Florey researchers creating a better quality of life for people living with mental health conditions

Mental health is one of the biggest health challenges facing our society today.

Over 2 in 5 Australians aged 16–85 are now estimated to have experienced a mental disorder at some time in their life, with 1 in 5 having experienced a mental disorder in the previous 12 months (data from the Australian Institute of Health and Welfare, (AIHW)).

There is a clear and pressing need to accelerate research into mental health conditions to improve the lives of people that live with them. This World Mental Health Day, we’re highlighting our impactful work on depression, addiction, schizophrenia, anxiety and the development of new treatments that our work is enabling.

The Florey’s neuroscientists are working globally with research collaborators, clinical partners and hospitals to create a better quality of life for people living with mental health conditions.

Professor Anthony Hannan – anxiety, depression and environmental factors

“I think a strength of the Florey is our research aimed at understanding the causes of, and thus moving towards effective treatments for, major psychiatric disorders, which constitute a large and growing health challenge”

A program of research in Professor Anthony Hannan’s team suggests that environmental influence on health start prior to conception, including through the paternal line. Discoveries using preclinical models suggest that what a father experiences before conception (including stress, exercise and diet) can change the epigenetics of his sperm and change what happens in the early embryo. This may also affect the later brain development and function of the offspring.

The pioneering epigenetic inheritance research at The Florey found not only that the father’s environmental exposures could affect the development of the offspring, but also brain maturation and function. Negative paternal experiences (such as chronically high stress levels prior to conception) might make the offspring more vulnerable and affect specific aspects of brain development relevant to depression and anxiety disorders.

Professor Hannan said: “Our work at The Florey is contributing to new approaches to prevent and treat specific brain disorders, including psychiatric disorders, to improve mental health. This new research has major implications in the context of what is known as Developmental Origins of Health and Disease. Understanding the developmental origins of brain health and disease can lead to new approaches for prevention and treatment.”

Professor Hannan’s team was also the first to show, in genetic models of Huntington’s disease and schizophrenia, that the gut microbiota (the population of microbes, including bacteria, in the gastrointestinal system) are altered, paralleling evidence that the gut microbiota are altered in clinical Huntington’s disease and schizophrenia. These findings can propel the development of new therapeutic approaches to target gut microbiota in order to improve brain health.

“Brain disorders represent one of the greatest challenges of the 21st century, imposing major burdens of disease. These disorders strike all sections of our communities, at all stages of life. Our Florey research is improving our understanding of brain disorders, including mental illness, to develop novel approaches for prevention and treatment,” Professor Hannan said.

Associate Professor Jess Nithianantharajah – schizophrenia and depression

Research by Associate Professor Jess Nithianantharajah is focused on developing new therapies that better target cognitive and mood symptoms in mental ill-health conditions like schizophrenia and depression, especially for those that are treatment-resistant to currently available treatments.

“We need improved treatment options that are safe, have less side-effects, effective, and can be tailored for individuals with mental conditions based on their specific symptoms. To deliver this, we need greater biological understandings in the processes that change in the brain in mental ill-health, as well as advanced preclinical models and tools to measure and refine the efficacy of novel therapies” Associate Professor Jess Nithianantharajah said.

Associate Professor Nithianantharajah’s research focuses on our understanding how changes in the molecular machinery that controls connectivity and communication in our brains can create either vulnerability or resilience to mental ill-health.

Associate Professor Nithianantharajah and team are taking a translation-focused approach to investigate how disruptions in the balance of excitatory-inhibitory connectivity in the brain leads to specific deficits in cognitive processing and regulation of mood.

As part of this, her team use innovative tools they have established to identify brain signatures that underlie disrupted behaviours, and measure real-time changes in neural activity in preclinical models of schizophrenia and depression. The ability to measure and control behaviour in preclinical models, using sophisticated behavioural and neural imaging systems provides advanced experimental approaches to deliver novel outcomes. Additionally, her team have combined these approaches with deep learning-based tools to enhance tracking of behaviour.

“Our approach allows us to objectively quantify a range of complex behavioural measures, identify how these behaviours may be disrupted in mental ill-health, and importantly investigate how well treatments restore these behavioural and neural changes. This work has enormous significance for the development of next-generation therapies, and critically, informing treatment selection and management for those suffering mental ill-health conditions like schizophrenia and depression.”

