Tag Archives: Schizophrenia

The New and Growing Interest in Mental Health: Where Should it Be Directed?

Mental health provision and mental health research are undergoing something of a renaissance. The subject has been the priority of successive governments, more people are entering mental health professions, and mental health attracts a financial premium under the Research Evaluation Framework, through which universities receive care funding. The biological basis of many mental health diseases has recently been unravelled – see for instance past News Blogs on the molecular biology of schizophrenia, and Alzheimer’s disease.[1] [2] From a philosophical standpoint the mind is now seen as a function of the brain, just as circulating the blood is a function of the heart. The interaction between the brain and the rest of the body, first discovered by observations on Alexis St. Martin in 1822, and later seen in ‘Tom’ in 1947,[3] is now a major source of investigation (see another article in this News Blog on a part of the brain called the amygdala).

>Much of this renewed attention on mental illness carries the, often implicit, implication that mental health treatment should improve. This is undoubtedly the case for many diseases at the severe end of the psychiatric spectrum. One does, however, have to wonder whether the traditional medical model that serves us well in diseases such as schizophrenia and autism, is really the right way to go for other conditions such as depression and anxiety, especially in their milder forms. Depression, one often reads, affects 30% of the population. But 30% represents a choice of threshold, since the definition of ‘caseness’ turns on where the line is drawn. If set at roughly one-third of the population one has to wonder about the logistics of supplying sufficient treatment. And even if the logistics can be managed, it still seems wrong to make ‘cases’ of fully a third of the human race. To put this another way, common problems, such as depression and obesity are best tackled at the societal level. Therapeutic services can then deal with the most serious end of the spectrum – people who really should be given a diagnostic label. This would seem to be the way to go for (at least) two reasons. First, many people (especially at the milder end of the spectrum, where normality elides into diseases) do not present to health services. Their mental health is important. Second, the brain is a ‘learning machine’ and it is hard to reverse harmful behaviours, such as eating disorders, once they have been firmly encoded in neural circuits. Mental health practitioners therefore have a preventive / public health responsibility to intervene by encouraging a wider ‘psycho-prophylactic’ approach. And this topic needs research support every bit as much as therapy. A population level approach would seem to have two broad components – a supportive environment, and encouraging resilience in the population.

Let us consider a supportive environment. Reducing bullying in schools is an archetypal example of an intervention to create a psychotropic environment. There is clear and present evidence that the victim (but not the perpetrator) is harmed by bullying, and there is also good evidence that the problem can be prevented.[4] How a psycho-therapeutic environment may look in other respects is less clear-cut. Workplace culture is likely to be important. The Whitehall studies show that a feeling of powerlessness is associated with stress and illness,[5] but putting this right is not a simple manner. For example, it is widely believed that an optimistic, or so-called ‘positive’, outlook is helpful in the workplace, but the experimental evidence actually points the other way. Being realistic about difficulties ahead and (often low) chances of success, is more helpful than a culture of poorly titrated optimism.[6]

There are many specific groups that are at risk of mental suffering and where environmental modification may help. While the workplace is stressful and a source of anxiety and depression, it has its antithesis in the loneliness that often accompanies old age. There is a fashion to try to keep everyone living independently in their homes for as long as possible. However, such an environment is likely to lead to increasing isolation. I think that communal living should be encouraged in the declining years between retirement and death.[7]

What about resilience in the population? To a degree, the workplace will always be stressful since competing interests and time pressures are inevitable. How can we increase resilience? Taking part in guides and scouts is associated with better mental health outcomes in young people.[8] Exercise has positive benefits on mental health across the age spectrum,[9] and team sports seem particularly beneficial. It is possible that we can encourage ‘mental hygiene’ by talking about it and encouraging healthy mental behaviours. I have a tendency to self-pity and so practice a kind of cognitive behavioural therapy on myself – I think of role models and count my blessings. Others practice ‘mindfulness’. We need to learn more about how to build resilience through experience. Where lies the balance between a bland life devoid of competition, and a ruthless environment creating ingrained winners and losers? I hypothesise that an environment where people are encouraged to have a go, but where coercion is avoided and failure is seen as par for the course, will prepare children for life’s vicissitudes. However, I suspect we are in the foothills of discovery in this regard.

