Burning down the house: reinventing drug discovery in psychiatry for the development of targeted therapies

Miller, Andrew H.; Raison, Charles L.

doi:10.1038/s41380-022-01887-y

Cited by 67Treatment of Major DepressionTryptophan and brain disordersMental Health and Psychiatry

Burning down the house: reinventing drug discovery in psychiatry for the development of targeted therapies

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Miller, Andrew H., Raison, Charles L.·2023·Molecular Psychiatry

DOI 10.1038/s41380-022-01887-yPMC PMC12262016

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Abstract

Despite advances in neuroscience, limited progress has been made in developing new and better medications for psychiatric disorders. Available treatments in psychiatry rely on a few classes of drugs that have a broad spectrum of activity across disorders with limited understanding of mechanism of action. While the added value of more targeted therapies is apparent, a dearth of pathophysiologic mechanisms exists to support targeted treatments, and where mechanisms have been identified and drugs developed, results have been disappointing. Based on serendipity and early successes that led to the current drug armamentarium, a haunting legacy endures that new drugs should align with outdated and overinclusive diagnostic categories, consistent with the idea that "one size fits all". This legacy has fostered clinical trial designs focused on heterogenous populations of patients with a single diagnosis and non-specific outcome variables. Disturbingly, this approach likely contributed to missed opportunities for drugs targeting the hypothalamic-pituitary-adrenal axis and now inflammation. Indeed, cause-and-effect data support the role of inflammatory processes in neurotransmitter alterations that disrupt specific neurocircuits and related behaviors. This pathway to pathology occurs across disorders and warrants clinical trial designs that enrich for patients with increased inflammation and use primary outcome variables associated with specific effects of inflammation on brain and behavior. Nevertheless, such trial designs have not been routinely employed, and results of anti-inflammatory treatments have been underwhelming. Thus, to accelerate development of targeted therapeutics including in the area of inflammation, regulatory agencies and the pharmaceutical industry must embrace treatments and trials focused on pathophysiologic pathways that impact specific symptom domains in subsets of patients, agnostic to diagnosis. Moreover, closer collaboration among basic and clinical investigators is needed to apply neuroscience knowledge to reveal disease mechanisms that drive psychiatric symptoms. Together, these efforts will support targeted treatments, ultimately leading to new and better therapeutics in psychiatry.

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Authors: Miller, A. H., & Raison, C. L.
Affiliations: Emory University (US)
University of Wisconsin–Madison (US)
Corresponding author: Miller, Andrew H.
ORCID: Miller, Andrew H.
Raison, Charles L.
Venue: Molecular Psychiatry
Publisher: Springer Science and Business Media LLC
Published: 2022-12-02
Volume: 28
Issue: 1
Pages: 68-75
ISSN: 1359-4184 (ISSN-L)
1476-5578
DOI: 10.1038/s41380-022-01887-y
PMC: PMC12262016
OpenAlex: W4310644014
Cited by: 67
References: 97
Citations by year: 2026: 8 · 2025: 24 · 2024: 23 · 2023: 12
FWCI: 2.12
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Molecular Psychiatry (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (R21 MH121891, R44 MH125480, R01 MH112076, R01 MH128872)
U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (UL1TR002378)
Topics: Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Social Sciences › Arts and Humanities › Philosophy › Mental Health and Psychiatry
Keywords: psychiatric drug discovery, targeted therapy, inflammation, hypothalamic-pituitary-adrenal axis, anti-inflammatory therapy, clinical trial design, diagnostic categories, pathophysiological mechanisms, neurotransmitter alterations, neural circuits, regulatory policy
MeSH terms: Humans, Hypothalamo-Hypophyseal System, Inflammation, Pituitary-Adrenal System, Psychiatry, Drug Discovery

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Burning down the house: reinventing drug discovery in psychiatry for the development of targeted therapies

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