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A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight

Molecular Psychiatry volume 18, pages 543–556 (2013)Cite this article

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Abstract

Schizophrenia is a chronic, severe and highly complex mental illness. Current treatments manage the positive symptoms, yet have minimal effects on the negative and cognitive symptoms, two prominent features of the disease with critical impact on the long-term morbidity. In addition, antipsychotic treatments trigger serious side effects that precipitate treatment discontinuation. Here, we show that activation of the trace amine-associated receptor 1 (TAAR1), a modulator of monoaminergic neurotransmission, represents a novel therapeutic option. In rodents, activation of TAAR1 by two novel and pharmacologically distinct compounds, the full agonist RO5256390 and the partial agonist RO5263397, blocks psychostimulant-induced hyperactivity and produces a brain activation pattern reminiscent of the antipsychotic drug olanzapine, suggesting antipsychotic-like properties. TAAR1 agonists do not induce catalepsy or weight gain; RO5263397 even reduced haloperidol-induced catalepsy and prevented olanzapine from increasing body weight and fat accumulation. Finally, TAAR1 activation promotes vigilance in rats and shows pro-cognitive and antidepressant-like properties in rodent and primate models. These data suggest that TAAR1 agonists may provide a novel and differentiated treatment of schizophrenia as compared with current medication standards: TAAR1 agonists may improve not only the positive symptoms but also the negative symptoms and cognitive deficits, without causing adverse effects such as motor impairments or weight gain.

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Acknowledgements

We acknowledge the continuous support by F. Hoffmann-La Roche and we thank C André, G Chiu, J Basile, H Dao, V Graf, M Maco, P Mortas, M-T Miss, S Debilly, C Waelti, S Schoeppenthau, T Bielser and M Brecheisen for excellent technical assistance; V Dall’Asen, MS Gruyer, C Rapp and J-P Parys for the pharmacokinetic in vivo studies and C Flament for the bioanalytical analysis; J Rodefer for the attentional set-shifting experiment; S Lazic for help with statistics; G Trube for valuable discussions and the Xenopus oocyte experiments; A Harmeier, L Steward, B Kuennecke, M von Kienlin, S Sewing, S Raab and AC Harrison for valuable discussion and input on the manuscript.

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Authors and Affiliations

  1. Pharmaceuticals Division, Neuroscience Research, F. Hoffmann-La Roche, Basel, Switzerland

    F G Revel, J-L Moreau, B Pouzet, R Mory, D Buchy, V Metzler, S Chaboz, A Bruns, T L Wallace, J G Wettstein & M C Hoener

  2. Neuroservice, Domaine de Saint-Hilaire, Aix en Provence, France

    A Bradaia

  3. Pharmaceuticals Division, Discovery Chemistry, F. Hoffmann-La Roche, Basel, Switzerland

    K Groebke Zbinden, G Galley & R D Norcross

  4. Pharmaceuticals Division, Pharmacokinetics & Drug Metabolism, F. Hoffmann-La Roche, Basel, Switzerland

    D Tuerck

  5. Biosciences Division, SRI International, Menlo Park, CA, USA

    S R Morairty, T S Kilduff & T L Wallace

  6. Pharmaceuticals Division, CNS Biomarker, F. Hoffmann-La Roche, Basel, Switzerland

    C Risterucci

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  1. F G Revel
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Correspondence to M C Hoener.

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All authors are employed by F. Hoffmann-La Roche, with exception of AB who is employed by Neuroservice, and SRM and TSK who are employed by SRI International. Research of AB, SRM and TSK was supported in part by F. Hoffmann-La Roche.

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Revel, F., Moreau, JL., Pouzet, B. et al. A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight. Mol Psychiatry 18, 543–556 (2013). https://doi.org/10.1038/mp.2012.57

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