New gene links to schizophrenia could open the door to improved treatments

New research has found that people who suffer from schizophrenia could have genetic errors which affect them in three different ways.

First, these errors could make people more susceptible to the disorder. Second, these errors could influence how they respond to treatment. And finally, they could interfere with the body’s natural response to environmental factors like stress, trauma and substance abuse that contribute to the disorder.

Our findings represent substantial strides towards understanding how genes and the environment come together to shape schizophrenia as a disorder. For sufferers, these developments are important because it opens up a range of new pathway options that could further clarify how individual sufferers respond to treatment.

For example, genetic errors in the genes responsible for the way the body metabolises treatment drugs may influence whether the drugs are absorbed properly, transported to the site where they need to function or cleared from the body quickly enough to avoid negative side effects.

Schizophrenia is a complex disorder. It affects how an individual thinks, feels and acts. Schizophrenics often find it difficult to tell the difference between real and imagined experiences. They battle to think clearly or express their emotional states effectively. They also struggle to behave within the bounds of generally accepted societal norms.

Understanding schizophrenia

Both genetic and environmental factors are responsible for the disorder developing, progressing and being treated. These factors also have an impact on how an individual responds to drug-based treatments. The way genetic elements and environmental factors interact has an impact on the symptoms schizophrenics present with, and how severe these may be.

The body has ways in which it reacts to these environmental influences. In a process called methylation, the body will turn certain genes off or on as it responds to these influences.

Our new research has found that the body does this by using certain core genes. These genes must therefore be working properly to turn other genes on or off.

Errors in the genetic code of these core genes could mean differences concerning the environment’s role in how an individual develops and manages schizophrenia. This means that the genetic machinery responsible for the body responding to environmental influences could be broken, or not functioning as it normally would. Once that happens, the body cannot necessarily naturally respond to the environmental factors influencing schizophrenia.

Until now, it has been generally accepted that schizophrenia is triggered only by a combination of environmental factors and genetics. It has also been understood that the body is always able to respond to these environmental factors. Our research adds to this but shows the pathway between an environmental influence and the body responding to it might not necessarily be a smooth road. The body’s expected response to an environmental influence may be a problem all on its own.

This additional consideration creates a new avenue of potential dysregulation. In trying to understand a person’s disorder and predict an effective treatment for them, the environment and genetics cannot be considered alone. The individual’s reaction to an environmental influence must also be looked at to see if, on a genetic level, it is as expected.

Previous research has shown a link between schizophrenia and the body’s immune response. The involvement of the immune system may be able to explain the body’s response in terms of environmental contributions towards developing and treating the disorder, like pre-natal trauma and stress.

Our research has also identified a master regulator gene associated with treatment outcomes in the same group of patients where errors in the core genes involved in the body’s response to environmental influences have been found.

Challenges with treatment

Mental health disorders affect an estimated 200 million people worldwide. Of these, between two and four million suffer from psychotic disorders, such as schizophrenia.

In lower to middle income countries, schizophrenia is associated with an immense burden. Treatment in these countries is far from optimal because of limited resources and compromised public healthcare systems.

Despite the majority of schizophrenia cases being isolated to middle- and lower-income countries, only 25% receive treatment. And of these, only half have a positive treatment outcome. The other half may be prone to developing adverse drug reactions such as weight gain, dystonia (continuous muscle spasms) or tardive dyskinesia (irregular, jerky movements).

There is no doubt that the current state of mental health treatment regimens needs to be improved. Pharmacogenomics, which attempts to predict an individual’s likely response to therapeutic drugs, bears much promise for this improvement.

A better treatment plan is needed

It is well established that people react differently to medication because of differences in some of the genes responsible for breaking down and transporting drug treatments through the body and excreting the drug.

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Personalised medicine involves tailoring treatments to a particular patient’s needs based on an understanding of these genetic differences and also any environmental influences.

Understanding which combination of changes contribute to which symptoms in less complex disorders is complicated enough. Because schizophrenia is such a complex disorder, it is even more intricate.

The challenge with schizophrenia is that the spectrum and severity of the symptoms that sufferers face is fairly wide because of the way in which the disorder develops and progresses.

One of the most promising ways to improve treatment outcomes is drug efficacy. Early diagnosis and consistent medication use is vital for the effective treatment of schizophrenia with minimal side effects.

Antipsychotics are currently the most effective treatments for schizophrenia. These are subdivided into first and second generation drugs. There are no major differences between the two classes in terms of treating the condition. The difference lies in the potential side effects, called adverse drug reactions or ADRs, which may develop.

Patients taking second generation antipsychotics are prone to substantial weight-gain, but they have a lower risk of developing neurological ADRs like tardive dyskinesia, dystonia and Parkinsonism. These side effects are common to first generation antipsychotics.

In South Africa and other lower-to-middle-income countries, first-generation antipsychotics are frequently used because they are cheaper and more easily available.

One of the main reasons for a poorer treatment outcomes in schizophrenia is patients failing to take the prescribed medication. Their reasons for non-compliance are often the severe side-effects.

Much of the work done and future research will require scientists to step outside the boxes previously labelled “known” or “understood” if we wish to uncover the underlying causes for complex disorders, such as those affecting mental health.

Nathaniel McGregor receives funding from the National Research Foundation (NRF).