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Post by Former NIMH Director Thomas Insel: The Case for Preemption

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Let’s start with some good news. Over the past few decades in the United States, we have seen dramatic reductions in mortality due to coronary artery disease (an over 60 percent reduction, with 1.1 millions deaths averted each year), AIDS (a 40 percent reduction, with over 30,000 deaths averted each year), and stroke (a 30 percent reduction, with over 20,000 deaths averted each year). Indeed, last month AIDS was declared a chronic disease, recognizing that a young person who becomes infected with HIV will likely survive for decades and die of other causes. These are extraordinary achievements, largely due to biomedical research. More specifically, research has taught us to detect each of these diseases early and intervene quickly to preempt later stages. The simple concept of “treatment as prevention,” whether to reduce heart attacks and strokes or to prevent the spread and advance of AIDS, has yielded better outcomes than treating the late stages of these disorders.

Unfortunately, when we look at the big picture and consider overall longevity, compared to the rest of the world, our news is not so good. A report out last week from the Institute of Medicine and the National Research Council describes high rates of mortality for Americans under 50, relative to rates of mortality in 18 other developed countries.1 It’s a sobering report. American men ranked last and American women ranked next to last in life expectancy within this age range. The authors cite car accidents, gun violence, and drug overdoses as factors contributing to higher mortality rates in this country. For people with mental disorders, the news from the United States is especially concerning. Suicide rates are trending higher not lower, especially in select demographic groups. Longevity, which has increased in the U.S. general population, remains shortened by years, possibly decades, in people with serious mental illness.

Is there a lesson to be learned from the successes of biomedical research? One observation that is driving the science of neurodegenerative disorders like Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease is that changes in the brain precede changes in behavior, sometimes by more than a decade. The brain appears wired to preserve behavior even in the face of massive cell death or cortical atrophy. Much of our research effort today in Alzheimer’s disease focuses on identifying these earlier stages and developing interventions that will preempt or forestall dementia. In Parkinson’s disease, where the symptoms only emerge after 80 percent of dopamine cells have been lost, if we could halt the disorder when only 40 percent of cells have died, the symptoms might be prevented.

What about mental disorders or, as we often call them, “behavioral disorders”? We now understand these as brain circuit disorders, but we define them based on changes in behavior. If the symptoms of psychosis are a late stage of schizophrenia, are we missing the most important time to intervene? A recent review looks at the evidence for a prodrome or high-risk syndrome before the psychosis of schizophrenia, analogous to the stages of heart disease before a heart attack.2 Most of the studies of this high-risk state have relied on behavioral symptoms, suggesting that we are already late in the process. Nevertheless, as this review concludes, this approach has already revealed an interlude before psychosis when intervention could prevent psychosis.

Of course, we face two big questions going forward in this research. First, can changes in brain function or some biomarker yield better prediction and longer lead-times for intervening to preempt psychosis? We now have the neuroimaging and cerebrospinal fluid measures in Alzheimer’s disease and the cardiac imaging and lipid measures in heart disease to define risk with more precision. Imagine the cognitive, imaging, and plasma measures that might redefine what we now call the risk state for schizophrenia so that early prediction becomes precise for any given individual.

The second question is how to intervene. The first studies with medications have been disappointing.2 We do not have a “statin” for preempting psychosis. But medication might not be the best way to build prefrontal circuits or strengthen executive function. Imagine a toolkit of interventions with cognitive training, family supports, and social engagement to prevent psychosis in even 20 percent of the 100,000 young people who will have a first episode this year.

The NIMH-supported North American Prodrome Longitudinal Study (NAPLS) has been on this path for the past decade. This dedicated consortium of scientists is not there yet, but already they are working on a combination of neurocognitive testing, neuroimaging, and plasma biomarkers that can redefine how we think about schizophrenia, revealing that psychosis is indeed a late event in a process that starts many years earlier. This year we will avert 1.1 million deaths from heart disease because we have not waited for a heart attack to diagnose and treat coronary artery disease. The 100,000 young Americans who will have a first episode of psychosis this year will join over 2 million with schizophrenia. Nearly 5 percent of people with schizophrenia will die by suicide. Our best hope of reducing mortality from this and other brain disorders will come from realizing that just like other medical disorders, we need to diagnose and intervene before the symptoms become manifest.

effect of early prevention on schizophrenia

Model of Psychosis Onset in Schizophrenia. Symptom severity, as indicated on the y axis, is lower in the earlier than later stages of the disease, as indicated by the x axis. Focusing on prevention could lessen the symptoms and possibly reduce disease progression.
Source: JAMA Psychiatry, January 2013



 1 National Research Council and Institute of Medicine. (2013). U.S. Health in International Perspective: Shorter Lives, Poorer Health. Panel on Understanding Cross-National Health Differences Among High-Income Countries, Steven H. Woolf and Laudan Aron, Eds. Committee on Population, Division of Behavioral and Social Sciences and Education, and Board on Population Health and Public Health Practice, Institute of Medicine. Washington, DC: The National Academies Press.

 2 Fusar-Poli P, Borgwardt S, Bechdolf A, Addington J, Riecher-Rössler A, Schultze-Lutter F, Keshavan M, Wood S, Ruhrmann S, Seidman LJ, Valmaggia L, Cannon T, Velthorst E, De Hann L, Cornblatt B, Bonoldi I, Birchwood M, McGlashan T, Carpenter W, McGorry P, Klosterkötter J, McGuire P, Yung A. The Psychosis High-Risk State. JAMA Psychiatry. 2013;70(1):107-120. doi:10.1001/jamapsychiatry.2013.269.