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A pathophysiological paradigm for the therapy of psychiatric disease

Nature Reviews Drug Discovery volume 4, pages 467–476 (2005)Cite this article

Abstract

Despite enormous progress in fundamental knowledge in neuroscience, no revolutionary therapies in psychiatry (and neurology) have emerged in the past ten years. Most drugs alleviate symptoms, rather than restoring the 'set point' of brain function from a pathological position to a more normal one. We propose a hypothesis-driven, systems-level approach to drug discovery and development that is based on pathophysiology and which uses new animal models.

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Figure 1: Effects of severe stress on hippocampal/prefrontal function.
Figure 2: The main memory systems of the brain.

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Authors and Affiliations

  1. Deputy Director of Research for Servier, Institut de Recherches Internationales Servier (IRIS), 11 rue des Moulineaux, Suresnes, 92150, France

    Michael Spedding

  2. senior scientist at INSERM, E0117 INSERM Paris-5, Hôpital Ste Anne, Bât. Paul Broca, 2 ter rue déAlésia, Paris, 75014, France

    Thérèse Jay

  3. Professor of Psychiatry t The International Center for Mental Health Policy, New York University Medical School, New York, New York, USA

    Jorge Costa e Silva

  4. President of Research and Development for Servier, Institut de Recherches Internationales Servier (IRIS), Courbevole, 92415, France

    Laurent Perret

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  1. Michael Spedding
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Corresponding author

Correspondence to Michael Spedding.

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Competing interests

L.P. and M.S. are employees of the Groupe de Recherches Servier.J.C.S. has a consultancy relationship with Servier and has performed experimental studies for Servier (and many other companies). T.J. has a contract with Servier relating to animal models of depression.

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DATABASES

Entrez Gene

5-HT1A receptor

MSS4

Tryptophan hydroxylase 2

OMIM

Friedrich's ataxia

Huntington's disease

Glossary

AMPAKINES

Positive allosteric modulators of AMPA receptors.

BRAIN-DERIVED NEUROPTROPHIC FACTOR

(BDNF). One of the main activity-dependent neurotrophic factors in the brain.

CELLULAR RESILIENCE

The property of being able to return to the original form, especially in the presence of stressors.

COMORBIDITY

The extent to which two diseases occur together in a given population.

DENDRITIC SPINES

The 'spine-like' extensions which project from dendrites to form specialized synaptic connections.

EXTRAPYRAMIDAL

The extrapyramidal motor system is a simplification of the basal ganglia, which also involves the circuits in habit memory.

HIPPOCAMPUS

Curved elevation of grey matter extending the entire length of the floor of the temporal horn of the lateral ventricle.

LONG-TERM POTENTIATION

(LTP). A long-lasting increase in current passing through a synapse.

LONG-TERM DEPRESSION

(LTD). A long-lasting reduction in current passing through a synapse.

PREFRONTAL CORTEX

The anterior part of the frontal cortex.

QTC PROLONGATION

Prolongation of the QT interval of the electrocardiogram, leading to a risk of arrhythmias.

RAPHE SYSTEM

The tracts of neurons involved in serotoninergic neurotrasmission.

TRANSNOSOGRAPHIC

Nosography is the description of diseases; a transnosographic approach is necessary if several psychiatric disorders may have common causes.

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Spedding, M., Jay, T., e Silva, J. et al. A pathophysiological paradigm for the therapy of psychiatric disease. Nat Rev Drug Discov 4, 467–476 (2005). https://doi.org/10.1038/nrd1753

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