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Depression is a highly prevalent and disabling mental illness characterized primarily by abnormalities of mood, cognition and behavior. Individuals with major depression frequently experience anhedonia, depressed mood, negative self-referential thinking, impaired concentration, suicidal ideation, abnormal psychomotor activity, and variable changes in appetite and sleep. Major depression is among the most studied idiopathic psychiatric conditions, with an increasingly well-understood neurobiology. These insights are a pre-requisite to the development of more targeted therapeutic strategies, and can be helpful in understanding this disorder in the context of medical illness.

In this chapter, an overview of the neurocircuits frequently implicated in mood disorders is first detailed to allow for a systems-level conceptualization of brain-behavior relationships in depression.1 This is followed by a discussion of in vivo human structural, neurochemical and functional neuroimaging findings and postmortem brain abnormalities in depressed subjects. Neuroendocrine, inflammatory, neurotransmitter, cellular–molecular and genetic–epigenetic disturbances associated with depression are also summarized to provide a comprehensive multi-level understanding of this illness. The frequently encountered clinical and neurobiological intersection of depression and anxiety is discussed in Box 2-1. It should also be noted that the neural circuits discussed in this chapter are the same distributed brain regions frequently implicated in mood related symptoms as a consequence of medical and neurological conditions discussed elsewhere in this book. Throughout the chapter, the term “depression” will be used synonymously with major depressive disorder, unless otherwise specified, though it is relevant to highlight that a dimensional, symptom-oriented approach is increasingly being taken across traditional diagnostic boundaries.


Depression is frequently comorbid with anxiety which includes generalized anxiety disorder, social phobia, posttraumatic stress disorder, and panic disorder among other disorders.185,186 From a dimensional perspective, this overlap may be referred to as an anxious depression. High trait anxiety and neuroticism have been shown to be risk factors for the development of depression,187 and depressed individuals show enhanced fear learning.188 From a systems-level perspective, neuroimaging research studies have started investigating brain–behavior relationships in individuals with anxious depression compared to nonanxious depressed individuals. For example, during an emotional conflict identification task that involved categorizing emotionally valenced faces while ignoring overlaid emotional words, depressed patients with and without comorbid generalized anxiety disorder similarly demonstrated impaired ventral anterior cingulate and amygdala activations and connectivity on functional magnetic resonance imaging (fMRI); depressed only individuals, however, showed additional recruitment of lateral prefrontal regions that positively associated with task performance.189 Resting-state functional connectivity analyses in a cohort of individuals with late-life anxious depression compared to nonanxious depressed subjects showed increased coupling of posterior Default Mode Network (DMN) regions and decreased coupling of anterior DMN in anxious depressed subjects.190 Structural analyses in a large group of patients with nonanxious depression, mixed anxiety disorders, and anxious depression demonstrated similar rostral anterior cingulate cortex gray matter volume reductions across all patient groups compared to healthy subjects.191 Electrophysiology studies ...

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