Brain researchers are overturning decades of dogma. Forget simple causal chains from genes to brain to behavior. Instead, argues award-winning neuroscientist Nicole Rust, the brain is a dynamic complex system—like the weather or a megacity—whose parts interact via feedback loops that are impossible to study in isolation from each other. And the revolution isn’t just theoretical: a bold cohort of experimentalists is uncovering mental health treatments that go beyond traditional drugs like SSRIs—such as psychedelic therapy, which may be able to rewire brains trapped in destructive loops.

A remarkable 20% of adults will suffer from a mood disorder such as depression. For those who try antidepressant medication, it will not work for half. We still don’t understand what's happening in the brain of someone who is experiencing a depressive episode, or even how antidepressants work—when they do. We don't even understand how our brains drive our everyday moods.

Why not? After all, neuroscience has been making discoveries about the brain at a rapid clip for decades. Why then haven't we made more progress toward understanding and treating depression? As described by one report from the Wellcome Trust, the persistent gap between new discoveries about the brain and new treatments for depression is a “troubling disconnection.” That disconnect is what inspired me to sit down and figure out what has been going wrong, reflected in my new book, Elusive Cures.

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For some disorders, like Alzheimer’s, it’s clear that the brain is what researchers should focus on to understand what causes the disease and how to treat it. In comparison, it’s less clear what to focus on for depression. Depression can be caused by experience, such as poverty, trauma or the death of a loved one. It can also follow from mental interpretations and mental simulations, such as the repetitive thinking, or rumination, about a problem that does not lead to a solution. Finally, depression can follow from the biology of the brain, as reflected by families with a genetically inherited predisposition for it. All these different types of causes must be linked in some way, but how exactly?

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Mood is part of a system teeming with feedback loops where causes (like our brains) lead to effects (like our moods, motivations and decisions) that feed back again as causes (to shape how our brains are wired up).

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Decades of brain research have envisioned these causes linked as a long chain. That chain begins with our genes, which are expressed to form brain cells. Those cells, in turn, shape brain circuits, and the activity in those circuits gives rise to all the things our brains do, such as seeing, remembering, and feeling emotions and moods. In this picture, our mental interpretations and experiences—such as trauma—determine the genes that are expressed, and this, in turn, shapes how the circuits in our brain are wired up—which is what we call learning.

When researchers who are looking to understand the causes of dysfunction envision the brain in this way, they aim to pinpoint the broken link in the chain so they can repair it. In the case of depression, the idea is that a broken link in the chain can be repaired with a treatment such as a pharmaceutical drug, brain stimulation, or behavioral therapy.