A Cure for the future

This article by Bruce Munro was originally published on odt.co.nz on 18 Aug 2024.

No-one really knows how many hundreds of thousands of people could end up with schizophrenia because of the Covid-19 global pandemic. Bruce Munro travels to Shanghai and talks to University of Otago’s Prof Ping Liu to find out about the race to detect, treat and prevent psychosis in the children of pregnant mother’s infected with the virus.

Dr Chunbo Li briskly walks the hallways of Shanghai Mental Health Centre (SMHC), its stairwells, connecting skybridges and more hallways. Not just because he is a busy man, second in charge of China’s largest psychiatric hospital, but also because this place is so large that walking any slower would render him merely a pedestrian rather than a top psychiatrist. The facility, opened in 1935, serves 26-million-person Shanghai’s mentally distressed and diseased citizens. Across two campuses, here in Xuhui, in southwest central Shanghai, and in Minhang, on the city’s southern outskirts, the Health Centre boasts more than 1300 staff, 37 wards and 2141 inpatient beds for 115,000 registered patients, including up to 4000 daily outpatients.

As well as treating psychiatric needs, the SMHC is a research hospital, attached to one of China’s top tertiary institutions, Shanghai Jiao Tong University. Two years ago, SMHC was made a National Centre for Mental Disorders, giving it a countrywide role in the psychological health of the world’s second most populous nation.

At the end of a hallway, where several people sit waiting, Dr Li enters a treatment room. In cubicles separated by curtains, patients are undertaking various tests, the resulting brain activity being monitored through electrodes on the scalp. It is just one of myriad research projects covering general and clinical psychiatry; mood disorder; addiction medicine; child, adolescent and geriatric psychiatry. The data and samples, collected over time, are a potential gold mine for the likes of University of Otago Department of Anatomy and School of Biomedical Sciences researcher Prof Ping Liu.

“When I visited, they showed me how many -80 degree freezers full of samples they have — they have huge resources,” Prof Liu says.

“We have ideas and analytical skills; they have data and samples. We want to collaborate together, but Covid has made that difficult.”

The global coronavirus pandemic has been both impetus and disrupter of joint Shanghai-Otago research to detect, prevent and treat virus-related schizophrenia. Plans for collaborative research were well under way when, in March, 2020, Covid-19 put the world into lockdown. A disturbing irony is that the research-stymieing pandemic has, at the same time, likely resulted in the births of hundreds of thousands of babies worldwide who are at high risk of later experiencing psychosis because their pregnant mothers caught Covid. So, with the SMHC door shut, Prof Liu and her research team pivoted and ploughed on; testing a drug that, at least in rats, seems to completely eradicate the risk of virus-related schizophrenia. Her eye, however, is still firmly on the link with Shanghai, hoping for a fresh chance to make use of the mental health centre’s vast resources for human trials of the potentially revolutionary drug and to develop an efficient way of detecting those who need it.

The notion viruses caught during pregnancy can cause future mental illness in a woman’s child is shocking but not new.

Connections between influenza and psychosis have been noted for at least the past 300 years. Widespread examples of what were then called melancholy, hysteria, mental prostration and insanity were noted after ‘flu epidemics as early as 1732, including the global Spanish Flu pandemic of 1919.

A link has also been long-noted between mental disease and season of birth. Studies during the 20th century showed children born in late-winter and spring had a higher chance of developing psychosis, the most obvious symptom of the disease, schizophrenia.

Psychosis can be experienced as hallucinations, delusions and disorganised thinking and speaking. Other symptoms can include low energy, lack of motivation and disconnection from emotions.

One in a hundred people are diagnosed with schizophrenia which, on average, reduces a person’s lifespan by 30 years.

These threads — virus, pregnant mother, schizophrenia — became the focus of dozens of studies during the second half of the past century and into this one.

By 2010, it was known that while about 1% of the general population was at risk of developing schizophrenia, the risk increased threefold for those whose mothers caught a ‘flu virus during pregnancy.

In February 2020 — as fears about a new possible virus pandemic grew, New Zealand confirmed its first case of Covid-19 and governments worldwide considered closing borders — a paper published in Frontiers of Psychiatry coincidentally summarised what was known about maternal infection and schizophrenia. That paper, marking the centenary of the Spanish Flu, stated that while there was still controversy about the biological processes at play, a likely cause was the mother’s immune system response to her infection, which somehow, in some cases, affected the unborn baby’s brain development, producing changes that put them at higher risk of debilitating schizophrenia.

Tackling that awful reality had been the goal of collaboration between the University of Otago and SMHC, birthed in 2016. That year, the New Zealand-China Non-Communicable Disease Research Collaboration Centre (NCD CRCC) was set up, headquartered, in New Zealand, at the University of Otago. The next year, the NCD CRCC organised a delegation from China to visit New Zealand, followed in 2018 by a reciprocal visit to China. Otago’s Prof Liu presented at both, garnering the attention of SMHC’s Dr Li and its chief psychiatrist Prof Jijun Wang.

Prof Liu had been raised in China and worked there for eight years as a medical doctor before coming to Dunedin, in the 1990s, to study for her PhD. For the past quarter century she has built an award-winning career at the University of Otago as a research scientist and international leader in arginine metabolism, a process that plays an important role in human health.

For many years, SMHC had taken an active interest in Clinical High Risk of psychosis syndrome (CHR), the latent state preceding full psychosis. There was a natural synergy with Prof Liu’s pioneering research on viruses and long-term neurological damage.

