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Review
. 2024 Dec 18:48:101166.
doi: 10.1016/j.lanepe.2024.101166. eCollection 2025 Jan.

Immuno-metabolic depression: from concept to implementation

Brenda W J H Penninx  1 , Femke Lamers  1 , Rick Jansen  1 , Michael Berk  2 , Golam M Khandaker  3   4   5   6 , Livia De Picker  7   8 , Yuri Milaneschi  1
Affiliations
Review

Immuno-metabolic depression: from concept to implementation

Brenda W J H Penninx et al. Lancet Reg Health Eur. .

Abstract

Major depressive disorder is a common, disabling mental disorder characterized by extensive etiological and phenotypic heterogeneity. This heterogeneity makes treatment approaches imprecise and often ineffective. Insight into the underlying biological mechanisms underpinning depression and its subtypes may enable more personalized treatments. In this review, we provide an overview of immuno-metabolic depression and illustrate that significant immuno-metabolic dysregulations are present in about 20-30% of people with depression. Such immuno-metabolic depression is characterized by the clustering of 1) atypical, energy-related depressive symptoms such as hypersomnia, fatigue, hyperphagia, and possibly anhedonia, 2) systemic low-grade inflammation with elevated levels of e.g., C-reactive protein, cytokines and glycoprotein acetyls, and 3) metabolic abnormalities involving e.g., obesity, dyslipidaemia, insulin and leptin resistance. Persons with immuno-metabolic depression are at a higher risk for cardiometabolic diseases and seem to respond less well to standard antidepressant treatment. Interventions targeting inflammation, metabolism or lifestyle may be more effective treatment options for individuals with immuno-metabolic depression, in line with principles of precision psychiatry.

Keywords: Depression; Dyslipidaemia; Inflammation; Metabolic alterations; Neurobiology; Precision psychiatry.

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Conflict of interest statement

BWJHP, GMK and YM are co-investigators in the ImmunoMIND consortium, funded by UK Research & Innovation as part of the UK national Mental Health Platform. BWJHP, LDP, and MB are members of the ECNP Immuno-NeuroPsychiatry Network, and BWJHP and LDP are also members of the ECNP Meta-network Depression.

Figures

Fig. 1
Fig. 1
Overview of the three key components of Immuno-Metabolic Depression (IMD).
Fig. 2
Fig. 2
A visual, simplified overview of risk and neurobiological mechanisms involved in the development of immuno-metabolic depression. Note: Information on increased imbalance in energy supply/demand (immuno-metabolic stress) is conveyed through interoceptive signals to the brain, which orchestrates congruent physiological and behavioural energy-saving/intake responses. Various factors, such as genetic predisposition or environmental challenges (e.g., overnutrition, stress/trauma) can disrupt this homeostatic system. For instance, elevated inflammatory signalling may lead to central insulin or leptin resistance and overall disconnection in homeostatic brain hubs. As a result, the interoceptive signals regarding body energy status are misread, pushing the system towards excessive energy-saving/intake responses (e.g., increased appetite, reduced activity). These outputs may, in turn, further amplify the system’s dysregulation (e.g., increasing inflammatory signalling) setting up a self-sustaining detrimental cycle.
Fig. 3
Fig. 3
Six key facts of the impact, burden, future research needs, and potential personalized treatment options for immuno-metabolic depression (IMD).
See this image and copyright information in PMC

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