Teasaponin supplementation offers promising results

Teasaponin supplementation offers promising results

In the future, a cup of tea may be just what the doctor orders to reduce the cognitive impairments associated with antipsychotic-induced obesity.

An animal study conducted by Dr Yinghua Yu at the University of Wollongong has found that teasaponin supplementation may be used to prevent neurodegeneration and improve cognitive deficits associated with obesity.

There is a high incidence of obesity and metabolic issues in mental disorders such as schizophrenia. The obesity can be caused by the disorder itself, or it could be a result of medication side effects or due to lifestyle factors. Dr Yu and Prof Huang are searching for a way to improve cognitive function by dealing with the first two causes.

People classified as obese are often leptin-resistant, which means that their brain has reduced levels of leptin, the hormone that stops us from feeling hunger once we’ve eaten. Leptin also facilitates learning and memory functioning in the brain.

Brain-derived neurotrophic factor (BDNF) promotes the brain’s ability to grow new neurones, which are also important for learning and memory. A high fat diet, which often results in obesity, reduces the amount of BDNF in the brain, however this can be reversed with the administration of leptin.

So, leptin is an important part of the brain’s ability to maintain particular cognitive functions and is an integral part of body’s way of maintaining a healthy weight, which made it an interesting therapeutic target to explore.

The recent study from Dr Yu found that teasaponin supplementation improved leptin signalling in the brain as well as the amount of BDNF growth caused by leptin. This may have beneficial effects in reducing cognitive decline associated with obesity.

It must be noted, however, that the dose of teasaponin obtained by frequently drinking tea is significantly lower than the doses in the study. Clinical trials are needed to determine the optimal dose in humans, as well as any risk of toxicity over long-term use.

New screening test identified

New screening test identified

The Australian Schizophrenia Research Bank has assisted researchers internationally with genetic and biological samples to support studies. Most recently, they have supplied a young Newcastle researcher with participants for her study.

Cognitive impairment in individuals with schizophrenia has been well-established in research. Individuals with schizophrenia have been found to have deficits in the areas of memory, executive functioning and attention. These impairments often don’t change too much over time and can impact on a person’s ability to live independently, retain employment and function comfortably in social settings.

In order to reduce these impacts, it is important for clinicians to be able to address and treat any cognitive difficulties. However, there is currently no screening test that is accurate, easy-to-use and widely available that can inform clinicians of the cognitive strengths or weaknesses of their patient.

The current study identified that the Audio Recorded Cognitive Screen (ARCS) could fill this gap. The ARCS is unique in that it is administered via an audio device such as an MP3 or CD player and participants record their answers in a response booklet, making it a test that is both easy to use and access. The administration of the tool requires minimal clinician supervision, no special training, and takes only 35 minutes.

Researchers tested a small group of people from the Australian Schizophrenia Research Bank database with and without schizophrenia and found that ARCS may be able to detect cognitive deficits associated with schizophrenia, particularly with regards to memory and verbal fluency.

“The minimal resources required to administer this test may make it attractive for many community-based clinical settings such as community mental health and disability employment services and could be useful in guiding treatment planning,” said study author Brooke Gelder.

Adversity and attention

Adversity and attention

Epigenetics is the study of how our environment influences the expression of our genes. Associate Professor Melissa Green’s (pictured) group has found an interesting link between childhood experiences and attention.

Exposure to traumatic experiences in the early stages of life, including various forms of abuse or neglect, parental divorce or mental illness, and poverty, are known to influence the development of disorders such as schizophrenia. These early experiences have a great impact on a child’s developing hypothalamic-pituitary-adrenal (HPA) axis, which is the body’s way of dealing with stress.

Prolonged exposure to stress in childhood has the potential to cause a variety of illnesses in adult life. Previous studies have noted that exposure to trauma in childhood can also affect cognition later in life for healthy adults, people with schizophrenia and people with borderline personality disorder.

This caused our researchers to wonder if the genetic region, FKBP5, which is associated with an impaired stress response system and in some psychotic disorders, also had an effect on cognition in people with schizophrenia.

The study found that people with and without schizophrenia who were exposed to childhood trauma and had a variant of the FKBP5 gene, performed worse on attention tasks than did participants who were not exposed to childhood maltreatment.

The schizophrenia group, whether or not they experienced adverse situations as children, also shared a disease-associated marker single nucleotide polymorphism (SNP; pronounced “snip”) that was associated with a worse performance on cognitive tests than the healthy controls.

“This is a great example of how environmental influences can alter how our genes express themselves,” says Assoc Prof Melissa Green. “The effect of poor childhood experiences on the FKBP5 variant not only influences whether or not a mental illness may develop, but also seems to affect cognitive functions in healthy people. This is something we’ve not realised before now and opens the door to many new exciting research opportunities.”