There is always a temptation to screen for illness when it cannot be fully prevented, but the screening can often do more harm than good, and this is true in mental health as well as a physical context. Certainly, routine debriefing after a major incident or difficult childbirth appears to be at best unhelpful. CLAHRC WM collaborator Swaran Singh and colleagues showed that screening for the prodromal symptoms of schizophrenia is also unhelpful as it produces an extremely high false positive rate.[10] Again, working out when screening is of net benefit is an important task for the future.

In conclusion, none of what I have written should be seen as a criticism of therapeutic research and practice. Rather, I argue for a broadening of scope, not only to find things that are predictive of poor mental health, but to find workable methods to improve mental health at a population level. Public mental health is an enduring topic in CLAHRC WM.

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford RJ. Psychiatry Comes of Age. NIHR CLAHRC West Midlands News Blog. 11 March 2016.
  2. Lilford RJ. A Fascinating Account of the Opening up of an Area of Scientific Enquiry. NIHR CLAHRC West Midlands News Blog. 11 November 2016.
  3. Wolf S. Stress and the Gut. Gastroenterol. 1967. 52(2):288-9.
  4. Menesini E & Salmivalli C. Bullying in schools: the state of knowledge and effective interventions. Psychol Health Med. 2017; 22(s1): 240-53.
  5. Bell R, Britton A, Brunner E, et al. Work Stress and Health: the Whitehall II study. London: Council of Civil Service Unions / Cabinet Office; 2004.
  6. Lilford RJ. Managing Staff: A Role for Tough Love? NIHR CLAHRC West Midlands News Blog. 2 September 2016.
  7. Lilford RJ. Encouraging Elderly People to Live Independent Lives: Bad Idea? NIHR CLAHRC West Midlands News Blog. 16 April 2014.
  8. Lilford RJ. Does Being a Guide or Scout as a Child Promote Mental Health in Adulthood?. NIHR CLAHRC West Midlands News Blog. 25 November 2016.
  9. Lilford RJ. On the High Prevalence of Mental Disorders. NIHR CLAHRC West Midlands News Blog. 7 March 2014.
  10. Perry BI, McIntosh G, Welch S, Singh S, Rees K. The association between first-episode psychosis and abnormal glycaemic control: systematic review and meta-analysis. Lancet Psychiatry. 2016; 3(11): 1049-58.

Okay Then, There is a Fourth Period of Whole-Scale Synaptic Pruning in the Grey Matter of the Brain

This News Blog has frequently discussed synaptic pruning [1] [2] – a process that occurs in the foetus at mid-gestation, children at around the age of two, and in late adolescence. Abnormalities in neural synaptic pruning are associated with diseases, such as schizophrenia and autism.[3] It turns out that there is another period of synaptic pruning – during pregnancy. Functional MRI shows that many areas of grey matter shrink in pregnancy. Greater pruning is associated with higher scores on standard questionnaires measuring a mother’s attachment to her baby.[4] More brain does not necessarily mean better brain.

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford RJ. Psychiatry Comes of Age. NIHR CLAHRC West Midlands News Blog. 11 March 2016.
  2. Lilford RJ. A Fascinating Account of the Opening Up of an Area of Scientific Enquiry. NIHR CLAHRC West Midlands News Blog. 11 November 2016.
  3. van Spronsen M, Hoogenraad CC. Synapse Pathology in Psychiatric and Neurologic Disease. Curr Neurol Neurosci Rep. 2010; 10(3): 207-14.
  4. Hoekzema E, Barba-Müller E, Pozzobon C, et al. Pregnancy leads to long-lasting changes in human brain structure. Nature Neurosci. 2016.

