What Does Inflammatory Depression Look Like, and How Can We Assess It?
Depression can look very different from one person to another. Our study asks whether a particular pattern of symptoms may point to inflammatory depression, and whether current depression scales are equipped to capture it.
When we think about depression, we often think first about sadness, hopelessness, or losing interest in things we once enjoyed. But depression is much more diverse than that. Two people can receive the same diagnosis and experience very different combinations of depressive symptoms.
For example, even the same symptomatologic areas can be affected in opposite ways: some people may sleep much more than usual, while others struggle with insomnia and have difficulty sleeping. Some people may experience increased appetite and weight gain, while others may eat less and lose weight. For some people, depression can also have a particularly physical manifestation, with persistent fatigue, difficulties concentrating, or simply feeling as though the body has run out of energy.
As a researcher and adjunct professor at IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, my work focuses on the biological and clinical factors involved in mood disorders for precision psychiatry. I am also a work-package leader in the ASPIRE study, which has been described before in Inspire the Mind.
In our recent study as part of the project, we asked whether some of these symptoms could help us better characterise an emerging concept in mental health research: the inflammatory subtype of major depressive disorder.
What Does Inflammation Have to Do With Depression?
Inflammation is part of the body’s natural defence system. When we have an infection or injury, our immune system produces an inflammatory response to help us recover.
But inflammation can also become persistent or dysregulated. Over the past few decades, researchers have found evidence of low-grade increased inflammatory activity in a subgroup of people with depression. Studies have linked inflammatory markers with symptoms including fatigue, changes in appetite and sleep, and anhedonia, the reduced ability to experience pleasure.
Higher levels of inflammation have also been associated with poorer responses to some conventional antidepressant treatments. This is particularly important considering that around one in three people with depression do not respond adequately to standard antidepressant treatment.
This does not mean that all depression is caused by inflammation, or that everyone experiencing these symptoms has increased inflammation. Depression is complex and can arise through many interacting biological, psychological, and social pathways.
Instead, the idea is that inflammation may play a particularly important role for some people with depression.
And identifying those people is where things get complicated.
The Problem: What does “inflammatory depression” actually look like?
Although research into inflammation and depression has grown rapidly, researchers have not yet agreed on exactly which symptoms should characterise an inflammatory subtype of major depressive disorder.
That matters.
If different studies define and measure this type of depression differently, their findings become harder to compare. We may even miss treatment effects simply because the questionnaires used in a clinical trial do not ask about the symptoms most relevant to inflammation. So, rather than starting with another laboratory experiment, we started with a deceptively simple question:
Which symptoms should we actually be looking for?
Asking experts to reach a consensus
We used a method called the Delphi method, in which experts answer a series of structured questionnaires designed to gradually identify areas of agreement. Our international panel brought together researchers, mental health professionals, including psychiatrists and psychologists, and people with lived experience of depression.
Members of the international ASPIRE consortium evaluated symptoms that previous research had linked to inflammation. They could also suggest additional symptoms that they believed were relevant.
This process identified ten candidate symptom domains:
fatigue or low energy
sleeping too much, aka hypersomnia
increased weight or appetite
cognitive difficulties, such as problems concentrating
lack of motivation
anhedonia, or reduced pleasure
loss of interest
a sensation of physical heaviness sometimes called leaden paralysis
slowed movement or thinking
insomnia
We then asked an independent group of experts from the European College of Neuropsychopharmacology’s Immuno-Neuropsychiatry Network to evaluate them. Five symptoms received support from both expert groups: fatigue or low energy, hypersomnia, increased weight or appetite, cognitive difficulties, and lack of motivation.
Importantly, this is a first framework rather than a diagnostic checklist. Some domains received weaker agreement than others, and further studies will need to test whether these symptoms actually correspond to biological markers of inflammation.
Are We Asking Patients the Right Questions?
Once we identified these symptoms, another problem became apparent. Many of the questionnaires traditionally used to measure depression do not assess them very well.
For example, commonly used scales can focus more heavily on what are sometimes considered “typical” or melancholic symptoms of depression, such as the aforementioned anhedonia, lack of emotional reactivity to positive events, and depressive symptoms being much worse in the morning. In contrast, less attention is given to symptoms that are not melancholic, such as sleeping too much, increased appetite, lack of motivation, or bodily heaviness.
Among the questionnaires we evaluated, the Inventory of Depressive Symptomatology (IDS) and its shorter version, the Quick Inventory of Depressive Symptomatology (QIDS), provided the most comprehensive coverage of the symptom profile identified in our study. This may sound like a technical detail about questionnaires. It isn’t. If we do not ask about symptoms, we are much less likely to understand their importance.
What People Living With Depression Told Us
This was particularly clear when we asked people with lived experience of depression to contribute to the study. Eleven members of the ASPIRE Patient Advisory Board evaluated how these symptoms affect different aspects of their lives. The identified symptoms were perceived as negatively affecting important areas, including relationships, leisure activities, work or education, and independence.
They also highlighted something perhaps even more important: the severity of these symptoms was not perceived as being extensively assessed or discussed during mental healthcare. Only fatigue/low energy and insomnia reached consensus as symptoms whose severity was extensively addressed by mental-health professionals. A person may therefore be struggling with exhaustion, motivation or cognitive difficulties that profoundly affect everyday life, while these experiences remain relatively peripheral in a clinical conversation.
Where Do We Go From Here?
Our findings do not establish a new diagnosis, nor do they mean that symptoms can be used on their own to determine whether someone has inflammation. Instead, they provide a framework that researchers can now test prospectively alongside biological measures of inflammation. If the associations are confirmed, better symptom assessment could help researchers identify patients for clinical trials and understand who might benefit from treatments targeting immune-inflammatory pathways.
The study therefore points towards a broader goal in psychiatry: moving away from assuming that one diagnosis represents one biological process and towards understanding the different pathways that may lead to apparently similar symptoms.
For clinicians, there is also a much simpler message: Ask about the symptoms that matter to people.
Fatigue, motivation, sleep, appetite and cognitive difficulties can easily be considered as secondary features of depression. For the person experiencing them, however, they may be among the most disabling parts of the illness.
Understanding depression better may therefore begin not only with new biomarkers or new treatments, but with something surprisingly basic: making sure we are asking the right questions.
