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Perspectives for an Integrated Biomarker Approach to Drug Discovery and Development

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Biomarkers for Psychiatric Disorders

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Abstract

Today’s psychopharmacological drugs remain focused on targets that were identified serendipitously more than half a century ago. As these targets have not proven to be at the core of the pathophysiology of the major psychiatric disorders, a better understanding of the disease biology seems a crucial step to identify more efficacious treatments. The tools to realize this goal include neuroendocrine, protein, transcription and genetic markers, neuroimaging and neurophysiological approaches. Obviously, the benefit for psychiatric patients of identifying a pattern of blood-based markers that combine information on the disease biology and treatment response would be enormous. Our transcription data from human blood cells suggest that this is a realistic possibility for the future. Ideally, markers identified in patients would be translated into distinct, hypothesis-driven animal models to facilitate conclusions on the potential therapeutic utility of novel compounds. The combined use of disease state and mechanistic models may characterize cellular and molecular mechanisms of various aspects of psychiatric disorders. This information, in turn, could help establish in vitro models that link cellular targets to (novel) pharmacological approaches. With the discussions around DSM-V, it can be hoped that ambitious research agenda will guide and stimulate systematic research into the biology and biological markers of psychiatric disorders.

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Abbreviations

Akt:

Serine/threonine-specific protein kinase

ANOVA:

Analysis of Variance

Bcl-2:

B-cell leukemia/lymphoma 2

BDNF:

Brain derived neurotrophic factor

CMS:

Chronic mild stress

CRF:

Corticotropin-releasing factor

DISC-1:

Disrupted-in-schizophrenia 1

DNA:

Deoxyribonucleic acid

DSM:

Diagnostic and Statistical Manual

DST:

Dexamethasone suppression test

FST:

Forced swim test

GR:

Glucocorticoid receptor

HAB:

rats High anxiety bred rats

HPA:

axis Hypothalamic–pituitary–adrenal axis

5-HT:

Serotonin

HUPO:

Human Proteome Organization

ICD:

International Classification of Diseases

LAB:

rats Low anxiety bred rats

LC:

Locus coeruleus

LH:

Learned helplessness

mGlu2/3:

Metabotropic glutamate 2/3 receptor

MPfc:

Medial prefrontal cortex

MR:

Mineralocorticoid receptor

NCE:

New Chemical Entity

NIMH:

National Institute of Mental Health

NRG1:

Neuregulin-1

PBMC:

Peripheral blood mononuclear cells

Pelora:

Penalized logistic regression

ProDaC:

Proteomics Data Collection

Qpcr:

Quantitative Polymerase-chain reaction

RNA:

Ribonucleic acid

SGZ:

Subgranular zone

SiRNA:

Small interfering ribonucleic acid

SLR:

Stepwise logistic regression

SVZ:

Subventricular zone

TST:

Tail suspension test

VEGF:

Vascular endothelial growth factor

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Acknowledgments

The authors thank Erik Mosekilde from the Technical University of Denmark for his contribution to the exploratory statistical analyses of the transcription data generated by Lundbeck Research USA. The work done by Erik Mosekilde and Wiktor Mazin was supported by the European Union through the Network of Excellence BioSim, Contract No. LSHB-CT-2004-005137.

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  1. Lundbeck Research USA, Paramus, NJ, 07652, USA

    Irina Antonijevic, Roman Artymyshyn, Carlos Forray, Sylvia Rabacchi, Kelli Smith, Chad Swanson, Joseph Tamm, Wiktor Mazin & Christophe Gerald

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  1. Irina Antonijevic
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    Antonijevic, I. et al. (2008). Perspectives for an Integrated Biomarker Approach to Drug Discovery and Development. In: Turck, C. (eds) Biomarkers for Psychiatric Disorders. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-79251-4_15

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