Season of Conception/Birth and Learning Disability

The CLAHRC WM Director was long aware that the season of conception/birth is correlated with the risk of developing schizophrenia.[1] That autism is also correlated with reproductive chronicity comes as a surprise to him.[2] It seems, however, to be a robust finding, since it is supported by a Scottish linkage study across educational and maternity records.[3] There was a highly statistically significant increased risk of autism and dyslexia among children conceived in the first quarter of the year, and this was not present for other neurological disorders, such as motor disorders (‘cerebral palsy’). The effect size was modest (about 11% relative risk increase) in this study of over 800,000 children. The cause of the association is unclear, but some viral infections and low vitamin D levels in mid-Winter are obvious (and potentially remediable) candidates. In the first News Blog of 2017 we shall discuss further a methodological limitation of database studies and how this problem may be mitigated. In the meantime, let’s add the above paper to our ever-growing list of imaginative and important linkage studies.

— Richard Lilford, CLAHRC WM Director

References:

  1. Castrogiovanni P, Iapichino S, Pacchierotti C, et al. Season of birth in psychiatry. A review. Neuropsychology. 1998; 37(4): 175-81.
  2. Mazumdar S, Liu KY, Susser E, et al. The Disappearing Seasonality of Autism Conceptions in California. PLoS One. 2012; 7(7): e41265.
  3. Mackay DF, Smith GCS, Cooper S-A, et al. Month of Conception and Learning Disabilities: A Record-Linkage Study of 801,592 Children. Am J Epidemiol. 2016; 184(7): 485-93.

Do Refugees Have a Higher Incidence of Schizophrenia than Immigrants?

Yes, at least according to a recent data linkage study of 1,191,004 Swedes, 24,123 refugees and 132,663 migrants arriving in Sweden.[1] While immigrants had an adjusted increase risk of 1.7, the increase was three-fold for refugees. The study was based on over 8.9 million person years of follow-up. Among refugees from sub-Saharan Africa the gradient between refugees and immigrants was not apparent, but the overall risk was higher. This finding is compatible with a more psychogenic provenance across both refugees and migrants in Africa and/or greater discrimination on arrival. Schizophrenia is a rare disease – the overall incidence was well under one in 1,000 in the above study, but the CLAHRC WM Director thinks it may be a bell-weather for higher population risk of other mental illness. Refugees are at risk of post-traumatic stress disorder.

— Richard Lilford, CLAHRC WM Director

References:

  1. Hollander AC, Dal H, Lewis G, et al. Refugee migration and risk of schizophrenia and other non-affective psychoses: cohort study of 1.3 million people in Sweden. BMJ. 2016; 352: i1030.

