Immune Dysregulation in Depression and Anxiety: A Review of the Immune Response in Disease and Treatment

Abstract

Rates of depression and anxiety have increased significantly in recent decades, with many patients experiencing treatment-resistant symptoms. Beyond psychiatric manifestations, these conditions are associated with heightened risks of suicide, cardiovascular disease, chronic pain, and fatigue. Emerging research suggests that neuroinflammation, immune dysregulation, and hypothalamic-pituitary-adrenal axis dysfunction contribute to their pathophysiology, often interacting bidirectionally with stress. While current first-line treatments primarily target neurotransmitter imbalances, many patients do not achieve symptom resolution, highlighting the need for novel approaches. This review explores the role of immune dysfunction, cytokine activity, and neurotransmitter interactions in depression and anxiety. Additionally, we examine how existing pharmacological and non-pharmacological interventions influence inflammation and immune responses. Understanding these mechanisms may pave the way for more integrative treatment strategies that combine immune modulation with traditional psychiatric therapies.

Keywords: anxiety; cytokine; depression; immune system; inflammation.

Figure 1

Inflammatory effects on tryptophan metabolism. The kynurenine pathway originates from the same precursor amino acid as serotonin. In times of inflammation, the effects of IDO are amplified and shift tryptophan [43].

Figure 2

PEA signaling in inflammation. Palmitoylethanolamide interacts with a number of receptors involved in inflammation. Direct activity with PPAR and indirect activity with cannabinoid receptors and TRPV1 allow it to exert anti-inflammatory effects [84].

Figure 3

PPAR-dependent NF-κB pathway suppression. In addition to the direct inhibition of IKK-induced activation of NF-κB, PPAR complexes with RXR, which allows for interfacing with the response elements in the nucleus and upregulates the transcription of IkB mRNA. The increase in IkB results in the blocking of active regions in the NF-κB complex and preventing pro-inflammatory signaling [86].

Figure 4

Omega-3 signaling in inflammation. Omega-3 compounds DHA and EPA and their downstream endocannabinoid products interact with cannabinoid receptors and PPAR to exert anti-inflammatory effects [101,102].