Somewhere there is a person asking a doctor, “why do I have depression? Nothing bad has happened to me.” And somewhere else there is a person who has been through a great deal of hardship and has never had a single depressed day.

The question that follows is why two people with apparently opposite lives should end up with psychological outcomes that run counter to what “ought” to happen. And the answer most people hear most often is that it comes down to brain chemistry.

How true is that explanation? And if it is true, what changed the chemistry in the first place?

Where the brain-chemistry explanation came from

The idea that depression is caused by a “chemical imbalance in the brain” — commonly rendered as “low serotonin” — has been extremely widespread over the past several decades. It began with the serotonin hypothesis in the 1960s and grew considerably more popular in the 1990s, alongside the rise of the SSRI class of antidepressants.

In 2022 a large systematic umbrella review led by a research team at University College London examined the evidence on the link between serotonin and depression comprehensively, and concluded that it found no consistent evidence sufficient to support depression being caused by low or dysfunctional serotonin levels. The paper was widely debated in medicine and widely reported in the media around the world.

That said, it needs to be put fairly and directly: the paper itself drew heavy criticism from other researchers. Thirty-six academics co-authored a rebuttal in the same journal, pointing out methodological limitations in the review and stating that the serotonin hypothesis was never proposed within psychiatry as the sole or complete explanation of depression in the first place — only as one of the mechanisms that may relate to the changes in the brain observed in depressed patients.

The significant point on which researchers on both sides agree is that the “chemical imbalance” account, simplified as far as it has been in media and public communication, is an explanation far simpler than the reality of a very complex condition.

Depression is multifactorial, not one cause

What psychiatry and psychology broadly agree on today is that depression is multifactorial — arising from a number of factors working together rather than any single cause. The model used to explain this academically is the biopsychosocial model, which holds that biological, psychological, and social factors all take part.

Put simply: if brain chemistry genuinely does change, the more important question is what changed it in the first place. And this is where the other factors take on their role.

What childhood experience contributes

One of the factors research has found most clearly linked to depression is childhood adversity — whether neglect, physical or emotional harm, or growing up in an unstable environment.

Neuroscience research has found that chronic stress in childhood is associated with changes in brain structure, particularly in the hippocampus and amygdala, the regions involved in memory and emotional processing. Stress during a period when the brain is still developing may affect how these systems function over the long term. The phenomenon is called stress sensitization, meaning that people with adverse childhood experience often carry greater sensitivity to stress later in life. An event another person might handle without difficulty may more readily trigger depressive symptoms in someone with that history.

This is part of the answer to why two people meeting similar circumstances in adulthood can respond in entirely different ways.

How personality relates

Research has found that certain personality characteristics are associated with greater risk of depression than others. Clear examples include perfectionism at excessive levels, low self-esteem, and excessive sensitivity in interpersonal relationships.

A study among male nursing students found that the combination of low self-esteem, a history of childhood adversity, perfectionism, and high perceived stress formed a significant pathway toward depression, with the self-esteem factor carrying the greatest weight in that model.

These personality characteristics do not arise from nowhere. They often relate to childhood experience and to the environment a person grew up in as well, which means the various factors under discussion here are all connected and influence one another rather than standing entirely apart.

How chronic stress changes the brain

Chronic stress in adulthood affects the brain in ways similar to stress in childhood, though the severity and the mechanisms involved may differ somewhat. Research has found chronic stress associated with continuous cortisol release, which over the long term relates to changes in neurons in the hippocampus and amygdala.

This explains why stress accumulated over a long period — from work, relationships, or life circumstances — can act as a trigger for depressive symptoms in some people, even without a single large or clearly identifiable event.

Is genetics involved?

This is another question people ask often, and the answer is yes, genuinely — though not in the way many people assume.

Twin studies have found that depression does have a genetic component, with heritability estimated at roughly 30–40%. This means genetic factors account for some of the difference between individuals, but do not determine the whole of it.

Large genome-wide studies in recent years have identified numerous gene loci linked to depression risk, but each locus has only a very small effect when considered on its own. Researchers describe this as a polygenic condition — arising from a great many genes working together rather than from one gene as a principal cause, as the simplified account would have it.

More important than the heritability figure is what researchers call gene-environment interaction. Genetics does not fix anyone’s fate. It sets a differing degree of sensitivity to environment from person to person. Someone with high genetic risk may never develop depressive symptoms at all if they grow up in a supportive and safe environment, while someone with lower genetic risk may develop symptoms if they meet stress or adversity severe enough.

Another way to put it: genetics is something like the baseline sensitivity of the nervous system a person is born with, while environment, childhood experience, personality, and the stress met in life determine whether that sensitivity is triggered into actual symptoms. This is why two people with the same family history of depression may have entirely different lives in this respect.

What neuroplasticity tells us

While the bad news is that stress can change brain structure adversely, the good news is that the brain has a property called neuroplasticity — the capacity to change and adapt throughout life.

That means the changes stress or adverse experience produce in the brain are not fixed and beyond repair. The brain can learn new patterns, form new neural connections, and gradually adjust the way it responds to stress and emotion — though it takes time and consistency.

This is hope with a genuine scientific basis beneath it, not simply reassurance with nothing behind it.

Where hypnotherapy can help

Since depression involves patterns of nervous-system response learned from accumulated experience — from childhood, from personality, and from chronic stress — there is a real place for work that engages those patterns at a subconscious level.

This needs saying plainly: hypnotherapy is not a direct treatment for depression, and it is not something that should be used in place of psychiatric care or medication prescribed by a doctor. What it may help with is working alongside patterns of thought, beliefs about oneself, and the circuitry of stress response held in the subconscious — one factor among the many involved in depression.

In addition, working with neuroplasticity through a process with direction to it may open the opportunity for the brain to learn new ways of responding to stress and to negative thought, in parallel with appropriate medical care.

At NBRH we think the question “is depression caused by chemistry or not” may not be the most useful one to ask. The more useful question is what the full set of factors is that leaves each person with a different level of risk — and how we can work with the factors that are changeable, such as patterns of thought and ways of responding to stress, in support of treatment already underway.

If you or someone close to you is facing symptoms you suspect may be depression, speaking with a psychiatrist or psychologist is the most important place to begin.

If you would like to understand how chronic stress affects the nervous system over time, “Stress Is Not the Enemy” fills in that part of the picture.

Is Depression Really Caused by Brain Chemistry — and What Changed the Chemistry in the First Place?