This month the American Psychiatric Association (APA) will publish the fifth edition of its guidebook for clinicians, the Diagnostic and Statistical Manual of Mental Disorders, or DSM-5. Researchers around the world have eagerly anticipated the new manual, which, in typical fashion, took around 14 years to revise. The DSM describes the symptoms of more than 300 officially recognized mental illnesses—depression, bipolar disorder, schizophrenia and others—helping counselors, psychiatrists and general care practitioners diagnose their patients. Yet it has a fundamental flaw: it says nothing about the biological underpinnings of mental disorders. In the past, that shortcoming reflected the science. For most of the DSM's history, investigators have not had a detailed understanding of what causes mental illness.

That excuse is no longer valid. Neuroscientists now understand some of the ways that brain circuits for memory, emotion and attention malfunction in various mental disorders. Since 2009 clinical psychologist Bruce Cuthbert and his team at the National Institute of Mental Health have been constructing a classification system based on recent research, which is revealing how the structure and activity of a mentally ill brain differs from that of a healthy one. The new framework will not replace the DSM, which is too important to discard, Cuthbert says. Rather he and his colleagues hope that future versions of the guide will incorporate information about the biology of mental illness to better distinguish one disorder from another.

Cuthbert, whose project may receive additional funding from the Obama administration's planned Brain Activity Map initiative, is encouraging researchers to study basic cognitive and biological processes implicated in many types of mental illness. Some scientists might explore how and why the neural circuits that detect threats and store fearful memories sometimes behave in unusual ways after traumatic events—the kinds of changes that are partially responsible for post-traumatic stress disorder. Others may investigate the neurobiology of hallucinations, disruptions in circadian rhythms, or precisely how drug addiction rewires the brain.

The ultimate goal is to provide new biological targets for medication. “We understand so much more about the brain than we used to,” Cuthbert says. “We are really in the middle of a big shift.”