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Disease and treatment

The quest to save people from the voices that kill

Voices that talk to you. They encourage you to kill yourself, stab somebody or contemplate how to kill yourself. This is reality for 1 of 100 people. Most often they do not know that the voices are not real, and 1 in 4 actually try to commit suicide. 2020 Novo Nordisk Prize recipient Merete Nordentoft has dedicated her life to studying suicide prevention and schizophrenia. Merete Nordentoft hopes for the future that the people at risk can be identified and helped when they are still children.

It seems unbelievable. Do people really hear these violent and terrifying threats about persecution and death? And do they really think anyone will poison them or kill their loved ones? The most unimaginable aspect, however, is that any one of us can develop schizophrenia, and when it strikes, it arrives surreptitiously like a slow distortion of the reality we think we know and have control over. However, people with schizophrenia can get help, and if they receive it early enough, they can learn to live with schizophrenia.

“Schizophrenia reduces people’s lives by 15–20 years on average. They have excess mortality from both unnatural causes of death such as suicide and accidents and natural causes, since they have an increased risk of dying from every somatic disease. The good news is that early treatment can help people with schizophrenia. We hope that in the future we can find the children at risk and their families, because early intervention could enable these children learn to cope early so they do not need to be removed from the home later on,” explains Merete Nordentoft.

Fascination with the brain

Mental disorders such as schizophrenia are common and extremely challenging for the people who have them and for their families and society. However, little was known 20 years ago about the increased suicide risk and general comorbidity that severely impair the quality of life and increase mortality. Although Merete Nordentoft already knew at a young age that she wanted to become a doctor, she was not aware of this scary and fascinating illness.

“It was almost a coincidence. I thought I might become a neurologist, but then I got this first position in psychiatry. The first 6 months of my first employment in a day hospital was very calm. I was almost bored, but then they opened an acute department where we had all the severe disorders such as first-onset psychosis, and that caught my attention, because I was really fascinated by how the brain creates these symptoms and how these people perceive the world.”

Merete Nordentoft’s fascination with the brain led her to start a research project in her first job to explore the clinical issues she encountered in her work. She consulted the people who had attempted suicide and inventoried them as her first project. A few years later, she carried out a PhD project at Bispebjerg Hospital, examining what happened when community mental health centres were implemented in the mental health services in Copenhagen.

“At that time, I thought that the people who would be most vulnerable to these changes, by which they are supposed to become more independent, would be those who used many services already. But we realized that the most vulnerable people were those who had their first contact with the mental health services, whereas almost nothing negative happened to those who had been in treatment for 10 years. So I became aware that the early phase of psychosis is a very vulnerable period in which many bad things can happen.”

An action plan

The study also made Merete Nordentoft realize that, if people are left untreated in the early phase of psychosis, many negative things can happen. For example, the risk of suicide is higher in the early years than later on.

“In Denmark we have 600 suicides every year, and about half involve people with mental disorders. This increased risk of suicide for people with mental disorders compared with the general population triggered my interest in exploring the causes of suicide.”

In 1993, she published a 10-year follow-up study of people who had attempted suicide in the prestigious British Medical Journal. The study showed that most people who attempted suicide were at high risk of succeeding because the risk factors were not very specific. A national strategy to prevent suicide was needed.

“In 1997, it was decided that we should have a national suicide prevention plan, so it was developed during 1997 and ready in 1998. In that connection, Preben Bo Mortensen was doing most of epidemiological studies to demonstrate which groups were most important. This work formed the basis for the actual action plan targeting the majority of the people who attempt suicide. I was chairing the committee preparing the action plan and so our collaboration began then.”

The rate declined

The epidemiological studies of Preben Bo Mortensen and Merete Nordentoft on the risk factors for suicide among young people were supposed to inform the work of the committee preparing the action plan, but the groundbreaking results also helped to change the views of both researchers and health professionals on suicide and on mental illness. A 2002 article in the British Medical Journal both affirmed and confirmed this hypothesis.

“Basically, the conclusion was that recognizing mental illness among young people and dealing with it appropriately could help prevent suicide. Further, we found that the high relative risk of suicide associated with low socioeconomic status of the parents seemed overestimated.”

The effect of the parents’ socioeconomic status decreased after the researchers adjusted for the family history of mental illness and suicide, which strongly affects the children’s suicidal tendencies. Denmark’s suicide rate had been extremely high in the 1980s, and when the action plan was adopted the number was 700–800 per year. It then declined to 600 and has been stable for years.

“We still need to do more work, because 600 is still far too many. People with schizophrenia have a 20 times higher risk than the general population. One quarter of the people with schizophrenia attempt suicide, and ultimately 5–8% die from it.”

Less focus on the disorder

The epidemiological studies had clearly shown that suicide rates can be reduced. A 2004 article in the British Medical Journal showed that the suicide rate declined among people with schizophrenia in Denmark from 1981 to 1997.

