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Post by Former NIMH Director Thomas Insel: Re-Thinking Classification of Mental Disorders

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A recent report in Nature Genetics reminds us of the challenges to classifying mental disorders. A meta-analysis of the largest sample of its kind to date has implicated genetic variation on Chromosome 3 with both bipolar disorder and depression. This follows hot on the heels of a study last summer that similarly linked bipolar disorder and schizophrenia to the same common variants in DNA sequence. Add these new genetic findings to the non-specificity of previously identified mutations, such as DISC-1 or the 16p11 deletion.  And consider the absence of specific biomarkers or treatments, the high prevalence of co-morbidity, and the clinical heterogeneity of each disorder and you can see why diagnosis continues to be one of the most confounding aspects of both research and practice in psychiatry.

This is not to say there has been no progress.  The various iterations of the Diagnostic and Statistical Manual of Mental Disorders (DSM) developed by the American Psychiatric Association and the psychiatric section of the International Classification of Diseases (ICD) developed by the World Health Organization have yielded a high degree of reliability.  This means that there is a high degree of agreement between clinicians and clear, reproducible criteria for the diagnosis of mental disorders.  Reliability is, of course, not the same as validity.  As NIMH research increasingly reveals the brain circuitry for various forms of mental distress, our hope is that we can look forward to a classification system validated by a deep knowledge of both the genetic risks and neural basis of mental illness.  This approach could transform not only diagnosis but treatment.  We know from studies of neurologic disorders, such as Parkinson’s disease and Huntington’s disease, that behavioral signs and symptoms are late manifestations of the underlying brain disorder.  Imagine the impact of identifying the neural basis of schizophrenia or mood disorders before the onset of disabling behavioral symptoms so that clinicians would regularly intervene to preempt psychosis or depression.

Can we develop a clinically useful diagnostic system based on neuroscience and genetics?  Not yet.  But, in the spirit of beginning a long journey, NIMH is taking its first step with the Research Domain Criteria (RDoC) project. RDoC makes no assumptions about current categories.  It will build a framework for studying mental illness across basic dimensions of mental functioning – such as emotion and cognition. Cutting across traditional diagnostic categories, it will encompass multiple levels of analysis, from genes to neural circuits to behaviors.  RDoC is not intended to supplant the diagnostic systems for practitioners, nor is it expected to even inform the ongoing revisions of the DSM and ICD.  In this initial phase, RDoC will be developed for the research community to help all of us break out of diagnostic formulations that may have more reliability than validity.  If RDoC is successful, it will yield a robust classification system that will become the basis for NIMH research on mental illness, from etiology to treatment.  RDoC will also provide new clinical models for translational studies in animals.

Initially, RDoC will focus on studies of fear and executive functioning/working memory, two areas with a deep literature on neural circuits and genetics. How will RDoC be developed?  RDoC will be an open source process, fully transparent and broadly inclusive. We will launch with a series of conferences beginning this Spring, and updated web postings. Major elements of the initiative are expected to be in place within 2 years, with long-term activities extending 5-10 years.  Our vision is a new classification with high reliability and validity based on a deep understanding of the neural basis of mental disorders.


Endophenotypes: bridging genomic complexity and disorder heterogeneity.
Insel TR, Cuthbert BN. Biol Psychiatry. 2009 Dec 1;66(11):988-9. No abstract available. PMID: 19900610

Classification issues in women's mental health: Clinical utility and etiological mechanisms. Cuthbert BN, Insel TR. Archives of Women's Mental Health, 2010. Epub ahead of print. PMID: 20058041

Neurocircuitry: a window into the networks underlying neuropsychiatric disease.
Haber SN, Rauch SL. Neuropsychopharmacology. 2010 Jan;35(1):1-3. No abstract available. PMID: 20010702