Modulation of neuroimmune cytokine networks by antidepressants: implications in mood regulation

Abstract

Major Depressive Disorder (MDD) is increasingly recognized as a neuroinflammatory condition characterized by dysregulated cytokine networks. This comprehensive review examines the immunomodulatory effects of antidepressant medications, revealing their significant impact on Th1/Th2 cytokine balance beyond their classical neurotransmitter actions. Clinical data show that diverse antidepressant classes consistently demonstrate immunomodulatory properties that extend beyond their classical neurotransmitter effects. These medications reduce pro-inflammatory markers (IFN-γ, TNF-α, IL-6) while enhancing anti-inflammatory cytokines (IL-10, TGF-β), effects particularly relevant for treatment-resistant cases with elevated baseline inflammation. The therapeutic potential of these immunoregulatory effects is supported by emerging interventions, including low-dose IL-2 immunotherapy, vagus nerve stimulation, and microbiota-targeted therapies, which show promise for specific depression subtypes. Importantly, these approaches appear most effective when guided by inflammatory biomarkers, suggesting a path toward personalized treatment strategies. By integrating findings from clinical studies and translational research, this work establishes immune modulation as a fundamental component of antidepressant action. The review provides a framework for developing next-generation treatments that target neuroimmune pathways in MDD, with particular emphasis on practical applications for treatment-resistant cases. These insights bridge the gap between neuropharmacology and clinical psychiatry, offering new therapeutic possibilities for patients with inflammation-associated depression.

Fig. 1. Neuroimmunological mechanisms of depression.

This figure depicts the interplaybetween the immune system and central nervous system (CNS) homeostasis. Disruption of the blood-brain barrier (BBB) increases brain access to immune cells and cytokines, activating microglia and promoting neuroinflammation. Similarly, peripheral inflammation, driven by immune cell activation and the release of peripheral cytokines (e.g., IL-1β, IL-6, TNF-α, IFN-γ) further contribute by altering vascular permeability and crossing or signaling to the brain. IFN-γ also activates IDO, diverting tryptophan from serotonin to neurotoxic kynurenine metabolites (e.g., 3-HK, QA), which are implicated in depressive symptoms. IDO Indoleamine 2,3-dioxygenase, IFN-γ Interferon-gamma, TNF-α Tumor Necrosis Factor-alpha, IL Interleukin, QA Quinolinic Acid, 3-HK 3-Hydroxykynurenine, Treg Regulatory T cells, CREB cAMP response element-binding protein, Htr1b 5-Hydroxytryptamine Receptor 1B. Created with BioRender (www.BioRender.com).

Fig. 2. Mechanisms of action of antidepressant classes and overview of neurotransmitter receptor groups and immune cells.

This figure illustrates the mechanisms by which different classes of antidepressants modulate neurotransmitter activity, as well as an overview of relevant neurotransmitter receptor groups and immune cell interactions. Monoamine Oxidase Inhibitors (MAOIs) inhibit the breakdown of neurotransmitters at nerve terminals, increasing the storage and subsequent release of norepinephrine (NE) and serotonin (5-HT), thereby enhancing their synaptic activity. Tricyclic Antidepressants (TCAs) prevent the reuptake of NE and 5-HT at the post-synaptic receptors, prolonging their effects. Selective Serotonin Reuptake Inhibitors (SSRIs) specifically inhibit the serotonin transporter (SERT), increasing serotonin levels while sparing norepinephrine transporters and minimizing interaction with peripheral receptors. Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) target both SERT and norepinephrine transporters (NET), increasing the availability of both neurotransmitters in the synapse, with minimal action on peripheral receptors. Created with BioRender.com.

Fig. 3. Neurotransmitter receptor groups on immune cells and their interactions with antidepressants.

Schematic representation of neurotransmitter receptors expressed on immune cells, including serotonin (5-HT), dopamine (DA), norepinephrine (NE), gamma-aminobutyric acid (GABA), acetylcholine (ACh), and histamine (H1). Different classes of antidepressants interact with these receptors, modulating immune function: SARIs (mast cells, B-cells), SSRIs (natural killer cells, dendritic cells, eosinophils), SNRIs (macrophages, dendritic cells), and NASSAs (monocytes). These interactions contribute to neuroimmune regulation, influencing inflammatory pathways and immune cell activity. SARIs serotonin antagonist and reuptake inhibitors, SSRIs selective serotonin reuptake inhibitors, SNRIs serotonin-norepinephrine reuptake inhibitors, NASSAs noradrenergic and specific serotonergic antidepressants, GABA(A)R/GABA(B)R gamma-aminobutyric acid receptors type A and B, AChR acetylcholine receptor. Created with BioRender.com.

Fig. 4. Bidirectional neuroimmune communication.

This figure illustrates the dynamic cross-talk between the nervous and immune systems, highlighting four primary interaction types: neuronal-neuronal, immune-neuronal, neuronal-immune, and immune-immune. Neurotransmitters, neuropeptides, and cytokines are shown as key chemical messengers facilitating these interactions, while their respective receptors are indicated for each communication pathway. The diagram emphasizes how these systems influence and regulate one another, providing insight into the complex mechanisms underlying neuroimmune modulation. Created with BioRender.com.