Clinical Biomarker Discoveries in Dopamine and Noradrenaline: Impact on Schizophrenia and Alzheimer’s Disease

Mental health research is not yet as advanced as other medical fields such as cancer or cardiovascular diseases. Just as cancer may manifest itself in different ways from one person to the next, and just as a treatment for one person may not be the right treatment for someone else, people with depression – and other mental illnesses – respond differently to different treatments. 

We do not yet understand enough about all of the causes of mental health problems, how we can prevent them, and how and why treatments and interventions work or don’t work on certain people. Unlike other diseases, there are no approved clinical tests for mental illness, such as blood and pathology, beyond self-reporting and evaluation. People living with mental illness often have to try multiple treatments to find one that works, often through a time-consuming and difficult process. 

There is an urgency for accurate and rapid treatment options, and to do this, we must identify objective measures that can reflect how someone will benefit from a specific treatment. These objective measures - called “biomarkers” – are biological and measurable indicators that reflect the severity or presence of a disease. In other words, biomarkers are physical indicators that can help in the diagnosis of particular mental illnesses and in treatment selection, as clinicians become able to quickly and reliably identify the right therapy for the right patient. This approach has led to breakthroughs in cardiovascular diseases, cancer, and infectious diseases – as mental illnesses are physical diseases of the brain, the impact of biomarker discovery in mental health care should be no exception.

Dr. Clifford Cassidy, a scientist at The Royal’s Institute of Mental Health Research
Dr. Clifford Cassidy, a scientist at The Royal’s Institute of Mental Health Research

In 2019, Dr. Clifford Cassidy, a scientist at The Royal’s Institute of Mental Health Research (IMHR), and his research team, made a ground-breaking discovery – a brain-based biomarker that uses neuromelanin-sensitive MRI (NM-MRI) to measure dopamine in the brain, which can help identify psychosis in people living with schizophrenia.  Through the use of NM-MRI, Dr. Cassidy was able to validate that neuromelanin can serve as a non-invasive proxy measure of dopamine function and integrity; and thus, as a biomarker for psychosis. The hope is that this discovery could eventually be integrated into clinical settings, to help psychiatrists make more precise diagnoses faster, and get patients on the correct course of treatment as early as possible.

When it comes to finding the right treatment for psychosis, the trial and error can take a toll on a patient. One drug in particular, clozapine, can have quite risky side effects that could become fatal, forcing the patient to have regular blood draws to monitor their physical health. It is seen as a last resort treatment for schizophrenia. Physicians will typically start a patient on first-line medications because of the limited side effects and safety of these drugs. However, for people who need to be on clozapine, they will have to go through trial and error with their doctor – costing the patient a lot of time and misery, as the trajectory of schizophrenia can be quite fast and if not treated early on, can be detrimental. 

Dr. Cassidy is using his NM-MRI biomarker at The Royal’s Brain Imaging Centre (BIC) to view levels of dopamine in a patient’s brain with schizophrenia. The dopamine level is a key factor in determining which medication treatment will work best for someone living with schizophrenia. Those with high levels of dopamine are more likely to respond better to first-line psychosis medication. For those patients with normal levels of dopamine, they are more likely to respond best to clozapine. The hope and study objective is that researchers will be able to use NM-MRI to see these brain differences and determine the best form of treatment early on in a schizophrenia diagnosis – eliminating trial and error, unnecessary side effects and wasted time for the patient.

In 2019, Dr. Cassidy used his skillset from building the neuromelanin imaging tool to look at dopamine in the brain and he created a neuromelanin imaging tool – what he calls a pipeline – to be able to look at the neurotransmitter noradrenaline, which, similar to dopamine, can be investigated using neuromelanin scanning. This new tool opened the door for studies of mental health disorders involving imbalance in noradrenaline, such as in Alzheimer’s disease and PTSD.

Dr. Cassidy has been working alongside a research team in Montreal who have already been focused on Alzheimer’s research using a unique dataset. That team recently made a discovery on how to predict Alzheimer’s disease using a blood test. 

However, what researchers still don’t know is why some people get Alzheimer’s disease and other people don’t, and if it is possible to prevent its progression in its early stages. 

“We need to understand the process of how this problem spreads in the brain,” says Dr. Cassidy. “There are many elements that go wrong in the brain with Alzheimer’s disease and we want to find out which ones are more important, which ones trigger other ones, and which ones are just side effects.”

Dr. Cassidy and his colleagues in Montreal are using brain imaging to look at four special measures – three of which have never been studied on this large of a scale and at the same time – in 200 study participants. 

They’re looking at amyloid beta (deposits that form plaques around brain cells), tau (deposits that form tangles within brain cells), the loss of tissue (gray matter) in the brain and Dr. Cassidy’s NM-MRI imaging tool. 

NM-MRI can be used to measure death of cells, so by using this as one of the imaging tools, the research team is able to see whether a person with Alzheimer’s disease is losing noradrenaline cells and how that relates to tau and amyloid in the brain. The loss of noradrenaline neurons is related to the loss of grey matter, so the goal of Dr. Cassidy’s portion of this potentially ground-breaking study is to see where the noradrenaline death fits into the bigger picture of the classic symptoms of Alzheimer’s. 

“There is a possibility that the loss of the noradrenaline system is quite relevant to one aspect of Alzheimer’s,” says Dr. Cassidy. “For instance, psychiatric symptoms in Alzheimer’s such as impulsive behaviour and depression. This would suggest potential treatments for such symptoms with drugs targeting the noradrenaline system. Alleviating these symptoms would help manage the burden of the illness.”

Several other NM-MRI imaging tool biomarker studies that Dr. Cassidy is working on in collaboration with other researchers, include a study examining Attention Deficit Hyperactivity Disorder medication on children and the ability to predict their response to medication using NM-MRI; cocaine use disorder and abnormalities in dopamine revealed by NM-MRI; examining the NM-MRI signal in Post-Traumatic Stress Disorder (PTSD) to develop brain-based biomarkers that will be clinically useful in determining which patients will respond best to which treatments for PTSD.

Click here to learn more about Dr. Clifford Cassidy’s biomarker research