Deeper into genetic challenges to psychiatric diagnosis

For my recent Observer article I discussed how genetic findings are providing some of the best evidence that psychiatric diagnoses do not represent discrete disorders.

As part of that I spoke to Michael Owen, a psychiatrist and researcher based at Cardiff University, who has been leading lots of the rethink on the nature of psychiatric disorders.

As a young PhD student I sat in on lots of Prof Owen’s hospital ward rounds and learnt a great deal about how science bumps up against the real world of individuals’ lives.

One of the things that most interested me about Owen’s work is that, back in the day, he was working towards finding ‘the genetics of’ schizophrenia, bipolar and so on.

But since then he and his colleagues have gathered a great deal of evidence that certain genetic differences raise the chances of developing a whole range of difficulties – from epilepsy to schizophrenia to ADHD – rather these differences being associated with any one disorder.

As many of these genetic changes can affect brain development in subtle ways, it is looking increasingly likely that genetics determines how sensitive we are to life events as the brain grows and develops – suggesting a neurodevelopmental theory of these disorders that considers both neurobiology and life experience as equally important.

I asked Owen several questions for the Observer article but I couldn’t reply the answers in full, so I’ve reproduced them below as they’re a fascinating insight into how genetics is challenging psychiatry.

I remember you looking for the ‘genes for schizophrenia’ – what changed your mind?

For most of our genetic studies we used conventional diagnostic criteria such as schizophrenia, bipolar disorder and ADHD. However, what we then did was look for overlap between the genetic signals across diagnostic categories and found that these were striking. This occurred not just for schizophrenia and bipolar disorder, which to me as an adult psychiatrist who treats these conditions was not surprising, but also between adult disorders like schizophrenia and childhood disorders like autism and ADHD.

What do the current categories of psychiatric diagnosis represent?

The current categories were based on the categories in general use by psychiatrists. They were formalized to make them more reliable and have been developed over the years to take into account developments in thinking and practice. They are broad groupings of patients based upon the clinical presentation especially the most prominent symptoms and other factors such as age at onset, and course of illness. In other words they describe syndromes (clinically recognizable features that tend to occur together) rather than distinct diseases. They are clinically useful in so far as they group patients in regard to potential treatments and likely outcome. The problem is that many doctors and scientists have come to assume that they do in fact represent distinct diseases with separate causes and distinct mechanisms. In fact the evidence, not just from molecular genetics, suggests that there is no clear demarcation between diagnostic categories in symptoms or causes (genetic or environmental).

There is an emerging belief which has been stimulated by recent genetic findings that it is perhaps best to view psychiatric disorders more in terms of constellations of symptoms and syndromes, which cross current diagnostic categories and view these in dimensional terms. This is reflected by the inclusion of dimensional measures in DSM5, which, it is hoped, will allow these new views to stimulate research and to be developed based on evidence.

In the meantime the current categories, slightly modified, remain the focus of DSM-5. But I think that there is a much greater awareness now that these are provisional and will replaced when the weight of scientific evidence is sufficiently strong.

The implications of recent findings are probably more pressing for research where there is a need to be less constrained by current diagnostic categories and to refocus onto the mechanisms underlying symptom domains rather than diagnostic categories. This in turn might lead to new diagnostic systems and markers. The discovery of specific risk genes that cut across diagnostic groupings offers one approach to investigating this that we will take forward in Cardiff.

There is a lot of talk of endophenotypes and intermediate phenotypes that attempt to break down symptoms into simpler form of difference and dysfunction in the mind and brain. How will we know when we have found a valid one?

Research into potential endophenotypes has clear intuitive appeal but I think interpretation of the findings is hampered by a couple of important conceptual issues. First, as you would expect from what I have already said, I don’t think we can expect to find endophenotypes for a diagnostic group as such. Rather we might expect them to relate to specific subcomponents of the syndrome (symptoms, groups of symptoms etc).

Second, the assumption that a putative endophenotype lies on the disease pathway (ie is intermediate between say gene and clinical phenotype) has to be proved and cannot just be assumed. For example there has been a lot of work on cognitive dysfunction and brain imaging in psychiatry and widespread abnormalities have been reported. But it cannot be assumed that an individual cognitive or imaging phenotype lies on the pathway to a particular clinical disorder of component of the disorder. This has to be proven either through an intervention study in humans or model systems (both currently challenging), or statistically which requires much larger studies than are usually undertaken. I think that many of the findings from imaging and cognition studies will turn out to be part of the broad phenotype resulting from whatever brain dysfunction is present and not on the causal pathway to psychiatric disorder.

Using the tools of biological psychiatry you have come to a conclusion often associated with psychiatry’s critics (that the diagnostic categories do not represent specific disorders). What reactions have you encountered from mainstream psychiatry?

I have found that most psychiatrists working at the front line are sympathetic. In fact psychiatrists already treat symptoms rather than diagnoses. For example they will consider prescribing an antipsychotic if someone is psychotic regardless of whether the diagnosis is schizophrenia or bipolar disorder. They also recognize that many patients don’t fall neatly into current categories. For example many patients have symptoms of both schizophrenia and bipolar disorder sometimes at the same time and sometimes at different time points. Also patients who fulfill diagnostic criteria for schizophrenia in adulthood often have histories of childhood diagnoses such as ADHD or autistic spectrum.

The inertia comes in part from the way in which services are structured. In particular the distinction between child and adult services has many justifications but it leads to patents with long term problems being transferred to a new team at a vulnerable age, receiving different care and sometimes a change in diagnosis. Many of us now feel that we should develop services that span late childhood and early adulthood to ensure continuity over this important period. There are also international differences. So in the US mood disorders (including bipolar) are often treated by different doctors in different clinics to schizophrenia.

There is also a justifiable unwillingness to discard the current system until there is strong evidence for a better approach. The inclusion of dimensional measures in DSM5 reflects the acceptance of the psychiatric establishment that change is needed and acknowledges the likely direction of travel. I think that psychiatry’s acknowledgment of its diagnostic shortcomings is a sign of its maturity. Psychiatric disorders are the most complex in medicine and some of the most disabling. We have treatments that help some of the people some of the time and we need to target these to the right people at the right time. By acknowledging the shortcomings of our current diagnostic categories we are recognizing the need to treat patients as individuals and the fact that the outcome of psychiatric disorders is highly variable.