Changing the landscape of psychiatric research:

What will the RDoC initiative by NIMH achieve?

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There's a lot wrong with current psychiatric classification. Every few years, the American Psychiatric Association comes up with a new set of labels and diagnostic criteria, but whereas the Diagnostic and Statistical Manual used to be seen as some kind of Bible for psychiatrists, the latest version, DSM5, has been greeted with hostility and derision. The number of diagnostic categories keeps multiplying without any commensurate increase in the evidence base to validate the categories. It has been argued that vested interests from pharmaceutical companies create pressures to medicalise normality so that everyone will sooner or later have a diagnosis (Frances, 2013). And even excluding such conflict of interest, there are concerns that such well-known categories as schizophrenia and depression lack reliability and validity (Kendell & Jablensky, 2003).

In 2013, Tom Insel, Director of the US funding agency, National Institute of Mental Health (NIMH), created a stir with a blogpost in which he criticised the DSM5 and laid out the vision of a new Research Domain Criteria (RDoC) project. This aimed "to transform diagnosis by incorporating genetics, imaging, cognitive science, and other levels of information to lay the foundation for a new classification system."

He drew parallels with physical medicine, where diagnosis is not made purely on the basis of symptoms, but also uses measures of underlying physiological function that help distinguish between conditions and indicate the most appropriate treatment. This, he argued, should be the goal of psychiatry, to go beyond presenting symptoms to underlying causes, reconceptualising disorders in terms of neural systems.

This has, of course, been a goal for many researchers for several years, but Insel expressed frustration at the lack of progress, noting that at present: "We cannot design a system based on biomarkers or cognitive performance because we lack the data". That being the case, he argued, a priority for NIMH should be to create a framework for collecting relevant data. This would entail casting aside conventional psychiatric diagnoses, working with dimensions rather than categories, and establishing links between genetic, neural and behavioural levels of description.

This represents a massive shift in research funding strategy, and some are uneasy about it. Nobody, as far as I am aware, is keen to defend the status quo, as represented by DSM.  As Insel remarked in his blogpost: "Patients with mental disorders deserve better". The issue is whether RDoC is going to make things any better. I see five big problems.

1. McLaren (2011) is among those querying the assumption that mental illnesses are 'disorders of brain circuits'. The goal of the RDoC program is to fill in a huge matrix with new research findings. The rows of the matrix are not the traditional diagnostic categories: instead they are five research domains: Negative Valence Systems, Positive Valence Systems, Cognitive Systems, Systems for Social Processes, Arousal/Regulatory Systems, each of which has subdivisions: e.g. Cognitive Systems is broken down into Attention, Perception, Working memory, Declarative memory, Language behavior and Cognitive (effortful) control. The columns of the matrix are Genes, Molecules, Cells, Circuits, Physiology, Behavior, Self-Reports, and Paradigms. Strikingly absent is anything about experience or environment.

This seems symptomatic of our age. I remember sitting through a conference presentation about a study investigating whether brain measures could predict response to cognitive behaviour therapy in depression.  OK, it's possible that they might, but what surprised me was that no measures of past life events or current social circumstances were included in the study. My intuitions may be wrong, but it would seem that these factors are likely to play a role. My impression is that some of the more successful interventions developed in recent years are based not on neurobiology or genetics, but on a detailed analysis of the phenomenology of mental illness, as illustrated, for example, by the work of my colleagues David Clark and Anke Ehlers. Consideration of such factors is strikingly absent from RDoC.

 2. The goal of the RDoC is ultimately to help patients, but the link with intervention is unclear. Suppose I become increasingly obsessed with checking electrical switches, such that I am unable to function in my job. Thanks to the RDoC program, I'm found to have a dysfunctional neural circuit. Presumably the benefit of this is that I could be given a new pharmacological intervention targeting that circuit, which will make me less obsessive. But how long will I stay on the drug? It's not given me any way to cope with the tendency of checking the unwanted thoughts that obtrude into my consciousness, and they are likely to recur when I come off it.  I'm not opposed to pharmacological interventions in principle, but they tend not to have a 'stop rule'. 

