Sometimes it’s hard to know whether depression starts with a feeling or a set of thoughts. The fog can seem to roll in out of the blue, or it can follow something clearly difficult, such as a significant loss. For some people, it creeps in gradually; for others it feels sudden and unexplained.
What science is clear on is this: depression doesn’t have a single cause. And it isn’t simply a matter of low serotonin levels, despite how often that idea is repeated.
How the serotonin story took hold
The idea that depression was caused by a serotonin deficit gained traction alongside the introduction of SSRIs. Pharmaceutical marketing played a major role in popularising the concept of a “chemical imbalance,” often framed as too little of a happy hormone.
I remember the excitement well. As a medical journalist, I attended the press launches and scientific meetings. There was a genuine sense of progress, a clear biological explanation paired with an effective treatment, and of course, lots of money for the pharmaceutical companies!
The difficulty is that the biology turned out to be more complex.
Serotonin is involved in mood regulation, but depression is not reliably explained by measuring how much serotonin someone has. What appears more relevant is how serotonin signalling functions.
In depression, serotonin signalling can be inefficient. Messages may be short-lived or poorly registered by the receiving brain cell, meaning signals related to emotional balance, perspective, and flexibility do not land as strongly.
Antidepressants do not add serotonin to the brain. They reduce how quickly it is cleared away, allowing existing serotonin to remain active for longer and exert a stronger signalling effect.
Over time, this repeated signalling is associated with gradual changes in how the brain responds emotionally, which helps explain why improvement, when it occurs, tends to be slow rather than immediate.
This points to something important. For many people, depression is not about a missing substance, but about how the brain functions when key systems become dysregulated over time.
Genetics: vulnerability, not inevitability
Family and twin studies consistently show that depression has a heritable component. Identical twins are more likely to both experience depression than fraternal twins or siblings.
However, heritability does not mean inevitability. Genetic factors appear to influence vulnerability rather than determine outcome. Many people with a genetic predisposition never develop depression, while others do so in the absence of any clear family history. Genes shape how sensitive a person’s brain and stress systems are to life events, but they do not cause depression in isolation.
Inflammation as an important pathway
One of the most significant developments in recent years has been growing interest in the relationship between depression and inflammation.
Inflammation is a normal and necessary part of immune function. Problems arise when inflammatory activity becomes chronic. Persistent low-grade inflammation has been associated with changes in neurotransmitter function, reduced motivation and pleasure, disrupted sleep, and diminished emotional flexibility.
Importantly, not all depression is inflammatory in nature. Research suggests that a subset of people with depression show measurable inflammatory changes, while others do not. Inflammation is therefore best understood as an important pathway for some people, rather than a universal explanation.
Stress, trauma, and chronic illness
Many of the experiences most strongly associated with depression are also associated with increased inflammatory signalling.
Chronic psychological stress is one of the most consistent risk factors. This refers not to everyday pressures, but to sustained or overwhelming stress such as trauma, bereavement, financial insecurity, relationship breakdown, or long periods of feeling unsafe or unsupported. Prolonged stress can disrupt cortisol regulation, impair sleep, and increase inflammatory activity, all of which affect mood and emotional resilience.
Early-life adversity may increase vulnerability further. Childhood abuse or neglect has been associated with long-term changes in stress regulation and emotional processing. In some people, these experiences appear to bias the developing brain toward heightened threat detection and reduced emotional regulation. Over time, this may increase susceptibility to depression, particularly under later stress.
Chronic physical illness can act through similar mechanisms. Ongoing illness places the body under continuous physiological stress, often increases inflammatory activity, disrupts sleep and energy levels, and constrains daily life. For some people, this combination is associated with reduced motivation, diminished pleasure, and emotional withdrawal.
In these contexts, thoughts such as “I’m broken” or “I’m a burden” are understandable responses to difficult circumstances. While such thoughts can contribute to maintaining depression, they are not irrational or purely cognitive errors. They often reflect lived reality interacting with biological vulnerability.
Sleep and hormones
Sleep disturbance deserves particular attention. Longitudinal studies suggest that poor sleep is not only a symptom of depression but can increase the risk of its onset and recurrence. Fragmented sleep and early waking are associated with altered stress hormone regulation, increased inflammation, and heightened emotional reactivity.
Hormonal factors also play a role for some people. Thyroid dysfunction is present in a minority of individuals with depression and can contribute to low energy and mood changes. Reproductive hormonal transitions, including the postpartum period, phases of the menstrual cycle, and menopause, are associated with increased risk of depressive symptoms in some individuals. These changes interact with stress and inflammatory systems rather than acting in isolation.
Thinking patterns and state effects
Depression is associated with characteristic patterns of thinking, including increased self-criticism, pessimism, and rigid or absolute interpretations of experience. While temperament influences emotional style, most people are not born with these thinking patterns.
Evidence suggests that depressive cognition is shaped by experience and is strongly influenced by the biological state of depression itself. When the brain is under chronic stress, sleep-deprived, and physiologically dysregulated, negative thinking becomes more likely and more convincing. This helps explain why cognitive patterns often soften as mood improves.
A final word on cause and blame
People are not born with depression as an illness. What they may be born with is vulnerability, a nervous system that is more sensitive to stress or disruption. For most people, depression appears to develop through the interaction of vulnerability with life experience, biological adaptation, and environmental pressure.
Even the thoughts that feel most convincing during depression are not fixed traits. They are part of a state, and states can change.
Understanding depression in this way moves us away from blame, whether of biology, personality, or mindset. Depression is not a flaw or a failure. It is a complex human response shaped by vulnerability and experience. And because it develops over time, it can also change over time.
In the next article, I’ll talk about options to treat depression based on other underlying causes of the illness
