REVIEW Depression: an inflammatory illness? Rajeev Krishnadas, 1,2 Jonathan Cavanagh 1,2 ABSTRACT Major depressive disorder (MDD) is associated with significant morbidity and mortality. Findings from preclinical and clinical studies suggest that psychiatric illnesses, particularly MDD, are associated with inflammatory processes. While it is unlikely that MDD is a primary ‘inflammatory’ disorder, there is now evidence to suggest that inflammation may play a subtle role in the pathophysiology of MDD. Most of the evidence that links inflammation to MDD comes from three observations: (a) one-third of those with major depression show elevated peripheral inflammatory biomarkers, even in the absence of a medical illness; (b) inflammatory illnesses are associated with greater rates of MDD; and (c) patients treated with cytokines are at greater risk of developing major depressive illness. We now know that the brain is not an immune privileged organ. Inflammatory mediators have been found to affect various substrates thought to be important in the aetiopathogenesis of MDD, including altered monoamine and glutamate neurotransmission, glucocorticoid receptor resistance and adult hippocampal neurogenesis. At a higher level, inflammation is thought to affect brain signalling patterns, cognition and the production of a constellation of symptoms, termed ‘sickness behaviour’. Inflammation may therefore play a role in the aetiology of depression, at least in a ‘cohort’ of vulnerable individuals. Inflammation may not only act as a precipitating factor that pushes a person into depression but also a perpetuating factor that may pose an obstacle to recovery. More importantly, inflammatory markers may aid in the diagnosis and prediction of treatment response, leading to the possibility of tailored treatments, thereby allowing stratification of what remains a heterogenous disorder. INTRODUCTION Mental, neurological and substance use disorders account for a significant proportion of the global burden of disease, surpassing that of cardiovascular disease and cancer. Major depressive disorder (MDD) is the third leading cause of disease burden. 1 Our understanding of the pathophysiology of MDD, while increasing, remains incomplete, despite major research funding over the past 20 years. A number of biological findings have been replicated and are proving fruitful in terms of research outcomes. However, bringing these find- ings together and translating those to effective treatments remain elusive. 2 The past two decades have witnessed a burgeoning area of preclinical and clinical research linking psychiatric illnesses to inflammatory processes. Most of this has arisen from an attempt to link these illnessesdparticularly MDDdwith ‘stress’ biology, and have raised the possibility of an ‘initial common pathway ’ whereby immune/ inflammatory and stress biomarkers combine to cause changes in brain structure and function. 3 Most of the evidence that links inflammation and MDD comes from three observations. 4 1. MDD (even in the absence of medical illness) is associated with raised inflammatory markers. 2. Inflammatory medical illnessesdboth CNS and peripheraldare associated with greater rates of major depression. 3. Patients treated with cytokines for various illnesses are at increased risk of developing major depressive illness. In this review, we discuss briefly each of the above observations. We then go on to discuss the possible mechanisms involved in the aetiopatho- genesis of MDD, in the context of inflammation. Finally, we discuss the possible translational implications of these findings. MDD IS ASSOCIATED WITH INCREASED INFLAMMATORY MARKERS Inflammation has been linked to depression in a number of ways. 45 More robust findings include: 1. Mean array value for inflammatory mediators/ markers is higher in MDD than normal, non- depressed subjects. 2. Approximately one-third of people with MDD have higher levels of inflammatory markers compared with the normal, non-depressed population. 3. These increases are more modest than in autoimmune or infectious diseasedfor example, 2e3 times higher than in healthy controls. However, as Raison and Miller point out, small physiological differences can have profound consequences over time, especially if they change in a consistent direction. Similar findings have been found in cardiovascular disease, stroke and diabetes. Alterations in serum and CSF concentrations of a number of inflammatory markers, including cytokines, chemokines and acute phase reactant proteins, have been found in patients with MDD, and exist in the absence of comorbid medical illness. The most replicated findings pertain to raised C reactive protein (CRP) and proin- flammatory cytokinesdtumour necrosis factor a (TNFa) and interleukin (IL)-6dconfirmed by at least two recent meta-analyses. 6 7 Both meta- analyses found significant heterogeneity among the included studies; however, there was no evidence of publication bias. More interestingly, there is evidence to say that this abnormality is corrected to an extent in response to antidepressant treatment. 1 Sackler Institute of Psychobiological Research, Institute of Health and Wellbeing, Southern General Hospital, Glasgow, UK 2 College of MVLS, University of Glasgow, Glasgow, UK Correspondence to Dr J Cavanagh, Sackler Institute of Psychobiological Research, Institute of Health and Wellbeing, Southern General Hospital, Glasgow G51 4TF, UK; jonathan.cavanagh@glasgow. ac.uk Received 4 November 2011 Revised 1 February 2012 Accepted 6 February 2012 Published Online First 15 March 2012 J Neurol Neurosurg Psychiatry 2012;83:495e502. doi:10.1136/jnnp-2011-301779 495 Neuropsychiatry group.bmj.com on May 3, 2012 - Published by jnnp.bmj.com Downloaded from