What Goes On in the Brain of a Person with Depression

This post was written by Gary Gilmour, DPhil

According to the World Health Organization, depression is the leading cause of disability around the world, afflicting 322 million individuals. That number equates to 4.4% of the world’s population. Fatigue, disinterest, and an inability to experience pleasure in normal activities can result in those with depression becoming isolated. In some, feelings of self-worthlessness can lead to suicidal ideation. Globally, one person dies from suicide every 40 seconds; 20 more people attempt suicide within the same time frame.

The statistics are sobering, and the prevalence of mental health disorders is increasing at an alarming rate. Most of us will not escape the clutches of depression, either by experiencing it ourselves or finding one of our family members, friends, or colleagues affected at some point in their lives. Symptoms are wide-ranging and each person has a different experience. And so, it is vitally important to recognise that someone living with depression will almost certainly present differently from the next person.

In recent years it has become clear that despite their individual symptoms, people with depression may indeed share common changes in patterns of brain activity. Advances in neuroscience and imaging techniques have furthered understanding of what goes on in the brain of someone suffering with depression, in terms of both structural and functional changes.

Depressive behaviours could serve as protective functions

A common starting point for researchers is to compare those with depression with those from a non-depressed group. Studies have revealed that some symptoms of depression, such as ruminative behaviours, are in fact entirely natural and, if time-limited, may actually serve a protective function during periods of stress or trauma. Many aspects of brain function in depression may not be qualitatively distinct from those of a person without the disorder.

Understanding how depressive behaviours such as feelings of hopelessness and low self-esteem become persistent and intense for some people but not for others could offer a rich seam of knowledge. It no longer seems likely that analysis of single, simple aspects of brain function will provide all the answers.

For instance, the serotonin hypothesis of depression has not always been substantiated, and pharmacological elevation of serotonin levels does not guarantee relief from depression. While structural alterations have been proposed across several brain regions, such as the hippocampus and prefrontal cortex, results are often inconsistent, and it can be difficult to disentangle cause from consequence.

One common denominator mechanism?

Advances in imaging technology implicate activity of the default mode network—a series of functionally connected regions thought to help build our sense of self and how we fit in the world—in the excessive ruminative behaviours often present in people with depression. The studies suggest one common denominator mechanism that may be responsible for a range of depressive symptoms.

As well as their self-outlook becoming more leaden and pessimistic, people with depression may also see the world through a biased lens. Many studies now show that people with depression display greater levels of attention to more negative aspects of their environment, for example finding it harder to recognise positive emotion in a person’s face. These changes in behaviour are likely underpinned by complicated changes in the ways different brain networks, including the default mode network, interact with each other.

Depression-related changes across different levels of brain function have the potential to interact with and reinforce one another. So, dwelling on the negative aspects of themselves and/or their environment may exacerbate unwillingness to participate in activity. An increasingly inactive lifestyle can raise levels of pro-inflammatory cytokines—chemicals in the blood associated with inflammation—which can further intensify cognitive disturbance, fatigue, and lethargy. The potential for a vicious circle of symptoms is born.

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Breaking the cycle

“Breaking the cycle” may be an apt analogy when it comes to the treatment of depression. Many effective treatments, be they drugs, electrical stimulation or behavioural therapies, help people with depression see themselves in a new light and re-engage more constructively with their environment. The biological underpinnings of these effects may literally involve regrowth of neurons in the brain. So perhaps it is not the elevation in serotonin levels by SSRIs that is behind any effectiveness but their ability to cause regrowth and rewiring in the brain.

In recent years, the most exciting developments in the field of neuroscience have related to the discovery of novel antidepressant agents that work much more rapidly than standard agents. The first compound to be approved in this area was the NMDA receptor antagonist esketamine, which can often offer immediate symptom relief, even in people who have not been helped by other forms of treatment.

Increased interest in serotonergic psychedelics

A great deal of interest is also now being placed on serotonergic psychedelics, a class of drugs that can induce transient (several hours, in the case of psilocybin) but profound altered states of consciousness. These effects are most probably principally driven by interaction with a subtype of serotonin receptor known as the 5HT2A receptor.

Classical psychedelics include agents such as psilocybin, LSD, and DMT, which are currently being tested for mental health conditions. Psychedelic agents engage with the serotonin system in a manner quite different from that of traditional SSRI agents. Research indicates that psychedelic agents temporarily disrupt established functional connections in the brain, particularly in the default mode network, making the brain temporarily more entropic or “disordered”. There is speculation that this is akin to a psychological “reset,” and it offers hope that people with depression may be able to see themselves from a new perspective as functional connections begin to re-establish.

The more we understand the symptoms of a person with depression, and how the brain functions in individuals, the better tailored and more effective new therapies will be. Ultimately, we need treatments that offer mental well-being and the opportunity to lead a full and meaningful life to all those suffering with depression.

Source: Source: Gary Gilmour DPhil, used with permission

Gary Gilmour is Vice-President of Preclinical Research at COMPASS Pathways. Gary studied Pharmacology at the University of Glasgow before completing a DPhil in Neuroscience at the University of Oxford. He has built his career in the pharmaceutical industry and has led novel target and discovery projects across a broad range of CNS indications. His approaches to drug discovery place high emphasis on translational validation and establishing a deeper understanding of the biological substrates underlying different disease-related symptoms.