Professor Andrew Lawrence – addiction and alcohol use disorder

Research by Professor Andrew Lawrence, Head of the Addiction Neuroscience Group, is looking at new potential treatment targets for alcohol use disorder.

AIHW analysis of the National Hospital Morbidity Database showed that alcohol accounted for nearly 3 in 5 drug-related hospitalisations in 2020–21 (57% or 86,400 hospitalisations). Alcohol has remained the most common drug recorded in drug-related hospitalisations over the 6 years to 2020–21.

The group has a project that focuses on the acetylcholine system. This chemical carries messages between nerve cells and specifically the M4 receptor which modulates dopamine release in a part of the brain called the striatum (composed of four regions responsible for executive function, affective processing, motivation, and motor functions). The M4 receptor is one of a family of proteins that acetylcholine acts upon to message between cells.

Researchers say after long-term drinking and abstinence there is a reduction in the expression of the M4 receptor in the striatum and believe that this might be part of the reason why people might still have a propensity to relapse.

Professor Lawrence and his team are now doing mechanistic experiments looking at circuits in the brain where this receptor is implicated in the motivation to obtain and consume alcohol, or relapse to alcohol seeking.

One experiment is through a longitudinal PET study, involving a novel radiotracer that labels this receptor and which researchers can then follow over a period of time in the same experimental subjects to see if and/or when the expression of this receptor recovers after long-term consumption and abstinence. They can also then see what the timeframe of recovery is and if the expression of the receptor does recover, it could mean that it is less susceptible to relapsing.

The researchers say that this approach could possibly be fast-tracked via a novel antipsychotic drug for schizophrenia that once approved could be repurposed for alcohol use disorders as it targets the same receptor. The compound activates the receptor thereby restoring impaired signaling between nerve cells to reduce the desire to consume alcohol.

“We think that the diminished signaling is contributing towards the desire to consume alcohol and relapse. When we boost that signaling artificially with the drug in the animal models, we reduce alcohol use and relapse, and we ultimately want to do that in humans. It’s something that we’re actively pursuing and have made some important discoveries.”

Professor Brian Dean – schizophrenia

Schizophrenia is a syndrome of disorders which means, to improve treatment outcomes, there is a need to be able to separate the different sub-groups within the syndrome to allow the delivery of more personalized medicine, as occurs for example in type 1 and type 2 diabetes.

In 2009, using tissue from the postmortem brain bank at The Florey, Professor Brian Dean and colleagues showed it was possible to separate 25% of people with schizophrenia into a separate sub-group because they had a profound loss of cortical muscarinic M1 receptors – which are crucial for learning and memory processes.

In a new study, Professor Dean has collaborated with researchers in the Departments of Psychiatry and Neuroscience, The Icahn School of Medicine at Mount Sinai, New York to replicate the 2009 findings in a new cohort of people with schizophrenia.

In addition, because of the data available on the clinical symptoms of the Mount Sinai donors, it was possible to show the sub-group were less cognitively impaired compared to other people with schizophrenia.

This finding is particularly timely as a drug that targets muscarinic M1 and M4 receptors to treat schizophrenia is close to being approved for used in the clinic.

“This is a huge step forward because at present all the treatments for schizophrenia work on the dopaminergic system of the brain. This new drug does something quite different and provides a whole new approach to treating schizophrenia. It is yet to be determined if this new treatment will be useful in all people with schizophrenia or whether those in the muscarinic receptor sub-group will be treatment resistant”.

“It is pleasing that our data on the role of muscarinic M1 and M4 receptors in the molecular pathology of schizophrenia is now extensively cited as being important supportive data in driving the development of this drug.”

During the replication study, it was also discovered that the subgroup have higher levels of another receptor which is called the alpha7 nicotinic receptor.

The alpha7 nicotinic receptor is very pro-cognitive – it aids cognition – so researchers can now understand that the reason there is subgroup of people with schizophrenia have better cognitive function is that they have higher levels of another receptor that is balancing out the problems with the muscarinic M1 receptor.

Professor Dean is also currently collaborating with colleagues at the Austin Hospital using PET imaging to replicate the finding in living people with schizophrenia.