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Cited by 348Tryptophan and brain disordersTreatment of Major DepressionStress Responses and Cortisol

Immune targets for therapeutic development in depression: towards precision medicine

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Drevets, Wayne C., Wittenberg, Gayle M., Bullmore, Edward T., Manji, Husseini K.·2022·Nature Reviews Drug Discovery
DOI 10.1038/s41573-021-00368-1PMC PMC8763135
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Abstract

Over the past two decades, compelling evidence has emerged indicating that immune mechanisms can contribute to the pathogenesis of major depressive disorder (MDD) and that drugs with primary immune targets can improve depressive symptoms. Patients with MDD are heterogeneous with respect to symptoms, treatment responses and biological correlates. Defining a narrower patient group based on biology could increase the treatment response rates in certain subgroups: a major advance in clinical psychiatry. For example, patients with MDD and elevated pro-inflammatory biomarkers are less likely to respond to conventional antidepressant drugs, but novel immune-based therapeutics could potentially address their unmet clinical needs. This article outlines a framework for developing drugs targeting a novel patient subtype within MDD and reviews the current state of neuroimmune drug development for mood disorders. We discuss evidence for a causal role of immune mechanisms in the pathogenesis of depression, together with targets under investigation in randomized controlled trials, biomarker evidence elucidating the link to neural mechanisms, biological and phenotypic patient selection strategies, and the unmet clinical need among patients with MDD.

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  • The sustained up-regulation of the IL-17 pathway and Lcn2 in chronic stress mirrors clinical observations in patients with anxiety or depression.

    “The sustained up-regulation of the IL-17 pathway and Lcn2 in chronic stress mirrors clinical observations in patients with anxiety or depression”

    From Comparative Analysis of HPA-Axis Dysregulation and Dynamic Molecular Mechanisms in Acute Versus Chronic Social Defeat Stress (2025) · cites this paper as [62]

    The 'Evidence for causality > Longitudinal and challenge studies' section reports that elevated IL-6 predicted a chronic course of depression, supporting the broader link between inflammation and clinical depression. The 'Immune drug development in MDD' section mentions TH17 cells, but the copy does not report sustained IL-17-pathway or Lcn2 up-regulation in patients with anxiety or depression, or establish that it mirrors changes under chronic stress (searched: IL-17, Lcn2, lipocalin-2). No page numbers were provided. (LLM, conf=0.84)

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Cited by

Sorted by citations

Authors
Drevets, W. C., Wittenberg, G. M., Bullmore, E. T., & Manji, H. K.
Affiliations
  • Janssen Research & Development (United States) (US)
  • University of Cambridge (GB)
  • Johnson & Johnson (United States) (US)
Corresponding author
Manji, Husseini K.
ORCID
Venue
Nature Reviews Drug Discovery
Publisher
Springer Science and Business Media LLC
Published
2022-01-17
Volume
21
Issue
3
Pages
224-244
ISSN
  • 1474-1776 (ISSN-L)
  • 1474-1784
DOI
10.1038/s41573-021-00368-1
PMC
PMC8763135
OpenAlex
W4206213217
Cited by
348
References
34
Citations by year
2026: 67 · 2025: 111 · 2024: 92 · 2023: 54 · 2022: 24
FWCI
5.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Drug Discovery (publishedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo
Funders
  • Wellcome Trust (104025/Z/14/Z)
  • National Institute for Health and Care Research (NIHR200256)
  • Medical Research Council (MC_G0802534, MR/L014815/1)
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
major depressive disorder, immune targets, precision medicine, pro-inflammatory markers, antidepressant response, patient subtyping, biomarkers, depression pathogenesis, mood disorders
MeSH terms
Antidepressive Agents, Depression, Major Depressive Disorder, Depressive Disorder, Major, Humans, Biomarkers, Precision Medicine

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