not be able to exert its anti-inflammatory effects in MDD is that glucocorticoid receptors on lymphocytes are altered and their expression down-regulated. This means that the expected restraining effects of cortisol on immune activation are lost, and instead there is further activation of the immune system.

Professor Pariante’s work has focused on trying to determine whether these changes are causal factors in the pathology of MDD, and on understanding their clinical and neurobiological relevance. In his lecture he touched on research into the neurobiology of inflammation in depression, including insights into the role indoleamine 2,3 dioxygenase (IOD) activation and of kynurenine – themes expanded upon by Professor Robert Dantzer of the MD Anderson Center in Dallas, Texas, USA.

Professor Pariante said that in MDD, particularly in patients who do not respond well to antidepressant therapy, levels of inflammatory biomarkers such as IL1beta, MIF and TNFalpha are raised. He added that this observation might, in the future, prove to be useful in predicting which patients are at risk of treatment failures.

Professor Dantzer described how current concepts of ‘immunopsychiatry’ have also flowed from serendipitous observations in clinical practice. He described how in the late 1990s, when cancer patients, particularly those with renal cell carcinoma, were treated with interferons, it was noted that patients developed severe changes in mood and cognitive symptoms characteristic of MDD.

Later research has shown that the increase in cytokines induced by interferon therapy activate IOD, leading to production of kynurenine – a ligand implicated in the regulation of immune pathways that can lead to neurotoxic or neurotropic effects.

The symposium highlighted that inflammation is in the research spotlight, with the parallel efforts of basic and clinical research suggesting a raft of new mechanisms and potential targets which may be important in the continued quest to find new ways to treat and manage MDD.

 

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.
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