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Interview: Marion Leboyer
Marion Leboyer

Marion Leboyer is the 2018 winner of the ECNP Neuropsychopharmacology Award, and she will be delivering her award lecture at this year’s congress on the topic of precision medicine in psychiatry.

Professor Leboyer has been a contributing author on hundreds of scientific papers published over the course of her career, alongside writing several books. She is no stranger to accolades either, having received the Inserm Prize for Public Health Research in 2002, the Foundation for Medical Research’s Jean Bernard Prize for Research in 2007, and the Mogens Schou Award for Research on bipolar disorder in 2011 by the International Society for Bipolar Disorders (ISBD).

Her research has centred on uncovering the genetic and environmental vulnerability factors of mental illnesses, as well as the identification of immune mechanisms and the investigation of dysfunctions of different circuits via brain imaging in various psychiatric disorders.

She has been involved in numerous studies in psychiatry genetics, starting in 2003 with the discovery of the first mutations of genes implicated in brain development in collaboration with Thomas Bourgeron (Jamain et al., 2003)1. As part of efforts aimed at sharing data collection and building biobanks, she and her laboratory have involved in collaborations co-ordinated by the Autism Genome Project Consortium2, the Psychiatry Genomics Consortium, and the Brainstorm Consortium, the latter two having recently published studies on the genetic commonalities between numerous psychiatric disorders3,4. With the International Consortium on Lithium Genetics (ConLiGen), collaborative efforts have been able to distinguish disorder subtypes and to elucidate phenomena such as lithium response and adherence5. On top of genetic risk factors Professor Leboyer has also been part of several large-scale research initiatives to uncover environmental risk factors such as urbanicity (Szoke et al., 2014)6, stress and infection. Establishing links between gene and environmental risk factors was thus the logical next step, beginning with discoveries in the field of immunopsychiatry7, most recently evidencing genes variants to explain why bipolar patients have a reduced response to infections8, as well as HLA-mediated proinflammatory processes9.

She is the CEO of the Fondation FondaMental (www.fondation-fondamental.org), a French scientific foundation consisting of a network of 43 expert centres, 77 research laboratories and seven advanced technology platforms. “This is a non-profit organisation which was created by the Ministry of Research in France in 2007,” explained Professor Leboyer in conversation with ECNP. “The goals of the foundation are four. First, to improve overall care for psychiatric disorders – by building platforms of diagnosis and research (which we call expert centres) where personalised advice is given to patients after a two-day assessment, while clinical data and biological samples are stored, shared between centres and analysed together (Henry et al., 201110; Schurhoff et al.,11). “The second aim is to galvanise research; the third is to improve education; and the fourth is destigmatisation – to improve knowledge in the public sphere in terms of what we know scientifically about psychiatric disorders.”

Addressing the theme of her upcoming lecture at the 31st ECNP Congress, Professor Leboyer described her vision of precision psychiatry, as combining clinical data with other types of information (e.g. omics, environment, brain imaging, and ecological momentary assessment) to uncover disease subtypes and to improve the way patients are diagnosed and the precision with which they are treated 12. This reflects a broader response to a system of classification and treatment rooted in symptoms, she explained: “psychiatric disorders, as of yet, are heterogeneous and overlapping, without valid biomarkers to delineate them and to identify homogeneous subgroups. Today, we have clinical diagnosis lacking external validation and biomarkers leading to specific mechanisms. This blocks the development of diagnostic tools, but also the development of precise, mechanisms-based treatments.

“The goal of precision medicine, as in cancer research13 or in cardiovascular disorders14, aims at identifying homogeneous subgroups based on thorough clinical and biological evaluation, but also on the use of machine-learning techniques to allow the identification of signatures to identify homogeneous subgroups, possibly explained by specific underlying biological mechanisms. These subgroups can then be aligned with animal models, enabling us to test mechanism-based treatments.”

This is very well developed in many areas of medicine but not yet in psychiatry partly because psychiatric symptoms emerge from complex sets of multimodal issues – as such, disorders are more constructively appreciated as heterogeneous syndromes rather than specific diseases15. Indeed, precision medicine has recently been described as a necessary facet of a continuing commitment to personalised medicine that is intrinsic to psychiatry16.

Recent developments in line with this conception include projects such as the Research Domain Criteria (RDoC)17, which works on a similar basis, using transdiagnostic categories that are supported by epidemiologic and genetic studies demonstrating commonalities across traditional clinical categories. “There are different visions about this,” clarified Professor Leboyer, “by splitting or lumping: either we are trying to identify transnosographical dimensions that cut across diagnostic categories; or the other extreme of the vision is that we are going to identify some very precise sub-phenotypes, which may be a small percentage in the overall spectrum of disorders, but which would be based on the specific biomarkers and aetiological mechanisms,18 such as the identification of what we recently called ‘autoimmune psychosis’ (Jezequel et al., 2017)19.

“The dream of precision medicine is to stop trying to identify biomarkers of the existing diagnostic classification, and to just look at what the disorders look like today – they are very heterogeneous and overlapping, as well as changing over time through different stages. We need to use different types of clinical tools along with biomarkers, environmental risk factors and even ecological momentary assessment, in order to do a very deep phenotype analysis.”

The concept of precision psychiatry was recently discussed in a paper by Professor Leboyer and colleagues, in which not only the importance of the confluence of technology and analytical capabilities was discussed, but also practical challenges ahead. The authors note that various diverse biological and environmental metrics must be integrated, in order to elucidate descriptions of the pathologies that in concert give rise to psychiatric disorders. This must be done in data-driven as well as theory-driven ways, and, importantly, demanding collaborative efforts between academia, industry and government in order to identify biomarkers and to bring about changes in policy and clinical practice.12

This concept has already demonstrated its worth, most notably in imaging and genomics with prominent findings from consortia such as Brainstorm, ENIGMA20, and the Psychiatric Genomics Consortium21 (recently reviewed by Mufford et al.22).

