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Progress in the Biology of Mental Health

The PNA recently came across a report of particular interest because it comes from the National Institute of Mental Health (NIMH) and not the NIH (most of the source of any research/information about pituitary and other neuroendocrine disorders). We have reprinted a small a portion of this article below along with the link. This section most closely addresses what eventually may be reported as a link between the mind and the body (i.e. the NIH and the NIMH). The report is entitled: "Twenty-five years of progress: A View from the NIMH and NINDS"

https://www.cell.com/neuron/abstract/S0896-6273%2813%2900898-2#MainText

Burden of Disease

The inconvenient truth in 2013 is that neuropsychiatric disorders represent the leading source of disease burden in the developed world for people between ages 15 and 49 (Lopez et al., 2006). Over the past 25 years, success against acute infectious diseases and infant mortality has left chronic, noncommunicable diseases as the largest source of disability. In contrast to heart disease or most forms of cancer, many neuropsychiatric disorders (e.g., autism, epilepsy, schizophrenia, intellectual disability) begin early in life and contribute to lifelong disability or reduced longevity. Indeed, these disorders are now the chronic diseases of the young and globally have become the largest source of years lived with disability (Whiteford et al., 2013). At the same time, neurodegenerative disorders have increasingly become the signature disabilities of an aging population. Changing demographics ensure that brain disorders will be a greater public health challenge in the coming decades.

The public health challenge is mortality as well as morbidity. Many brain disorders are fatal. Stroke is the fourth leading cause of death in the United States and second globally. Death occurs within 5 years of a diagnosis of amyotrophic lateral sclerosis (ALS), 10 years after symptoms of Alzheimer's disease, and twenty after symptoms of Huntington's disease. The risk of sudden unexplained death in epilepsy is 24 times greater than that in the general population (Neligan et al., 2011). For serious mental illnesses, like schizophrenia and bipolar disorder, suicide is common. Indeed, most suicides involve a mental disorder, and there are now over 38,000 suicides in the United States, more than twice the number of homicides and more than the number of motor vehicle fatalities (CDC, 2013). It has been reported that, in the United States, people with serious mental illness die at least 8 years earlier than those without these illnesses (Druss and Walker, 2011). Suicide accounts for only a small fraction of this early mortality, most of which results from chronic medical conditions that are poorly treated in this population.

Perhaps it should not be surprising, given the high morbidity and mortality, that the cost of neuropsychiatric disorders trumps other chronic, noncommunicable disorders. In a World Economic Forum study of projected costs, neuropsychiatric disorders were estimated to be the most costly, accounting for more than cancer, diabetes, and chronic respiratory diseases combined (Bloom et al., 2011). For Alzheimer's disease alone, costs of care in the United States in 2010 have been estimated as between $157 billion and $225 billion (Hurd et al., 2013), with projections of costs surpassing $1 trillion in 2050.

These sobering statistics about brain disorders stand in stark contrast to the progress in neurobiology. Why the gap? Why has 25 years of "explosive growth" in neurobiology failed to reduce the morbidity or mortality of virtually all brain disorders? One explanation is that our basic science is misguided, not relevant to clinical problems. Another explanation, which we favor, is that we do not know enough yet to translate basic neurobiology into the new diagnostics and therapeutics that will transform public health outcomes. Let's look at both of these possibilities.

Relevance of Basic Science to Clinical Care

Although clinical progress is usually measured in breakthrough therapies, progress in improving diagnostics, elucidating disease pathogenesis, and generating biomarkers can be as important and may be a prerequisite for better treatments. Since 1988, there has been considerable scientific progress on brain disorders.

In the past 25 years, genetic mutations underlying a myriad of inherited neurologic disorders have been identified. These discoveries now enable rapid and accurate diagnosis, reducing or even eliminating the diagnostic odyssey, and in some cases even allow for presymptomatic diagnosis. Whole-exome sequencing of families with affected individuals promises to uncover genetic causes of scores of diseases and already has identified de novo mutations for a number of the childhood epilepsies (Allen et al., 2013). For neurodegenerative disorders, rare disease-causing mutations in common conditions such as Alzheimer's disease (APP, presenilin) and Parkinson's disease (synuclein, Parkin, Pink1, LRRK2) and rare diseases like ALS (superoxide dismutase, C9orf72) are shedding light on causative molecular pathways (Bertram and Tanzi, 2005). These pathways in turn may lead to "druggable targets" for potential disease-modifying therapy. In the near term, projects like the Alzheimer's Disease Neuroimaging Initiative are yielding biomarkers to track disease progression in patients. For Alzheimer's disease, it is possible to image sentinel molecules, like tau- and β-amyloid, and to measure them in cerebrospinal fluid, as well as track hippocampal atrophy (Toledo et al., 2013). Similar efforts are underway in Parkinson's disease. The impact of these kinds of biomarkers can be seen in multiple sclerosis, where the prevention of gadolinium-enhancing MRI lesions has accelerated the development of treatments (Bermel et al., 2013).

While we still lack biomarkers for mental disorders, the tools of basic science are now beginning to change how we approach diagnosis. The discovery of shared genetics, often implicating genes critical for brain development, has supported a new formulation of mental disorders as neurodevelopmental disorders (Smoller et al., 2013). With functional MR and PET imaging, specific circuits have been implicated in depression, obsessive-compulsive disorder, and posttraumatic stress disorder (Insel, 2010). A new approach to classification of psychiatric disorders, called the Research Domain Criteria (RDoC) project, is based on cognitive domains and circuitry (Cuthbert and Insel, 2013). RDoC attempts to transform diagnosis by building on the findings of neuroscience and cognitive science, rather than relying solely on presenting symptoms, as done for the past century. This approach presumes that what we now call "depression" or "schizophrenia" are, in fact, many different disorders with distinct underlying biological causes that require different treatments. While this approach is not ready for clinical use, it demonstrates the extent to which mental disorders are now addressed as brain disorders, or, more specifically, as brain circuit disorders.

Across brain disorders, whether primarily neurologic or psychiatric, there is an increasing recognition that behavioral symptoms are late manifestations of disease. This insight for Alzheimer's, Parkinson's, schizophrenia, and autism represents a fundamental shift in emphasis, similar to the shift in the treatment of atherosclerosis and hypertension before they cause ischemic heart disease or stroke. This preemptive approach focuses on early detection of brain changes and the development of early interventions that can prevent or forestall neurodegenerative or neurodevelopmental disorders.

 

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