Will neurobiology rise to the translational challenges and opportunities of late-life geriatric psychiatry?

Improved care and treatments of subjects suffering from age-related brain illnesses will come through a better understanding of basic biologic mechanisms engaged during both normal and pathologic states. The urgency of this statement is underscored by the rapidly growing aging population and extending longevity, topics often debated in the columns of this journal and summarized by Evans 1 in this issue and by the large gaps in the current knowledge of the biologic bases of aging and of aging of the brain in particular. The premise that the biologic understanding of age- and brain-related mechanisms will lead to strategies and therapies to treat and prevent neuropsychiatric disorders of late life and to promote healthy and successful aging rests on the following tenets. First, complex brain functions and disorders are the expression of deregulated biologic functions that span multiple biologic scales, from genes and cells up to neural networks and behaviors. Second, the complexity of the brain under health and disease conditions can be deconstructed down to biologic levels that are amenable to molecular targeting. Indeed, the field of investigation of the neurobiology of diseases is concerned with cellular and molecular mechanisms of those illnesses and with the identification of targets that can be used to manipulate biologic and functional outcomes. However, current therapeutic agents used in psychiatry originate mostly from the serendipitous discovery of compounds displaying clinical efficacy, as illustrated by antidepressants and neuroleptics for instance, and successes in the rational design of new drugs have been limited to tweaking the chemistry and targets of existing compounds. Indeed, de novo strategies aimed at developing new therapeutics, based on knowledge of deregulated biologic pathways in psychiatric disorders, have been rare and unsuccessful. Therfore, the major challenge of advancing neurobiologic understanding and new drug discovery is not unique to late-life geriatric psychiatry. However, would the added complexity of the multiple brain changes and compounded pathologies that occur with advanced aging put this challenge beyond the reach of systematic neurobiologic investigations? To begin answering this question, it is worth stepping back and looking at some principles that guide neurobiologic investigations of disease states. The first principle is that of a bottom-up characterization of disease mechanisms from genes, cells, and local circuits, all the way to the expression of behavioral symptom dimensions. This approach often relies on more tractable biologic models (cellbased or animal-based studies) and samples (e.g., postmortem human brain) and contrasts greatly with the clinical characterization of psychiatric disorders, which is based on clusters of symptoms in the absence of underlying biologic knowledge. A second guiding principle is the investigation of biologic changes against the specificities of the “control” groups. Although this principle is self-evident and shared with the field of clinical research, “control”