Promise of Precision Medicine in Psychiatry Nears Reality

Liam Davenport

October 10, 2018

BARCELONA, Spain — Innovative approaches and widespread data sharing are essential in psychiatry to improve patient care and deliver on the long-held promise of precision medicine, a leading European expert says.

In a plenary lecture delivered here at the 31st European College of Neuropsychopharmacology (ECNP) Congress, Marion Leboyer, MD, PhD, professor of psychiatry, University of Paris-Est, Créteil, France, called for the creation of a virtual institute to leverage big data and build partnerships to speed the development of novel psychiatric treatments.

She told a packed auditorium that much of the science needed to bring precision medicine to target different subgroups of patients is already in place, but that innovative, disruptive approaches are needed to bring that science to the clinic.

Leboyer delivered the lecture as part of winning the 2018 ECNP Neuropsychopharmacology Award, which was given in recognition of her outstanding achievements in identifying genetic and environmental risk factors in major psychiatric disorders.

The hope is that precision medicine in psychiatry will transform the diagnosis, treatment, and prognosis of patients with severe psychiatric disorders.

"Today, bipolar disorders, depression, schizophrenia, autism spectrum disorders, OCD [obsessive compulsive disorder], and so many more are known to be clearly heterogeneous, to be overlapping, to be progressive, with different stages that we don't know precisely how to describe, and to be chronic," she said.

The good news, said Leboyer, is that in addition to clinical data on psychiatric and somatic symptoms, brain imaging, and genetics, "we have tools to enable us to perform deep phenotyping."

This massive amount of data, she said, can now be analyzed with "big data" or machine learning. It is hoped that algorithms can be created to identify homogeneous subgroups of patients who can be stratified and treated with precise therapeutic strategies.

These could include target-based treatments, such as probiotics, immunomodulators, cell therapy, psychosocial treatments, gene therapy, deep brain stimulation, and vagal nerve stimulation.

"Today, we're at a stage where we use empirical medicine, and we use one treatment for all, using evidence-based medicine. For example, we use SSRIs [selective serotonin reuptake inhibitors] for major depressive disorder," said Leboyer.

However, she believes the time for the use of precision medicine in the clinic is not far away and that practitioners will soon be able to administer specific treatments to subgroups of patients with particular biological signatures.

She gave as an example the possibility of using anti-inflammatory treatments for depressed patients who have an inflammatory signature.

In contrast, she believes the availability of personalized medicine, tailored to individual patients, is a long way off.

Thinking Outside the Box

Leboyer believes three values will lead to the implementation of precision medicine in psychiatry — thinking outside the box, sharing, and caring.

She said that daring to think outside the box initially led her to challenge the psychoanalytic theories of autism that were prevalent at the start of her career and to identify genetic pathways that underpin the disease.

As part of a collaborative effort, Leboyer and her colleagues found that functional gene mutations in the cell adhesion neuroligin (NLGN) molecules are associated with autism and Asperger's syndrome, along with mutations in the synaptic scaffolding protein SHANK3.

Moreover, the team found that a neurodevelopmental pathway involving both NLGN and SHANK is present in up to 5% of patients with autism spectrum disorders.

The researchers went on to demonstrate that in individuals with autism spectrum disorders, plasma levels of serotonin are increased and that this is linked to low levels of the neurohormone melatonin in the blood, gastrointestinal tract, and pineal gland via a pathway mediated by N-acetyl serotonin.

Leboyer and colleagues next investigated the environmental and genetic factors associated with schizophrenia in the European Union–funded EU-GEI project, which underscored the differences in the prevalence of psychosis between urban and rural areas.

They further examined the relationship between environmental risk factors and inflammation in bipolar disorders at the prenatal/perinatal, childhood, adolescent, and adult stages.

Leboyer and colleagues not only demonstrated that gene-environment interactions may promote inflammation in these patients but also that a genetically related reduction in response to infectious pathogens may be a risk factor for bipolar disorders.

Various environmental factors that trigger acute inflammation were identified as being important at different stages of development. These included infection during the perinatal period, severe childhood stress, and an unhealthy lifestyle in adulthood.

Moreover, they were able to develop the hypothesis that exposure to infectious agents during crucial stages of life may transactivate a human endogenous retrovirus (HERV) that subsequently induces neurotoxic and proinflammatory effects.

Good Data Not Enough

These HERVs, Leboyer and colleagues believe, may be the "missing link" between environmental factors and the triggering of psychotic disorders. They form 8% of the human genome, can be reactivated by environmental triggers to cause a de novo genetic disorder, and are associated with autoimmune disorders.

