Neuropeptide Y offers a new biological target for treatment-resistant depression through stress and inflammation pathways | Research

The takeaway

Decreased cerebrospinal NPY levels and altered hippocampal NPY receptor expression in treatment-resistant depression patients suggest NPY restoration—via intranasal delivery or receptor-selective modulation—as a novel therapeutic approach.

NPY depleted in TRD
Decreased cerebrospinal NPY and reduced receptor expression in stress-related brain regions suggest NPY restoration as a novel antidepressant strategy

What the researchers found

Decreased CSF NPY in TRD patients. Reduced NPY receptor expression in stress-related brain regions. Animal models: NPY dysregulation in chronic stress with altered hippocampal signaling and HPA axis. Therapeutic targets: intranasal NPY, receptor-selective modulators.

Why it matters

TRD affects about one-third of depressed patients and has few effective treatments. NPY represents a biologically grounded target distinct from serotonin/norepinephrine pathways targeted by conventional antidepressants.

How the study worked

Narrative review synthesizing preclinical (animal stress models) and clinical (CSF biomarker, receptor expression) evidence for NPY in TRD.

What this study cannot tell us

Review format. Clinical NPY data limited. Intranasal NPY delivery still experimental. Causation vs association for NPY decreases in TRD unclear.

How to read the evidence

Review of preclinical and clinical evidence. Good biological rationale but therapeutic applications are still experimental.

When this study was published

Published in 2025.

The bigger picture

Moving beyond serotonin-based depression treatment toward neuropeptide targets could transform mental health care. NPY's involvement in stress, inflammation, and neuroplasticity makes it a uniquely comprehensive target for treatment-resistant cases.

Questions still open

Will intranasal NPY clinical trials show efficacy for TRD?
Which NPY receptor subtype is most important for antidepressant effects?
Could NPY levels serve as biomarkers to predict TRD?

Common questions

What is treatment-resistant depression?

TRD is depression that does not improve with standard antidepressant medications (typically after trying 2+ drugs). It affects about one-third of depressed patients and is a major unmet medical need. This review identifies neuropeptide Y as a potential new treatment target.

How could NPY help depression?

NPY regulates stress responses, inflammation, and brain plasticity—all disrupted in depression. People with TRD have lower NPY levels in their brain fluid. Restoring NPY through nasal spray delivery or drugs that activate NPY receptors could address depression through fundamentally different mechanisms than current antidepressants.

Read the original research

Neuropeptide Y as a multifaceted modulator of neuroplasticity, Neuroinflammation, and HPA axis dysregulation: Perceptions into treatment-resistant depression.

Neuropeptides, 112, 102538

View on PubMed ↗Publisher’s paper ↗

Citation

Singanwad, Priyanka; Tatode, Amol; Qutub, Mohammad; Taksande, Brijesh; Umekar, Milind; Trivedi, Rashmi; Premchandani, Tanvi. (2025). Neuropeptide Y as a multifaceted modulator of neuroplasticity, Neuroinflammation, and HPA axis dysregulation: Perceptions into treatment-resistant depression.. Neuropeptides, 112, 102538. https://doi.org/10.1016/j.npep.2025.102538