Peripheral inflammatory biomarkers define biotypes of bipolar depression

Area of Science:

• Neuroscience and Psychiatry
• Immunology
• Machine Learning in Medicine

Background:

• Bipolar depression is associated with inflammation and anhedonia.
• Tumor necrosis factor-alpha (TNF-α) inhibitors like infliximab are being investigated for treatment-resistant depression.
• Identifying patient subgroups who benefit from anti-TNF therapy is crucial for personalized medicine.

Purpose of the Study:

• To identify biological moderators of response to infliximab in bipolar depression.
• To explore the relationship between inflammatory biotypes, neuroinflammation, and pro-hedonic effects of infliximab.

Main Methods:

• A 12-week randomized, placebo-controlled trial involving 60 individuals with bipolar depression.
• Peripheral cytokine measurements were used to derive three inflammatory biotypes via machine learning.
• Neuronal origin-enriched extracellular vesicle (NEV) protein concentrations were analyzed using principal axis factoring.

Main Results:

• Participants classified as biotype 3 showed greater improvements in anhedonia with infliximab compared to biotypes 1 and 2.
• Biotype 3 patients exhibited distinct baseline cytokine profiles and differential changes in NEV protein factors (NEV1 and NEV2) after infliximab treatment.
• Changes in NEV1 and NEV2 scores were associated with symptom reduction in biotype 3 patients treated with infliximab.

Conclusions:

• Inflammatory biotypes can predict response to infliximab in bipolar depression.
• The pro-hedonic effects of infliximab may depend on the modulation of TNF-α signaling pathways, including NF-κB, IRS1, and MAPK.
• These findings support the potential for precision medicine approaches in treating bipolar depression based on inflammatory profiles.