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Group-II metabotropic glutamate receptor ligands as adjunctive drugs in the treatment of depression: a new strategy to shorten the latency of antidepressant medication?

Molecular Psychiatry volume 12, pages 704–706 (2007)Cite this article

Unipolar depression is a major public health problem and will be the second most prevalent cause of illness-induced disability by the year 2020 according to the World Health Organization. There are several antidepressant drugs that are effective and relatively safe, but they all require a long latency (usually 3–4 weeks) to improve depressive symptoms. This latency seriously complicates the management of severely depressed patients, who are at high risk for suicide during the early phases of treatment. Paradoxically, suicide attempts may even increase during the first days of antidepressant medication because of the shorter latency of drug-induced psychomotor activation. Fast-active drugs or adjunctive drugs that shorten the clinical latency of classical antidepressants will provide a major breakthrough in the treatment of depression. Recent evidence suggests that glutamate receptors are potential targets for antidepressant drugs.1 These receptors are subdivided into two major classes: (i) ionotropic glutamate receptors (i.e. alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate, N-Methyl-D-aspartate (NMDA) and kainate receptors), which are ligand-gated ion channels; and (ii) metabotropic glutamate (mGlu) receptors, which are coupled to G proteins. NMDA receptor antagonists produce beneficial effects in animal models of depression,2, 3, 4 but their potential use in humans is limited by their strong impact on excitatory synaptic transmission, which results in serious adverse effects, such as sedation, ataxia and impairment of learning and memory.5 Drugs acting at mGlu receptors should offer a better profile of tolerability because these receptors ‘modulate’ rather than mediate synaptic transmission in the central nervous system.6, 7 mGlu receptors form a family of eight subtypes subdivided into three groups on the basis of their amino-acid sequence, pharmacological profile and transduction mechanisms. Group-I mGlu receptors (mGlu1 and mGlu5 receptors) are coupled to Gq, and their activation stimulates polyphosphoinositide (PI) hydrolysis leading to mobilization of intracellular Ca2+ and activation of protein kinase C. Group-II (mGlu2 and mGlu3) and group-III (mGlu4, mGlu6, mGlu7 and mGlu8) receptors are all coupled to Gi/o proteins. Their activation inhibits cAMP formation and indirectly affects synaptic transmission and neurotransmitter release by modulating membrane Ca2+ and K+ channels.8 Subtype-selective ligands are now available that either bind to the glutamate-binding domain of mGlu receptors or interact with an allosteric site acting as receptor enhancers or negative modulators.9 Drugs that inhibit group-I mGlu receptors (particularly the mGlu5 receptor antagonists, 2-methyl-6-(phenylethynyl)-pyridine and ((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine), inhibit group-II mGlu receptors (3-(3,4-dichloro-benzyloxy)-2-amino-6-fluorobicyclo(hexane-2,6-dicarboxylic acid 6-heptyl ester and 2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl)-3-(xanth-9-yl)propionate (LY341495)) or activate group-III receptors (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid, (RS)-4-phosphonophenylglycine and (N-phenyl-7-(hydroxyimino)cyclopropane(b)chromen-1-acarboxamide) are effective in animal models of depression, and, in same cases, produce behavioral effects that are consistent with an antidepressant activity.10, 11

Taken together, these data raise the attractive possibility that mGlu2/3 receptor ligands (either low doses of agonists or antagonists) may be used as adjunctive drugs to shorten the latency of antidepressant medication, provided that these drugs will also show a good profile of safety and tolerability, as can be predicted from animal studies.

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Acknowledgements

Supported in part by the Swedish Medical Research Council Grant 10414 to AAM. LY379268 was a generous gift from Eli-Lilly Research Laboratories (Indianapolis, US) to FN.

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Authors and Affiliations

  1. Department of Human Physiology and Pharmacology, University of Rome ‘La Sapienza’, Piazzale Aldo Moro, Rome, Italy

    F Matrisciano, I Panaccione, L Iacovelli & F Nicoletti

  2. Department of Psychiatry and Psychological Medicine, Sant'Andrea Hospital, University of Rome ‘La Sapienza’, Rome, Italy

    F Matrisciano, R Tatarelli & P Girardi

  3. Department of Pharmacology and Anesthesiology, University of Padova, Padova, Italy

    M Zusso & P Giusti

  4. Department of Clinical Neuroscience – Psychiatry, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden

    A A Mathé & S H M Gruber

  5. INM Neuromed, Pozzilli, Italy

    F Nicoletti

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Matrisciano, F., Panaccione, I., Zusso, M. et al. Group-II metabotropic glutamate receptor ligands as adjunctive drugs in the treatment of depression: a new strategy to shorten the latency of antidepressant medication?. Mol Psychiatry 12, 704–706 (2007). https://doi.org/10.1038/sj.mp.4002005

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