June 3, 2015

expert reaction to cause of schizophrenia

Attempting to uncover the cause of schizophrenia, scientists publishing in the journal Neuron have reported that disrupted chemical signalling is a cause rather than an effect of the disease, and suggest that this may be in part due to specific genetic mutations.

Prof. Sir Robin Murray, Professor of Psychiatric Research, King’s College London’s Institute of Psychiatry, Psychology and Neuroscience, said:

“We know that psychotic symptoms (hallucinations and delusions) result from an excess synthesis of the neurotransmitter dopamine in part of the brain called the striatum.  Environmental factors that can provoke the symptoms (e.g. childhood adversity, threatening life events, drug abuse) all increase the synthesis of striatal dopamine. But only a small proportion of people who experience such events go psychotic. This suggests that some people are genetically susceptible to such events because their control of dopamine is less stable.

“This paper builds on previous work from the same group implicating variants in the genes involved in brain excitation (glutamate genes) whereas this new paper implicates the genes involved in inhibition (GABA genes). In short, people who develop schizophrenia are vulnerable to environmental risk factors because of genetic variants in the systems  which determine the balance between excitatory (Glutamate) and GABA (inhibitory) control of dopamine synthesis.

“At present our drugs for  schizophrenia crudely block the effects of excessive dopamine, but don’t affect the causes of the excessive dopamine  (i.e. Like taking aspirin for pain rather treating the cause of the pain). The implication of this paper is that it would be more sensible instead to develop drugs which regulate the balance between the glutamate and GABA systems controlling synthesis of dopamine.”

Dr James Stone, Clinical Senior Lecturer, King’s College London’s Institute of Psychiatry, Psychology & Neuroscience and Honorary Senior Lecturer, Imperial College London, said:

“In this study, the authors have looked at specific rare genetic mutations called copy number variants in a very large number of patients with schizophrenia. Although they are present in a very small percentage of patients with schizophrenia, they confer a greatly increased risk of the illness (2-60x), which is much more than occur with the more common “risk” genes. This means that the function they are involved in is likely to be close to the actual underlying pathology in schizophrenia – particularly in affected individuals. The authors have shown, in the largest sample so far, that CNVs associated with schizophrenia are primarily involved in neurotransmission – specifically via inihibitory – GABAergic and excitatory – glutamatergic – pathways. There has been a lot of evidence from other (non-genetic) studies that implicate glutamate and GABAergic abnormalities in schizophrenia, but this is the strongest evidence so far that these systems are involved in the development of schizophrenia (at least in the small subset of patients who have these high risk CNVs).

“The work is robust, from one of the world’s leading centres in this research, and the data strongly support the findings.

“The data confirm what has been hypothesised about the neurochemical basis of schizophrenia, but which other genetic studies using different approaches (genome wide association studies) have not been able to fully confirm – namely that glutamatergic and GABAergic abnormalities may give rise to schizophrenic symptoms.

“This study suggests that novel drugs targeting GABAergic and glutamatergic mechanisms might be a fruitful approach to treating patients with schizophrenia – particularly those who do not fully respond to currently available (dopamine-blocking) drugs.

Prof. Jeremy Hall, Professor of Psychiatry and Neuroscience, Director of Neuroscience and Mental Health Research Institute, Cardiff University, said:

“This is a very interesting study which highlights the importance of genetic variation in inhibitory (GABAergic) neurons as well as excitatory neurons in risk for schizophrenia.

“What is particularly important is that whilst there is a lot of previous evidence for GABAergic abnormalities in schizophrenia, they could often be seen as potentially secondary to other disease processes. However, having found genetic risk factors in the GABA pathway shows that these inhibitory changes can also be a primary risk factor.

“Another very exciting aspect of the paper is the strong overlap of the identified risk genes with genes known to be involved in associative learning and prediction – again providing primary support for earlier studies which have implicated altered learning processes in the pathogenesis of symptoms such as delusions and hallucinations.”

Dr Michael Bloomfield, Clinical Lecturer in Psychiatry, MRC Clinical Sciences Centre and University College London, said:

“Schizophrenia is a potentially devastating mental illness. Whilst psychological and social factors increase the risk of schizophrenia, the illness is highly heritable – meaning that a certain amount of the likelihood of developing the illness should be explained by our individual genetic make-up.

“However, unlike some illnesses, studying the genetics of schizophrenia has been particularly difficult as it is likely that the risk of developing the disorder will, in most cases, be determined by lots of different genes working in combination with each other – and these will vary from person to person. In recent years, medical researchers have used a technique called GWAS (genome wide association studies – pronounced jee-waz) in relatively large numbers of patients to try and solve this puzzle. This new study combines genetic information from three different large studies.

“It has been known for some time that patients with schizophrenia may have abnormalities in certain neurotransmitters. These are the natural chemicals involved in brain cells ‘talking’ to each other. Two of the main chemicals identified as being important in schizophrenia so far have been dopamine and glutamate.

“Importantly, this new genetic study also implicates the brain chemical GABA.  Since most medicines for schizophrenia work by blocking dopamine, it may be that in the future we can develop better targeted treatments that change work on the brain’s GABA chemistry – once the results from this study are verified in brain scanning studies.

“However, even in identical twins, who have near identical genes, the chance of one twin developing schizophrenia if the other twin has the disorder is 50%. This means that we must still understand how other risk factors for schizophrenia, including heavy cannabis use, migration, living in big cities and psychological trauma, give rise to schizophrenia so that in the future we might be able to prevent the illness before it takes hold.

“Until then, we must continue our search for better medicines and improved psychological therapies to help people with schizophrenia.”

‘Novel findings from CNVs implicate inhibitory and excitatory signalling complexes in schizophrenia’ by Pocklington et al. published in Neuron on Wednesday 3rd June. 

Declared interests

Prof. Murray: No interests received

Dr Stone: “I have received honoraria from Janssen Pharmaceuticals, Behrenberg Bank, AstraZeneca, Pfizer, Sunovion and Hoffman-La Roche Ltd.”

Prof. Hall: “The authors are my colleagues.”

Dr Bloomfield: “I am a member of the Royal College of Psychiatrists, a trainee member of the British Association of Psychopharmacology and a young member of the European College of Neuropsychopharmacology. I conduct research funded by the Medical Research Council and the National Institute of Health Research. I work in medical research at the Medical Research Council and University College London. I work clinically in the National Health Service. I have no other financial interests to declare.”