Levels of HERV envelope protein mRNA have also been found to be significantly increased in both bipolar and schizophrenia patients in comparison with healthy persons.

"We hope that, one day, in the subgroup of patients carrying the envelope protein, we'll be able to antibody that will neutralize this envelope protein, thus blocking an upstream pathogenic agonist, without impairing any physiological functions," Leboyer said.

However, she noted, it's not enough to produce good data, even when they are published in premier, peer-reviewed journals, because policy makers "don't [typically] read Science or Nature, and it's very difficult to explain these results to them."

In light of this, Leboyer and colleagues began working with health economists to develop clear information to help convince policy makers to increase funding for psychiatric research.

Initially, they compared funding for psychiatric research in France, the United Kingdom, and the United States. The health and economic impact of psychiatric disorders are similar in these three countries. They found that although the United States spent 11% and the United Kingdom spent 7% of all its health research funds on psychiatry, France spent only 2%.

The researchers went on to identify six mental health research priorities as part of the Roadmap for Mental Health in European Research project. These included support for research into the prevention of mental health disorders, a focus on the causal mechanism of mental health disorders, the development of research networks, and action to reduce the stigma associated with mental illness.

The second value that Leboyer described is to share. She highlighted her work with the Psychiatric Genomics Consortium, which includes more than 400 researchers worldwide and has access to large databases of psychiatric patients and control persons, as well as genetic data.

Another example is that of the International Consortium on Lithium Genetics, which has been able to establish the importance of HLA genes in the response to lithium for patients with bipolar affective disorder.

The sharing of neuroimaging data in another project involving North American and European centers has led to the identification of the role of the frontolimbic network in patients with bipolar disorder. It was discovered that this network is associated with emotional reactivity, early trauma, and genetic factors and that it can be modified by psychoeducation.

Widespread Data Sharing

Leboyer is director of the Fondation FondaMental. This institution is a network of expert centers that share tools, databases, and biobanks. Patients are assessed in exactly the same way in each center, and each center has expertise in different disorders.

This has allowed the development of in-depth and standardized assessments of psychiatric disorders, leading to a common and shared resource linked to specific research databases, all of which can be accessed online.

This approach has led to findings that show the importance of somatic and psychiatric comorbidity in patients with bipolar disorders and schizophrenia and has led to the identification of risk factors associated with a poor trajectory for patients with bipolar disorders.

Leboyer said her findings have been used to develop innovative treatments for autism, the use of brain imaging to describe mindfulness, and the application of immune signatures in the choice of antipsychotic treatments.

However, she believes much more progress could be made toward the goal of developing precision medicine in psychiatry with the establishment of a virtual institute dedicated to this goal.

"Such an institute would help us to continue sharing platforms, data, and innovation in order to reduce the time, the cost, and the risk of developing new treatment strategies," she said.

"It could also allow disruptive national and international collaborations to bring forward new diagnostic tools, better understanding of causes, and innovative both in prevention and treatments."

She believes such a virtual institute could help psychiatrists take advantage of the technological opportunities of machine learning and help develop public-private partnerships between academia, biotech, industry, government, patients, families, and societies.

"So far, we are about to finish the first stage of this virtual institute, which has been created under the auspices of Fondation FondaMental," Leboyer said.

This will contain different blocks to allow projects to be shared, to find partners for projects, to find grants, to locate databases and biobanks, and to take part in events and conferences.

Bright Future

Following Leboyer's presentation, Gitta Moos Knudsen, MD, PhD, clinical professor and chief physician, Departments of Clinical Medicine, Neurology, Psychiatry and Sensory Sciences, Copenhagen University Hospital, and president-elect of the ECNP, in speaking to Medscape Medical News, described Leboyer's approach as "visionary" and clearly showed "how our new technologies are pointing towards a brighter future for patients."

She added that talking about precision medicine at this time "is key and very timely for how we see the whole field moving towards a brighter future based on science and scientific achievements."

Knudsen said that collaboration and data sharing are not only crucial for psychiatry. "I think it's key to any medical disorder that we're dealing with."

Noting the ECNP's efforts in this area, she added that "replication is also very important.

"We can have very interesting observations, but if we cannot replicate those observations, then it's not going to be helpful, it's going to take us down the wrong way."

The participants have disclosed no relevant financial relationships.

31st European College of Neuropsychopharmacology (ECNP) Congress. Abstract PL.01.01, presented October 7, 2018.

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