There are psychological interventions that tackle the symptoms and the cognitive processes that underlie them more directly.  Could better knowledge of neurobiological correlates help develop more of these?  I guess it is possible, but my overall sense is that this translational potential is exaggerated – just as with the current hype around 'educational neuroscience'. The RDoC program embodies a mistaken belief that neuroscientific research is inherently better than psychological research because it deals with primary causes, when in fact it cannot capture key clinical phenomena. For instance, the distinction between a compulsive hand-washer and a compulsive checker is unlikely to have a clear brain correlate, yet we need to know about the specific symptoms of the individual to help them overcome them.

3. Those proposing RDoC appear to have a naive view of the potential of genetics to inform psychiatry.  It's worth quoting in detail from their vision of the kinds of study that would be encouraged by NIMH, as stated here:

Recent studies have shown that a number of genes reported to confer risk for schizophrenia, such as DISC1 (“Disrupted in schizophrenia”) and neuregulin, actually appear to be similar in risk for unipolar and bipolar mood disorders. ... Thus, in one potential design, inclusion criteria might simply consist of all patients seen for evaluation at a psychotic disorders treatment unit. The independent variable might comprise two groups of patients: One group would be positive and the other negative for one or more risk gene configurations (SNP or CNV), with the groups matched on demographics such as age, sex, and education. Dependent variables could be responses to a set of cognitive paradigms, and clinical status on a variety of symptom measures. Analyses would be conducted to compare the pattern of differences in responses to the cognitive or emotional tasks in patients who are positive and negative for the risk configurations.

This sounds to me like a recipe for wasting a huge amount of research funding. The effect sizes of most behavioural/cognitive genetic associations are tiny and so one would need an enormous sample size to see differences related to genotype. Coupled with an open-ended search for differences between genotypes on a battery of cognitive measures, this would undoubtedly generate some 'significant' results which could go on to mislead the field for some time before a failure to replicate was achieved (cf. Munafò, & Gage, 2013).

The NIMH website notes that "the current diagnostic system is not informed by recent breakthroughs in genetics". There is good reason for that: to date, the genetic findings have been disappointing. Such associations as are found either indicate extremely rare and heterogeneous mutations of large effect and/or involve common genetic variants whose small effects are not of clinical significance. We cannot know what the future holds, but to date talk of 'breakthroughs' is misleading.

4. Some of the entries in the RDoC matrix also suggest a lack of appreciation of the difference between studying individual differences versus group effects.  The RDoC program is focused on understanding individual differences. That requires particularly stringent criteria for measures, which need to be adequately reliable, valid and sensitive to pick up differences between people.  I appreciate that the published RDoC matrices are seen as a starting-point and not as definitive, but I would recommend that more thought goes into establishing the psychometric credibility of measures before embarking on expensive studies looking for correlations between genes, brains and behaviour. If the rank ordering of a group of people on a measure is not the same from one occasion to another, or if there are substantial floor or ceiling effects, that measure is not going to be much use as an indicator of an underlying construct. Furthermore, if different versions of a task that are supposed to tap into a single construct give different patterns of results, then we need a rethink – see e.g. Foti et al, 2013; Shilling et al, 2013, for examples.  Such considerations are often ignored by those attempting to move experimental work into a translational phase. If we are really to achieve 'precision medicine' we need precise measures.

5. The matrix as it stands does not give much confidence that the RDoC approach will give clearer gene-brain-behaviour links than traditional psychiatric categories.

For instance, BDNF appears in the Gene column of the matrix for the constructs of acute threat, auditory perception, declarative memory, goal selection, and response selection. COMT appears with threat, loss, frustrative nonreward, reward learning, goal selection, response selection and reception of facial communication. Of course, it's early days. The whole purpose of the enterprise is to flesh out the matrix with more detailed and accurate information. Nevertheless, the attempts at summarising what is known to date do not inspire confidence that this goal will be achieved.

