Precision Psychiatry Is the Future. Europe Can Lead the Way

This is a proposal to develop precision psychiatry as a new approach to the treatment of psychiatric disorders in Europe through innovative, mechanism-based treatment strategies. Research and innovation in precision psychiatry is an important step to improve the prevention, diagnosis, and treatment of major mental disorders. A precision psychiatry initiative in Europe can accelerate transformative applications in the clinic by linking existing and future databases in the European Union that contain cohort data on mental disorders and identifying mechanism-based homogenous subgroups and/or transdiagnostic dimensions; working with stakeholders to develop new guidelines for preclinical and clinical research; and pursuing stakeholder discussions on the need to develop new guidelines for personalized treatment.

Introduction

Mental disorders, such as major mood disorders and suicidal behavior, anxiety disorders, psychosis, and autism spectrum disorders, are chronic, progressive conditions that start early in life and represent the leading source of years lost due to disability from medical illness. They constituted five of the top 10 causes of disability according to the 2019 Global Burden of Disease Study,[1] and in addition to psychosocial suffering, psychiatric disorders also reduce life expectancy by 15 to 20 years due to medical comorbidities and suicide.

In the European Union, it is estimated that over 80 million women and men of all ages (i.e., up to 27% of the general population) will experience some form of mental disorder. The total estimated cost of psychiatric disorders in Europe is 600 billion euros — 4% of the EU’s GDP — due mostly to indirect costs. This is more costly than the combined burden of cancer and diabetes, thus making mental disorders a major challenge for European health strategy in the 21st century.

Despite important progress in neuroscience, greater knowledge of environmental and genetic risk factors, and an understanding that psychiatric disorders are not only disorders of the brain but of multiple body systems, pharmacological treatments for psychiatric patients have not meaningfully changed in the past 50 years. Pharmacological interventions in psychiatry are not specific to valid diagnostic entities, nor do they work through precise mechanisms. Today, most pharmaceutical companies have left the field or have developed drugs with modest efficacy and broad-spectrum activity, instead of targeting specific subgroups. Thus, patients are still treated with a combination of nonspecific drugs that have largely been discovered by serendipity, whose mechanisms are not well understood, and for which we have little knowledge on how to predict which will work for individual patients. This probably explains why a third of patients experience persisting symptoms and another third develop adverse effects, while the remaining third respond positively to conventional psychotropic treatments.

This situation has been attributed to the limitations of animal models for testing behavior-like phenotypes, the wrong drugs being given to individual patients, and/or the lack of valid endpoints for clinical trials. The worrying predicament is best explained, however, by the fact that the biological underpinnings of psychiatric disorders are poorly understood and thus are not precisely targeted in the context of how clinical diagnoses are currently classified. Thus, there is an urgent need to personalize the treatment for the individual patient instead of relying on trials and errors. Finding a new taxonomy based on the pathophysiology of homogeneous subgroups or transdiagnostic dimensions will be key.

Today, a revolution is under way. Through a quest to improve the precision of classification and treatment strategies, recent discoveries have raised questions about the classical nosology of overlapping, comorbid, and heterogeneous clinical entities. The development of technology (e.g., related to brain imaging, omics, exposome, connectome, artificial intelligence, and other digital tools); collaborations across disciplines; and successes in psychiatric genomics, immuno-psychiatry, and the development of a circuit-based understanding of psychiatric illness are all challenging traditional diagnostic classification and thus the notion of therapeutic specificity.

This new avenue is developing similarly to oncology or cardiology, where biomarkers have enabled the stratification of patients while mechanism-based treatments have improved prognosis irrespective of clinical entity. In the field of psychiatry, this requires research in mental disorders to precisely identify homogeneous subgroups with specific pathophysiological abnormalities that can be targeted by mechanism-based treatments and/or dimensions that cut across diagnoses but whose pathological mechanisms can be specifically targeted and treated.

Thus, as in other fields of medicine, we need to disentangle the heterogeneity of psychiatric disorders as they are currently defined, which hampers the development of personalized treatment. To move toward precision psychiatry, we need to convince regulatory agencies, the health industry, and health care professionals that the current diagnostic entities (which are often comorbid and overlap across clinical entities) are too broad, thus preventing the discovery of specific mechanism-based therapeutic approaches.

