From too much and too little towards stratified psychiatry and pathophysiology
Authors: Francisco Xavier Castellanos
Journal: World Psychiatry (2013)

As J. Rapoport points out in her incisive commentary, pediatric psychopharmacology stands now at the crossroads of both too much and too little. Certainly, the number of options now available to clinicians far exceeds the resources physicians could draw on even two decades ago. However, appreciation of this apparent cornucopia is tempered by awareness of how limited therapeutic benefits tend to be when examined in controlled studies and by increasing insight into the numerous secondary adverse effects that inevitably accrue. Too little benefit, too many adverse effects. Rapoport eloquently echoes the observation that all of our present psychopharmacological options emerged as a result of serendipity based on conditions that no longer exist – chiefly the ability to carefully observe patient responses to systematic treatment trials during long-term inpatient hospitalizations 1. To advance the field, she urges us to seek ways of recapturing opportunities that may once again lead to fortuitous discovery. One benefit of the extension of health care benefits in the United States, dubbed “Obamacare”, is the requirement for the universal adoption of electronic medical records. Such systems could provide the basis for “psychopharmacological epidemiology” in what is arguably the most adventuresome health care system in the industrialized world. Heretofore, much of the clinical experimentation conducted under conditions of apparent necessity has been inaccessible to investigators. Adoption of harmonized medical record systems that can be searchable, while protecting patient privacy and confidentiality, could provide the essential infrastructure for recapturing serendipity 1. However, simply trolling large data sets is unlikely to yield much clinical bounty. The needle of occasional therapeutic benefit is too slender to detect within the haystack of clinical complexity and the Tower of Babel of existing clinical records. As Rapoport notes, the optimism regarding repurposing older medications for psychiatric disorders has not been matched by much evidence of success to date. The answer, we hope, lies in shifting from the illusory distant goal of “personalized medicine” to the more modest and attainable one of “stratified psychiatry”, as recently advocated in the context of developing clinical tests 2. As shown by the example of human epidermal growth factor subtype 2 (HER2) in breast, ovarian, endometrial, non-small-cell lung and even gastric cancer 2, identification of effective means of stratifying on the basis of prognosis can lead to the development of effective novel therapeutic agents, in that case, the monoclonal antibody trastuzumab, also known as Herceptin. So, what lessons can we glean from the molecular therapeutic advances being attained in oncology? Chiefly, that we must reinvigorate our efforts to understand pathophysiology. As psychiatrists cannot access brain tissue with the same facility as oncologists probe tumor samples, we will need to further develop indirect methods, such as those based on human induced pluripotent stem cells, as noted by Rapoport in her conclusion. Regardless of the method, the overarching goal needs to be to understand physiology, and the many ways it goes awry in pathophysiology. We must think in terms of systems, networks, and above all, functions. Fortunately, many of the elements and components required to carry out this endeavor are close at hand. Human brain function is increasingly being appreciated in terms of large-scale neural systems, i.e., spatially defined networks, which capture and condense complexity which would otherwise remain unimaginable 3-5. In the dazzling field of molecular genetics, simplistic notions that common variants would account for much of the substantial heritability of psychiatric disorders have been replaced by a focus on biological pathways and their underlying genetic networks 6. Genetic markers are no longer sought as sufficient clues to pathogenesis, but rather as indicators of the relevant physiological processes which can become targets for intervention. An illustration of our near-term objective was provided two decades ago by D. Klein in his seminal consideration of “false suffocation alarms, spontaneous panics, and related conditions” 7. Klein arrayed myriad clinical and laboratory observations in light of an evolutionarily motivated theory of the etiology of panic disorder, i.e., that spontaneous panic attacks result from dysfunction of an inborn suffocation alarm system. This formulation made sense of seemingly inconsistent observations and has motivated hundreds of subsequent reports, many of them relevant to anxiety disorders in children and adolescents. However, the greater lesson is encoded in the conclusion, which would be well adopted in pediatric psychopharmacology and clinical neuroscience: “The history of medicine amply demonstrates the value of the splitting diagnostic approach as well as the dangers of hardening of the categories. An active experimental, therapeutic, and physiologic challenge approach to psychopathology may move us from symptoms to a grasp of deranged circuitry” 7.