Psychiatric Genetic Revolution – is calcium the key?

DNA Rendering. Photo: ynse. used under CretaiveCommons

DNA Rendering. Photo: ynse. used under CreativeCommons

Dr. Berrettini and I published Principles of Psychiatric Genetics in late 2012. Since then, there have been several interesting developments in Psychiatric Genetics worth calling your attention to. The first is a set of articles from the Cross-Disorder Group of the Psychiatric Genomics Consortium (PGC). The PGC has revolutionized the field of psychiatric genetics in the last decade by bringing together investigators from around the world to pool their carefully collected clinical samples in order to provide the numbers for powerful analyses of common gene variants in major psychiatric disorders such as schizophrenia and bipolar disorder. Whereas the original genome-wide association studies in psychiatry included ~1000 cases and 1000 controls, we are now able to amass collections of 25,000 cases with schizophrenia and 37,000 controls because investigators have come together under the PGC umbrella. This has provided the power to detect more than 100 common single gene variants associated with schizophrenia.

The particular article I wanted to feature was one from the Cross-Disorder Group in that consortium (Cross-Disorder Group of the PGC, Lancet, 2013). Samples were combined from persons with schizophrenia, bipolar disorder, depression, attention-deficit hyperactivity disorder, and autism. There were four single gene variants that were identified from the group of disorders considered together. The fascinating aspect of this was that two of the four were genes controlling calcium channels in the brain. The investigators were also able to test an entire group of calcium-channel related genes (72 genes in all) and demonstrate that variations in this set of gene markers was associated with vulnerability to these conditions, especially to schizophrenia and bipolar disorder. This is a new finding in psychiatry, and it is potentially very relevant to clinical management of these conditions. Calcium channel abnormalities have been described in these disorders, but this hypothesis was not central to a consideration of the neurobiology of these disorders. Over the past three decades, much more energy has been spent on theories involving neurotransmitters such as serotonin, dopamine, and norepinephrine. However, it may be that calcium channel signaling problems are causal to neurotransmitter variation. Calcium flow into the cell is necessary for cell excitation and signaling. Many of the critical second messenger systems in the cell (which carry a signal within the cell after a neurotransmitter hits its target receptor) are dependent on calcium.

Calcium channel inhibitors are available, and have been used to treat cardiovascular conditions for several decades (e.g., verapamil, nifedipine, nimodipine) . They have also been used to treat psychiatric conditions, with some success, but not consistent success. It may be that these agents must be targeted to specific individuals who demonstrate calcium channel gene abnormalities. Or it may be that newly designed drugs with more subtle effects on calcium activity are needed. In any case, this seems like an important clue with ramifications for our understanding of the biology of these disorders, as well as possible treatment strategies.

Another paper from the same group was published later in 2013 (Lee et al, Nature Genetics). This used a method for analyzing the heritability of medical conditions based on genome-wide data. Even if the power is not adequate to identify all of the gene variants individually, you can use the available information on gene arrays (small plastic chips that contain short sequences from every gene in the genome) to test whether or not you have captured some of the variation or not. It could be that testing every gene in the genome in this way would still not give you much information about diagnosis. This was thought to be the case for several years after these techniques were introduced. Many investigators felt that psychiatric disorders were simply too complex in their inheritance to be analyzed by the gene chips. There was too much “missing heritability” (evidence of inheritance from family studies that was not able to be tracked to variations at the gene level). This recent paper demonstrated convincingly that this idea is not true. The psychiatric disorders are analyzable at the level of individual gene variants and functions. We now can be confident that 25-40% of the reason that one person becomes ill with schizophrenia or major depression or autism while another person does not is related to common genetic variation that can be measured in the laboratory. We don’t yet know what all the pertinent genes do but we can anticipate that the answers will be available to us in the coming years. Part of the answer probably relates to calcium channel genes, as noted above.

There is another set of data from this paper that is tremendously important for our ideas of psychiatric diagnosis. For the past hundred years, we have clearly separated schizophrenia (a chronic disorder) and bipolar disorder (an episodic condition). There are different treatments for these conditions and different expectations for how well people will do in overcoming the symptoms. One of the lessons from the latest round of genetic analyses is that there is substantial overlap in the genetic vulnerability factors for the two disorders. The “covariance” between schizophrenia and bipolar disorder is 25-30%. Therefore we should expect that some of the disruption in neurobiological systems will be the same for the two disorders and some will be different. This is consistent with evidence from genetic linkage studies summarized by my colleague Dr. Berrettini some years ago and it is consistent with recent family studies as well. The new information, though, is more specific regarding the amount of overlap. It suggests that we should consider these two diseases similar in type and origin.

John I. Nurnberger, Jr. is co-editor of Principles of Psychiatric Genetics (out now).

Principles of Psychiatric Genetics

Renaming Schizophrenia

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The name “Schizophrenia” is the subject of a new Forum in the journal Psychological Medicine. An article written by Bill George and Aadt Klijn, Foreign Affairs co-coordinators for Anoiksis (the Dutch association of and for people with a psychotic vulnerability), has been reflected on by various commentators.

Anoiksis has introduced a new name for the disease schizophrenia: psychosis susceptibility syndrome (PSS) with the aim that together with the old name, its attached prejudices, misleading significance and stigma can be thrown overboard.

Schizophrenia is a term loaded with negative connotations, since it still conveys an image of people with schizophrenia as all being unreliable, dangerous ‘lunatics’. The term consequently lends itself to stigma and self-stigma. Society stamps persons with schizophrenia with a negative hallmark; people diagnosed with schizophrenia then take the negative blueprint to themselves and this gives rise to a negative self-image. Not only does the term call up prejudices, it maintains misunderstandings, because schizophrenia means split personality and is therefore a misnomer. A split personality is in fact quite another disorder and has nothing to do with what we currently call schizophrenia.

