Innovative screening models for the discovery of new schizophrenia drug therapies: an integrated approach

ABSTRACT

Introduction: Schizophrenia is a severe psychiatric disorder affecting millions worldwide. However, available treatment options do not fully address the disease. Whereas current antipsychotics may control psychotic symptoms, they seem notoriously ineffective in improving negative and cognitive symptoms or in preventing functional decline. As the etiology of schizophrenia eludes us, the development of valid animal models for screening new drug targets appears to be a strenuous task.

Areas covered: In this review, the authors present the key concepts that validate animal models of schizophrenia, as well as the different screening approaches for novel schizophrenia treatments. The models covered are either based on major neurotransmitter systems or neurodevelopmental, immune, and genetic approaches.

Expert opinion: Sadly, due to inertia, research focuses on developing ‘anti-psychotics’, instead of ‘anti-schizophrenia’ drugs that would tackle the entire syndrome of schizophrenia. Whereas no perfect model may ever exist, combining different experimental designs may enhance validity, as the over-reliance on a single model is inappropriate. Multi-model approaches incorporating vulnerability, the ‘two-hit’ hypothesis, and endophenotypes offer a promise for developing new strategies for schizophrenia treatment. Forward and reverse translation between preclinical and clinical research will increase the probability of success and limit failures in drug development.

KEYWORDS:

• Schizophrenia
• animal models
• behavior
• sex differences
• antipsychotics
• drug development

Abbreviations

5-HT: 5-Hydroxy-Tryptamine (serotonin)

AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

CNTRICS: Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia

COMT: Catechol-O-methyltransferase

DISC1: Disrupted in Schizophrenia 1

GABA: γ-aminobutyric acid

HLA: human leukocyte antigen

LDL: low-density lipoprotein

MAM: methylazomethanol

MAP/ERK: mitogen-activated protein/Extracellular signal-regulated kinases

MATRICS: Measurement and Treatment Research to Improve Cognition in Schizophrenia

mGluR: metabotropic glutamate receptor

NMDA: N-Methyl-D-aspartic acid

NVHL: Neonatal ventral hippocampal lesion

PCP: phencyclidine

PFC: prefrontal cortex

poly(I:C): polyinosinic-polycytidylic acid.

Article Highlights

• Animal models are, by definition, simulation platforms, and cannot perfectly replicate human disease.

• Despite the unmet need for new ‘anti-schizophrenia’ drugs, industry has, by inertia, only offered new antipsychotics which do not improve chronic debilitating symptoms.

• Comprehensive screening of novel compounds is impossible when a single animal model is used; a multi-model approach is required to simulate the temporal course in humans.

• A simplistic, unidirectional translation of promising preclinical findings, results in failure at the clinical trial stage.

• Enhanced bi-directional interaction between preclinical and clinical research, as well as improved methodology, will reduce failures and increase successes, benefiting schizophrenia research, and appropriate treatment.

This box summarizes the key points contained in the article.

Declaration of interest

N Kokras and C Dalla have received honoraria and financial support from Janssen-Cilag and Elpen S.A, which are not relevant to this article. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.