Psychiatry Comes of Age

In a recent post the CLAHRC WM Director opined that psychiatry was taking its first reductive steps – we are starting to understand the neurochemical mechanisms behind diseases that appear in the mind. Well our toddler has started to run and the new era has been ushered in with a brilliant recent publication in Nature.[1] The story starts, as it increasingly does in modern science, with a large collaborative effort – in this case the international Psychiatric Genomics Consortium, which carries out genetic association studies. Their Biobank harbours 39,000 cases of schizophrenia and 45,000 controls. There are many genetic polymorphisms across the genome that are associated with schizophrenia – about 100 in fact, as mentioned in a previous post. But one constellation of polymorphisms stands out in terms of the strength of its association with schizophrenia. This constellation resides in the HLA gene cluster. Genes in this cluster encode proteins that help the immune system identify foreign antigens, such as those found on the cell surface of microbes or transplanted tissue. Polymorphisms in the HLA cluster are associated with autoimmune disease, meaning that the immune system has mistakenly identified an antigen on a normal host cell for attack. Does this mean that schizophrenia might be an autoimmune disease? Well, sometimes perhaps (see below), but there is another mechanism by which HLA variants may predispose to this devastating disease. It turns out that the part of the HLA complex most closely associated with schizophrenia is the gene responsible for one of the complement proteins known as complement component 4. And this molecule is not just active in eliminating pathogens and cellular debris – it also affects nerve cells by directly accelerating the pruning of synapses. Synaptic pruning is a normal part of adolescent brain remoulding, but excessive pruning, associated with over-active complement 4, features as part of the pathogenesis in many cases of schizophrenia.[1] Enter NIHR CLAHRC East of England Director Peter Jones. Jones hypothesises that around 10% of cases of acute onset schizophrenia result from an acute autoimmune brain syndrome. He is testing this hypothesis by means of a RCT involving immunosuppression. Presumably it is no co-incidence that some cases of schizophrenia result from a form of autoimmune disease, and that genes in the HLA constellation are so frequently associated with schizophrenia. If so, much of the damage may have been done when the acute brain syndrome appears – we may need to look for an earlier, more tightly targeted therapy, and we suspect that preventing complement-mediated damage will play a role. Incidentally, this is a further example of massive scientific achievement emanating from an international collaborative effort, rather than the genius of just one individual. The future prominent scientist will increasingly be the one with the social skills to engineer a prominent place for herself on the committees that shape protocols and scientific papers, such as the Global Burden of Disease project discussed in a recent post.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Sekar A, Bialas AR, de Rivera H, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016; 530: 177-83.

Unfinished business

Readers of this News Blog will know that the NIHR CLAHRC WM has a strong mental health theme. Professor Swaran Singh (University of Warwick) drew the Director’s attention to a recent provocative paper by Wunderink et al.[1] This is a seven year follow-up of a randomised controlled trial (RCT) comparing standard maintenance antipsychotic chemotherapy with an early dose reduction/ discontinuation strategy in patients with first-episode psychosis. While the reduction/ discontinuation strategy resulted in a higher relapse rate within two years, this difference had disappeared at seven years and patients in the reduction/ discontinuation arm had better functional status. Since exposure to antipsychotic drugs has been shown to be associated with reduced brain volume in humans (even after trying to control for illness severity),[2] and in normal primates,[3] [4] this study has potentially massive implications for the future research agenda in schizophrenia. For instance, it would be informative to understand the effect of these medicines, which cross the placental and blood-brain-barriers with ease,[5] on the foetal brain.[6]

–Richard Lilford, Director of CLAHRC WM

References

[1] Wunderink L, Nieboer RM, Wiersma D, Sytema S, Nienhuis FJ. Recovery in Remitted First-Episode Psychosis at 7 Years of Follow-up of an Early Dose Reduction/Discontinuation or Maintenance Treatment Strategy: Long-term Follow-up of a 2-Year Randomized Clinical Trial. JAMA Psych. 2013; 70(9): 913-20.

[2] Ho B, Andreasen NC, Ziebell S, Pierson R, Magnotta V. Long-term Antipsychotic Treatment and Brain Volumes: A Longitudinal Study of First-Episode Schizophrenia. Arch Gen Psychiatry. 2011;68(2):128-137.

[3] Dorph-Petersen KA, Pierri JN, Perel JM, Sun Z, Sampson AR, Lewis DA. The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys. Neuropsychopharmacology. 2005;30(9):1649-61.

[4] Konopaske GT, Dorph-Petersen KA, Sweet RA, et al. Effect of chronic antipsychotic exposure on astrocyte and oligodendrocyte numbers in macaque monkeys. Biol Psychiatry. 2008; 63(8): 759-65.

[5] Masud Iqbal M, Aneja A, Rahman A, et al. The Potential Risks of Commonly Prescribed Antipsychotics. Psych. 2005; 2(8): 36-44.

[6] Bodén R, Lundgren M, Brandt L, Reutfors J, Kieler H. Antipsychotics During Pregnancy: Relation to Fetal and Maternal Metabolic EffectsArch Gen Psychiatry. 2012;69(7):715-721