scope:

Preface

A great deal has been written about current medical foes in our society. Obesity, diabetes, depression, and dementia are all critical health issues with ramifications beyond the physical health of our nation. In the United States, obesity and diabetes have reached epidemic levels, not only among adults, but also among children and adolescents. In 1990, the rate of depression was estimated at 11 million people, and the estimate of the annual cost of depression was $44 billion (1). The rate of depression in any given year is estimated to be 9.5% (2), and with an estimated population of 301,139,947 million, this estimate has enormous implications for the economy and the mental and physical health of our nation. The growing rates of depression in the United States are already reflected in the use of psychotropic medications, as antidepressants are the most often prescribed medications in the United States. Finally, as the population in the United States and the western world ages, the rate of dementia grows precipitously, doubling after age 85. These statistics only highlight the growing concern of the effects of physical and psychological illness and the critical need for new research and funding on the proper diagnosis and treatment of illnesses.

It is estimated that approximately 50% of the population aged 50 years and older have a diagnosis of major depression. Four million adults in the United States alone carry a diagnosis of dementia and 16 million have diabetes. It is not a coincidence then that these three Ds (diabetes, depression, and dementia) are so prevalent in our society. There are numerous biological and psychosocial explanations to them, and this book is focused on the biological concepts of these diseases. The aim is to educate clinicians of all specialties on pathophysiology and interrelationship among the three Ds, in order to formulate optimal approaches to their diagnosis and treatments.

As will be described in this book, bidirectional relationships exist between diabetes and depression and depression and dementia. There is also a notion of Alzheimer's disease being a form of diabetes of the brain. Because of this degree of reciprocity between the brain and the body (soma), it is plausible to postulate that depressive illness is not just a psychiatric disease-as diabetes is not just an endocrine disorder, nor that dementia is just a neurodegenerative disease per se-but that all of these diseases represent complex psychoneuroendocrine conditions requiring a complex multisystem approach to their prevention and treatment. Though this conceptmay seemobvious, is not firmly established as a thinking paradigm in the clinical community. This book will thus serve as a resource and a guide to development of early diagnoses and interventions among afflicted individuals with one or more of these three Ds to protect them fromdamage and irreversible changes.

Metabolic syndrome refers to a cluster of symptoms that increase the risk of morbidity and mortality from cardiovascular disease and diabetes (3). As such, this nosology has been a subject of intense debate with regard to its definitions causality or utility in clinical psychiatry. Part of the complexity regarding metabolic syndrome is the fact that there is not a single internationally agreed-upon definition. As such, we have included a chapter by Gerald Reaven, the father of Syndrome X, which provides an elegant overview of insulin resistance syndrome and an argument for its superior clinical relevance in lieu of metabolic syndrome.

As mentioned above, the findings from several areas of research suggest that there is a link between depression and the risk of dementia. In retrospective studies of patients with Alzheimer's disease, a history of depression has been found to be associated with late-onset Alzheimer's disease (4-6). In prospective community sample studies, depressive symptoms at the baseline evaluation were associated with an increased risk of incident dementia (7,8). Likewise, a fair number of patients with depression have been found to develop dementia (9-12).

Long-standing-especially, poorly controlled-diabetes has been shown to cause both diffuse and focal changes in the brain, which are manifested as cognitive decline. These effects are mediated by metabolic disturbances on neurons as well vascular disease and hypertension. In turn, diabetes is closely associated with depressive symptoms and depressive disorders, with comorbidity ranging between 40% and 70% (13). Cognitive declines are also commonly present among patients with primary affective disorders and are unrelated to psychosocial consequences of living with a chronic disease.

The reciprocal links between the nervous system and endocrine systems underlie changes in the brain and body in both depressive illness and diabetes. Depressive disorder is associated with blunted central serotonin release (13), which, in turn, has been associated with metabolic dysfunction (14). If the metabolic dysfunction is associated with increased risk of developing cognitive impairment and, ultimately, dementia, then early identification and treatment of these conditions may offer avenues for primary prevention of neurodegenerative illness.

Another possible mechanism for adverse consequence of insulin resistance in the central nervous system is a high level of inflammation. Specifically, inflammatory processes are widely implicated in the pathophysiology of diabetes and cardiovascular disease, as well as in cognitive impairment. Among the suggested explanations are the independent effects of atherosclerosis and associated inflammation on cognitive decline (15), although metabolic dysfunction and inflammation may have cumulative effect on vasculature, manifested by changes in periphery (cardiovascular disease) and central nervous system (cognitive decline). Our last chapter provides an overview and synthesis of the major connecting links between insulin resistance and other aspects of brain function.

Several other mediators of the reciprocal interaction between the CNS and insulin resistance include glucocorticoids (cortisol), insulin, serotonin, and glutamate among others. The concept of a final common pathway can be applied to these interactions, as the most likely place of convergence in action of these biomarkers is the hippocampus. Specifically, the hippocampus is a central brain structure involved in regulation of mood and cognition and is specifically sensitive to cortisol, insulin, serotonin, and other neuromediators. A number of chapters in this monograph will address the anatomy and physiology of hippocampus with an emphasis on the integration of various influences in the three Ds.

While insulin affects hippocampal structures involved in body weight regulation (16), it also it influences memory processing (17-25). There are central insulin receptors predominantly located in the hippocampus and adjacent limbic structures (26,27). Currently, the investigation of intranasal administration of insulin is promising, as it specifically targets hippocampal function. In fact, studies have suggested improvement in hippocampal- specific declarative memory upon intranasal administration of insulin. Though, it should be noted that such improvements may be the result of the effects of insulin on cortisol concentrations. In addition, cortisol is a well-known endotoxin with regard to hippocampal neurons, by binding to hippocampal glucocorticoid receptors, inhibiting synaptic longterm potentiation and decreasing hippocampal glutamate turn over (28). Therefore, a decrease in cortisol may be behind improving effects of insulin on hippocampal functioning (29).

Finally, even as the neurodegeneration ensues, the impaired metabolic processes may be modulated to affect the disease course. In the chapter by Craft and colleagues, their current findings on the role of insulin resistance in patients with Alzheimer's disease offer potential ways to modify this dysfunction. Certainly, lifestyle and other modifiable risk factors are attractive methods for disease prevention and overall wellness. Nevertheless, it is as important to be knowledgeable about the intricate links behind the disease formation, as it is to offer patients nonpharmacological interventions at an earlier stage when the impact is not as pronounced. With that, I highly recommend this volume and hope that the reader will find it not only informative, but provocative of new research directions in solving a fascinating puzzle of the three Ds.