Where Are the Clinical Tests for Psychiatric Disorders?

Examination room, World War 1 (Otis Historical Archives Nat'l Museum of Health & Medicine).


The lack of laboratory diagnostic tests for mental disorders, along with the shady marketing practices of the pharmaceutical industry, are often viewed as the most fatal flaws in the medical practice of psychiatry. This is especially true among critics of psychiatry, but doctors in other medical specialties tend to have a dismal opinion of psychiatry¹ as well (Fazel & Ebmeier, 2009). Widespread perceptions that the field is relatively low in scientific precision, and that the patients have a poor prognosis, are among the possible reasons for this. An interesting comparison of medical students in two Spanish-speaking countries revealed greater respect for psychiatry in Barcelona than in Medellín (Pailhez et al. 2010; PDF):

The differences can be partly explained by the sociocultural contexts of Barcelona and Medellín. For example, students from Barcelona (where the neuroscientific model has greater influence) agreed more with a medically oriented position of psychiatry and that psychiatry is scientific, precise, and a valid branch of medicine.

This lack of respect from other medical professionals, not to mention from consumer/survivor advocates, puts neuroscientists in an awkward position. We believe in neurobiological explanations for the full gamut of human behavior,² yet we're left to defend a specialty that relies on clinical interviews and a disputed classification system. There is in fact a large and growing literature on structural and functional differences between the brains of those with and without psychiatric disorders, but these discoveries have not yet translated into reliable diagnostic tests.


Why has it taken so long for biological psychiatry to develop clinical tests?

A new perspectives paper by three prominent figures in biological psychiatry (Kapur, Phillips, & Insel, 2012)³ asks this precise question. They begin by describing the scope of the problem:

Biological psychiatry aims to understand mental disorders in terms of the biological function of the nervous system. By several measures it has been a tremendous success—thousands of scientific papers and hundreds of books devoted to this subject; legions of dedicated scientists and over 60 dedicated professional societies worldwide; and a profound impact on the public's perception of mental disorders. Despite these successes, it has not led to clinical tests that can be routinely used in the diagnosis and treatment of mental disorders. In the early 2000s, a series of white papers expressed hope that the advances in genetics, imaging and new technologies might lead to a biologically supported psychiatric classification and diagnostic system. But a decade later, as we stand at the threshold of a new version of the DSM, there are few biological clinical tests central to diagnosing psychiatric illnesses (other than those used to exclude physical illnesses). This article explores why this journey has been difficult for psychiatry and what can be done about it.

The question of "why" revolves around the "missing gold standard" - a biologically valid concept of a specific mental illness. During the Decade of the Brain (1990-1999) there was considerable optimism that advances in neuroimaging and genetics would lead to improvements in the validity of psychiatric diagnoses. However, that didn't happen. Many of the genetic association studies in schizophrenia failed to replicate, for instance. Readers of this blog (and others) know the problems and limitations inherent in contemporary neuroimaging, no less the methods of 15-20 years ago. In the Decade after The Decade of the Brain, Dr. Thomas Insel noted that 90s-era research in biological psychiatry focused on how treatments work, rather than the causes of disease. Looking ahead, he sees new views of mental disorders as circuit disorders are one reason for renewed optimism.

In the present commentary, Kapur et al. (2012) discuss how the ongoing issues with DSM-5 hinder the search for clinical tests:

On the one hand, these successive editions of DSM and ICD lead to increasing psychometric precision. On the other hand, the ever increasing fractionation of mental distress into smaller and more numerous categories, without a priori biological validity, makes it harder to find specific biomedical tests that diagnose or predict the disorders.

Additional problems fall under the heading of Underpowered Studies and Approximate Replications:

One might expect that failure to replicate the findings would induce scientists to lose interest in the given area and to move on to findings with more robust effects. Unfortunately, an initial underpowered study is often followed by another study of similar size but with a few additional measures and variables to give it some novelty and distinction. These subsequent studies usually have only modest statistical power to decisively confirm or refute the original finding, but do have sufficient multiplicity of new measures to generate some significant finding—even though not precisely the one observed in the first study—thus providing an ‘approximate replication’.²⁶ As a result, the ‘literature’ in the field grows without decisively replicating/rejecting the precise original finding, but instead creates a penumbra of ‘P<0.05’ findings around the first.

What can be done about it?