Meet the researcher – Juan Olaya

Meet the researcher – Juan Olaya

Although he started his degree in psychology, it was a neuroscience unit that led Juan Olaya to become interested in understanding the possible causes of schizophrenia. “What I found really interesting was what causes mental illness to occur,” he explains. “I’m fascinated by the biological, mechanistic basis. Studying neuroscience allows me to explore the ‘how’ of mental illness. The brain is incredibly complex and intricate. Studying it makes me want to know more about how things can go wrong and how we can fix it.”

This interest in the “how” of mental illness has led him to explore the Neuregulin 1 type III (NRG1 III) mRNA that is increased in the brains of people at risk of developing schizophrenia. Using a mouse model that has an overexpression of this particular transcript, Juan has found that not only do these mice display schizophrenia-like symptoms, they may also be able to explain how an overabundance of NRG1 III may lead to the development of schizophrenia.

Understanding these mechanisms has the potential to lead to new therapeutic targets for a particular subset of schizophrenia patients. Indeed, identifying new therapies to treat schizophrenia is an aspect of future research that most appeals to Juan.

“Due to the heterogeneity of the disease, two patients can have similar symptoms, such as hallucinations, delusions and social withdrawal,” says Juan, “however what may cause their symptoms may be very different. Person A may have an inflammatory response, while person B may have a genetic mutation on the NRG1 gene. So I think a large part of the research should look at how to identify a subset of patients who are defined not by their symptoms, but by the underlying cause of schizophrenia. We need to hone in on that. We can then find a tailored therapeutic response that is effective in preventing or treating that particular subset of schizophrenia. I think that is the future of schizophrenia research.”

Protecting kids’ mental health

Protecting kids’ mental health

Improving how children feel about themselves and others may have an important knock-on effect for their future mental health, especially if they experience psychotic-like symptoms.

In the first study of its kind, Dr Kristin Laurens has been part of a group of researchers interested in how schematic beliefs – that is, beliefs formed early in life and shaped by childhood experience – may be associated with unusual, or psychotic-like, experiences in children. It is thought that improving negative schematic beliefs in young people may be a useful therapeutic target for those at risk of developing psychosis.

Schemas influence how we interpret the actions of others, process our emotions and behave. If the schemas are negative they may cause a person to believe they are unlovable or worthless, or that other people are untrustworthy or judgemental. These negative beliefs about the self or others are more often seen in people with psychosis, when compared with the beliefs held by healthy individuals.

Psychotic-like experiences are non-clinical forms of symptoms that are reported by people with psychosis, such as hearing voices that others can’t hear, feelings of being watched or having special power. These are common in young people in the general population, but persistence of these experiences is associated with distress and increases the likelihood of later mental health problems.

If addressed early, for example as part of a cognitive-behavioural intervention, the chance to improve negative schemas before they become fixed beliefs in adulthood may have beneficial outcomes for young people who have experienced distressing, psychotic-like experiences.

“Our study found that negative schemas in childhood are associated with psychotic-like experiences in children and that schema-change work is an important therapeutic focus,” says Dr Laurens. “Such interventions include considering how the negative beliefs arose, how they are maintained, their influence on day-to-day functioning and the benefits of changing the incorrect beliefs.”

An associated study has also found that these negative beliefs about self and others influence how the experience of being bullied impacts on children’s psychotic-like experiences. “If we intervene early, we can teach these children ways to reduce their negative beliefs and build the kind of resilience that will help them better deal with victimisation experiences like bullying,” says Dr Laurens. “Creating resilience is a great way to protect the future mental health of our children.”

Meet the researcher

Meet the researcher

Growing up with a bright, studious neighbour whose company he enjoyed was one of the primary reasons that Yiru Zhang decided to pursue a career in medical research. As a teen Yiru saw first-hand how the onset of schizophrenia diverted his friend and neighbour from her scholarly ambitions, and felt called to understand what caused the disorder and how it could be better treated.

“We went to school together,” Yiru recalls. “She was very smart. We shared ideas about science and talked about our future and our ambitions. Then, in the middle of high school she was diagnosed with schizophrenia. That was 15 years ago in China and at that time you would be checked into hospital and you would be unable to go to school.

“When I finished university and was thinking about a Master’s degree my friend was finally checked out of hospital and the doctors said that she could try to take the exam to get into university. Because she was very smart, she did it, but still she was not as good as before. That’s when I realised that mental illness is a serious problem that can have lasting consequences. But we don’t know how to help because we don’t know what causes mental illness. That’s my dream, I want to do medical research to understand what is happening in the brain to cause illnesses like schizophrenia.”

Yiru pursued study in biotechnology in both China and Canberra, at the Australian National University, which led to starting his medical research career at NeuRA in 2013, working with Prof Cyndi Shannon Weickert and Dr Vibeke Catts.