Lessons From the Past

Today, the field is held back by a nosology that has good inter-rater reliability, but that has seen no validation of any diagnostic entity by specific biomarkers that would inform diagnosis, possibly irrespective of existing diagnostic entities. The lack of progress in the development of drugs is largely due to the fact that patients are seldom prescreened for specific biomarkers before being included in clinical trials. Neither are they commonly prescreened for the pathology, subgroup, and/or dimensions of interest to potentially respond to a specific drug. Both clinicians and regulatory agencies still work under the notion of “one size fits all,” which has induced errors and failures of clinical trials in past decades.[2]

For example, it has been demonstrated that immune dysfunctions characterize almost 40% of psychiatric patients. Genome-wide association studies (GWAS) and case-control studies of gene variants have shown that patients with psychiatric disorders have immunogenetic backgrounds that put them at risk when exposed to a stressful situation.[3] Still, no clinical study has stratified patients according to their immunogenetic background. A very large number of studies have found increased inflammation in the blood, guts, and brains of patients with neurodevelopmental disorders and major mood and psychotic disorders, but very few clinical trials select patients according to their inflammatory status. Furthermore, the primary endpoints of clinical trials have been clinical scales of depression, anxiety, or psychosis, and very rarely clinical dimensions known to be correlated with inflammation or markers of inflammation, such as anhedonia.

Lessons From the Present

Linking the dimensions of an individual’s symptoms that cut across disorders and are associated with specific underlying etiological mechanisms could help identify personalized treatments. The field of precision psychiatry could benefit from the numerous existing European cohorts that perform deep-phenotyping; they could enable the creation of multimodal and interoperable databases that could promote research and innovation toward the discovery and validation of bio-clinical signatures with meaningful dimensions. 

The situation is again similar to that of oncology, where patients for years were treated with chemotherapies that were discovered by serendipity, developed for cancers defined by their tissue specificity, and had severe side effects. A better understanding of biological mechanisms, and in particular of immuno-oncology, led to the recent development of a large array of new classes of mechanism-based drugs that target pathophysiology but not cancer type or location. In psychiatry, we need to rethink the molecular basis of disorders and target their causes irrespective of abnormal behavior within or across disorders.

For example, the use of inflammation as a candidate pathway shows that this strategy is doable now, as several homogeneous subgroups with possible targeted treatments have been identified. For example, autoimmune psychosis — defined by the presence of autoantibodies targeting brain receptors, such as NMDA receptors — have been described and found in different clinical entities, irrespective of the psychiatric diagnosis.[4] Another example could be found in the activation of abnormal kynurenine pathways by cytokines, leading to diminished serotonin, impulsivity, and suicidality. This could be treated with IDO inhibitors, which would block the transformation of tryptophan into kynurenine metabolite.

Another major example comes from the basic research that led to the discovery of immuno-metabolic pathways leading to chronic inflammation. This can also help us identify meaningful subgroups across major disorders to whom personalized therapeutic strategies could be offered, from prevention to early intervention, including specific dietary interventions, microbiomic therapy, and mechanism-based treatments.[5]

In addition, the EU-funded PRISM project[6] has provided new insights into the transdiagnostic and translational biological mechanisms underlying social dysfunction, a common phenotype across a wide range of psychiatric and neurological disorders. For example, it was found that social dysfunction is transdiagnostically associated with default mode network (DMN) dysconnectivity in schizophrenia and Alzheimer's disease.[7] This provides novel insights into how neural circuits underlie the transdiagnostic and translational behavioral domain, which can be “back-translated” to animals to test for causality.

Brain stimulation techniques that use electrical activity to modulate brain function present one alternative to pharmacological agents. These have been discovered and are starting to be applied in target brain regions for specific patient subgroups, depending on their circuit patterns as defined by brain-based markers.[8]

Tools to Develop Precision Psychiatry in Europe

The acceleration of precision psychiatry will require creating a new dynamic in Europe for research and innovation. To reach the necessary critical mass, new European structures and platforms will be necessary to foster interaction between scientists, health care professionals, and industry; to inform policymakers and regulatory agencies; and to implement discoveries in clinical practice.