“At the forefront of our effort is the ultimate goal to better treat our patients within the framework of precision medicine,” summarised Professor Leboyer. “Along with national and international specialists in immunology – in particular Ryad Tamouza, Laurent Groc, Nicolas Glaichenhaus, Hervé Perron in France, along with Bob Yolken and Faith Dickerson in the US –  we have demonstrated the interaction of immune-genetic background with environmental risk factors such as infectious agents or stress, leading to persistent low-grade inflammation, increased permeability of gut barriers, increased abnormalities of the microbiome, and perpetuated production of autoantibodies against brain and peripheral targets.

“The immune system, its different intricacies with environmental risk factors, its objective biomarkers and pathways – these are all targets for drug discoveries in psychiatric disorders. Trying to precisely identify subgroups that will respond to mechanisms-based treatments, I am actively engaged in clinical trials with drugs such as antibiotics or cell therapy  in autism, with probiotics or immune-modulators in depression, and with veinoglobulins in autoimmune psychosis.

Concluding the interview, Professor Leboyer commented on her long-standing relationship with ECNP, and the significance of receiving the Neuropsychopharmacology Award: “Of course it is a great honour when one’s work is acknowledged, and ECNP has always been a beacon of innovation, inclusion and the celebration of psychiatric research in Europe and beyond. I hope it will also bring more interest into this very exciting field – perhaps especially from the Young Scientists, who might be thinking about what research paths to choose.”

Professor Leboyer presents her Plenary Lecture, ‘On the road to precision medicine in psychiatry’, on Sunday morning of the congress at 11:15.

References
1. Jamain S, Quach H, Betancur C et al. Paris Autism Research International Sibpair Study. Mutations of the X-linked neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet. 2003 May;34(1):27-29.
2. Autism Genome Project Consortium; Szatmari P, Paterson AD, Zwaigenbaum L et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet. 2007 Mar;39(3):319-28.
3. Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet. 2013 Apr 20;381(9875):1371-79.
4. Brainstorm Consortium, Anttila V, Bulik-Sullivan B et al. Analysis of shared heritability in common disorders of the brain. Science. 2018 Jun 22;360(6395). pii: eaap8757.
5. International Consortium on Lithium Genetics (ConLi+Gen), Amare AT, Schubert KO et al. Association of polygenic score for schizophrenia and HLA antigen and inflammation genes with response to lithium in bipolar affective disorder : A genome-wide association study. JAMA Psychiatry. 2018 Jan 1;75(1):65-74.
6. Szoke A, Baudin G, Saba G et al. Prevalence of psychotic disorders in an urban area of France. BMC Psychiatry, 2015 Aug 25;15:204.
7. Leboyer M, Berk M, Yolken RH et al. Immuno-psychiatry: an agenda for clinical practice and innovative research. BMC Med. 2016 Oct 28;14(1):173.
8. Oliveira J, Oliveira-Maia Aj, Tamouza R et al. Infectious and immunogenetic factors in bipolar disorder. Acta Psychiatr Scand. 2017 Oct;136(4):409-423.
9. Tamouza R, Oliveira J, Etain B et al. HLA genetics in bipolar disorder. Acta Psychiatr Scand. 2018 Jun 4.
10. Henry C, Etain B, Mathieu F et al.A French network of bipolar expert centres: A model to close the gap between evidence-based medicine and routine practice. J Affect Disord. 2011 Jun;131(1-3):358-63.
11. Schürhoff F, Fond G, Berna F et al; FondaMental Academic Centers of Expertise for Schizophrnia (FACE-SZ) collaborators. A national network of schizophrenia expert centres: An innovative tool to bridge the research-practice gap. European Psychiatry.  2015 Sep;30(6):728-35.
12. Fernandes BS, Williams LM, Steiner J et al. The new field of 'precision psychiatry'. BMC Med. 2017 Apr 13;15(1):80.
13. Shin SH, Bode AM, Dong Z. Precision medicine: the foundation of future cancer therapeutics. NPJ Precis Oncol. 2017 Apr 24;1(1):12.
14. Leopold JA, Loscalzo J. Emerging Role of Precision Medicine in Cardiovascular Disease. Circ Res. 2018 Apr 27;122(9):1302-1315.
15. Paulus MP. Pragmatism instead of mechanism: a Call for impactful biological psychiatry. JAMA Psychiatry. 2015;72:631-632.
16. Fraguas D, Díaz-Caneja CM, State MW et al. Mental disorders of known aetiology and precision medicine in psychiatry: a promising but neglected alliance. Psychol Med. 2017 Jan;47(2):193-197.
17. Cuthbert BN. Research Domain Criteria: toward future psychiatric nosologies. Dialogues Clin Neurosci. 2015 Mar;17(1):89-97.
18. Leboyer M, Schurhoff F. Searching across diagnostic boundaries. Schizophr Bull. 2014 Sep; 40(5):946-8.
19. Jézéquel J, Johansson Em, Gréa H et al. Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients. Nat Commun. 2017 Nov 27;8(1):1791.
20. Thompson PM, Stein JL, Medland SE et al. The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data. Brain Imaging Behav. 2014 Jun;8(2):153-82.
21. Sullivan PF, Agrawal A, Bulik CM et al. Psychiatric Genomics: An Update and an Agenda. Am J Psychiatry. 2018 Jan 1;175(1):15-27.
22. Mufford MS, Stein DJ, Dalvie S et al. Neuroimaging genomics in psychiatry-a translational approach. Genome Med. 2017 Nov 27;9(1):102.
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