Searching for biomarkers in the fluidity of mental ill-health.

Abstract

World Psychiatry 22:2 June 2023 ply of earlier clozapine utilization, it is not about earlier utilization for all. Rather, the biomarker would guide earlier utilization by clinicians only for that group of patients with a SCI value that indexes likely nonresponse to conventional antipsychotics. A trial such as this one, if successful, would have the potential to change prescribing and regulatory guidelines specifically for patients assessed by the SCI as likely not to respond to conventional antipsychotics. This could mean that a biomarker in psychiatry would have realworld impact, when currently there is no such case. An opportunity could exist in the same trial to incorporate melanocortin 4 receptor genotype, which confers a nearly fivefold increased risk of weight gain in relation to antipsychotic exposure. Similarly, while agranulocytosis is rare, an allele in the HLADQB1 gene carries a ~15 fold increased risk of this potentially lethal event. Therefore, one could stratify patients on multiple biomarkers, maximizing potential gains and minimizing potential harms, in the same clinical trial. Costeffectiveness analyses could further strengthen the case. Saving even one day in hospital would likely offset the costs of the magnetic resonance imaging (MRI) and genetic tests. If we are serious about getting biomarkers into clinical practice, the biomarker/ biological field and the psychiatric services field should work together for successful implementation. Engaging patients and family members with lived experience would be important. A parent who has wit nessed his/her teenager or young adult child recovering from early psychosis thanks to the use of a given biomarker would be a powerful advocate, providing a lived experience voice that could help support the scale and spread (i.e., the implementation) of that biomarker into clinical practice. In addition, engaging policy makers who may have a say in health system incentives early in the process, as well as the relevant regulatory agencies, would be wise. Practice change is notoriously difficult. Even the implementation of measurementbased care in mental health clinics, e.g. us ing a scale routinely to guide treatment decisions, may be a challenge. If we have the data to bring MRI results or a genetic test into the clinic, the challenge of implementation may be even greater. Fortunately, in relation to the SCI biomarker example in early psychosis, the presence of networks of clinics that are part of a learning health system – e.g. via EPINET in the US, as well as similar initiatives in Canada, Australia and elsewhere – could be as good of an environment as we might hope for to propel successful translational efforts into clinical practice. In that sense, the time is now as well, and the broader notion of precision medicine, implementation science, and a learning health care system has been described, and could be applied in psychiatry. Much of the focus of the comprehensive review by AbiDhargam et al is on adult psychiatry. However, the peak age of onset of mental illness is 14.5 years of age. When describing or planning for biomarker evaluation in anxiety or depression, where many cases have their onset during adolescence, one could argue that most studies should be conducted at that timepoint in the lifespan. The dynamic evolution of men tal illness at that timepoint also offers pri mary and secondary prevention opportunities. For instance, 75% of all index psychotic episodes have already presented for mental health care earlier in life for other mental illness. Therefore, capitalizing on our knowledge of the windows of brain devel opment that are paired with windows of on set of mental illness (and substance use) could assist in more optimal study design related to timing. Furthermore, funders might consi der investing in “master observational trials”, which have been dubbed “a new class of master protocol to advance precision medicine”, currently emerging in oncology. The master observational trial is a prospective, observational trial that broadly accepts patients and collects comprehensive data on each. All of the information is tied to gether in a prospective observational registry using standardized reporting and metrics. The goal of these trials, which would be of tremendous benefit to psychiatry, is to harness the power of real world data to advance biomarker discovery and test the clinical utility of precisionbased and personalized medicine.