Depression may be linked to chronic inflammatory processes in the body and brain, according to a review by Professor Raz Yirmiya. Research shows that factors such as stress and inflammation activate immune cells in the brain, which eventually become depleted, worsening depression.
Depression is one of the most common psychiatric conditions and a significant cause of human suffering.
Although research has made significant progress in understanding the underlying biological processes, the exact mechanisms that drive depression remain unclear, making it difficult to develop more effective treatments.
In recent decades, a new hypothesis has gained traction: inflammation may play a central role in depression. According to Professor Raz Yirmiya of the Hebrew University of Jerusalem, studies show that chronic inflammation, both in the brain and in the body, may contribute to the onset and maintenance of depression.
Yirmiya reviewed the history of research in this area, noting that inflammation often elevates immune markers in people with depression and that certain anti-inflammatory treatments can alleviate symptoms in some cases.
The search methodology, focused on identifying the 100 most cited experimental articles listed in the ISI Web of Science, ensured an unbiased selection of references.
The four main sections of this review summarize the substantial evidence supporting the inflammatory basis of depression, highlighting:
The elevation of inflammatory markers in individuals with depression in general and in several subpopulations and specific conditions in particular;
The induction of depressed mood and related symptoms after exogenous administration of inflammatory stimuli;
Evidence showing that conventional antidepressants have anti-inflammatory properties and that anti-inflammatory drugs can act as effective antidepressants in certain cases;
Interactions between inflammatory processes and specific brain regions and neurochemical systems are believed to underlie the development of depression.
Experimental studies have shown that healthy people who received agents that activate the immune response experienced temporary depressive symptoms, which could be controlled with antidepressants or anti-inflammatory drugs.
This suggests that the inflammatory response may be closely linked to depressive symptoms. The review explores how factors such as stress and traumatic events can activate immune cells in the brain, called microglia.
The initial activation of these cells can, in the long term, lead to their depletion and worsening of depressive symptoms. This cycle, activation and subsequent degeneration of microglia, could be a mirror of the processes that maintain depression over time.
Professor Yirmiya’s research also suggests that certain groups, such as the elderly, people with chronic physical illnesses, and those who have faced adversity in childhood, are particularly susceptible to depression triggered by inflammation.
The review proposes that these insights could pave the way for more personalized treatments that take into account each patient’s inflammatory profile.
Anti-inflammatory and microglial-protective therapies may therefore be an effective alternative in some cases, offering new treatment options where conventional antidepressants have failed.
This study highlights the potential for personalized immunological approaches to depression, signaling an important shift in the field. By targeting treatments to patients’ specific biological needs, we may be able to help more people find relief from a condition that continues to be a leading cause of global disability.
A summarized model of the inflammatory basis of depression.
A) Under quiescent physiological conditions, bidirectional communication between peripheral organs and the brain maintains homeostasis and adaptive neurobehavioral functioning.
The brain is protected by the blood-brain barrier, comprising tight junction proteins (e.g., claudin 5 − Cldn5) and astrocytic endfeet. Thus, information from the periphery to the brain and vice versa is mediated by specific pathways (e.g., vagus nerve, sympathetic nervous system, and hormonal signals).
Protective information from the gut is transmitted by microbiome-derived molecules, e.g., short-chain fatty acids (SCFAs), serotonin, and GABA. Mood is regulated by multiple connections between limbic structures and frontal cortical areas, including the anterior cingulate cortex (ACC), ventromedial and medial prefrontal cortex (vmPFC and mPFC), supplementary motor area (SMA), striatum, amygdala, and hippocampus (red arrows).
B) Within the brain, interactions between multiple cell types contribute to adaptive behavior, mood, and cognition. Neuroplasticity involves the formation and pruning of synapses (blue and white neuronal dendritic spines, respectively), as well as neurogenesis from neural precursor cells (NPCs).