He is currently working on two projects, with a third in the pipeline. The first is to understand what might cause the reduction in cortical volume in the brains of people with schizophrenia as compared with healthy controls. Within the schizophrenia group those with high inflammation markers had less cortical volume than those with low levels of inflammation markers. This lends weight to the belief that inflammation plays a strong role in cortical volume loss.

The second project is to understand whether oxidative stress, which is common in schizophrenia, may also contribute to this cortical reduction. If this is found to be accurate, it may lead to drug treatments that can reduce levels of oxidative stress in the brain, which may lead to an improvement in symptoms.

Yiru’s areas of research will help us to better understand some of the cellular and molecular mechanisms at play in schizophrenia; a dream he has been working towards for many, many years. “At the beginning of each October I give a small gift to Cyndi,” he says, “to thank her for giving me this great opportunity so I can finally understand what schizophrenia is and what happens to those diagnosed with it.” Cyndi thinks the best gift of all is to have bright students like Yiru from all around the world come to the Schizophrenia Research Lab in Sydney to devote time and talent to help solve the mysteries of schizophrenia.

Yiru is a recipient of the A.M. Wood Postgraduate Scholarship for Schizophrenia Research via Schizophrenia Research Institute.

Advancing our knowledge

Advancing our knowledge

An invite-only workshop attended by several of our researchers last year revealed such a depth of knowledge that a special issue of a peer-reviewed journal will be published to celebrate the advances made by our scientists.

In 2014, Professor Pat Michie (pictured), from the University of Newcastle, organised a two-day workshop that brought together 15 of the world’s foremost authorities on mismatch negativity (MMN), an auditory brain response that has been shown to be reduced in people with schizophrenia. In fact, the world first report of this finding was published by Australian researchers in 1991.

The workshop, which was called Understanding the Neurobiology of Mismatch Negativity and the Relevance to Schizophrenia, was held at the Hunter Medical Research Institute and featured six international speakers as well as many Institute-affiliated researchers.

The aim of the workshop was to bring together neuroscientists with expertise in auditory system functioning, mismatch negativity and schizophrenia researchers so that they could share their insights and attempt to more fully understand the biological reasons for reduced MMN in people with schizophrenia. “The area has become a lot more complicated,” Prof Michie laughed. “It’s a case of the more we know, the more we realise we don’t know.”

In actuality, the workshop highlighted the incredible depth of knowledge of the group, which will be shared in a special edition of the peer-reviewed journal Biological Psychology at the end of this year. Each of the presenting speakers, including Drs Vibeke Catts, Lauren Harms and Juanita Todd as well as Profs Pat Michie, Cyndi Shannon Weickert and Ulli Schall, has contributed a paper that summarises their talks and will further our understanding of the connection between MMN and schizophrenia.

Understanding the generation of MMN as well stimulus specific adaptation (SSA) and the role that impaired NMDA (a particular type of glutamate receptor) neurotransmission plays in both of these responses may help in identifying who is at risk of developing schizophrenia and direct future research into possible new drug treatments. It’s an incredibly interesting and fruitful area of research.

“It’s an honour to guest edit this issue of Biological Psychology,” Prof Michie said. “More than 25 years ago Prof. Risto Näätänen and I published a paper that first identified MMN in detail in this very same journal. The paper has since been cited 500 times in subsequent research. So to bring a whole new generation’s worth of research to the journal is incredibly gratifying.”

Guiding future research

Guiding future research

Our scientists have been asked to compile a special edition of Schizophrenia Research, looking specifically at the hormones implicated in the disorder.

The September issue of peer-reviewed journal Schizophrenia Research, will this year be guest-edited by Prof Cyndi Shannon Weickert with assistance from Dr Tertia Purves-Tyson and Katie Allen (pictured), who were invited to bring together a collection of articles that examine the influence of hormones in schizophrenia.

“It’s a real honour to be asked to do this,” says Prof Shannon Weickert. “It’s timely to consider the effect of sex hormones on schizophrenia given the recent success of our CASSI clinical trial. Because we had this breakthrough we’ve gathered together recent studies that examine how sex hormones are involved and how we can better utilise them.”

The articles in the special issue will cover everything from basic research to clinical studies and offer insights into how hormones may contribute to molecular and behavioural changes in schizophrenia.

Although oestrogens have received the most attention, it has become clear that testosterone and oxytocin may also play an important role in schizophrenia and the modulation of symptoms. Harnessing these hormones may lead to adjunctive therapies, especially targeting cognitive symptoms, which are currently the most disabling and un-treated aspect of schizophrenia.

Themed issues of journals tend to garner more attention from their readership, which includes not just schizophrenia researchers but other neuroscientists, psychiatrists and clinicians from around the world. These themed issues in scientific journals often get cited frequently. This special issue will help inform the schizophrenia research community of these important studies and guide the focus for future research.

