Dialogues in Clinical Neuroscience, vol. 8, n° 3 : « Drug Discovery and Proof of Concept »

2006. Editor in Chief : Jean-Paul MACHER, MD.

Dialogues in Clinical Neuroscience is a quarterly publication that aims to serve as an interface between clinical neuropsychiatry and the neurosciences by providing state-of-the-art information and original insights into relevant clinical, biological, and therapeutic aspects. Each issue adresse a specific topic, and also publishes free contributions in the field of neuroscience as well as other non-topic-related material. All contributions are reviewed by members of the Editorial Board and submitted to expert consultants for peer review.


Dear Colleagues,

Clinical neuroscience is a field in which subjective elements of human psychology and objective data about the brain exist alongside each other. The range of this scientific discipline has become extensive, and thus specifically targeted paraclinical investigations have emerged, with the opportunity to validate clinicat and nonclinical observations.

Two major questions now arise :
• First, the understanding of the pathophysiology of central nervous system diseases and the validation of quantifiable and reproducible indicators relevant to their identification.
• Second, the identification, as early as possible during the development of a drug, of its molecular targets and the consequences of its action on these targets, as well as its pharmacodynamics.

Currently, there is no commonly agreed-on exhaustive research approach which can provide definite answers to these questions, but certain approaches, highlighting the mechanism of diseases, and the mode of action of products designed to treat them, have increased our knowledge in the area. These approaches, based on both clinicat and fundamental technologies, (neurobiology, pharmacodynamies, in vivo and in vitro models, dynamic and functional cerebral imaging, etc) lead to what is known as « proof of concept. » Proof of concept is achieved when a sertes of techniques provide early confirmation of the validity of a given hypothesis concerning a disease or its treatment.

There are three principal fields for the application of proof of concept :
• Preclinical (animal studies)
• Clinical studies in healthy volunteers
• Clinicat studies in patients.
The characteristics of the mechanisms of mental diseases, as well as those of new medications, must be appropriately taken into account to provide us with relevant answers to the many questions arising during drug development. Moreover, this development should involve the smallest number of subjects, with the least invasive investigations possible, and the minimum doses of the product.

We have selected, for this issue of Dialogues in Clinical Neuroscience, several original approaches describing new facets of this area ; these contributions are from a selection of remarkable authors, whom I would like to thank warmly for their contribution. I would also like to thank Pierre Schulz for being the Coordinating Editor of this issue.

This also represents for me an opportunity to point out that Professor Manfred Ackenheil shared with me, over many years, ideas and projects on the theme of proof of concept. Manfred Ackenheil has just passed away ; it is with great sadness that I bring you this news, both on my own behalf and that of the Editorial Board of Dialogues in Clinical Neuroscience, of which he was a founding member. He was working as the Coordinating Editor of issue no 32 of our journal, and this issue, to be published in early 2007, will be an « In Memoriam » issue dedicated to Manfred Ackenheil-a tribute to a man of science and to a friend.

Jean-Paul MACHER, MD


State of the Art
Expression profiling of drug response-from genes to pathways
Ralf Herwig, Hans Lehrach (Germany)

Pharmacological Aspects
New directions for drug discovery
Michael Spedding (France)

Contributions of molecular biology to antipsychotic drug discovery : promises fulfilled or unfulfilled ?
Bryan L.Roth (USA)

Membrane transporter proteins : a challenge for CNS drug development
François Girardin (Switzerland)

Experimental animal models for the simulation of dépression and anxiety
Eberhard Fuchs, Gabriele Fliigge (Germany)

Clinicat Research
The role of serendipity in drug discovery
Thomas A. Ban (USA)

Surrogate outcomes in neurology, psychiatry, and psychopharmacology
Luc Staner (France)

Free Paper
Functional genomics in postmortem human brain : abnormalities in a DISC1 molecular pathway in schizophrenia
Barbara K. Lipska, Shruti N Mitkus, Shiny V Mathew, Robert Fatula, Thomas M. Hyde, Daniel R. Weinberger, Joel E. Kleinman (USA)

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