Recommendations

To achieve these goals, it is urgent to implement the following:

1. Develop large-scale training data by establishing a platform to identify existing European cohorts and their databases, describe the clinical and biological phenotypes the databases contain, and determine the methods needed to enable data exchange. The development of research infrastructure support for sustained medical cohort studies will be particularly needed.
2. Identify relevant transdiagnostic and translational bio-clinical dimensions based on quantitative biological parameters and mechanism-based-treatments to enrich future databases and prepare preclinical and clinical trials.
3. Support large, longitudinal, deeply phenotyped cohorts of patients in Europe with mental disorders using genomics, brain imaging, exposome maps, and other digital tools to build coordinated, harmonized, interoperable, and multimodal databases.
4. Back-translate human findings to animals to test for causality, thus expanding our knowledge on biological mechanisms and accelerating research and innovation in the drug discovery process.
5. Favor multidisciplinary research between academia, industry, health economists, regulatory agencies, patient associations, policy entrepreneurs, ethicists, and philosophers to accelerate the translation of precision psychiatry and to ensure that proposed changes are appropriate.
6. Develop research and innovation to measure the actual societal and economic impact of psychiatry among Europeans to inform policy- and decision-makers.
7. Write new guidelines for clinical trials that emphasize the need to stratify patients based on mechanism-based bio-clinical signatures while informing regulatory authorities, funding agencies, and policymakers about the obstacles that strict adherence to broad and unspecific clinical entities present to the development of precision psychiatry.
8. Accelerate innovation by launching a new biomedical economic sector for precision psychiatry, including tools for diagnosis such as digital tools, algorithms, and biomarkers as well as innovative therapies such as biotherapy, immunotherapy, brain stimulation techniques, and tools to improve lifestyle.
9. Develop a European network for research in precision mental health clinics based on the experiences of French and German centers of excellence, enabling them to offer systematic and standardized assessments in order to make personalized recommendations and rapidly implement innovations for patients.
10. Create a community of patients to trigger participatory action research (PAR) and accelerate precision psychiatry.
11. Initiate alignment among countries in Europe and beyond to achieve the transition to precision psychiatry for every patient.

Expected Impacts: Socioeconomic Factors, the Emerging Mental Health Industrial Sector, and the Economics of Mental Health Care

The development of early and precise diagnostic tools and effective treatments will reduce the burden of disabilities associated with mental disorders, which can affect every aspect of a person’s life as well as their family. Moreover, the economic impacts include losses in productivity, as the symptoms can make it difficult to perform a job, and the removal of non-professional caregivers from the workforce.

In addition, improving mental health will reduce the financial burden of chronic mental disorders on health care systems. Today, mental disorders such as depression, anxiety disorders, psychosis, and drug addiction affect more than 1 in 6 people. They are the leading cause of disability and the No. 2 cause of deaths worldwide. They cost an estimated total of over 600 billion euros in Europe in 2015, while at the global level, the combined annual cost of care, especially for dementia, mood disorders, and anxiety disorders, amounts to hundreds of billions of euros. Costs are growing at a high rate due to the world’s aging population.

Precision psychiatry will address these challenges. Investment in prevention, research, and innovation in psychiatry represents one of the highest returns on investment in health care.[9] While the initial investment needed is high, the return on investment is one of the highest across all medical fields, with the presence of multiple targeted therapies for homogenous subgroups and precise endpoints lowering economic risk and increasing the potential gain.

However, the amount of financial support for research and innovation in psychiatry in Europe concerningly does not match that in other fields or continents. There is thus a great risk that Europe may lose momentum in the development of precision psychiatry, and particularly in the area of clinical translation, if an urgent action plan is not launched. To give Europe a competitive advantage, we need to strengthen the opportunities to bring together researchers, the health workforce, and companies to expand the possibilities of developing diagnostic and therapeutic tools.

Conclusion

It is critical that we find the right treatment for the right patient, instead of treating patients wrongly diagnosed using diagnostic criteria that have a good inter-rater reliability but a poor validity. In order to accelerate precision psychiatry medicine and accomplish this, we urgently need a new, open infrastructure for research and innovation that allows academics, industry, patients, and policymakers to work together and draw on European forces in an interdisciplinary effort. Enter a European precision psychiatry initiative.

