It is an exciting time for all things neuroscience. President Obama’s BRAIN initiative is dedicated to funding much-needed research on the brain—what Francis Collins, Director of the National Institutes of Health, has dubbed humanity’s “final frontier.” The integration of the behavioral, cognitive, and social sciences has further boosted efforts to shed light on “the most complex organ in the known universe.” So why have decades of mental disorder research failed to make significant progress? Instead of pushing back the frontiers of medicine, how did psychiatry arrive at today’s devastating standstill?

Stuck in the Past

Psychiatric medications have improved little in the past half century, which is concerning given that one in four Americans is diagnosed annually with mental illness. In fact, not a single novel drug has entered the psychiatric market in more than three decades. Most of the medications in use today were discovered unintentionally in the fifties and sixties.

The problem lies in our still-crude understanding of the biology of normal brain function, let alone psychiatric disorders. Psychopharmacology assumes that individuals with the same mental disorder diagnosis will present similar symptoms and neural anomalies that will respond to the same treatments. In reality, clinical presentations are profoundly diverse due to the diagnostic criteria defined in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM).

Nicknamed the psychiatric “bible,” the diagnoses in the DSM are determined by behavioral observations. Clinicians run through checklists of symptoms and put a disorder label on a patient if he fulfills some fraction of the criteria. Not only is this process subjective, but the criteria touch upon many sectors of behavior, overlapping with other disorder categories in the process. This has allowed for high heterogeneity of symptoms, with prevalent illnesses like major depression racking up to an estimated 1,497 possible clinical profiles.

With such disparity within diagnoses—which determine what treatments are prescribed, as well as eligibility for clinical studies—it is no surprise that we have been unable to produce robust findings that may finally elucidate the psychological and neurobiological mechanisms at play. Consequently, we have not moved beyond trial-and-error treatment; and patients unresponsive to the first, second, or third randomly-selected medications are literally paying for it.

Looking Ahead

As current psychiatric diagnostic practice is crippling efforts to understand and treat the human brain, the National Institute of Mental Health (NIMH) hopes to jumpstart a new era of clinical thinking with its Research Domain Criteria (RDoC) project. Since findings are defying traditional diagnostic boundaries, RDoC is shifting psychiatry towards “dimensionality,” not only category. According to proponents Bruce Cuthbert and Thomas Insel, the initiative provides funding for pathophysiology research integrating genomics, behavior, and neurobiology. By accounting for these dimensions of dysfunction, the ultimate goal is a new classification framework that will better aid in detection, prognosis, treatment, and even prevention.

The initiative provides funding for pathophysiology research integrating genomics, behavior, and neurobiology.

Biomarkers from neuroimaging and genetic analyses will hopefully serve to stratify patients based on their unique biosignatures. Not only would this combat the heterogeneity problem, but doing so would facilitate identification of optimal treatments matched to patients’ conditions. This sparks hope for personalized or “precision medicine,” in which specific pathophysiologies may be identified and corrected. This is not the immediate aim of RDoC though. As psychiatry lags behind the rest of medicine in achieving precision medicine, most experts expect at least a generation before such a breakthrough in mental disorder research is plausible. After all, there are high hurdles to overcome, given the complexity of the human brain and its inaccessibility to direct study.

It is a revolutionary and still controversial idea that mental diseases are merely “extremes on a spectrum of normal functioning.” Extensive research will have to be conducted to establish cut-off points in dysfunction that require different clinical action. If the DSM is to work in tandem with RDoC, perhaps the latter will provide a basis to subtype the umbrella-term diagnoses of the former.

Despite the optimism, some objections to the RDoC initiative do warrant consideration. Several researchers warn against oversimplifying complex psychiatric illnesses by naturalizing their origins. Disorders may also share seemingly similar abnormalities and symptoms, but that may not entail that their causations and required interventions are the same.

So yes, the time is ripe for a major shift in the field. But even RDoC leaders, Cuthbert and Insel, admit the approach is “so new that unforeseen obstacles surely await the pioneers in this area.” We may find that the brain is far more complex than we had ever imagined. Regardless, as mentioned in an Economist article, “there is a deal of searching to do yet before human nature gives up its secrets.”

About The Author

Ien Li