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The Rise of Immuno-metabolic Depression

Exploring the intersection of depression and cardiometabolic health

Everything that you start out with is a tool, but your hope is that it actually comprises a theory.

- Cormac McCarthy, Stella Maris-

“The Rise of Immuno-Metabolic Depression” was the title of a symposium at the 2022 meeting of the PsychoNeuroImmunology Research Society (PNIRS). I was invited together with other speakers from diverse fields of psychiatric research at the symposium, where we presented results obtained from different types of studies exploring the novel concept of “Immuno-Metabolic Depression” (throughout the piece I will use the acronym IMD for the sake of conciseness).

But what is exactly IMD? In broad terms, this label is generically applied to research examining biological processes related to immunity (the body's defence system against pathogens) and metabolism (the body's conversion and utilisation of energy) in depression. Nevertheless, a clear definition of IMD is not yet available in the scientific literature and the speakers at the PNRIS symposium provided different descriptions.

I am a clinical psychologist and researcher in Psychiatry and Epidemiology at the Department of Psychiatry of Amsterdam UMC. In 2020, I proposed together with other colleagues a model of IMD, which was based on our previous research and progressively shaped in the attempt to address a specific research question.

The connection between depression and cardiometabolic diseases

The prevalence of depression among subjects with medical diseases is elevated. For instance, among subjects with cardio-metabolic diseases (e.g., coronary heart diseases, diabetes) up to 30% suffer from depression; proportion that is much lower (~5%) in the general population. Multiple complex mechanisms could explain the strong connection between depression and cardiometabolic diseases: psychological maladjustment to the disease, unhealthy behaviors (smoking, sedentariness, excessive alcohol consumptions), lack of treatment adherence, effect of medications and common underlying biological pathways influencing both conditions. A recent study showed that poor body health, particularly of the metabolic and immune systems, is a common manifestation in several neuropsychiatric disorders including depression.

Results from longitudinal cohort studies (which are studies that follow a group of subjects over an extended period of time to examine how their health changes) showed that depression subsequently increases the risk of cardiovascular morbidity and mortality with about 80%. It has been estimated that a substantial part of the increased mortality of depressed patients is due to biological dysregulations such as obesity or metabolic syndrome (high blood levels of glucose and triglycerides and lower levels of the “good” cholesterol, high blood pressure and excess fat around the waist) which are precursors of cardiometabolic conditions. However, not all individuals suffering from depression develop such biological alterations and related cardiometabolic disease.

Depression is very heterogeneous: individuals with the same diagnosis exhibit very different symptom profiles and biological mechanisms. Thus, a crucial question is “who are the depressed subjects at higher risk to develop cardiometabolic diseases?”.

Around this research question, we built our IMD model.

We started by focusing on relevant biological mechanisms for the development of cardiometabolic diseases, such as inflammation (determined by a low-grade chronic activation of the immune system) or alterations in metabolites involved in energy storage (lipids) or hormones governing the body energy intake/expenditure balance (leptin and insulin). We then examined which of the very diverse symptom profiles expressed in depression are more consistently linked with these immuno-metabolic biological alterations. We found across different studies that these immuno-metabolic dysregulations tend to cluster consistently with depressive symptoms indicating a shift in the body homeostasis toward an increased need of energy, such as increased appetite, increased sleepiness, fatigue, and leaden paralysis (that is feeling that the limbs are weighed down).

Furthermore, we showed that the connection between some of these symptoms and biological dysregulations arises from a common genetic vulnerability: for instance, subjects expressing symptoms like increased appetite during their depressive episodes had also an increased genetic risk to develop inflammatory and metabolic dysregulations.

In our model, the clustering between energy-related symptoms and biological processes is the expression of IMD. To convey my idea of IMD I often borrow the concept of “field” from physics, where a force is applied to all points in a space. If the space is depression, the area in which the IMD “field” is stronger, characterized by high expression of energy-related symptoms and immuno-metabolic biological dysregulations, is the area in which depression overlaps with cardiometabolic disease (see the schematic figure).

Image created by Yuri Milaneschi

A tool for the clinic?

Following the expression of IMD-related symptoms and biological alterations, we could identify a portion of depressed patients at higher risk of developing cardiometabolic complications. Could this application of IMD be useful in the clinic? Certainly.

The identification of patients at higher cardiometabolic risk may be relevant for secondary prevention efforts, where the cardiovascular and metabolic health status of this subgroup of depressed subjects could be more closely monitored to prevent the onset of highly disabling diseases. Furthermore, we could also think of a more direct impact on depression treatment strategies: IMD could be used as a tool to stratify and select depressed patients to offer treatments targeting specifically the identified altered biological mechanisms, such as inflammation.

We are currently testing this approach in the INFLAMED clinical trial at our department, that I am leading together with my colleague Femke Lamers. This study aims to test the efficacy of adding an anti-inflammatory medication in the treatment of a selected group of depressed patients expressing IMD features, which include elevated energy-related symptoms (increased appetite, increased sleepiness, fatigue, leaden paralysis) and raised inflammatory blood markers.

Other ongoing clinical trials are similarly testing anti-inflammatory add-on treatments for depressed subject selected with criteria in line with those of IMD, such as high levels of inflammation and depressive somatic symptoms including fatigue and appetite/sleep alterations (the INSIGHT trial in UK), or obesity (the SIMCODE trial in Germany). Results from this new generation of clinical studies will provide key insights on the validity of this stratified approach and will be helpful in the development and refinement of the IMD research hypothesis.

Multiple perspectives: the blind men and the IMD elephant.

The image of IMD described here is taken from a very specific point of observation: our point of observation, which is enabled and simultaneously limited by the type of research methodology we apply (mainly epidemiological analyses of large-scale studies). This means that our image of IMD is a partial image because it is limited to the type of data that we could measure and test in our research. This may explain, for instance, why the speakers at the PNIRS symposium provided different descriptions of IMD: partial images of the same phenomenon taken from different points of research observation.

Various groups are exploring this research area with different approaches, focusing on different depressive symptoms (e.g., anhedonia, the inability to experience pleasure), biological processes (e.g., mitochondrial respiration, the process by which cells produce energy) and subjects (e.g., those with overweight/obesity).

This multiplicity of perspectives reminded me of the ancient parable in which a group of blind men come across an elephant for the first time and try to describe it according to the limited portion of the animal’s body they were touching. One man touches the elephant's trunk and says “It's a snake”, another touches its leg and says “It's a tree”, while another touches its side and says “It's a wall”.

At the current stage of research on IMD this conceptual confusion is vital and necessary; a strict definition of IMD would only chain our scientific ingenuity.

It is only with time, when these multiple research perspectives converge and be integrated, that we will have a more comprehensive image of IMD and its potential usefulness to improve the care of depressed patients at risk for cardiometabolic consequences.

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