After such a list of objections to RDoC, I do have one good thing to say about it, which is that it appears to be encouraging and embracing data-sharing and open science. This will be an important advance that may help us find out more quickly which avenues are worth exploring and which are cul-de-sacs. I suspect we will find out some useful things from the RDoC project: I just have reservations as to whether they will be of any benefit to psychiatry, or more importantly, to psychiatric patients.

References
Foti, D., Kotov, R., & Hajcak, G. (2013). Psychometric considerations in using error-related brain activity as a biomarker in psychotic disorders. Journal of Abnormal Psychology, 122(2), 520-531. doi: 10.1037/a0032618

Frances, A. (2013). Saving normal: An insider's revolt against out-of-control psychiatric diagnosis, DSM-5, big pharma, and the medicalization of ordinary life. New York: HarperCollins.

Kendell, R., & Jablensky, A. (2003). Distinguishing between the validity and utility of psychiatric diagnoses. American Journal of Psychiatry, 160, 4-12.

McLaren, N. (2011). Cells, Circuits, and Syndromes: A Critical Commentary on the NIMH Research Domain Criteria Project Ethical Human Psychology and Psychiatry, 13 (3), 229-236 DOI: 10.1891/1559-4343.13.3.229

Munafò, M. R., & Gage, S. H. (2013). Improving the reliability and reporting of genetic association studies. Drug and Alcohol Dependence(0). doi: http://dx.doi.org/10.1016/j.drugalcdep.2013.03.023

Shilling, V. M., Chetwynd, A., & Rabbitt, P. M. A. (2002). Individual inconsistency across measures of inhibition: an investigation of the construct validity of inhibition in older adults. Neuropsychologia, 40, 605-619.


This article (Figshare version) can be cited as:
 Bishop, Dorothy V M (2014): Changing the landscape of psychiatric research: What will the RDoC initiative by NIMH achieve?. figshare. http://dx.doi.org/10.6084/m9.figshare.1030210  


P.S.8th October 2015. 
RDoC is in the news again, leading Jon Roiser to send me a tweet asking whether my views expressed re social factors were just intuitions or evidence-based. That's a good question, given the importance I attach to evidence. So is there any evidence that past life events or current social situation predict response to intervention in depression? 
I have to confess I am not an expert in this area. My views are largely formed from what I learned years ago when training as a clinical psychologist, when research by Brown and Harris showed life events were potent predictors of depression:

Brown, G.W. & Harris, T.O. (1978). Social origins of depression: A study of psychiatric disorder in women. London: Tavistock. 

These studies were not on intervention, but it does seem plausible that the same factors that are associated with initial onset will also influence response to intervention. Thus it seems reasonable that it would be harder to treat someone's depression if they are still experiencing the factors that led to the initial depression, e.g. living in an abusive relationship, coping with the death of a loved one, or experiencing financial stress.
In response to Jon's query, I did a small trawl through recent articles in Web of Science; I have only looked at abstracts for these, so don't know how good quality the evidence is, but the general impression is that social factors and life events are still regarded as important factors in the etiology of depression - and therefore might also be expected to influence response to intervention. Here's a handful of papers:

Colman, I., Zeng, Y., McMartin, S. E., Naicker, K., Ataullahjan, A., Weeks, M., . . . Galambos, N. L. (2014). Protective factors against depression during the transition from adolescence to adulthood: Findings from a national Canadian cohort. Preventive Medicine, 65, 28-32. doi: 10.1016/j.ypmed.2014.04.008

Cwik, M., Barlow, A., Tingey, L., Goklish, N., Larzelere-Hinton, F., Craig, M., & Walkup, J. T. (2015). Exploring Risk and Protective Factors with a Community Sample of American Indian Adolescents Who Attempted Suicide. Archives of Suicide Research, 19(2), 172-189. doi: 10.1080/13811118.2015.1004472

Dour, H. J., Wiley, J. F., Roy-Byrne, P., Stein, M. B., Sullivan, G., Sherbourne, C. D., . . . Craske, M. G. (2014). Perceived social support mediates anxiety and depressive symptom changes following primary care intervention. Depression and Anxiety, 31(5), 436-442. doi: 10.1002/da.22216

