The last few months have been a good time for readers of reviews in the field of schizophrenia and bipolar disorder genetics. What makes the recent batch more impressive is that they are not merely collating primary research but using that data to construct theories and models that seek to provide an overview of the biological systems failing in these conditions. It is that â€˜added valueâ€™ that makes these papers â€˜even better than the real thingâ€™, where the â€˜real thingâ€™ is the incremental output of most primary papers. Below Iâ€™ve listed three of the best and provided a summary for those who canâ€™t access the primary papers.
A pathological paradigm for the therapy of psychiatric disease
Spedding, Jay, Costa e Silva and Perret.
Not a light read but an important review nevertheless. This paper deals with the past, present and future of drug therapies for psychiatric illness, perhaps with a bias towards depression and affective disorders, but with valuable lessons for schizophrenia and bipolar disorder too. What separates this from just a summary of drug trials and clinical outcomes is that the authors have a set of criteria they believe will lead to better therapies. These are: an understanding of the precise brain regions affected in each disorder and the targeting of specific drugs to them and, once there, these drugs should re-establish normal physiological â€˜set pointsâ€™. According to the authors, these set points can be thought of as changeable states of â€˜plasticityâ€™ - the levels of connectedness/communication between nerve cells.
Like the next review, the authors have focussed on a few key neural circuits in which plasticity properties have been well described. They integrate this knowledge with our current understanding of several polymorphisms in neurotransmitter systems as well as highlighting the influence of stress on these pathways.
The authors have, therefore, managed to bridge the gaps between several disparate fields of research in an attempt to synthesize a holistic model for rational therapy design. While not fully explaining how measurable readouts for therapy-mediated changes in plasticity might be obtained, the review does a good job in exposing the reader to the various levels of physiology affected by these conditions.
Intermediate phenotypes and genetic mechanisms of psychiatric disorders
Meyer-Lindenberg and Weinberger
What is an â€˜intermediate phenotypeâ€™? To quote the authors:
â€œAs genes do not encode for psychopathology, it is reasonable to expect that the association or penetrance of gene effects will be greater at the level of relatively more simple and biologically based phenotypes.â€?
Put simply, a car is not made for breaking down (except a white Ford Fiesta â€˜Popular Plusâ€™ 1986 vintage which I spent Â£Â£Â£Â£ on but sold for enough money to buy a tub of ice cream)…. itâ€™s made for travelling. Therefore, it is not always immediately obvious from the outside what is going on when it stops working. However, if you have a rudimentary understanding of the normal performance of basic engine systems then you might be able to figure out whatâ€™s wrong and pin it down to individual components.
The authors argue the schizophrenia is too complex and varied to be examined in any way other than by breaking it down into smaller functional units â€“ these are the â€˜intermediate phenotypesâ€™ that are also described as â€˜endophenotypesâ€™ by others. They list a number of these such as electrophysiology, neurochemistry and neuropsychology but really focus the review on what functional imaging studies have told us. Two brain circuits are described:
1) Cortex/thalamus > neostriatum > globus pallidus > substantia nigra > prefrontal cortex.
2) Dorso-lateral prefrontal cortex <> hippocampal formation
which are observable in action during these functional brain imaging studies. These circuits can be tied in with particular neuropsychological correlates (episodic memory, working memory, emotional regulation, reward) which in turn can be placed in the context of the features of schizophrenia (the first two) or depression (the last two). The authors explain how traditionally gene polymorphisms can be tested for their effect on these phenotypic systems allowing a prediction to be made whether they might have relevance to the disease state. With respect to their main hypothesis, the authors also show how gene polymorphisms can examined in an analogous way using their effect on the function of the two neural circuits as the intermediate phenotypic readout.
This is cutting edge technical stuff and the correlation between particular gene polymorphisms (e.g. in the DISC1 and COMT genes) and precise functional changes in particular brain regions has been nothing less than spectacular. Actually, this success is why I have certain conceptual issues with this approach. The kind of sample numbers (cases studied) involved are relatively low compared to the numbers employed in straight genetic studies trying to match up particular genetic changes with the disease state and yet the former are yielding statistically robust findings while the latter are most definitely not. This could be telling us one of three things:
1) Like the deleterious effects that many, many gene knockout experiments have on mouse learning and memory tests/electrophysiology, the biology of these circuits might be very susceptible to genetic changes.
2) The distance between gene polymorphism and intermediate phenotype is a lot less than between intermediate phenotype (or gene polymorphism) and disease. i.e. other genes/intermediate phenotypes are required in parallel before the sub-clinical becomes clinical.
3) Testing a pre-selected genotype for defined functional neural changes is a much purer experiment than asking whether your particular population of schizophrenia cases is enriched for that genotype (i.e. it avoids locus and allelic heterogeneity issues).
So there are several questions to be answered (as the authors acknowledge) such as the heritability of these functional brain activities, their extent of variation in the disease state, the contribution of other, less tractable neural circuits to disease and, most importantly, the effect of the emerging better-characterised pathogenic polymorphisms/haplotypes. Overall, however, this is a thought-provoking review which bodes well for a deeper understanding of the building blocks of mental illness â€“ a subject discussed in a previous post.
Neurobiology of Schizophrenia
Ross, Margolis, Reading, Pletnikov and Coyle
Out of the three, this is perhaps the best review for the novice to dive into. It is an impressively comprehensive â€˜State of the Nationâ€™ piece for psychiatric disorders - as befits its publication in the prestigious journal Neuron: normally a place where schizophrenia and bipolar disorder donâ€™t get a look in. Like its cousin, Cell, Neuron is a journal that, in my opinion, sometimes suffers from its preference for rather turgid, hard-core cell biology/electrophysiology. Does this mean that this field of psychiatric genetics is gathering a veneer of respectability?
The paper begins with a suggestion that we should look to the established genetics of neurodegenerative diseases such as Parkinsonâ€™s and Alzheimerâ€™s to get a model for the genetic architecture of schizophrenia and bipolar disorder: rare mutations can tell us a lot about the biology of the disorders even if they donâ€™t affect the majority of sufferers. They also suggest disorders of the brain such as Lissencephaly can be a model for the Neurodevelopmental Hypothesis of psychiatric illnesses.
This review also goes into the basics of endophenotypes, as described above, and also mentions the work into neuropsychology, neuroimaging, neuropathology, pathophysiology and recent progress in pharmacology. After introducing the readers to these fields, the review then shifts gear into a summary of genetic progress. This covers animal models and the key methodologies employed in the field for the identification of candidate genes: linkage, association and cytogenetics. 19 candidate genes are listed in their â€˜Billboardâ€™ chart. In fact, Iâ€™m embarrassed to say I didnâ€™t even recognise a couple of the acts on this chart so thereâ€™s some homework for meâ€¦.but, equally, I couldnâ€™t see a few expected names either. I think the Schizophrenia Research Forum has a current list of â€˜topâ€™ candidate genesâ€¦..I wonder if it would be profitable for this blog to do so as well? Neuregulin, Dysbindin, D Amino Acid Oxidase Activator, COMT and DISC1 are described in more detail, particularly the advanced state of cell biological investigation into the last of these.
Overall, this is the current gold-standard review of the field â€“ required reading for all. Just as important is the feeling that the reader gets when going through it: this is a field that is maturing nicely and with a lot to be positive about.