“Our theory was that this may have resulted from better psychiatric treatment, reduced access to means of suicide or improved treatment after suicide attempts. People admitted to hospital with schizophrenia had the highest risk of suicide in the first year after their first admission.”

Alongside the suicide studies, Merete Nordentoft had already started the OPUS study in 1998, in which 547 young people with schizophrenia had 2 years of very intensive treatment versus 2 years of standard treatment and then were followed up after 1 year and 2 years.

“We named it OPUS because we wanted to express that instruments should play together and need a conductor, so we needed things to be coordinated. The people with the disorder meet a more interdisciplinary team consisting of psychologists, psychiatrists, occupational therapists and social workers. In this way, you coordinate the efforts to solve the challenges the people with the disorder have in their everyday lives instead of just focusing on the disorder.”

And it worked. The group that received the OPUS treatment had fewer hallucinations and delusions and fewer negative symptoms such as social withdrawal, passivity and lack of expression compared with standard treatment. There was also less substance abuse and fewer bad days.

“The very general picture was that the people with the disorder were more satisfied with the treatment, as were their parents, because they learned more about their children’s symptoms. They spent less time hospitalized in psychiatric wards and spent less time in institutions, so they learned how to organize themselves and manage their symptoms and their situation. I think that the long-term effect was more about improving social functioning.”

International impact

The OPUS studies were such a great success that the researchers got funding for follow-up 5, 10 and 20 years afterwards and for another trial investigating which interventions are needed to sustain the positive effects. So today the participants can be used as a cohort to show the prognosis of schizophrenia and related disorders in a modern context, and the researchers do not have to rely on old textbooks from when treatment was completely different. But more importantly, the OPUS treatment became standard all over Denmark.

“We had to push when we had the initial results, but all the public authorities were very positive, so they wanted us to keep the staff members who were trained and they wanted to transform it into a permanent service. Later on, through state funding, it was disseminated in several waves to implement it further. Further, some of the patients were actually able to explain how this has meant a difference. They were really great spokespeople for themselves.”

In 2005, the experiences in working with intensive early intervention even led to a set of international clinical guidelines for early psychosis. The experiences from Merete Nordentoft’s OPUS trial were key to the guidelines, which mentioned the importance of early identification and treatment.

“The longer you live with untreated or poorly treated psychotic conditions, the worse is the outcome and the higher is the risk of unwanted outcomes, such as suicide. Other undesired outcomes include homicide, although this is seldom, attacking somebody, social isolation and deterioration of social conditions. So many negative things can happen if you do not treat early, and treating somebody who has had a psychotic disorder for many years is much more difficult.”

Voices and the cannabis link

Merete Nordentoft’s group recently initiated a new trial aiming to help people who hear voices. The idea is to test whether simulation training in a virtual environment can reduce auditory hallucinations and distress. With a voice-transforming program, the voice of the therapist can be modified so it sounds similar to the voice the person with schizophrenia used to hear. The therapist can interact with this person by switching between acting as the nasty voice and the supportive therapist. Hopefully this will help the person with schizophrenia to stand up against the voices, be able to stop listening to them and stop believing that they are omnipotent.

An example of some of the possible consequences of untreated psychosis came from Merete Nordentoft’s study of homeless people in Denmark from 1999 to 2009. Of the 32,711 registered homeless people (23,040 men and 9671 women), 14,381 men and 5632 women had mental disorders. The life expectancy of these homeless people was 22 years lower for men and 17 years lower for women than for the general population. Substance abuse disorder was the most frequent mortality risk.

“I also went around to identify homeless people with schizophrenia and interviewed them. They were so convinced that their delusions were real that they would never even think of seeking help, so they were convinced that they were being followed and they had many conditions. The women were the most visible ones, so that was why the study was called shopping bag ladies. Fourteen of the 15 interviewees had schizophrenia with massive delusions and hallucinations.”

For the men, substance abuse disorder was one of the main reasons for their mental disorder, and substance abuse is one of the main risk factors for schizophrenia. Merete Nordentoft’s group has carried out several studies examining the risk of transitioning from being diagnosed with cannabis abuse to developing psychotic disorder.

“Several of our studies have shown that substance abuse, especially cannabis abuse, is associated with a higher risk of developing schizophrenia, and we also demonstrated within this OPUS study that those who continued using cannabis had a higher risk of continuing to have severe psychotic symptoms than those who stopped.”

Lifespan reduced by 15–20 years

With the OPUS trials, the importance of early intervention became the gold standard, so today people with schizophrenia are treated with both antipsychotic medication and psychosocial interventions in which they learn about the symptoms and warning signs, and their families are also involved.

“Many things can improve the prognosis. Maybe they can stay get more targeted support from their parents. And also some measures can help the treatment to become more effective, such as having more knowledge about their own symptoms and knowing more about what to do with the symptoms. Our data showed that, after 1 year, half the people with schizophrenia do not have psychotic symptoms anymore, so that is a really positive outcome.”