Kemner, S. M., Mesman, E., Nolen, W. A., Eijckemans, M. J. C., & Hillegers, M. H. J. (2015). The role of life events and psychological factors in the onset of first and recurrent mood episodes in bipolar offspring: results from the Dutch Bipolar Offspring Study. Psychological Medicine, 45(12), 2571-2581. doi: 10.1017/s0033291715000495

Sheidow, A. J., Henry, D. B., Tolan, P. H., & Strachan, M. K. (2014). The Role of Stress Exposure and Family Functioning in Internalizing Outcomes of Urban Families. Journal of Child and Family Studies, 23(8), 1351-1365. doi: 10.1007/s10826-013-9793-3

I'd be happy to consider alternative evidence, but my view is that if we want to look at brain or gene predictors, we'd do well to also assess life events and social factors - things that are relatively easy to measure, might explain a significant proportion of variance, and could also possibly provide a mechanism to account for neurobiological findings. 

 

My thoughts on the dyslexia debate

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During February, there was widespread media coverage of a forthcoming book by Julian Elliott and Elena Grigorenko called The Dyslexia Debate. I've seen an advance copy of the book, whose central message is to argue that the construct of dyslexia lacks coherence. Quite simply, dyslexia does not constitute a natural category, in terms of cognitive profile, neurobiology or genetics.

The authors' arguments are backed by a large body of research: people have tried over many years to find something distinctive about dyslexia, without success. Some children are good at reading and others are not, but it's arbitrary where you place a cutoff to specify that a child has a problem. There's a popular belief that you can identify dyslexics in terms of a particular ability profile, and that affected children have a particular kind of brain organisation that makes them do things like reverse letters (b vs d) or have left-right confusion. In fact, those types of problem are common in typically-developing children at early stages of learning to read and appear to be as much a symptom as a cause of reading problems. Researchers have found neurobiological and genetic correlates of developmental reading problems, but the effects tend to be small and inconsistent from person to person: you could not currently diagnose dyslexia on the basis of brain scans or genetic analysis. It is, of course, possible that one day we may hit upon a new diagnostic test that does clearly differentiate a dyslexic subgroup from other poor readers, but many of us in the field are dubious as to whether this will ever happen.
 
The first thing to get clear is that Elliott and Grigorenko are not denying the reality of children's reading problems. Their point is a much more specific one about the way we conceptualise reading difficulties and how this affects access to services in everyday life. Their concern is that "dyslexia" implies we are dealing with a specific medical syndrome. Their view is that no such syndrome exists and it is not helpful to behave as if it does. How should we respond to this? I think we need to distinguish three questions:

1. Should we identify those in need of extra help?

Children vary in the ease with which they learn to read. Some need only the briefest exposure to books to crack the code; others struggle for years despite skilled help from expert teachers.
I think most people who have spent time with poor readers (and I would include Elliott and Grigorenko among these) would conclude that the answer to question #1 is yes. It doesn't matter whether those in the latter group have a distinct medical syndrome or not: It is up to us to ensure that all get the best teaching.

2. How should we identify those in need of extra help?

Elliott wrote a piece in the Times Higher Education where he argued that dyslexia diagnoses in Universities were skyrocketing, and that some people were unfairly exploiting the system in order to get accommodations such as a laptop computer and extra time in exams. To my mind, the problem here is less to do with the "dyslexia" label, and more to do with the haphazard way in which individuals are identified, and the lack of consistent criteria for determining who needs extra help. Like Elliott, I think it is entirely right that we should make accommodations for students who have serious difficulties in processing written information at speed. However, as he highlights, the current system is based on an unsustainable idea that "dyslexia" is a distinct disorder that can be reliably identified, and which is often diagnosed on the basis of supposed markers of dyslexia that have no scientific basis. So the current system is both invalid and unfair. Instead, it would be sensible to settle on consistent criteria for allocating extra help to students who are struggling, and to ensure that extra resources are directed to those who are most needy. As Castles and colleagues have noted, there are guidelines that can be used to identify those with severe and persistent problems, but they are not well-known or widely applied.

