As with dropsy, what we call major depression will someday probably be subdivided into myriad more homogeneous and limited biological disorders that link to specific genes, either directly through patterns in the genome or through epigenetic changes in gene expression. Thus, someday under the umbrella of depressive conditions we may have diseases like “hypo–BDNF disease” or “TNF–alpha–itis,” or “stress–sensitive gliopathy disorder.”
Or maybe not. Maybe depression will always remain a complex emergent phenomenon that requires multiple interacting alterations in genes linked to each other in thousands of different ways, all of which contribute a measurable, but incomplete, amount to the risk of developing depression or one of its closely related affective spectrum disorder syndromes.
Whichever of these musings proves true, it is patently clear that the syndrome we currently call major depression will never be unambiguously or completely related to underlying genetic or epigenetic abnormalities. Hence, as researchers are increasingly realizing, the quest to find a gene (or even genes) for major depression is a little like Don Quixote’s quest for windmills. A similar fate almost certainly awaits all attempts to find biomarkers that will prove a person is depressed. Rather, what we are discovering is that certain genes predispose to certain functional and structural patterns in the brain (and probably the body) that promote the manifestation of mood disorder symptoms in certain environmental contexts,16 especially situations of environmental challenge17 (typically adversity, but also opportunity18).
We close this installment by referring our readers to the Figure, which attempts to portray these ideas visually. Although current DSM diagnoses arose in large part from early attempts to create a standardized language to aid psychiatric research, many of us have come to view them as actual disease entities that are related to specific underlying genetically specified mechanisms that we just haven’t identified yet. This view is portrayed on the left side of the Figure, in which primary genetic abnormalities are directly linked to currently articulated psychiatric conditions. In this view, the neurobiology of depression would be expected to mirror both its genetic determinants and its symptomatic manifestations in simple and straightforward ways. Hence, research tends to focus on finding genes that produce clearly demarcated abnormalities that manifest as specific symptoms. Conversely, much research is given over to devising more and more specific symptom–based disease states that might (with luck!) tie more closely to underlying genetic abnormalities.
On the other hand, we would suggest that the diagram on the right of the Figure more accurately reflects recent findings from mind–body neurobiology. In this view, multiple genes contribute in complicated ways to larger, functionally interconnected brain–body systems, with the result that a wide variety of genetic “abnormalities” can have fairly similar physiological effects on this larger circuitry5,15 (or opposite effects when genetic abnormalities cancel each other out19).
In the case of major depression and related conditions, significant evidence implicates genes involved in pathways that evolved to recognize environmental dangers and opportunities and successfully adapt to them, especially predators and pathogens.1 Not surprisingly, these pathways tend to become dysregulated in fairly stereotypical ways in genetically vulnerable individuals exposed to environmental adversity (including overwhelming opportunity—think of young rock stars!). These patterns of disruption have as one of their primary outputs the production of a range of symptoms. Symptoms are markers of these disruption patterns, but these patterns produce symptom clusters only probabilistically, with the actual symptoms experienced by individual patients probably reflecting genetic and environmental vulnerabilities specific to the individual.
In reifying our diagnostic categories, in studying and treating them like discrete diseases, we may be guilty of what Daniel Dennett has called “greedy reductionism.”20 We’ve missed an intermediate level of explanation that is essential to understand these conditions and which we know an increasing amount about. This intermediate level reflects the contribution of genes and environment to extended patterns of brain–body dysregulation that, while stereotyped, are not 100% consistent between individuals or even within the same individual over time. These patterns contribute to major depression certainly, but they also promote all other symptom states characterized by misery, ennui, exhaustion, anxiety, pain, and impaired sleep and cognition.12,21,23 (On the other hand, in gifted individuals they may also promote great art or the grit to assume positions of tremendous leadership.24,25)
