First described in 1908 by the Swiss psychiatrist Eugen Bleuler, schizophrenia is a severe mental disorder characterised by loss of contact with reality. This includes hearing or seeing things that are made up by the mind (hallucinations), and unusual beliefs in something that is not real (delusions). In addition, individuals with schizophrenia often present with so-called “negative symptoms”, which include a lack of motivation and interest, difficulty in experiencing pleasure, and an inability to experience emotions fully.
Over the decades, researchers have tried to establish the causes of schizophrenia and to identify the best strategies to prevent and treat the disorder. However, due to its complex nature, the biological mechanisms behind schizophrenia are still not fully understood.
I am a postdoctoral researcher in the neurobiology of mental disorders and, in this article, I will walk you through the most relevant findings in schizophrenia research and the exciting future directions of the field!
Genetics
If you have watched the movie “A Beautiful Mind”, you will know that John Nash was a brilliant mathematician with schizophrenia who won the Nobel Prize in Economics in the 90’s. You may not know that he had a child, Johnny Nash, who inherited from his father, not only his math skills but also schizophrenia. This is because schizophrenia is a heritable disorder that tends to run in families. However, the genetics of schizophrenia are extremely complicated, and having a parent with schizophrenia does not mean that the offspring will also present the disorder. In fact, only around 1 in 10 children of people with schizophrenia will also present with this disorder if they have one affected parent, and almost 1 in 3 if both parents are affected.
Over the last few years, genetics studies have demonstrated that schizophrenia is highly polygenic, which means that there are thousands of genes which are responsible for the illness. In particular, the risk of schizophrenia is associated both with common genetic variants that minimally increase the susceptibility to the disorder and a few rare genetic variants that, differently, increase the risk substantially. In addition, genes associated with the risk of schizophrenia are not disorder-specific but also observed in other psychiatric disorders, including attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, bipolar disorder, major depression and obsessive-compulsive disorder. In other words, if someone in a family has schizophrenia, up to 1 in 20 relatives will present with another psychiatric disorder.
Genetic research in schizophrenia is making substantial progress, and big groups like the Psychiatric Genomics Consortium are enabling rapid advancements in elucidating the genetic basis of schizophrenia. However, current genomic strategies only explain around 40% of the heritability of the disorder and several challenges lay ahead. The application of new technologies to large and diverse samples will hopefully allow scientists to overcome the limits of current genetic research and help clarify the pathway between genetic risk and the expression of symptoms in schizophrenia.
Neuroimaging
Have you ever hurt your knee and your doctor has prescribed you an MRI to see if your ligaments were damaged? That same MRI scan can be used to see if the brains of people with schizophrenia present differences in terms of structure or activity compared to the brains of people who do not have schizophrenia. Unlike the knee though, this cannot be done by simply looking at one image, rather researchers need to look at brain images of many individuals with schizophrenia to see if they differ from brain images of people without schizophrenia.
This was first done in 1984 on a small sample of 14 individuals. Since then, thousands of MRI studies have identified changes in brain structure and activity in people with schizophrenia compared to people who do not present with the disorder. These studies have been fundamental to advancing our knowledge of the brain abnormalities that characterise schizophrenia, which include a loss of volume of the outermost layer of the brain (also known as grey matter), higher activity of the seahorse-looking structure called the hippocampus and abnormalities in how different areas of the brain communicate. However, so far, MRI studies have not been able to provide useful information to identify the disorder or guide treatment in a single person.
But here comes the exciting news! Thanks to recent advances in artificial intelligence techniques, researchers have started to use brain images not only to distinguish people with schizophrenia from people without schizophrenia but also to predict the course of the illness and response to treatment. This represents a huge step forward which might potentially revolutionize the field by providing new methods for the diagnosis, treatment, and prevention of the disorder. Scientists are not there yet, but hopefully one day the diagnosis of schizophrenia will not be very different from the diagnosis of a problem with your ligament in the knee. And even more importantly, by studying how the brain develops over time, we will be able to prevent the disorder before it appears.
Neurotransmitters and pharmacological research
Neurotransmitters are chemicals in our body that allow neurons to communicate with each other. Among these, dopamine is considered the most important neurotransmitter in schizophrenia, responsible for delusions, hallucinations, mood changes and cognitive problems. In addition, other neurotransmitters like glutamate, GABA, acetylcholine, serotonin, and norepinephrine play a central role in the development of the disorder.
Pharmacological research in the field of schizophrenia is in continuous evolution, and several new drugs (also called antipsychotics) are being developed. While dopamine receptors have been the main target of antipsychotics in the past, new antipsychotic drugs mainly focus on multi-target combination therapy. Among these, there is brilaroxazine, a drug currently under study that acts on both serotonin and dopamine receptors but in a different way from other antipsychotics. In addition, in the present psychiatric pharmacological pipeline, new medications act via novel mechanisms of action. Some of the most promising antipsychotics include drugs that activate the muscarinic acetylcholine receptor, a receptor that is also involved in regulating the heart and other body functions, and that has proven particularly useful in improving cognitive deficits in neurological and psychiatric disorders. In addition, scientists are developing and testing trace amine-associated receptor (TAAR1) agonists, molecules that influence the neurotransmission of dopamine, glutamate, and serotonin. Either as a single agent or in combination with other molecules, TAAR1 agonists have proven to be effective in the treatment of negative symptoms and cognitive deficits of schizophrenia. Furthermore, new positive results come from the study of voltage-gated sodium channel blockers, drugs which inhibit sodium channels located in the membrane of neurons, where they regulate neuronal electrical firing and can normalise excessive release of potentially neurotoxic brain chemicals, like glutamate. And that’s not all. New advancements in genetics have allowed researchers to identify biomarkers that are able not only to match people with schizophrenia to the most effective medications but also to measure response to treatment.
This is very exciting, but let’s keep in mind that the path from the lab to clinical practice is long and difficult, and not all these new drugs will be approved by regulatory systems. Nevertheless, the field is moving forward fast and new drugs with the potential to help millions of people with schizophrenia will soon become available.
Future Directions
Since 1908, huge steps have been made towards a better understanding of the mechanisms that cause schizophrenia and the best ways to prevent and treat it. However, there is still much to understand, and advancements in technology will help researchers reach this goal.
First, greater integration of large biological datasets (the so-called “omics”) will clarify the path from genes (genomics) to gene readouts (transcriptomics) to proteins (proteomics) involved in schizophrenia, ultimately unveiling the complex biology of the disorder. Then, advanced artificial intelligence techniques will allow researchers to analyse large datasets and develop models based on clinical, cognitive, biological and neuroimaging data able to predict the disorder, its course, and response to treatments. This will improve early intervention and prevention strategies and will allow us to create a personalised psychiatry, where treatment plans will be tailored to a person’s specific genetic and biological profiles.
Overall, schizophrenia research is making significant progress. By understanding the underlying causes and developing more targeted treatments, researchers are working towards a future where prevention, early detection and effective treatment of schizophrenia will be a routine reality.
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