Overview of Depression
Depression is a chronic, recurring, and potentially life-threatening illness that affects up to 20% of the population across the globe. It is one of the top ten causes of morbidity and mortality worldwide based on the World Health Organization. It is highly heritable, with roughly 40-50% of the risk for depression being genetic, although the specific genes that underlie this risk have not yet been identified. The remaining 50-60% of the non-genetic risk also remains poorly defined, with suggestions that early childhood trauma, emotional stress, physical illness, and even viral infections may be involved. Most experts agree that depression should be viewed as a syndrome, not a disease. Thus, the highly variable symptom compilation that is used to define depression (Box 1: Diagnosis of Depression), and the highly variable course of the illness and its response to various treatments, indicate that depression subsumes numerous disease states of distinct etiology and perhaps distinct pathophysiology. In fact, the lack of bona fide objective diagnostic tests for depression, beyond a compilation of symptoms, means that the diagnosis of the syndrome is quite variable, with no clear line distinguishing people who have mild clinical depression from those who are simply having a tough time in the course of normal life.
One key factor for this lack of objective diagnostic tests for depression is our still limited knowledge of the brain regions and neural circuits that are involved in the condition: if one could biopsy someone with depression, it is far from clear where one would obtain the biopsy. Moreover, given the heterogeneity of the illness, different regions might well be involved in different individuals. While the site of the pathology is unknown, there is growing knowledge of the brain regions that might mediate the diverse symptoms of depression. The hippocampus (located in the brain's temporal lobes) and frontal regions of cerebral cortex (in the very frontal poles of the brain) have received the most attention, particularly in animal studies of depression. These regions would be expected to be particularly associated with cognitive abnormalities that are seen in many patients with depression, such as memory impairments and feelings of worthlessness, hopelessness, guilt, doom, and suicidality. Also implicated is the amygdala (also located in the temporal lobes), best studied for its role in establishing associations between aversive or rewarding stimuli and their associated environmental cues. A role for the brain's reward pathways, for example, dopaminergic neurons in the VTA (ventral tegmental area) of the midbrain and their target regions in the front part of the brain, in particular, the NAc (nucleus accumbens), has been proposed based on the prevalence of anhedonia and decreased motivation and energy level in most individuals with depression. Similarly, abnormalities in appetite, sleep and circadian rhythms have suggested the involvement of the hypothalamus (located at the very based on the brain) as well. Human brain imaging studies and examination of postmortem brain tissue from people with depression support the contribution of these and several other brain regions to depression, but no clear consensus has yet evolved.
Figure 1 shows the location of these various regions in human brain, Figure 2 illustrates the many inter-connections among these regions, which highlight the important fact that these regions do not function in isolation of one another, but rather are part of highly integrated circuits. Figure 3 shows these regions in animation.