On the simple and the complex in psychiatry, with reference to DSM 5 and research domain criteria.

Aspiring to simple theories has been at the centre of the scientific quest to understand nature. In medicine, this aspiration found its best exemplars in diseases entirely attributable to specific causal factors, such as infectious diseases (micro organisms invading a body and being transmitted within populations) or Mendelian hereditary diseases (highly penetrant mutations transmitted within families). As desirable for their elegance and simplicity as these models may seem for all pathological conditions, they remain rather exceptional in medicine. Most human diseases are not causally simple, and psychiatric disorders are no exception. In contrast to many medical disciplines where biomarkers and gold-standard diag nostic tests have been well established, psychiatry nosology relies entirely on descriptive criteria, often in the form of behavioural disturbances and dysfunction, along with a few combinatory rules to define disorders. Patients’ clinical presentations may differ drastically within the same diagnostic category. For example, it is possible to diagnose schizophrenia in 2 patients who do not share any symptoms. Also, using the current criteria for attention-deficit/hyperactivity disorder (ADHD), we can define more than 3000 different forms of ADHD by combining the 18 items listed in the DSM IV! This heterogeneity/complexity in phenotypic expression is often invoked as one of the major barriers to progress in identifying causal factors underlying psychiatric disorders and achieving the simplicity observed in Mendelian disorders or infectious diseases. Could this phenotypic complexity (plurality in Occam’s dictum) be simplified to achieve causal discoveries, or is it necessary and irreducible? In psychiatry, ultimate clinical descriptors will always rely on subjective complaints, such as sadness, anxiety, fatigue, obsessions and suicidality. Contrary to many other fields of medicine, these descriptors cannot and, I believe, will not be reduced to physical signs and symptoms that can be explained by other physical events in the same way that heart failure, for example, may be explained by a truncating mutation in a myosine gene (or other molecular failures). Nevertheless, this does not preclude the possibility that the current psychiatric syndromes, with their intrinsic subjectivity, could be reshaped in a way that their genetic, biological, neuro logic al and psychological correlates will be easier to identify so that future classification of mental disorders will integrate some of these markers to achieve better definition of disorders and possibly better treatments. This theorizing has been rampant in psychiatric genetic research. The concept of endophenotypes, or traits that are more prevalent in patients compared with the general population and that cluster in patients’ nonaffected relatives, has been advanced as one of the means to study the genetics of schizophrenia and other mental disorders. These endophenotypes might be behavioural dimensions, electrophysiological abnormalities, abnormal brain structure or function, or cellular dysfunction. It is argued that complex psychiatric syndromes need to be deconstructed into simpler phenotypes to decipher their genetic underpinnings. The popularity of this concept is evident in that a PubMed search for the term “endo phenotype” (Mar. 21, 2013) yielded 1969 studies, most of which (1952) were published after the year 2000. This concept is often depicted by images where endophenotypes are midway between the risk gene and complex psychiatric disorders. These endophenotypes are also called “intermediate” phenotypes, serving to bridge pathways to discovery from simple cellular effects to neural networks to more complex behavioural dimensions. It is also often stated metaphorically that endophenotypes are “closer” to the gene effect than complex disorders and that they represent simpler clues to genetic underpinnings. This simpler “geography” of behaviours and their determinants appeals to both clinicians and researchers. Indeed, the American Psychiatric Association (APA) task force on DSM 5 proposed that a dimensional approach to psychiatric diagnoses be included in the DSM 5 in the hope that such an approach would, among other things, improve the validity of diagnoses. Parallel to these efforts,