These interactions are mediated by neurotransmitters and neuromodulators (e.g., glutamate (Glu), GABA, serotonin (5-HT), norepinephrine (NE), dopamine (DA), ATP, D-Serine, and prostaglandin-E2 (PGE2)), growth factors (e.g., BDNF, IGF-1, GDNF, VEGF), low-level cytokines, checkpoint ligands, and their receptors (e.g., CD200-CD200R, CX3CL1-CX3CR1). The synthesis of serotonin from tryptophan is facilitated by tryptophan hydroxylase (TH) and contributes to mental health.
C) During infection, injury, neurological conditions, or exposure to chronic psychological stress, immune cells secrete inflammatory cytokines, chemokines, prostaglandins, and neopterin, and the liver secretes acute phase proteins (APPs). LPS leakage from the GI tract further promotes inflammatory processes, while the secretion of SCFA, serotonin, and GABA (which exert anti-inflammatory effects) is suppressed.
Inflammatory mediators increase BBB permeability, for example by downregulating Cldn-5, and can therefore penetrate more easily into the brain, together with the infiltration of immune cells, particularly monocytes. All these processes are bidirectionally connected to the activation of the sympathetic nervous system (represented by wider green arrows) and stress-related hormonal systems.
Depressive symptoms are induced by inflammation-associated brain changes, including increased subcallosal ACC reactivity and reduced connectivity (represented by thinner red arrows) of the ACC to the ventral striatum, mPFC, and amygdala (resulting in disturbed emotional regulation), suppressed striatal dopamine levels and neural reactivity to reward, along with reduced striatal connectivity to the vmPFC (resulting in anhedonia) and the SMA (resulting in psychomotor retardation).
D) Within the brain, inflammation-induced changes include:
1) Proliferation of microglia and alterations in morphological, transcriptional, and biochemical parameters, including activation of IDO and KMO. These enzymes elevate the production of the kynurenine metabolite QUIN, which pathologically activates neuronal NMDA receptors.
2) Astrocytic activation and secretion of several inflammatory mediators.
3) Reduced secretion of neurotrophic factors and suppression of neurogenesis.
4) Neuronal changes such as increased pruning and reduced formation of synapses and dendrites, reduced secretion of checkpoint molecules, increased production of danger signals (e.g. HMGB1 and soluble fractalkine (sCX3CR1), and decreased serotonin synthesis.
E) Long-term depression (many years in humans or weeks in rodents) is associated with microglial decline and degeneration, reflected by microglial apoptosis, reduced density, assumed dystrophic morphology, and transcriptional changes. This condition is particularly evident in females. Astrocytes also undergo apoptosis, decreased density, and degeneration.
Severe decreases in neurotrophic factors continue to contribute to synapse and dendrite atrophy and further decrease in neurogenesis. These changes are associated with shrinkage of entire brain areas, such as the hippocampus and prefrontal cortex.
READ MORE:
The inflammatory underpinning of depression: An historical perspective
Raz Yirmiya
Brain, Behavior, and Immunity. Volume 122, November 2024, Pages 433-443
Abstract:
Over the last thirty years, substantial evidence has accumulated in support of the hypothesis that dysregulation of inflammatory processes plays a critical role in the pathophysiology of depression. This review traces the evolution of research supporting this link, discussing key findings from several major investigative fronts: Alterations in inflammatory markers associated with depression; Mood changes following the exogenous administration of inflammatory challenges; The anti-inflammatory properties of traditional antidepressants and the promising antidepressant effects of anti-inflammatory drugs. Additionally, it explores how inflammatory processes interact with specific brain regions and neurochemical systems to drive depressive pathology. A thorough analysis of the 100 most-cited experimental studies on the topic ensures a comprehensive, transparent and unbiased collection of references. This methodological approach offers a panoramic view of the inflammation-depression nexus, shedding light on the complexity of its mechanisms and their connections to psychiatric categorizations, symptoms, demographics, and life events. Synthesizing insights from this extensive research, the review presents an integrative model of the biological foundations of inflammation-associated depression. It posits that we have reached a critical juncture where the translation of this knowledge into personalized immunomodulatory treatments for depression is not just possible, but imperative.
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