Despite the improvements, there is still much to be done. This was demonstrated by a 2013 study showing that women with mental disorders have about 15 years’ lower life expectancy than the general population and 20 years lower for men. Mortality from somatic diseases was increased two- to threefold, and excess mortality from external causes ranged from three- to 77-fold.

“Mortality from suicide was highest among people with affective disorders and personality disorders. The effects of schizophrenia on the number of years of potential life lost and life expectancy seem to be substantial and not to have lessened over time. So even though much has happened with the OPUS development, interventions and initiatives to reduce this mortality gap still urgently need to be implemented.”

A genetic factor

Today Merete Nordentoft heads a research unit of more than 60 researchers, with 40 employed in clinical studies and more than 20 working on epidemiological research. Since 2012, she has also been one of the six principal investigators in the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH). As part of iPSYCH, she initiated the major Danish High Risk and Resilience Study VIA 7 – a cohort study of 522 7-year-old children with 0, 1 or 2 parents with schizophrenia or bipolar disorder.

“There has been a logical track in my research career. I started by studying people with mental disorders who already used considerable mental health services. Then we examined people with their first psychotic episode, and now we are starting an effort for these children who are at risk of developing mental disorders later in life because their parents are sick. In other words, we are trying to determine whether we can intervene at an earlier stage than when everything has gone so wrong that people end up homeless on the street.”

The aim is to identify new and targetable biological and clinical markers of the early risk of psychosis. Today, both genetic and environmental factors are known to be involved. Up to 15% of the genetic risk has been explained. In the studies, the strongest factor inversely related to poor outcome is the polygenic risk for educational attainment.

“Your genes partly explain the likelihood of completing a long educational programme. Of course, you can influence this yourself, but people can be genetically predisposed to being able to complete a long educational programme. This is less likely for the children who have early symptoms of mental disorder, but this is related to the home environment and how well functioning their parents or other caregivers are, so genes and environment also interact.”

A big surprise

Early intervention has proved to be crucial in combating schizophrenia and other mental disorders. Given the many environmental risk factors – responsible for 60–70% of the total risk – much can be done. Even though Merete Nordentoft and her colleagues are still exploring new risk factors, such as infections, the most important current focus is the children and their parents.

“This started out with epidemiology, in which we found out that the children of people with severe mental disorders, including schizophrenia, bipolar disorder and others, had a higher risk of developing a mental disorder. So this is an important high-risk group, because we can prevent mental disorders but we could also maybe improve in intervening in the social conditions.”

The researchers also showed that these children were less likely to complete primary and lower-secondary school and were more likely to be removed from the home and placed outside, so they knew that this is a vulnerable group.

“We called the project the Danish High Risk and Resilience Study – VIA 7 because the children were 7 years old when we started, and they were recruited if their parents had either schizophrenia or bipolar disorder. We assessed them very thoroughly and interviewed both their parents. We got many data showing that the children whose parents had schizophrenia were more likely to have neurocognitive deficits, social cognitive deficits, poorer motor function, poorer language, poorer quality of life and a less optimal home environment.”

Nevertheless, the researchers examined the numbers more closely and found to their great surprise that half the children with parents with schizophrenia were not affected and were at the same level as the control group, whereas 25% of the children were affected on all domains. The researchers aim to invent a tool that more easily can identify the children at higher risk and provide treatment earlier.

“Our experiences from interviews with the parents of these children is that they experience that they cannot get the support they need, so I think more thorough mapping would enable us to find families in which early intervention could prevent removal from the home later. Through early support for these families, I think it is possible to prevent them from starting to develop delusions, hallucinations and the poor self-confidence often seen among people with schizophrenia.”

The 2020 Novo Nordisk Prize is awarded to Merete Nordentoft, Clinical Professor, University of Copenhagen and Preben Bo Mortensen, Professor and Scientific Director, iPSYCH, Aarhus University.

Merete Nordentoft
Clinical Professor
Merete Nordentoft is an expert in epidemiology, suicidal behavior, psychopathology and early intervention in psychosis. She was PI for many large randomized clinical trials, evaluating the effect of psychosocial intervention, of which the Danish OPUS trial (specialized assertive intervention in first episode psychosis) is the most well known. She has worked with suicide prevention at a national level since 1997. Together with a group of epidemiologist from Nordic countries, she has proved that life expectancy in schizophrenia is 15 to 20 years shorter than in the general population. She is involved as one of the PI’s in iPSYCH, the Lundbeck FoundationInitiative For Integrative Psychiatric Research, which aims at investigating genetic and environmental causes of mental disorders. The initiation of the large Danish High Risk and Resilience Study VIA 7 is an important part of iPSYCH. She was given the prestigious award “Global Excellence in Health” in 2012.