Analysis: recent research suggests that schizophrenia is actually a dysfunction of the brain’s blood vessels

By Matthew Campbell, TCD

Schizophrenia is a brain disorder that affects approximately one percent of the population and nearly 1.5 million people are newly diagnosed each year globally. It is characterised clinically by delusions (fixed and false beliefs), hallucinations (visual and auditory), and disorganised thinking and speech and begins in early adulthood, usually in the late teens, and continues throughout an individual’s life. To put this in context, if you graduated from secondary school in a class of about 100 students, the likelihood is that at least one of your classmates would have gone on to develop schizophrenia in the years after leaving school.

Contrary to common conceptions, schizophrenia does not involve split personalities, but rather has been described by sufferers as "having a shattered mind". Symptoms of the condition can lead to abnormal social behaviours, depression, anxiety and often times social marginalisation of those affected and indeed their families. A lesser appreciated fact is that the average life expectancy of people living with schizophrenia can be between 10 to 25 years less than normal.

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RTÉ News report on new research into the underlying causes for schizophrenia

We now know that schizophrenia has a very strong underlying genetic component. As studies in identical twins who share an identical genome (i.e., all of their DNA) show, if one twin suffers from schizophrenia, the other has up to an 80 percent chance of developing the condition. However, large-scale genetic studies in hundreds of thousands of individuals with or without schizophrenia suggest that it is a highly complex polygenic disorder involving multiple genes while also having causative environmental stimuli and stressors. 

Current treatment options for patients largely and almost exclusively include the use of anti-psychotic therapies and adjunct psychosocial therapy, including psychotherapy and cognitive behavioural therapy. However, anti-psychotic drugs are often discontinued by patients due to inefficacy or intolerable side effects. One major side-effect is inexorable weight gain, with some patients choosing to live with the symptoms of schizophrenia rather than gaining weight uncontrollably.

There is now a very clear and urgent need to better understand the underlying molecular aetiology of schizophrenia and to develop new forms of therapy for this debilitating condition. In recent years, my own laboratory at the Smurfit Institute of Genetics at TCD has been studying schizophrenia from a completely different angle. We are working on the hypothesis that schizophrenia is actually a dysfunction of the brain’s blood vessels. In the same manner that cardiovascular diseases are the result of damaged and unhealthy blood vessels in and around the heart, our recent research is highly suggestive that schizophrenia is a cerebrovascular disease, with the brain’s blood vessels being the main culprit for disease onset.

We know that there are approximately 100 billion neurons in a human brain but they need an extensive and elaborate blood supply

The brain is a very high energy demanding organ and requires up to 25 percent of our daily energy intake.  A quarter of the energy in that sandwich you ate at lunchtime is going to making your brain function optimally.  We know that there are approximately 100 billion neurons in a human brain but, given the massive energy requirements for these neurons, they need an extensive and elaborate blood supply. In fact, the vascular network in the brain is so extensive that the capillaries would stretch from Dublin to Paris if lined up side by side. Added to this, the surface area of these blood vessels cumulatively would cover a tennis court. 

This means that every neuron in the human brain will be perfused by its own capillary. Our lab has been at the forefront in recent years in identifying that it is these small capillaries that become dysfunctional in schizophrenia. The capillaries in the brain are unlike those in other parts of the body.  They very strictly regulate what gets into and out of the brain, forming a very tight seal that is referred to as the Blood-Brain Barrier (BBB). We believe that it is this BBB that goes awry in schizophrenia, essentially allowing unwanted and toxic material into the brain, inducing abnormal neuronal functioning.

Recognising that schizophrenia is a disease of the cerebral vasculature will revolutionise how this condition is treated and lead to improved medicines for patients living with the condition. To use the analogy of cardiovascular diseases, all of the drugs currently on the market to prevent heart attacks and strokes do not actually function at the level of the cardiac tissue, but make the blood vessels in and around the heart more stable and, as a consequence, the cardiac tissue becomes more stable. The same should hold true for the brain - make the cerebrovasculature stable and therefore the brain will take care of itself. 

Our findings are not limited to schizophrenia and they are already leading to a greater understanding of other neuropsychiatric conditions. There is great hope that our research will lead to the next generation of drugs to treat these unnecessarily stigmatised conditions and alleviate the suffering of patients and their families in the future.

Prof Matthew Campbell is Director of the Neurovascular Genetics laboratory in the Smurfit Institute of Genetics at TCD where he is also a Lecturer. In 2013, he was awarded Science Foundation Ireland's (SFI) most prestigious prize for young researchers, the President of Ireland Young Researcher Award (PIYRA).  In 2014, he was awarded the Genentech/ARVO fellowship for his ophthalmology-focused work related to AMD. In 2018, he was awarded one of the inaugural Irish Research Council (IRC) laureate awards for his research on schizophrenia. He is also a principal investigator in FutureNeuro, the SFI Research Centre for chronic and rare neurological diseases.

The views expressed here are those of the author and do not represent or reflect the views of RTÉ