Evaluation of state and trait biomarkers in healthy volunteers for the development of novel drug treatments in schizophrenia
Abstract
Antipsychotic drugs are the mainstay of treatment for schizophrenia but they have little effect on core negative symptoms or cognitive impairment. To meet the deficiencies of current treatments, novel potential compounds are emerging from preclinical research but translation to clinical success has been poor. This article evaluates the possibility that cognitive and physiological abnormalities in schizophrenia can be used as central nervous system biomarkers to predict, in healthy volunteers, the likely efficacy of entirely new pharmacological approaches to treatment. Early detection of efficacy would focus resource on rapidly developing, effective drugs. We review the relevance of selected cognitive and physiological abnormalities as biomarkers in schizophrenia and three of its surrogate populations: (i) healthy volunteers with high trait schizotypy; (ii) unaffected relatives of patients; and (iii) healthy volunteers in a state of cortical glutamate disinhibition induced by low-dose ketamine. Several biomarkers are abnormal in these groups and in some instances there has been exploratory work to determine their sensitivity to drug action. They are generally insensitive to current antipsychotics and therefore their predictive validity cannot be established until novel, therapeutically useful drugs are discovered. Until then such biomarker studies can provide evidence of drugs engaging with the mechanism of interest and encouragement of the concept.
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Conditional discrimination tasks have been suggested as a useful translational paradigm for assessing the cognitive inflexibility observed in neuropsychiatric disease.
“Conditional discrimination tasks have been suggested as a useful translational paradigm for assessing the cognitive inflexibility observed in neuropsychiatric disease [43].”
From Linking haploinsufficiency of the autism- and schizophrenia-associated gene Cyfip1 with striatal-limbic-cortical network dysfunction and cognitive inflexibility (2024) · cites this paper as [43]
The Biconditional learning section (p. 9) says conditional discrimination tasks assess how task-setting cues control performance and links difficulty applying such cues to cognitive deficits in schizophrenia. It describes human and animal versions, but notes that few human studies exist and that animal drug effects have not yet been shown to reproduce in humans. The claim extends this schizophrenia-focused discussion to neuropsychiatric disease generally and presents the task’s translational usefulness more broadly than the paper establishes. (LLM, conf=0.82)
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Haddon, J. E., Titherage, D., Heckenast, J. R., Carter, J., Owen, M. J., Hall, J., Wilkinson, L. S., & Jones, M. W. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-02969-x · Cited by 6 · see citing works
Self-citation
- Authors
- Koychev, I., Barkus, E., Ettinger, U., Killcross, S., Roiser, J. P., Wilkinson, L., & Deakin, B.
- Affiliations
- University of Manchester (GB)
- University of Wollongong (AU)
- Ludwig-Maximilians-Universität München (DE)
- UNSW Sydney (AU)
- University College London (GB)
- Cardiff University (GB)
- Neuroscience and Psychiatry Unit, School of Community Based Medicine, University of Manchester, Manchester, UK.
- Corresponding author
- Koychev, Ivan
- Venue
- Journal of Psychopharmacology
- Publisher
- SAGE Publications
- Published
- 2011-09
- Volume
- 25
- Issue
- 9
- Pages
- 1207-1225
- ISSN
- 0269-8811 (ISSN-L)
- 1461-7285
- OpenAlex
- W2133035449
- Cited by
- 24
- References
- 18
- Citations by year
- 2024: 2 · 2023: 1 · 2020: 1 · 2019: 1 · 2018: 3 · 2017: 1 · 2016: 2 · 2015: 3 · 2014: 2 · 2013: 5 · 2012: 2
- FWCI
- 2.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Psychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Research Online (University of Wollongong) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
- Figshare (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- National Institute for Health and Care Research (NF-SI-0509-10229)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Social Sciences › Arts and Humanities › Philosophy › Mental Health and Psychiatry
- Keywords
- schizophrenia, biomarkers, antipsychotic drugs, cognitive impairment, negative symptoms, schizotypy, unaffected relatives, ketamine, drug efficacy prediction, healthy volunteers, translational research
- MeSH terms
- Animals, Cognition Disorders, Humans, Schizophrenia, Antipsychotic Agents, Drug Design, Biomarkers, Research Subjects, Translational Research, Biomedical, Healthy Volunteers
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