Brain imaging and schizophrenia

Taking schizophrenia as an example, there are clearly demonstrable differences in the brains of individuals with schizophrenia compared with those of controls. It was first shown in the 1970s that people with schizophrenia had enlarged cerebral ventricles.^{Reference Crow and Johnstone3} Since then abnormalities in both grey and white matter have been convincingly demonstrated in the disorder.^{Reference Olabi, Ellison-Wright, McIntosh, Wood, Bullmore and Lawrie4} More sophisticated brain-imaging techniques have allowed the discovery in recent years that differences in brain volume are present even in medication-naive individuals with first-episode psychosis.^{Reference Kahn and Sommer5} It seems increasingly likely that there are differences in volume even before the at-risk mental state, although this remains difficult to prove definitively.^{Reference Takahashi and Suzuki6–Reference Nenadic, Dietzek, Schönfeld, Lorenz, Gussew and Reichenbach8}

Recently developed scientific techniques such as the use of induced pluripotent stem cells to create a ‘cortex in a dish’ (aka brain organoids) have allowed tantalising insights into why these imaging abnormalities may emerge. Using cells from individuals with schizophrenia (some with a range of predisposing genetic abnormalities) multiple studies have shown abnormalities such as impaired cellular differentiation and synapse formation.^{Reference Robicsek, Karry, Petit, Salman-Kesner, Müller and Klein9–Reference Johnstone, Vasistha, Barbu, Dando, Burr and Christopher11}

These studies add to the emerging hypothesis that the brain of someone at risk of schizophrenia differs from controls at an early stage and that these differences increase as psychosis emerges. These neuroscientific findings are a good fit with the long-standing findings from more psychosocially focused research that differences can be seen in childhood behaviour in those who later develop schizophrenia.^{Reference Niemi, Suvisaari, Tuulio-Henriksson and Lönnqvist12–Reference Davidson, Reichenberg, Rabinowitz, Weiser, Kaplan and Mark15} They also suggest that, to develop better treatments for schizophrenia, we need to look beyond compounds targeting dopamine receptors.

Genetics in intellectual disability and depression

I would also challenge Professor Kingdon's assertion that no genetic findings of use to the practising psychiatrist have been found for the major mental illnesses. Genetic testing for copy number variants is starting to form part of practice in intellectual disability services.^{Reference Wolfe, Strydom, Morrogh, Carter, Cutajar and Eyeoyibo16,Reference Adlington, Smith, Crabtree, Win, Rennie and Khodatars17} Using his example of depression he is correct to say that the much vaunted candidate genes studied in the 1990s and 2000s have not been replicated in later, large studies.^{Reference Border, Johnson, Evans, Smolen, Berley and Sullivan18} However, more recent, vastly better powered studies have produced findings of greater potential use. The most recent genome-wide association study on depression found 87 independent loci that were associated with depression, with a startling lack of genes involved in the 5-HT system.^{Reference Howard, Adams, Clarke, Hafferty, Gibson and Shirali19} This may suggest that, although drugs acting on the 5-HT system are effective in treating depression for many people, disturbances in 5-HT are not the cause of depression. Findings such as these are likely to be of great benefit in developing new treatments.

Epigenetics and treatment targetting

Neuroscience can also help us to explain the link between life events, which are frequently assessed in psychosocial research, and mental health outcomes. For example, epigenetic studies have shown that maternal behaviour influences the expression of genes, including those involved in the glucocorticoid stress response.^{Reference McGowan, Suderman, Sasaki, Huang, Hallett and Meaney20,Reference Weaver, Cervoni, Champagne, D'Alessio, Sharma and Seckl21} Because this work was done in rats it was possible to demonstrate that this effect was not genetic as it was abolished by cross-fostering with more affectionate mothers.^{Reference Weaver, Cervoni, Champagne, D'Alessio, Sharma and Seckl21} Childhood maltreatment such as physical abuse has long been recognised as a risk factor for mental illness. Recent genetic and epigenetic studies are helping us to understand why some people are more resilient to the effects of this abuse than others.^{Reference Thibodeau, Masyn, Rogosch and Cicchetti22,Reference Dunn, Soare, Zhu, Simpkin, Suderman and Klengel23} It has been suggested by some authors that this information could be used to better target childhood interventions, such as providing more intensive interventions to those likely to be least resilient to the effects of childhood maltreatment.