3. What terminology should we use to refer to those we identify?

So can we just agree that we need to find consistent ways of identifying poor readers and do away with the term "dyslexia"? While this might seem a logical response to the evidence, I think we should not underestimate the implications in practice. On the positive side, we'd get rid of the idea that we're dealing with a special condition that forms a distinct syndrome. Since few scientists would attempt to defend that notion, this would be a good thing. But we should also be aware of negative consequences.

Those commenting on the dyslexia debate so far have talked about it as if it is a particular issue relating to literacy difficulties, but in fact it's just one instance of a much more pervasive problem.  Other neurodevelopmental disorders such as autism spectrum disorder, specific language impairment, attention deficit hyperactivity disorder, developmental dyspraxia and dyscalculia are all beset by the same issues: there is no diagnostic biomarker, the condition is defined purely in terms of behaviour, different disorders overlap and there's no clear boundary between disorder and normality.
 
Similar issues have been much discussed in relation to adult psychiatric disorders, which are also diagnosed in terms of behavioural features rather than biological tests. In a fascinating paper, Kendell and Jablensky (2003) came to the conclusion that the categories of schizophrenia and depression are massively problematic in terms of validity and reliability – that is to say, just like dyslexia, they don't constitute natural categories clearly demarcated from other disorders, and furthermore, people can't even agree on who merits these diagnoses. So should we just stop using the labels? Kendell and Jablensky considered this possibility but concluded it would be impossible to abandon terms like schizophrenia and depression, on the grounds that they have utility. These labels have been used for many years by practitioners to determine the most effective intervention, and by researchers interested in discovering the underlying causes and likely outcome of a disorder. Similarly, using the construct of "dyslexia" we have discovered much about the nature of the cognitive deficits that characterise many poor readers, about underlying causes, about outcomes, and about effectiveness of intervention. For instance, we know that genes play a part in determining who is a poor reader, and that many children who have poor literacy skills also have subtle problems with oral language.
 
This argument, though, is not really watertight. We may congratulate ourselves on what we have learned, but on the other hand, it could be argued that there are also barriers to progress that arise from continued use of imprecise terms. It's clear to anyone who knows the research literature that findings can vary from study to study and from child to child within a study. This does not necessarily invalidate the research – it's rare to obtain perfect consistency of findings even within mainstream medicine – but it does make many people wonder whether we might obtain clearer results if we took a different approach. But then we have to consider what alternative approach would be better.

I suggested a few years ago that it might be helpful to treat neurodevelopmental disorders differently, as multidimensional composites, rather than regarding problems with reading, language, arithmetic, attention, motor skills and social behaviour as separate conditions. However, I did not really expect anyone to embrace this idea, as it would be too radical a change, and we are too wedded to current terminology.

Here too, comparisons with psychiatry are interesting. Last year, Tom Insel, director of the US National Institute of Mental Health, ruffled feathers by stating that his organisation would be reorienting its research away from traditional psychiatric diagnostic categories, to develop Research Domain Criteria, i.e. "new ways of classifying mental disorders based on dimensions of observable behavior and neurobiological measures." Yet the domains that are proposed seem to me just as arbitrary as the original diagnostic categories, and the associations between genetic, neurobiological and behavioural measures are mostly weak and poorly understood. So although Insel's vision might seem a rational way of trying to make sense of psychiatric disorders, it is years away from being clinically applicable – as he is the first to admit.  Even though multivariate, dimensional classification seems more logical, our current categories of autism, schizophrenia and dyslexia, though imperfect, may be as good as we can manage in terms of utility in day-to-day clinical practice.

Perhaps the strongest arguments in favour of retention of a term like "dyslexia" come not from science but from public perception. Like it or not, "dyslexia" has been around for over 100 years. In that time, a range of organisations have sprung up to help people with this diagnosis. Some of the most passionate defences of the dyslexia label come from those who have built up a sense of identity around this condition, and who feel they benefit from being part of a community that can offer information and support – see, for instance, this comment by the International Dyslexia Association to the suggestion that "dyslexia" be removed from the DSM5.

