This is the third article of the brand-new series inspired by EU-PEARL (EUropean-Patient-cEntric clinicAl tRial pLatforms). The EU-PEARL project aims to shape the future of clinical trials, creating a framework for platform trials.
I started my journey in psychiatric research a few years ago. My interest is understanding the biological aspects of psychiatric conditions. Thus, every alteration in the body that might be linked with abnormal mental functioning, both as a cause and a consequence. Here, I would like to share some thoughts on precision medicine and platform trials (which we have learned about in the previous articles in this series), and I wish to convey to you the importance of these two aspects in psychiatry.
In psychiatry, we are dealing with complex disorders. It is therefore challenging to recognize the biological correlates of a disease, and to identify effective, tailored treatments to improve at best the well-being of patients.
A clinical trial is an effective method to test how “good” a medication is for a certain disease, exploring new ways of treatment and prevention.
However, it comes with a significant limitation. A clinical trial usually tests one drug at a time. This makes the process quite slow, and not very adaptive to new discoveries in terms of new potential treatments. The platform trial design can counteract this drawback as it can test various treatments at the same time. It is quite flexible in offering new medication under investigation to trial participants.
However, this approach has not been used yet in psychiatry.
I have recently joined the EUropean-Patient-cEntric clinicAl tRial pLatforms (EU-PEARL) project. It is a collaboration between different perspectives. For example, the pharmaceutical industry, research and clinical centres, and patient representatives.
EU-PEARL aims to identify targeted treatments by innovating the clinical trial procedure.
The EU-PEARL project focuses on four main disease areas among which is Major Depressive Disorder. The centrepiece of the project is to create a well-established network to develop an “integrated research platform” (IRP). To explain it a bit in detail, the IRP includes two types of study designs. A longitudinal natural history study (LNHS) and the aforementioned platform trial.
An LNHS is an observational study. It simply observes what is happening to gather health data. This will help to explore the progression of a disease and to better identify effective treatments. This study combined with the platform trial will be a crucial pool of information to offer targeted treatments in a shorter period of time.
“Why do we need targeted treatments and how can precision medicine come in to help?”
The current state of medicine involves specific treatments for specific diagnoses. Yet, the matter is far more complex. The one-size-fits-all approach has several limitations.
For example, we know that only a sub-group of patients with depression might show clinical improvement following antidepressant treatment. And we know that they have some particular clinical features which can help to develop better strategies for the clinical management of these individuals. Or again, a percentage of patients might exhibit different side effects than others, or even more severe.
Thus, there is still the necessity to improve patient clinical care. The availability of tailored medications will help in enhancing the well-being of patients. A fundamental help in this process comes from precision medicine.
But what is it?
Precision medicine is an approach based on the core belief of patient centricity.
The human genome project took the first step towards precision medicine around 20 years ago, by offering the possibility to improve clinical care based on genetic features (genes are information inherited from our parents which define our specific features). This has taken the research focus from the diagnosis to a patient’s individual characteristics. In fact, the primary concept of precision medicine is the study of individual variability (differences between patients) in “genes, environment, and lifestyle”.
Individual variability is an integral part of the diagnosis and prevention processes in precision medicine. In other words, this approach puts the spotlight on individual differences to offer a targeted treatment reached after careful evaluation of patients’ characteristics.
Oncological (cancer) research is an outstanding example of precision medicine and of the use of platform trials. Precision oncology identifies molecular profiles of a tumour. This research area produces specific treatments based on biological and molecular information. Thus, the analysis of biological samples (for instance, blood) helps in identifying specific markers. These markers could give information about who is more likely to respond to a specific treatment or which might be helpful in the assessment.
It would be helpful to broaden this approach from the oncological field to other medical areas, such as psychiatry. This would improve screening procedures, diagnosis processes and prevention strategies.
And the use of platform trials is highly valuable in speeding up the process.
“So, what about precision medicine in psychiatry?”
Adopting a precision approach in psychiatry would be a paradigm shift. A change of perspective. There have been relevant advances. Steps forward to get closer to precision psychiatry.
A new perspective in psychiatry is the Research Domain Criteria (RDoC). This approach moves from a symptom-based diagnosis — what we routinely use in everyday conversations with a doctor — to a biological/genetic-based diagnosis. It will open new paths in the treatment of mental health conditions. And most of all, it will deepen the knowledge of psychological and biological alterations in psychiatric disorders.
As the National Institute of Mental Health (NIHM) stated, RDoC’ s “goal is to foster new research approaches that will lead to better diagnosis, prevention, intervention, and cures” in mental health.
Another step towards precision medicine in psychiatry is the detection of specific biomarkers (biological characteristics linked to biological and pathogenic processes, and that can be easily measured).
For instance, inflammation is a mechanism that has recently drawn interest in psychiatry. As I explained in my previous blog, inflammation is an indication that the immune system (that is a defence line fighting infections and external intruders) in your body is over-activated. Inflammation has been studied in the context of depression, and in particular in treatment-resistant depression (TRD) (those patients who don’t respond to common antidepressants).
In the MINocycline in DEPression (MINDEP) clinical trial, we investigated the efficacy of add-on minocycline treatment (an antibiotic that has also anti-inflammatory and antidepressant properties) in TRD patients. We found that only those patients with increased (above 3 mg/L) C-reactive protein (CRP), that is, a marker of inflammation, exhibit greater improvement in depressive symptoms, but not those patients with a CRP below that same cut-off.
In simple terms, we identified a threshold that allows us to understand and possibly to predict which TRD patients best benefit from minocycline treatment alongside their antidepressant therapy.
Per se, this is already an important discovery in the area of precision psychiatry. But, we wanted to take a further step in this direction.
Thus, we decided to look at the role of sex in the same study (the MINDEP clinical trial). We detected sex-specific roles of inflammatory biomarkers in predicting treatment response. Our data found that CRP might be a relevant biomarker for female TRD patients, whereas interleukin (IL)-6 (that is another inflammatory biomarker) would be better for both sexes.
These are just pilot data, but they well represent a model of how stratification of the population, biological data and sex differences can be leveraged towards a precision psychiatry.
Psychiatry is a newbie in the field of precision medicine. However, psychiatric research and the mental health care system have started moving towards the development of specific patient-centric tailored care. This will contribute to better describing the phenotypes (observable features) of a specific diagnosis, and to better defining uncertain areas, such as the severity or duration cut-offs used in psychiatry to define a disorder. Moreover, it will help identify early markers (signs) of a disease and its risk factors.
This approach side by side with the detection of specific biomarkers will be essential elements in precision psychiatry.
The identification of specific biological profiles will speed up the diagnostic process and the identification of effective treatments in psychiatry. Precision medicine will guarantee improved prevention and clinical care. It will spare many patients from experiencing unwanted side effects, towards more precise and efficient therapeutic treatments. And it will bring improvement to all of those people who are not helped by our current therapeutic approaches.