This June we launched the ASPIRE study, aiming to understand how we can use inflammation blood tests to identify people with depression who can be helped by anti-inflammatories. Led by myself at King’s College London, the ASPIRE study (‘Advanced stratification of people with depression based on inflammation’) brings together investigators from 8 countries (Australia, Belgium, France, Germany, Italy, South Africa, The Netherlands, USA), including two associations of people with lived experience of mental health problems.
As a psychiatrist dedicated to helping people with depression, the most frustrating aspect of my work is the difficulty in predicting who will respond to which antidepressant strategy. This is particularly relevant to people with “treatment-resistant” depression, who have not improved with two or more standard antidepressants. This study may change this. This is our aspiration.
At Inspire the Mind, we have often discussed the clear evidence that 20-30% of people with depression, and even more people with depression who are not responding to antidepressants, have increased levels of inflammation in the blood. Inflammation is activated when we face a threat that could lead to infections, such as a physical assault, but it can also be activated by being stressed. Indeed, during depression, the increased inflammation is part of a general activation of the biological stress response system: ultimately, depression is, both psychologically and biologically, a condition of chronic stress.
From a clinical point of view, this activation of the inflammatory system directly affects the brain, making the person more likely to stay depressed (for example, by changing how brain cells and brain areas communicate between themselves) and less likely to respond to antidepressants (for example, by changing the brain chemicals that are the target of antidepressants). As such, dampening this inflammation with anti-inflammatory medications – drugs such ibuprofen, celecoxib or aspirin, used for inflammatory disorders such rheumatoid arthritis – should have beneficial antidepressants effects, by rescuing the brain changes induced by the inflammation.
Indeed, some studies, including ours, have demonstrated that adding an anti-inflammatory medication to an antidepressant improves depressive symptoms in people who had not previously responded to antidepressants – but only if their levels of blood inflammation are measurably high. Other studies in people with low levels of inflammation have shown no such beneficial effects.
And this where ASPIRE steps in to try to address exactly this question: what is the best blood inflammatory biomarker(s) that accurately predict successful response to an anti-inflammatory? And, connected to this question, are there clinical features that accurately predict the response to anti-inflammatories: for example, the type of depressive symptoms a person experience, or physical health abnormalities such as obesity and excessive sugar levels in the blood? Moreover, are there brain changes induced by inflammation that accurately predict the response to anti-inflammatories and that could be measured by taking pictures of the brain via brain scans? We will then put all of this information together in a “decision tool” and test our ability to predict the response to anti-inflammatories using this decision tool in a new clinical trial.
The work is divided across seven work packages.
Work Package 1: Systematic Reviews and Meta-Analyses of Inflammation Related Clinical Predictors. We aim to gather a large amount of data by thoroughly reviewing previous research investigating anti-inflammatory medications in depression. We will also perform additional analyses to see how factors like age and sex-at-birth affect treatment response.
Work Package 2: Laboratory Analyses of Inflammation Related Blood-Based Biomarkers. We will focus on well-known blood-based inflammatory biomarkers, which are biological molecules measured in the blood and used to assess a person’s levels of inflammation. We will re-analyse biomarkers from over 1,200 participants across many clinical trials using anti-inflammatory medications in people with depression.
Work Package 3: Meta-Analysis of Blood-Based Biomarkers. We will combine all the data gathered from work packages 1 and 2, including data from other collaborators, that focus on biomarkers measured in blood and that are related to the immune system and metabolism.
Work Package 4: Meta-Analysis of Inflammation-Related Neuroimaging Markers. We will look at alterations in the brain's structure (structural data) and how different brain regions function and interact with one another (functional data), from clinical trials using anti-inflammatory medications in people with depression.
Work Package 5: Generating a Machine Learning Tool. We will use a machine-learning approach to develop a decision tool that identifies individuals with depression who will respond to an anti-inflammatory and thus benefit from accessing these drugs.
Work Package 6: Feasibility, Proof-of-Concept Study to Test Decision Tool. We will run a 12-week study to see if we can use the decision tool to identify the people with depression who will improve using an anti-inflammatory.
Work Package 7: Views of People with lived experience and Dissemination Findings. The views of people with lived experience (PWLE) are at the core of the ASPIRE project. In this work package, we will explore opinions on the notions of using anti-inflammatories to treat depression. We will also focus on sharing all the research we have done in ASPIRE with the wider public, for awareness and education.
And indeed, at the heart of the study are people with lived experience. Alongside playing a crucial role in the conception and design of ASPIRE, the study will amplify the voices of those affected by depression and advocate for better treatments and understanding.
The study aims to change public perception of the role of inflammation in mental health and, in general, on the importance of mind-body interaction in mental disorders.
Further information on the study can be found at www.aspirestudy.org, @aspireresearchstudy on Instagram and @theaspirestudy on X.
Members of ASPIRE Consortium
King's College London, UK: Carmine Pariante, Anthony Woods, Caitlin Pentland, Courtney Worrell, Giulia Lombardo, Lea Schmid, Luca Sforzini, Melisa Kose, Naghmeh Nikkheslat, Nicole Mariani, Zuzanna Zajkowska, Valeria Mondelli
Amsterdam University Medical Centre, The Netherlands: Brenda Penninx, Femke Lamers, Yuri Milaneschi
Cardiff University, UK: Neil Harrison
Charité University, Berlin, Germany: Christian Otte, Julian Hellmann-Regen, Deniz Dogan, Stefan Gold
Deakin University, Australia: Jane Meier, Michael Berk, Olivia Dean
Emory University, Atlanta, USA: Andy Miller, Jennifer Felger
Foundation FondaMental, Paris, France: Federico Cevoli, Marion Leboyer, Bruno Aouizerate
IRCCS Ospedale San Raffaele, Milan, Italy: Alessandro Mioli, Benedetta Vai, Camilla Monopoli, Francesco Benedetti, Sara Poletti
IRCCS Fatebenefratelli, Brescia, Italy: Floriana De Cillis, Annamaria Cattaneo
Libera Virginia Cavaliere
Istituto Superiore di Sanità, Rome, Italy: Claudia Delli Colli, Igor Branchi
GAMIAN Europe, Brussels, Belgium: Erik Van Der Eyken, Fanni-Laura Mäntylä, Nigel Olisa
South African Depression and Anxiety Group (SADAG), Cape Town, South Africa: Cassey Chambers Ofentse Hanyana
University of Antwerp, Belgium: Céline Wessa, Livia De Picker, Manuel Morrens, Violette Coppens
University of Bristol, UK: Golam Khandaker, Eimar Foley
University of Cape Town, South Africa: Dan Stein, Nadia Hoffman, Shuretta Thomas
University of Melbourne, Australia: Ben Harrison, Christopher Davey
University of Muenster, Germany: Bernhard Baune