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This book has focused upon the prevalent and important interface of depression and medical illness. The clinical, personal, familial, societal, and financial impacts of this interaction are tremendous. The state of our knowledge and experience concerning this nexus has been detailed, across the spectrum of medical conditions, populations, and settings. Much of this understanding has been facilitated by recent advances in scientific methods, and much has resulted from of careful clinical observation. These converging approaches have been discussed, and resultant principles have been explicated. With this substantial foundation, what are we building toward?

In essence, the goal is a mechanistic understanding that can provide diagnostic and therapeutic tools to improve outcomes, and guide clinical decision making. To accomplish this goal, one must utilize evolving approaches to chart the biopsychosocial intersection of depression and medical illness. This requires a characterization of the heterogeneity of depressive illness, of the range of medical illnesses, and of the types of mechanistic interrelationships among them. It also requires an elucidation of the final common brain pathways mediating depressive symptoms, as well as the pathophysiologic pathways and the etiological factors and interactions affecting those brain pathways in the context of medical illness.


Depression, even Major Depression, is not a unitary phenomenon. It is currently defined descriptively, and a patient can meet clinical criteria with different symptom constellations. Furthermore, there can be considerable overlap with other psychiatric syndromes, including anxiety disorders. With advances in translational research, it will be possible to stratify patients along a dimensional spectrum, within and across DSM categories, through deep phenotyping, multi-modal biomarkers and informatics.1 This will result in a mechanism-based taxonomy of depressive/mood disorders, with implications for treatment targets that modulate the relevant biological substrate, through pharmacologic, cognitive-behavioral or brain stimulation approaches.2 For example, there is increasing evidence for an anhedonic syndromic subtype with prominent lack of interest or pleasure in activities, associated with ventral striatum/nucleus accumbens, dopaminergic reward/motivation circuit dysfunction (Fig. 24-1).3,4

Figure 24-1

Activation Differences in Ventral Striatal and Dorsomedial Frontal Regions in Response to P Positive Words in Depressed Patients Compared With Healthy Subjects. In part A, axial slices reveal significant decreases in activation to positive stimuli in depressed patients compared with healthy subjects; left image: bilateral ventral striatum, with the left contrast maximum falling in the region of the nucleus accumbens (hypothalamic and thalamic decreases are also visible); right image: left dorsomedial frontal gyrus (Brodmann's area 9). In part B, within-group, by condition barplots at the statistical maxima of the bilateral ventral striatal findings in the positive between-group condition, revealed these findings to be due to a decrease in activation to positive stimuli in depressed subjects coupled with an increase in healthy comparison subjects.

Patterns of distributed brain ...

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