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  • Review Article
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Neuropeptide receptor ligands as drugs for psychiatric diseases: the end of the beginning?

Nature Reviews Drug Discovery volume 11, pages 462–478 (2012)Cite this article

Subjects

Key Points

  • The search for novel drugs for psychiatric disorders is driven by the growing medical need to improve on the effectiveness and side-effect profile of currently available therapies.

  • The rapid advances in understanding the structure and regulation of genes encoding neuropeptides, the characterization of their receptors, the synthesis of non-peptide receptor ligands and the wealth of animal data have made neuropeptide receptors attractive therapeutic targets for the treatment of psychiatric disorders.

  • However, clinical studies with synthetic neuropeptide ligands have been unable to confirm the promise predicted by animal studies.

  • In this Review, we analyse preclinical and clinical results for neuropeptide receptor ligands that have been studied in clinical trials for psychiatric diseases, including agents that target the receptors for tachykinins, corticotropin-releasing factor, vasopressin and neurotensin, and suggest new ways to exploit the full potential of these candidate drugs.

  • Although drugs targeting neuropeptide receptors have not met their expectations, we do not believe that the whole concept should be considered a failure.

  • Among the most commonly noted reasons for the failure to successfully develop neuropeptide receptor ligands for psychiatric disorders is the poor predictivity of the animal models that have been used to screen these molecules. Drug selection based on data from animal models must be much more stringent and use a variety of models assessing different aspects of the disease.

  • The future development of drugs targeting neuropeptide receptors also has to bear in mind the specificity of their mechanism of action. Genetic tests and biomarkers are needed to identify subgroups of patients in whom a specific neuropeptidergic mechanism accounts for the clinical condition and who would thus be anticipated to benefit from a specific drug intervention.

Abstract

The search for novel drugs for treating psychiatric disorders is driven by the growing medical need to improve on the effectiveness and side-effect profile of currently available therapies. Given the wealth of preclinical data supporting the role of neuropeptides in modulating behaviour, pharmaceutical companies have been attempting to target neuropeptide receptors for over two decades. However, clinical studies with synthetic neuropeptide ligands have been unable to confirm the promise predicted by studies in animal models. Here, we analyse preclinical and clinical results for neuropeptide receptor ligands that have been studied in clinical trials for psychiatric diseases, including agents that target the receptors for tachykinins, corticotropin-releasing factor, vasopressin and neurotensin, and suggest new ways to exploit the full potential of these candidate drugs.

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Figure 1: Neurokinin, corticotropin-releasing factor, vasopressin and neurotensin pathways (and their receptors) in regions of the rat brain.
Figure 2: Outcome of experiments that investigated the effects of synthetic neurokinin receptor, CRFR1 and V1B receptor antagonists in animal models of anxiety from 1990 to 2011.

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Acknowledgements

We thank S. Beeské and H. Junkert for their editorial assistance.

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Authors and Affiliations

  1. Sanofi, Exploratory Unit, Chilly-Mazarin, 91385, France

    Guy Griebel

  2. Max Planck Institute of Psychiatry, Kraepelinstraße 10, Munich, D-80804, Germany

    Florian Holsboer

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Correspondence to Guy Griebel.

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Competing interests

Florian Holsboer is cofounder of HMNC (HolsboerMaschmeyer NeuroChemie) GmbH, a biotechnology company aiming to develop new personalized treatments for treating depression.

Supplementary information

Supplementary Information, Table 1

Drugs in clinical development for the treatment of schizophrenia, anxiety and major depressive disorders as of November 2011 (PDF 150 kb)

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FURTHER INFORMATION

ClinicalTrials.gov website

GSK Clinical Study Register

Sanofi website — 28 April 2011 press release

Glossary

Hypothalamic–pituitary–adrenal axis

A tightly linked, interdependent endocrine structure that comprises a major peripheral part of the stress system, the main function of which is to maintain basal and stress-related homeostasis.

Neurogenesis

The growth and development of nerve tissues.

Cyclic AMP response element-binding protein

A cellular transcription factor that binds to certain DNA sequences called cyclic AMP response elements, thereby increasing or decreasing the transcription of downstream genes.

Forced swim test

A screening model of depression in rodents that measures immobility in a beaker half-filled with water as a measure of despair behaviour. This test has been widely used in the discovery of monoamine-based drugs because of its high predictive validity.

Limbic structures

Set of areas of the brain including the amygdala, anterior thalamic nuclei, fornix, hippocampus, limbic cortex and septum, which have a modulatory role in various functions including emotion, memory and olfaction.

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Griebel, G., Holsboer, F. Neuropeptide receptor ligands as drugs for psychiatric diseases: the end of the beginning?. Nat Rev Drug Discov 11, 462–478 (2012). https://doi.org/10.1038/nrd3702

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