Understanding the genetic foundations of schizophrenia

Understanding the genetic foundations of schizophrenia

Associate Professor Murray Cairns has been awarded $US 100,000 to investigate the genetic alterations that result in schizophrenia.

“It’s hard to convey just how exciting this project is without going into the complexities of genetics,” Assoc. Professor Murray Cairns says on the phone from Newcastle. “The technology we have available gives us an unprecedented ability to manipulate and edit the genome directly. We hope that by doing this we will come to understand what causes schizophrenia.”

Dr Cairns has recently won a US$100,000 grant from the Brain and Behaviour Research Foundation to help fund his explorations into the miniscule world of genetics and biochemistry. His aim is to finely map the genetic variation associated with schizophrenia by determining the molecular mechanisms affecting the alteration of gene activity at specific genetic mutations.

Schizophrenia is a highly heritable disorder, which means that it will often be passed on from one generation to the next. However, there is not one single gene that can be held responsible for schizophrenia, but several.

If thought about in terms of a map, the Genome-Wide Association Study that last year identified 108 new genetic loci associated with schizophrenia has provided us with a few “towns” in which to locate the genetic mutations. Disease-associated marker single nucleotide polymorphisms (SNPs; pronounced “snips”) provide us with a “suburb” to explore on the genome. What we really need, is the “street” or gene. Even better would be an indication of the biochemical problem-causing “house” or mutation affecting the function of the gene.

“Genetics isn’t yet as precise as people imagine,” concedes Dr Cairns. “A marker SNP that is associated with schizophrenia will in many cases be linked to change affecting a large segment of the genome including several genes and the non-coding sequences. So what we hope to do is precisely ‘edit’ a genome to create cell lines that contain only the variation we predict is responsible for the change in gene expression associated with schizophrenia. In this way we can define the precise mutation and gene that is responsible for the biochemical changes adding risk for the disorder. When we’ve done that we’ll know that this variation is a useful target for which we can develop new treatments.”

Delving into the genetic causes of schizophrenia not only helps us to understand the origins of the disorder, but opens up new diagnostic and therapeutic possibilities. It is a project whose scope could span years but Dr Cairns believes that the wealth of information that will be revealed will have a great impact on how we understand, treat and one day cure schizophrenia.

The results are in!

The results are in!

A little over five years ago, we sent out a request for volunteers to participate in the Cognitive and Affective Symptoms in Schizophrenia Intervention (CASSI) clinical trial. Now, we are pleased to report the exciting findings!

Previous studies conducted by the Schizophrenia Research Lab* found that there is a faulty gene that affects oestrogen receptors in the brains of some people with schizophrenia. The CASSI trial, led by Professor Cyndi Shannon Weickert, tested a drug that acts on the brain’s oestrogen receptors and found that it improved memory and attention in people with schizophrenia.

Prof Shannon Weickert has long suspected that sex hormones may influence the course of schizophrenia as the onset of the disorder typically occurs in late adolescence. As well, the age of onset, course, presentation and response to treatment is different in women compared with men. Women have a greater likelihood of developing first-episode psychosis or experience worsening symptoms when oestrogen levels are low. During pregnancy, when oestrogen levels are high, some women experience a reduction in symptoms, leading researchers to believe that oestrogen has a protective role in schizophrenia.

Cognitive deficits are currently one of the characteristics of schizophrenia that is least responsive to treatment. “I noticed that issues with memory and attention were not being improved and felt motivated to develop additional therapies or treatments that would address this oversight,” says Prof Shannon Weickert. “I felt that these areas were incredibly important in a person’s day-to-day functioning and could drastically improve quality of life.”

Sex hormones such as oestrogen are known to have beneficial effects in the hippocampus and prefrontal cortex, areas of the brain that are also associated with memory and attention. Seeing how stimulation of the oestrogen receptor might influence brain activity, memory and attention was the purpose of the CASSI trial.

The results, recently published in the leading journal in psychiatry, Molecular Psychiatry, revealed that raloxifene, a drug used to treat cancer and osteoporosis, when taken daily alongside antipsychotic medication, stimulates brain activity and improved verbal memory, attention and processing speed in both men and women with schizophrenia.

“This is absolutely the result we were hoping for,” says Prof Shannon Weickert. “Addressing these problems means we may be able to improve the ability of people suffering from schizophrenia to function better socially and maintain employment. It also opens the door to exploring other, new treatment options that address cognitive deficits.”

If you are interested in being involved in a clinical trial for a new treatment strategy being explored by the Schizophrenia Research Lab, click here.

 

*The Schizophrenia Research Laboratory is a joint initiative of the Schizophrenia Research Institute, Neuroscience Research Australia (NeuRA), University of New South Wales, and the Macquarie Group Foundation. It is supported by the NSW Ministry of Health.