Precision Psychiatry: How Far Off Are We?

It is estimated that one in eight people worldwide live with a mental health condition¹—a figure that has likely risen following the COVID-19 pandemic.² Accurate diagnosis is pivotal to providing effective treatment, but psychological assessments often fall short of providing timely, objective answers and underfunded, under-resourced healthcare systems are failing to clear long waiting lists.

Part of the difficulty in identifying mental health disorders is that there is no single test to determine a diagnosis—and, unlike in organic illnesses, there are no FDA-approved laboratory-based diagnostics at all. Such a test would base psychiatric diagnosis on objective physical measures, such as biomarkers, rather than relying on self-reported accounts and clinical interviews that are often littered with biases³ that can impact clinical judgment⁴ and lead to diagnostic error.⁵ However, though it’s a research area brimming with promise, it is also fraught with challenges, including identifying reliable biomarkers and navigating the many factors involved in the onset of psychiatric disorders.

Predictive power

Scientists are aware that many mental illnesses have a biological component; however, mental health disorders derive from a complex interplay of social, psychological, and biological factors—that is, there is no one driving force behind a person’s mental state. The nature-nurture debate has been argued extensively in psychology,⁶ but modern experts now acknowledge how nature and nurture work together to impact mental health.⁷ For example, twin studies show that schizophrenia is largely influenced by genetics,⁸ but even a person with a family history of schizophrenia may not develop the disorder in their lifetime. The impact on developing a lab-based test? Genetic testing may reveal the risk genes associated with the disorder, and blood tests can rule out alternative explanations for psychosis symptoms. But genetic testing does not account for the environmental or psychological factors that contribute to schizophrenia onset and cannot definitively diagnose the disorder.

To improve prediction of schizophrenia symptoms, Johns Hopkins University researchers recently found blood gene expression biomarkers associated with hallucinations (PPP3CB, DLG1, ENPP2, ZEB2, and RTN4) and delusions (AUTS2, MACROD2, NR4A2, PDE4D, PDP1, and RORA) in people with schizophrenia and showed that they were predictive of future psychiatric hospitalization.⁹ Some of these biomarkers are already targeted by existing treatments, demonstrating precision psychiatry’s potential for using biomarkers to match patients to specific medications. In a press release, the researchers stated that some of the top biomarkers were better predictors of hallucinations and delusions than standard psychiatric measures. This better performance suggests the test could alleviate subjectivity and bias in evaluating hallucinations and delusions and enhance the accuracy of psychological assessment.¹⁰

The fluctuating brain

Mental health is dynamic and can vary in response to a range of internal and external factors over time. However, blood tests represent one moment in time and do not reflect some of the more volatile physical aspects—such as cortisol secretion¹¹—associated with mental health disorders.

Researchers have explored the potential of using extracellular vesicle (EV) mRNAs in peripheral blood to monitor the state of the brain and predict postpartum depression.¹² “We discovered the presence of brain-specific mRNAs packaged into EVs circulating in blood; in other words, the brain appears to release mRNAs into the bloodstream,” senior researcher Sarven Sabunciyan tells Clinical Diagnostics Insider. “The level of these EV mRNAs in blood appear to reflect changes in the brain—if the brain makes more of an RNA, it releases more into the bloodstream. Our preliminary data found that the level of brain-specific EV mRNAs in blood changes in people with postpartum depression, showing that it may be possible to predict postpartum depression via measuring brain-specific EV mRNAs in blood.”

When asked about future plans to gain FDA approval, Sabunciyan says, “We need to examine many more individuals to identify individual brain-specific mRNAs that change robustly in a diverse population. We can then create a cost-effective, simple diagnostic test and apply for FDA approval once this is accomplished.”

Fundamental challenges

Finding these extra samples can be difficult, however, and aside from the challenges associated with lab-based testing for mental health disorders, scientists also face obstacles during the research process. “Finding appropriate samples can be particularly challenging; for example, we need samples collected from individuals while they were depressed or experiencing mania or hallucinations. Such samples are rare and require time and expense to collect,” says Sabunciyan.

Mental health research and services are also seriously underfunded, not just in the US, but across the world¹³—further delaying research progress into biological mental health tests. Sabunciyan says, “Given the various economic and political issues facing governments, the amount of money available for medical research is very limited. Researchers spend an inordinate amount of time writing grants and worthwhile research is delayed by years because of the absence of funding.”

A supporting role for the lab

Laboratory tests can be used to rule out any physical illness that might explain the patient’s symptoms; for example, if a patient presents with symptoms of depression, a physician may order a complete blood count to check for anemia to explain fatigue¹⁴ or a thyroid function panel to rule out mood symptoms resulting from an under- or overactive thyroid. Currently, biological lab tests are not necessary or sufficient for diagnosing most mental health disorders. Rather than reduce psychiatric disorders to their biological causes, lab tests could help to improve the validity of psychological assessments and provide an objective measurement alongside clinical judgment. Should the FDA approve any tests in future, it is likely that expert clinical judgment will still be needed to interpret their results and examine the context in which the person is experiencing symptoms.

References:

1. 1. World Health Organization. Mental disorders. June 8, 2023. https://www.who.int/news-room/fact-sheets/detail/mental-disorders.

1. 1. World Health Organization. Mental Health and COVID-19: Early evidence of the pandemic’s impact: Scientific brief. March 2, 2022. https://www.who.int/publications/i/item/WHO-2019-nCoV-Sci_Brief-Mental_health-2022.1.

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1. 1. Nature vs. Nurture. Psychology Today. https://www.psychologytoday.com/us/basics/nature-vs-nurture.

1. 1. Katch V. Nature vs. nurture? It’s both. Michigan Today. December 16, 2022. https://michigantoday.umich.edu/2022/12/16/nature-vs-nurture-its-both.

1. 1. Hilker R et al. Heritability of schizophrenia and schizophrenia spectrum based on the nationwide Danish twin register. Biol Psychiatry. 2018;83(6):492–498. doi:10.1016/j.biopsych.2017.08.017.

1. 1. Hill MD et al. Precision medicine for psychotic disorders: objective assessment, risk prediction, and pharmacogenomics. Mol Psychiatry. 2024; online ahead of print. doi:10.1038/s41380-024-02433-8.

1. 1. Blood test predicts psychosis risk, most effective treatments. Indiana University School of Medicine. February 8, 2024. https://medicine.iu.edu/news/2024/02/psychosis-blood-test.

1. 1. Dziurkowska E, Wesolowski M. Cortisol as a biomarker of mental disorder severity. J Clin Med. 2021;10(21):5204. doi:10.3390/jcm10215204.

1. 1. Smirnova L et al. Blood extracellular vesicles carrying brain-specific mRNAs are potential biomarkers for detecting gene expression changes in the female brain. Mol Psychiatry. 2024; online ahead of print. doi:10.1038/s41380-023-02384-6.

1. 1. Mahomed F. Addressing the problem of severe underinvestment in mental health and well-being from a human rights perspective. Health Hum Rights. 2020;22(1):35–49.

1. 1. Schimelpfening N. Is There a Depression Blood Test? Verywell Mind. October 24, 2023. https://www.verywellmind.com/is-there-a-blood-test-for-depression-1066915.