With support from the Ministry of Business Innovation and Employment (MBIE) and NCD CRCC, a plan was drawn up to work together — using SMHC’s comprehensive bank of blood and tissue samples and Prof Liu’s research pointing to changes in arginine metabolites in the blood and brain of schizophrenia patients — to try to develop a blood biomarker to detect those at risk before they developed the disease.

“There’s a need to find a good blood biomarker. Because taking a blood sample would be a simple, non-invasive way of testing whether someone was likely to develop schizophrenia. That’s why we have a common interest,” Prof Liu explains.

A good plan, except for the black swan event that became the global Covid-19 pandemic; closing borders, locking people in household bubbles, killing between three and seven million individuals, infecting 755 million worldwide.

Even before Covid, the global cost of mental illness was set to rise significantly.

An article published in Foreign Affairs, in 2015, tried to draw attention to a 2010 report by scholars from the Harvard School of Public Health and the World Economic Forum predicting a coming tidal wave of noncommunicable diseases. Between 2010 and 2030, chronic noncommunicable diseases would reduce global GDP by $46.7 trillion, the report estimated. The added surprise in the report was the prediction the largest source of those burgeoning costs would be mental disorders; by 2030 the global cost of mental illness would be more than heart disease, cancer, diabetes and respiratory diseases combined.

Covid will likely add to that, but by how much is unclear.

One estimate, based on the calculation more than nine million women so far have been infected with Covid while pregnant, suggests more than 274,000 babies born since the start of the pandemic are at risk of schizophrenia due to maternal viral infection.

“Some research has already shown the association between Covid infection of mothers and their offspring … showing developmental delays and some brain changes,” Prof Liu says.

“I don’t have a specific number … but around the world it will likely be a big problem.

“So, now, we really need to develop whatever intervention strategies we can to help those children.”

Without the ability to send or receive researchers during China’s lengthy lockdown, only one piece of joint Shanghai-Otago research was able to proceed; examining the blood profile of unsaturated fatty acids. It produced some promising results. They found five blood markers that were consistently different in CHR patients compared with control participants. And one of those markers appears to detect the change from high risk to symptomatic schizophrenia.

“More work still needs to be done, but it looks like this marker can be used to predict that in a couple of years a person will have full psychosis,” Prof Liu says.

Beyond that, Prof Liu and her Otago team have focused on what research they could do here — trialling a drug on schizophrenia-symptomatic rats to test her theory about a possible way to treat and prevent the disease.

During this time, Prof Liu herself has twice been infected with Covid; the first was by far the worst.

“It was awful. I had three months off work. It affected my heart, my vestibular system; I had brain fog and a lot of fatigue. I’m not yet 100% recovered.”

Surprisingly, one of the key tools for diagnosing schizophrenia is startle response.

For most people, a small noise preceding a loud noise reduces how startled they are by the second noise. Not so for the person with schizophrenia who is almost as startled as when only exposed to a single loud noise.

“So, this impairment is a benchmark test for schizophrenia patients clinically,” Prof Liu says.

And the same goes for rats.

Built on evidence exposure to a virus during pregnancy likely triggers an immune system response in the mother that, in a few cases, damages foetal brain development, Prof Liu has used a well-established Maternal Immune Activation (MIA) animal model to test interventions.

In plain speak, the MIA model animal is a pregnant rat which, when injected with a viral infection mimic, produces pups displaying this startle response deficit, a sure sign of schizophrenia.

The researchers, with funding from the Neurological Foundation of New Zealand, have then treated the afflicted animals — pregnant mothers, newborn pups and pre-adolescent pups — with the potentially beneficial drug.

The results, as yet unpublished, are exciting Prof Liu.

Although she will not name the drug, she says it is having a dramatic beneficial effect.

“The research is still ongoing. But we found with our drug treatment all three can be fully rescued from the [startle response] deficits, which is really amazing.”

She points to bar graphs showing schizophrenia symptom deficits in pregnant MIA mother rats and their offspring.

The next line on each bar graph shows the response after being given the drug. The line is back on par with the control rats; the schizophrenia symptoms are gone.

And that “cure” is for the pups treated in utero as well as for pups treated after birth, both as newborns and after being weaned.

“I have been working on this particular drug for many years. If our data is really good then potentially we can translate this animal work to humans, to a clinical setting.”

That is where Shanghai might come back in to the frame.

“Shanghai would have some advantages because of its much bigger population.

“In New Zealand, it would be pretty difficult to find enough offspring who were affected by Covid prenatally. But in Shanghai, from conversation with [Dr] Chunbo, they probably have a system.

“They have monitored this, so, probably there’s great potential in the future.”

This is all a wee way off.

Prof Liu does not like to hazard a guess but, pressed, says getting an effective treatment for MIA schizophrenia to the point it can be prescribed by doctors to members of the public could take another five to 10 years.

There is also the matter of trying to identify and develop an effective blood biomarker, to easily determine exactly which children are at risk.

Collaboration with SMHC on this makes good sense, Prof Liu says.

“They have collected a lot of blood samples over a lot of years, of people with CHR and those who have converted to full psychosis. They also have neuro-imaging, electro-physiological examinations, genetic tests, and behavioural assessment of all kinds. So they have a very rich database that would be very helpful.”

An effective preventive and treatment for maternal infection schizophrenia, in tandem with a reliable and simple biomarker test, would be an enormous scientific, medical and human breakthrough. The drug could be given to pregnant mothers who caught a viral infection, or retrospectively to their at-risk offspring, freeing hundreds of thousands of children from the threat of developing this life-limiting and life-shortening disease.

“I’m 60 now. I don’t know how many years I still have here at Otago,” Prof Liu says.

“But I really hope I’ll be able to see this through. For the sake of the children, we need to do it.”