Dr Aaron Hudson, PhD, vice president, global marketing and strategy at SCIEX, a Danaher operating company, talks about the mental health and the challenges of biomarker discovery with the latest published research from Dr Alexander Behnke, PhD, a researcher at the Department of Clinical and Biological Psychology at the University of Ulm, Germany.
The pandemic has certainly impacted mental health, and while some people have benefitted from changes such as working from home, many others have suffered increased stress levels during this time. World Mental Health Day focused on this new normal and how to make mental health care a reality for all. Cutting edge research is continuously pushing the boundaries of what we understand about mental health and how we can advance therapies to treat it. Let us explore whether there are ways to detect stress and changes in mental health that could enable proactive and pre-emptive action.
Dr Alexander Behnke, PhD, a researcher at the Department of Clinical and Biological Psychology at the University of Ulm, Germany, is investigating whether there are biomarkers for psychological stress and resilience factors that can be measured using non-invasive sampling techniques, such as the 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 sense 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 for our “fight or flight” responses in dangerous situations, triggering rapid physiological changes to 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 stress relieved, cortisol levels drop and the physiological changes revert back to normal, allowing the body to recuperate. But if stress becomes chronic, then the physiological changes persist and become maladaptive, subjecting the body to extra “wear and tear” that can be detrimental to physical and mental health and accelerate ageing.
Along with cortisol and the HPA axis, there are many other chemicals and endocrine systems involved, including the hypothalamus–pituitary–gonadal (HPG) axis and endocannabinoid system. Stress-induced changes in the HPA, HPG, and endocannabinoid systems have been implicated in the aetiology 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 and 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. This was the first time that these chemicals had been measured concurrently from the same hair samples. The chemicals measured were cortisol, cortisone, testosterone, endocannabinoids, and N-acylethanolamines, a class of chemical that is closely related to endocannabinoids in chemical structure and biological function. By analysing the 3cm of hair nearest the scalp, they were able to measure the retrospective output of cortisol and other chemicals in the body for the previous three months. The chemicals extracted from the hair were analysed using 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 the women with MDD had lower cortisol and cortisone levels in their hair than the non-depressed women. The hair concentrations of testosterone, endocannabinoids, and N-acylethanolamines did not differ between the groups. These findings corroborate other hair analysis studies, which quite consistently found lower glucocorticoid levels and no difference in testosterone levels associated with MDD. Also, findings were inconsistent between studies regarding whether endocannabinoid, and N-acylethanolamine levels differed between these populations.
The challenges of biomarker discovery for mental health and disease
Intuitively, it follows that stress—especially prolonged stress—can lead to depression. However, testing this hypothesis is far from simple. Like many mental disorders, there are multiple, inter-dependent factors at play: from genetic hardwiring, through neurodevelopment and semi-adaptive biochemical processes, to psychology and environmental stressors. Elucidating the psychosocial and physiological mechanisms involved and their biomarkers is therefore incredibly challenging.
A critical hindrance often encountered in studies of mental disorders is that of overly broad diagnostic criteria and therefore, poorly defined study population. Mental illnesses are largely diagnosed based on signs and symptoms, with few definitive, objective diagnostic tests available. Illnesses that present the same clinically and are, therefore, diagnosed as the same disorder, may actually be two or more diseases with different underlying pathologies. This effectively muddies the picture clinically and scientifically.
One solution is to focus on individual signs or symptoms, which is how schizophrenia managed to identify putative chromosomes and genes involved in the syndrome. Another, similar approach is that of Research Domain Criteria (RDoC), a research framework for new approaches to investigating mental disorders, developed by the US National Institute of Mental Health. It integrates multiple levels of information—from genomics and circuits to behaviour and self-reports—to explore the basic dimensions of functioning, spanning the full spectrum of human behaviour – from normal to abnormal. The goal is to understand the nature of mental health and illness, in terms of varying degrees and types of dysfunctions in general psychological and/or biological systems.
Looking to the future
As we continue to recalibrate to the “new normal” that is emerging as COVID-19 becomes endemic rather than a pandemic, research and resources have been refocused on mental health and disease. The pandemic heightened several risk factors generally associated with poor mental health, resulting in a significant and unprecedented worsening of people’s mental health. To address this looming crisis, OECD countries have responded with decisive efforts to scale‑up mental health services, and implement measures to control risk factors, and thereby reduce mental distress for some. Meantime, researchers such as Dr Behnke and his team are contributing to the growing body of literature and data, which, with novel approaches such as RDoC, could one day be meta-analysed using AI-powered tools to discover actionable biomarkers for specific mental states that could inform clinical diagnoses, personalised therapies, and even help prevent the development of mental disorders in the first place.