The quest to develop a new taxonomy based on an understanding of the pathophysiology of homogeneous subgroups or transdiagnostic dimensions represents a revolution in the field — one that is predicated on a new paradigm of stratifying mental disorders and employs existing European resources. A new infrastructure will allow us to advance the translation of both mechanism-based discoveries and novel therapeutic strategies — thus enabling trials for stratified subgroups of psychiatric patients and, ultimately, the promise of mechanism-based medicine.

Endnotes

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[1] “Global Burden of Disease Study 2019 (GBD 2019) Data Resources,” Global Health Data Exchange, Institute for Health Metrics and Evaluation, University of Washington, https://ghdx.healthdata.org/gbd-2019.

[2] Andrew H. Miller and Charles L. Raison, “Burning Down the House: Reinventing Drug Discovery in Psychiatry for the Development of Targeted Therapies,” Molecular Psychiatry 28 (December 2022): 68–75, https://doi.org/10.1038/s41380-022-01887-y.

[3] Ryad Tamouza, Rajagopal Krishnamoorthy, and Marion Leboyer, “Understanding the Genetic Contribution of the Human Leukocyte Antigen System to Common Major Psychiatric Disorders in a World Pandemic Context,” Brain, Behavior, and Immunity 91 (January 2021): 731–739, https://doi.org/10.1016/j.bbi.2020.09.033. 

[4] Thomas A. Pollack et al., “Autoimmune Psychosis: An International Consensus on an Approach to the Diagnosis and Management of Psychosis of Suspected Autoimmune Origin,” Lancet Psychiatry 7, no. 1 (January 2020): 93–108, https://doi.org/10.1016/s2215-0366(19)30290-1.

[5] Wayne C. Drevets et al., “Immune Targets for Therapeutic Development in Depression: Towards Precision Medicine,” Nature Reviews Drug Discovery 21 (January 2022): 224–244, https://doi.org/10.1038/s41573-021-00368-1.

[6] Martien J. Kras et al., “A Quantitative Approach to Neuropsychiatry: The Why and the How,” Neuroscience & Biobehavioral Reviews 97 (February 2019): 3–9, https://pubmed.ncbi.nlm.nih.gov/29246661/.

[7] Ilja M.J. Saris et al., “Social Dysfunction is Transdiagnostically Associated with Default Mode Network Dysconnectivity in Schizophrenia and Alzheimer’s Disease,” World Journal of Biological Psychiatry 23, no. 4 (March-April 2022): 264–277, https://pubmed.ncbi.nlm.nih.gov/34378488/.

[8] Katherine W. Scangos et al., “New and Emerging Approaches to Treat Psychiatric Disorders,” Nature Medicine 29 (February 2023): 317–333, https://doi.org/10.1038/s41591-022-02197-0.

[9] Martin Stepanek et. al, The Return of Investment for Preventive Healthcare Programmes: A Calculation Framework for GSK’s Partnership for Prevention (P4P), RAND Europe, 2017, www.rand.org/randeurope/research/projects/roi-preventive-healthcare-programmes.html.

 

 

The authors would like to thank the following experts for reviewing this piece:

Ole A. Andreassen, Director, Norwegian Centre for Mental Disorders Research (NORMENT), a Centre of Excellence; Professor of Psychiatry, University of Oslo, Oslo University Hospital (Norway)

Suzanne Dickson, President, European Brain Council (EBC); Professor of Physiology/Neuroendocrinology, University of Gothenburg (Sweden)

Peter Falkai, Professor of Psychiatry and Chair, Department of Psychiatry and Psychotherapy, University of Munich; President, European Psychiatric Association (EPA), Munich Center for Neurosciences (Germany)

Martien Kas, President, European College of Neuropsychopharmacology (ECNP); Professor of Behavioural Neuroscience, University of Groningen (The Netherlands)

Andrew H. Miller, Professor of Psychiatry, William P. Timmie Professor of Psychiatry and Behavioral Sciences,Vice Chair of Research, Department of Psychiatry and Behavioral Sciences, and Director, Behavioral Immunology Program, Emory University School of Medicine (USA)

Brenda W.J.H. Penninx, Professor of Psychiatric Epidemiology, Amsterdam University Medical Centers (UMC) (The Netherlands)

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