Not much, if the search is for screening tests like mammograms and Pap smears in healthy women:

Few biological screening tests have been developed without a plausible and understandable link to the aetiology or pathophysiology of the disease—thus biological screening for most psychiatric disorders seems distant.

How about diagnostic tests? Here, too, don't hold your breath:

The prospects of ‘diagnostic tests’ for DSM entities remain distant for reasons articulated above, and it seems unlikely that we will replace the 300-disorder taxonomy of the DSM-5 with an alternative biologically based classification system anytime soon. Therefore the real opportunity for psychiatry is to use the emerging advances in genetics, molecular biology, imaging and cognitive science to supplement, rather than replace, the symptom-driven diagnosis. It is often like this in the rest of medicine [e.g., asthma, arthritis].

Instead, the goal should be to create a "stratified psychiatry" of phenotypic or genotypic subtypes - although they caution that the promise of "personalized medicine" has not been obtained in other specialties either. But they point to discovery of the gene mutation resulting in overexpression of HER2 in breast cancer, and the development of monoclonal antibody treatments, as one success story. This type of stratification doesn't require a complete understanding of the etiology of breast cancer.

Within psychiatry, one can view the diagnostic category of schizophrenia (for example) as a collection of symptoms or disorders that can vary across individuals (Bakker et al., 2004, 2007; Cobia et al., 2011; Hallmayer et al., 2005; Jablensky, 2006; Williams et al., 2007), despite the DSM-5 recommendation to eliminate the DSM-IV schizophrenia subtypes.

What is needed is a change in research culture that looks beyond DSM-5. Psychiatric disorders often do not display clear diagnostic boundaries, and co-morbidity is common. The authors take this opportunity to promote the Research Domain Criteria project, a topic I covered extensively in a previous post:

The National Institute of Mental Health (NIMH) in the U.S. is starting to take a different approach to the classification of psychiatric disorders, one that incorporates dimensions of observable behavior as well as neurobiological measures. The aim of the Research Domain Criteria (RDoC) project...

...is to define basic dimensions of functioning (such as fear circuitry or working memory) to be studied across multiple levels of analysis, from genes to neural circuits to behaviors, cutting across disorders as traditionally defined.

Other recommendations include longitudinal studies, data sharing (e.g., 1000 Functional Connectomes Project, Psychiatric GWAS Consortium), and a shift from reporting P-values to effect sizes (i.e., minimal significance testing vs. identifying a meaningful clinical effect). Ultimately, the complexity of the brain is a stringent limitation, but in their opinion is one that can be overcome:

The delay is understandable given the later start than the rest of medicine, the complexity of the brain, the nascence of neuroscientific techniques and the evolving nature of psychiatric nosology. On the other hand, the opportunity afforded by the progress in genomics and imaging combined with the computational abilities is unprecedented and could deliver useful clinical tests. These tests will identify homogenous populations for whom one could develop targeted new therapeutics thus realising a vision of a new stratified psychiatry that cuts across the traditional diagnostic boundaries while simultaneously transforming them.

NIMH paylines are now at the 15th percentile for established investigators and the 18th percentile for new investigators, which is better than in recent years [and better than the anemic 7th percentile at the National Cancer Institute], so perhaps there is some reason for optimism after all.


Footnotes

¹ For a defense of psychiatry as a profession, see the wonderful Shrink Rap blog post on Why Psychiatry is a Wonderful Medical Specialty.

² However, to quote my previous post...

This is not to say that society, culture, environment, and personal experiences play no role in the manifestation of "psychopathology".

³ Dr. Kapur is the Dean of the Institute of Psychiatry at King’s College London, Dr. Phillips is the Director of the Canadian Institutes of Health Research's Institute of Neurosciences (Mental Health and Addiction), and Dr. Insel is the Director of NIMH.


References

Fazel S, Ebmeier KP. (2009). Specialty choice in UK junior doctors: is psychiatry the least popular specialty for UK and international medical graduates? BMC Med Educ. 9:77.

Kapur S, Phillips AG, & Insel TR (2012). Why has it taken so long for biological psychiatry to develop clinical tests and what to do about it? Molecular psychiatry PMID: 22869033

Pailhez G, Bulbena A, López C, Balon R. (2010). Views of psychiatry: a comparison between medical students from Barcelona and Medellín. Acad Psychiatry 34:61-6. {PDF}