One could, of course, argue, that we shouldn't stick with a label just because it has always been there – if we were to adopt that line of argument, we'd still be talking about "maladjusted" and "educationally subnormal" children. But it's clear that many of those diagnosed with dyslexia do see this label as positive. In particular many people worry that if they were to simply switch to a more neutral, less medical term, such as "poor readers", this could trivialise reading problems, and lead people to assume that the difficulties are just caused by poor teaching. Furthermore, legal entitlement to special help under disability legislation could disappear. This, I think, is a key part of the problem, which can get overlooked when just focusing on the scientific evidence: what you call a condition determines two things: how seriously people take it, and where they place blame for the difficulties and responsibility for doing something about it.

To illustrate my point, see this recent piece in the Daily Mail by Peter Hitchens, which appeared under the headline: "Dyslexia is NOT a disease. It is an excuse for bad teachers". This displays a remarkably simplistic world view in which a poor reader either has a "disease", in which case they are blameless victims of an external force, or else it is someone's fault – in this case lacklustre teachers.

In his triumphalist piece against the "pseudoscience and quackery" of dyslexia, Peter Hitchens achieves exactly the opposite of what he intends. This is because he demonstrates one negative consequence of removing the label, which is that many people will no longer think that children who struggle to read need any kind of special help. Instead, we'll be told that "What they need, what we all need, is proper old-fashioned teaching."

A rather more sophisticated version of the same argument was given in the Green Paper that introduced the Government's proposed revision to legislation for Special Educational Needs (SEN) (see: my blogpost on this). There it was stated that too many children were being over-identified with SEN: “Previous measures of school performance created perverse incentives to over-identify children as having SEN. There is compelling evidence that these labels of SEN have perpetuated a culture of low expectations and have not led to the right support being put in place.” (point 22).

We really need to escape this polarised view of children's problems being caused either by a medical disease or by poor teaching. Yes, some children's reading may be held back because their teachers either don't know about or reject evidence-based methods of teaching, but it is seldom black and white, and some children fail despite intensive, high-quality teaching.

My concern is that those holding the purse-strings have a strong incentive to blame all problems on bad teaching or bad parenting, as it absolves them of any responsibility to do anything about them. We need to recognise that for most children, the causal influences are likely to be complex and may involve both constitutional factors and aspects of home and school environment. Unfortunately, most people don't seem able to deal with this complexity, and the language we use determines how problems are viewed. At present we are between a rock and a hard place. The rock is the term "dyslexia", which has inaccurate connotations of a distinct neurobiological syndrome. The hard place is a term like "poor readers" which leads people to think we are dealing with a trivial problem caused by bad teaching.

As Allen Frances argued in the case of psychiatry, we need to resist a growing tendency to use medical labels for what is essentially normal behaviour. However, he wisely notes that this should not blind us to the reality that there are people with problems that are severe, clearcut, and unlikely to go away on their own.  In the current debate, several commentators have made this point and have added that it doesn't really matter what we call them; the more important issue is to ensure affected individuals get appropriate help. But I'd suggest it does matter, because the label we use does much more than just identify a subset of people: it carries connotations of causation, blame and responsibility. While I can see all the disadvantages of the dyslexia label outlined by Elliott and Grigorenko, I think it will survive into the future because it provides many people with a positive view of their difficulties which also helps them get taken seriously. For that reason, I think we may find it easier to work with the label and try to ensure it is used in a consistent and meaningful way, rather than to argue for its abolition.

Reference
Kendell, R., & Jablensky, A. (2003). Distinguishing between the validity and utility of psychiatric diagnoses American Journal of Psychiatry, 160 (1) DOI: 10.1176/appi.ajp.160.1.4


This article (Figshare version) can be cited as:
Bishop, Dorothy V M (2014): My thoughts on the dyslexia debate. figshare
http://dx.doi.org/10.6084/m9.figshare.1030404