By Michael O’Donovan, Cardiff University
There are lots of medicines available to help with the symptoms of schizophrenia. Some are a bit more effective than others. Some have side effects that make them better suited to particular patients. But fundamentally, they all work pretty much in the same way; they all reduce the activity of a chemical in the brain called dopamine.
For those who do not respond well to this type of treatment, or for some reason cannot take it, there are no radically different options, despite 60 years of pharmaceutical research. In other areas of medicine, like cancer and heart disease, improved understanding of disease mechanisms has led to the identification of a wide range of drug targets. But unfortunately, the causes of schizophrenia remain obscure.
Identifying these mechanisms is therefore a critical step towards improving the outcomes for those with the disorder. In the largest genetic study of its kind, published in Nature, we discovered not just a few, but more than 100 specific regions – or loci – of the genome which contain genes that affect risk, and have been able to identify a genetic link to a protein that is the only known target in schizophrenia drug treatment.
What’s more, several of the findings appear to implicate genes that have little-known function in the brain, but are present in cells that are important in the immune system, which could mean completely new avenues for study.
The search for ‘schizophrenia genes’
It has been known for a long time that genes play a big part in schizophrenia. Although they are not the only factors, the fact that they are involved provides an opportunity to get a grip on how the disorder is caused.
If specific genes that affect risk can be identified, researchers can then figure out what these genes do, which will in turn tell us what sorts of things might be going wrong in schizophrenia.
But the genetics of schizophrenia is complicated, meaning that in any one person, many genes are involved and that in different people, different sets of genes are involved. This has made linking specific genes to the disorder difficult and is why it took such a brute force genomic approach, involving hundreds of researchers and tens of thousands of people with schizophrenia as well as people unaffected by the disorder.
Some of the genes that have been linked to schizophrenia are involved in biological processes that are prime suspects for contributing to the disorder. Several genes, for example, are important in how a brain chemical called glutamate functions. Others are involved in regulating the calcium content of nerve cells.
However most of the findings involve genes whose functions are not evidently related to previous hypotheses, which means they can give us entirely new insights into how the disorder is caused.
Dopamine receptor D2
One of the most encouraging findings for developing future treatments is that our research identified a link between schizophrenia and a gene called dopamine receptor D2 (DR2D) – a gene that happens to be responsible for producing the very protein, also called DR2D, that is blocked by all the currently available, effective medicines. This finding suggests proteins made by some of the other genes we have identified could also themselves be therapeutic targets.
Even if these proteins aren’t suitable or effective treatment targets, then at a minimum the wealth of findings provides a rational starting point for multiple avenues of investigation that are likely to deliver a much better understanding of the disorder – and, it is then reasonable to hope, a new range of treatments. One such avenue is the findings concerning the immune system.
A disabling condition
Schizophrenia affects about 1% of the population at some point in their lives, usually starting in a person’s late teens or early 20s, and has tended to attract a lot of attention because of quite dramatic symptoms like hearing terrifying voices that are not really there (hallucinations) or developing odd or frightening delusions, such as complex conspiracies involving governments, aliens, or demons, or that bodies or minds are being controlled by external forces such as magic or X-rays.
Less well known, but probably even more disabling, is that people with schizophrenia often develop changes in mood and become apathetic about their surroundings. Medical and psychological treatments combined with social interventions can be very effective for many, but a sizable proportion of people don’t respond well to available treatments and instead develop lifelong disability, tormented by their symptoms, socially withdrawn to the point of isolation, unemployed and financially impoverished – even homeless. Many only function by reliance on their parents.
Converting even one gene finding into a new and effective treatment for schizophrenia would more than justify the generous donation of time and DNA provided by the tens of thousands of patient volunteers, the efforts of the researchers and the financial support from government bodies, charities and private donations, that it has taken to get to this stage of genetic discovery.
Michael O’Donovan does not work for, consult to, own shares in or receive funding from any company or organisation that would benefit from this article, and has no relevant affiliations.