TY - JOUR
T1 - Beyond antipsychotics
T2 - a twenty-first century update for preclinical development of schizophrenia therapeutics
AU - Spark, Daisy L.
AU - Fornito, Alex
AU - Langmead, Christopher J.
AU - Stewart, Gregory D.
N1 - Funding Information:
This review was supported by the Monash Institute of Pharmaceutical Sciences and the Turner Institute for Brain and Mental Health, Monash University. The authors have no conflict of interest to disclose.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Despite 50+ years of drug discovery, current antipsychotics have limited efficacy against negative and cognitive symptoms of schizophrenia, and are ineffective—with the exception of clozapine—against any symptom domain for patients who are treatment resistant. Novel therapeutics with diverse non-dopamine D2 receptor targets have been explored extensively in clinical trials, yet often fail due to a lack of efficacy despite showing promise in preclinical development. This lack of translation between preclinical and clinical efficacy suggests a systematic failure in current methods that determine efficacy in preclinical rodent models. In this review, we critically evaluate rodent models and behavioural tests used to determine preclinical efficacy, and look to clinical research to provide a roadmap for developing improved translational measures. We highlight the dependence of preclinical models and tests on dopamine-centric theories of dysfunction and how this has contributed towards a self-reinforcing loop away from clinically meaningful predictions of efficacy. We review recent clinical findings of distinct dopamine-mediated dysfunction of corticostriatal circuits in patients with treatment-resistant vs. non-treatment-resistant schizophrenia and suggest criteria for establishing rodent models to reflect such differences, with a focus on objective, translational measures. Finally, we review current schizophrenia drug discovery and propose a framework where preclinical models are validated against objective, clinically informed measures and preclinical tests of efficacy map onto those used clinically.
AB - Despite 50+ years of drug discovery, current antipsychotics have limited efficacy against negative and cognitive symptoms of schizophrenia, and are ineffective—with the exception of clozapine—against any symptom domain for patients who are treatment resistant. Novel therapeutics with diverse non-dopamine D2 receptor targets have been explored extensively in clinical trials, yet often fail due to a lack of efficacy despite showing promise in preclinical development. This lack of translation between preclinical and clinical efficacy suggests a systematic failure in current methods that determine efficacy in preclinical rodent models. In this review, we critically evaluate rodent models and behavioural tests used to determine preclinical efficacy, and look to clinical research to provide a roadmap for developing improved translational measures. We highlight the dependence of preclinical models and tests on dopamine-centric theories of dysfunction and how this has contributed towards a self-reinforcing loop away from clinically meaningful predictions of efficacy. We review recent clinical findings of distinct dopamine-mediated dysfunction of corticostriatal circuits in patients with treatment-resistant vs. non-treatment-resistant schizophrenia and suggest criteria for establishing rodent models to reflect such differences, with a focus on objective, translational measures. Finally, we review current schizophrenia drug discovery and propose a framework where preclinical models are validated against objective, clinically informed measures and preclinical tests of efficacy map onto those used clinically.
UR - http://www.scopus.com/inward/record.url?scp=85128027362&partnerID=8YFLogxK
U2 - 10.1038/s41398-022-01904-2
DO - 10.1038/s41398-022-01904-2
M3 - Review Article
C2 - 35393394
AN - SCOPUS:85128027362
SN - 2158-3188
VL - 12
JO - Translational Psychiatry
JF - Translational Psychiatry
IS - 1
M1 - 147
ER -