Aaron Hudson, MD, PhD, Vice President of Global Strategy and Marketing at SCIEX, a Danaher Operating Company, discusses mental health and the challenges of biomarker discovery with the latest published research from Alexander Behnke, MD, PhD, a researcher at the Department of Clinical and Biological Psychology at the University of Ulm, Germany.
The pandemic has certainly taken a toll on mental health, and while some people have benefited from changes like working from home, many others have experienced increased levels of stress during this time. World Mental Health Day focused on this new normal and how to make mental health care a reality for everyone. Cutting-edge research continually pushes the boundaries of what we understand about mental health and how we can advance therapies to treat it. Let’s explore whether there are ways to detect stress and changes in mental health that could allow proactive and preventative action.
Alexander Behnke, MD, PhD, a researcher at the Department of Biological and Clinical Psychology at the University of Ulm, Germany, is investigating whether there are biomarkers for psychological stress and resilience factors that can be measured by noninvasive sampling techniques, such as Mass Spectrometric Analysis of Hair Samples. As with many mental health and disease research studies, his findings paint a complex picture.
Cortisol, the “stress hormone” and other potential biomarkers of stress
When we feel danger, the hypothalamus and pituitary gland in our brain trigger the release of chemicals, including cortisol from the adrenal glands, in what is known as the hypothalamic-pituitary-adrenal (HPA) axis. These chemicals are vital to our “fight or flight” responses in dangerous situations, triggering rapid physiological changes in multiple organ systems, including the musculoskeletal, cardiovascular, endocrine, and nervous systems. Glucocorticoids, such as cortisol, are responsible for several of these changes. Once the danger has passed and the stress has been relieved, cortisol levels drop and physiological changes return to normal, allowing the body to recover. But if the stress becomes chronic, then the physiological changes persist and become maladaptive, subjecting the body to additional “wear and tear” that can be detrimental to physical and mental health and accelerate aging.
Along with cortisol and the HPA axis, there are many other chemicals and endocrine systems involved, including the hypothalamic-pituitary-gonadal (HPG) axis and the endocannabinoid system. Stress-induced changes in the HPA, HPG, and endocannabinoid systems have been implicated in the etiology of stress-related mental illnesses, such as major depressive disorder (MDD). Despite much research investigating various aspects of this central hypothesis, the answer remains unclear as there is often conflicting evidence.
To try to shed more light on some of these ambiguities, Dr. Behnke decided to measure the levels of several chemicals from multiple endocrine systems at the same time from hair samples and compare them between women with MDD and women without MDD. This was the first time that these chemicals had been measured simultaneously in the same hair samples. The chemicals measured were cortisol, cortisone, testosterone, endocannabinoids, and North-acylethanolamines, a class of chemical that is closely related to endocannabinoids in chemical structure and biological function. By analyzing the 3 cm of hair closest to the scalp, they were able to measure the retrospective production of cortisol and other chemicals in the body over the previous three months. The chemicals extracted from the hair were analyzed by high-performance liquid chromatography followed by tandem mass spectrometry on a SCIEX TripleTOF 6600 mass spectrometer, a method that provided high resolution of the multiple chemicals in the hair.
They found that women with MDD had lower levels of cortisol and cortisone in their hair than women without depression. Hair concentrations of testosterone, endocannabinoids, and North-acylethanolamines did not differ between groups. These findings corroborate other hair analysis studies, which fairly consistently found lower levels of glucocorticoids and no difference in testosterone levels associated with MDD. Furthermore, the findings were inconsistent across studies regarding whether endocannabinoids and North-acylethanolamine levels differed between these populations.
The challenges of biomarker discovery for mental health and illness
Intuitively, it follows that stress, especially prolonged stress, can lead to depression. However, testing this hypothesis is far from simple. Like many mental disorders, multiple interdependent factors are at play: from genetic wiring, through neurodevelopmental and semi-adaptive biochemical processes, to psychological and environmental stressors. Therefore, elucidating the psychosocial and physiological mechanisms involved and their biomarkers is incredibly challenging.
A critical obstacle often encountered in studies of mental disorders is that of overbroad diagnostic criteria and thus poorly defined study population. Mental illnesses are largely diagnosed on the basis of signs and symptoms, with few definitive and objective diagnostic tests available. Diseases that present clinically in the same way, and are therefore diagnosed as the same disorder, may actually be two or more diseases with different underlying pathologies. This effectively clouds the picture clinically and scientifically.
One solution is to focus on individual signs or symptoms, which is how schizophrenia managed to identify the putative chromosomes and genes involved in the syndrome. Another similar approach is the Research Domain Criteria (RDoC), a research framework for new approaches to research mental disorders, developed by the US National Institute of Mental Health. It integrates multiple levels of information, from genomics and circuits to behavior and self-reports, to explore the basic dimensions of functioning, encompassing the full spectrum of human behavior, from normal to abnormal. The goal is to understand the nature of mental health and illness, in terms of various degrees and types of dysfunctions in general psychological and/or biological systems.
Looking to the future
As we continue to recalibrate the “new normal” that is emerging as COVID-19 becomes endemic rather than pandemic, research and resources have been refocused on mental health and illness. The pandemic increased several risk factors generally associated with poor mental health, resulting in an unprecedented and significant worsening of people’s mental health. To deal with this looming crisis, OECD countries have responded with decisive efforts to expand mental health services and implement measures to control risk factors and thus reduce mental distress for some. Meanwhile, researchers like Dr. Behnke and his team are contributing to the growing body of literature and data that, with novel approaches like RDoC, could one day be meta-analysed using AI-powered tools to uncover actionable biomarkers for specific mental states. that could inform clinical diagnoses, personalized therapies, and even help prevent mental disorders from developing in the first place.
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