Recently the World Health Organisation has been approached with a request to recognise the new name – currently the name PSS is not recognised either nationally or internationally.

Anoiksis has chosen the name Psychosis Susceptibility Syndrome (PSS) – the reasoning is as follows:

  • Psychosis: because of the unreality of hallucinations and delusions.
  • Susceptibility: because patients are not necessarily continually psychotic (but it is latent).
  • Syndrome: because this word includes the negative and cognitive symptoms also associated with the disease. Negative symptoms include lack of feelings and energy while cognitive symptoms may be problems with concentration and memory or a reduced capacity for problem-solving for example.

Full commentaries have been provided by several people, who generally agree with the idea of changing the name, but argue that the biggest change will come from changing the public perception of schizophrenia.

Dr Brabban and colleagues comment, “There is no doubt that for many, the diagnosis of schizophrenia can be as debilitating as the associated symptoms. The word ‘schizophrenia’ appears to do more harm than good, more frequently communicating prejudice and misinformation than fact and hope. It is indisputable that the stigma surrounding the term schizophrenia can in itself lead to misery for many with the diagnosis. Therefore, any label that removes some of these disadvantages would be a welcome change.”

Professor Bentall states, “Schizophrenia has been a contested label for many years not only because it is associated with stigma, but also because it fails to achieve any of the purposes for which it was originally designed. Rebranding schizophrenia solves none of these problems. By replacing one ill-fitting label with another, we do nothing to advance psychiatric research or to develop better treatment plans for our patients.

“It is not hard to locate some of these causes [of stigma]. Without a doubt, one is the media’s treatment of schizophrenia, which consistently over-emphasizes the risk of dangerous behaviour by patients, conveying the impression that people with psychosis are responsible for an epidemic of interpersonal violence. The reality is, of course, quite different. Whereas there is an increased risk of violence associated with psychosis, most of this is attributable to co-morbid substance abuse and most psychiatric patients pose absolutely no risk to their neighbours.

“The problem has become not whether to replace schizophrenia, but what to replace it with. Simple re-labelling will do nothing to address the many scientific and clinical limitations of the categorical approach to diagnosis. Nor is it likely to address the problem of stigma, which arises out of background assumptions about the nature of severe mental illness. To persuade the general public to be more accepting of people with mental illness, we must persuade them that psychosis arises, in part, understandably from adverse life experiences (while of course acknowledging that genetic factors must play some role), that it does not necessarily lead to violence, and that recovery is possible.”

“Forum”, can be viewed free of charge for a limited time and comprises 5 articles

View the original competition poster here.

View the winning name poster (English language) here.

The utility of non-psychiatric phenotype in diagnosing secondary psychosis, and of psychopathology in diagnosing primary psychosis

Blog post by Rudolf N. Cardinal, clinical research associate, Department of Psychiatry, University of Cambridge, and honorary specialist registrar, Cambridgeshire and Peterborough NHS Foundation Trust, and Edward T. Bullmore, professor of psychiatry, University of Cambridge.

Psychosis originally meant any kind of disordered mental state [1], and subsequently a severe mental disorder involving loss of contact with reality [2, 3]. Nowadays it may be defined (1) narrowly as the presence of delusions and/or hallucinations without insight, or (2) more broadly to include delusions and/or hallucinations with insight into their hallucinatory nature, or (3) more broadly still to include disordered thought or speech, or (4) yet more broadly to include severe behavioural abnormalities including behavioural disorganization, gross excitement and overactivity, or psychomotor retardation and catatonia [4, 5]. Different classificatory systems vary slightly in their definition [4, 5]. Read more of this post

23rd ECNP Congress -The European College of Neuropsychopharmacology

Mental disorders, such as depression, anxiety disorders, addiction and schizophrenia are the core challenge of most health care systems around the world. In the EU alone, each year 27% of the total adult population – this corresponds to 83 Million citizens – suffer from mental disorders. Depression alone affects almost 20 million ranking in the EU as the most disabling disorder of all diseases. Unless appropriately treated, mental disorders are typically associated with a wide range of complications and sequelae for the subjects affected, their partners and families as well as society as a whole, and they can be lethal. Suicide – a frequent complication of depression and other mental disorders – is a major cause of premature death in Europe with over 160.000 completed suicides every year; rates of attempted suicides are at least 10 times higher. Read more of this post

Does traumatic brain injury ‘cause’ schizophrenia?

Blog Post by Perminder Sachdev, Professor of Neuropsychiatry at the School of Psychiatry, University of New South Wales, Sydney, and Clinical Director of the Neuropsychiatric Institute, the Price of Wales Hospital, Sydney

Welcome to my first Cambridge Medicine blog. For this, I have chosen a topic which I have had to confront recently from a medico-legal viewpoint. There have been a number of competent reviews of this topic, but somehow clarity has not been achieved. While not attempting to review the topic once again, I present some reasons why a causal relationship between schizophrenia and traumatic brain injury is difficult to establish. While this does not pose a major problem for Psychiatry, it makes lawyers trying to argue for their clients quite nervous. Read more of this post

A Meeting of Minds – Cambridge Clinical Neuroscience and Mental Health Symposium

Blog Post by Jenny Ridge, Academic & Professional Marketing, Medicine

neuroscience logoThe Cambridge Clinical Neuroscience and Mental Health Symposium starts today, with Press authors ready to speak on the most up-to-date research.

Organised by Cambridge Neuroscience, whose mission is to increase our fundamental understanding of brain function and enhance quality of life, the Symposium is a highly significant event for all neuroscientists. The Symposium connects the varied and vast areas of neuroscience research and teaching that takes place across the University of Cambridge and affiliated institutions and is vital to furthering the aims of Cambridge Neuroscience.

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