Tue Feb 17

What causes depression? What we know, don’t know and suspect

Written by: Caroline Gurvich, Associate Professor and Clinical Neuropsychologist, Monash University

Depression is a complex and deeply personal experience. While almost everyone has periods of sadness, low mood or grief, depression is different. Major depressive disorder is persistent, interferes with day-to-day activities, and can affect work, life and relationships.

One in five people ^[1] will experience depression in their lifetime. Women are nearly twice ^[2] as likely as men to develop it – a disparity that emerges around puberty and persists into adulthood.

But what causes it? The short answer is: many different things.

While there are various theories, we know brain chemistry, genes, hormones, stress, lifestyle and personality can all play a role. How these interact can vary greatly from one person to another.

An imbalance of brain chemicals?

The traditional “monoamine hypothesis ^[3]” of depression was proposed more than half a century ago, in the 1950s. This theory suggests ^[4] the root cause of depression is a deficiency in certain brain chemicals (or neurotransmitters) called monoamines – serotonin, dopamine and norepinephrine.

Several antidepressants have been developed based on this. They primarily work by increasing levels of monoamines ^[5] such as serotonin.

However, it has become clear that the “chemical imbalance” explanation is an oversimplification.

Research ^[6] over the past few decades has not found consistent evidence that individuals with depression always have lower levels of serotonin, or any single neurotransmitter.

And while antidepressants can increase serotonin levels within hours, improvements in mood typically take days or weeks to emerge ^[7]. This delay suggests depression cannot be explained by neurotransmitter levels alone.

Current understanding recognises depression as a complex condition influenced by multiple interacting factors, including genetics, trauma, medications, diet, sleep patterns and social interactions.

Genetic factors can increase your risk

According to one 2021 review ^[8], around 30 to 50% of the risk someone will develop depression may be inherited.

No single “depression gene” has been found. But large studies have identified over 100 genetic risk markers on chromosomes.

The genetic risk of depression is also thought to be “polygenic ^[9]”. This means multiple genetic variants (each carrying a small effect) interact and collectively contribute to someone’s genetic risk.

One important and longstanding research question has been whether there is a genetic reason women are more likely than men to develop depression.

In 2025, a large study ^[10] revealed substantial overlap between men and women’s genetic risk. However, on average, women with depression tend to carry more of the genetic variants linked to depression.

This suggests that there may be a greater genetic risk for depression in women and perhaps a stronger environmental influence on depression risk in men.

Still, carrying a genetic risk does not mean someone will necessarily develop depression. The interplay between genetic and non-genetic factors is complex.

Hormones and biological sex

Hormones – the body’s chemical messengers – also play an important role in mood and wellbeing.

In women, estrogen and progesterone levels naturally fluctuate across different life stages, including the menstrual cycle, pregnancy, the period after childbirth and menopause.

Our 2025 review ^[11] found some women are more sensitive to these normal hormonal shifts, and more vulnerable to mood disturbances.

For instance, in the premenstrual phase of their cycle, around 8% of women experience a severe depression, with intense mood swings and irritability, called premenstrual dysphoric disorder ^[12].

Similarly, the dramatic hormonal changes during pregnancy and after childbirth (combined with sleep loss and stress) can contribute to postnatal depression.

Later in life, fluctuating and falling estrogen levels during the menopause transition years may also increase the risk of developing depressive symptoms or intensify existing ones.

Hormonal contraceptives – which contain synthetic forms of estrogen and progesterone – have also been linked to mood changes and depression symptoms. In fact, these are some of the most common reasons women stop taking them.

These effects appear to depend on the specific type and amount of progesterone ^[14] used in the formulation.

These findings show how hormones can act as biological triggers, and help explain why women are statistically more likely to experience depression at certain stages of life.

The effect of hormones on depression in men has predominantly focused on the protective role of testosterone, but findings remain inconclusive ^[15].

Stress is another important factor

Chronic or repeated stress can have lasting effects on both the brain and body ^[16].

When we experience stress, our bodies activate the hypothalamic–pituitary–adrenal (HPA) axis, also known as the “stress-response system”. This helps us cope by maintaining balance in our body – what scientists call physiological homeostasis.

But when stress is constant or overwhelming, this system can become dysregulated. Stressful or traumatic experiences in childhood – such as neglect, abuse or severe adversity – can also disrupt the stress-response system.

As a result, we overproduce the stress hormone cortisol. High or persistent cortisol levels can alter ^[17] the structure and functioning of key brain areas (the hippocampus and pre-frontal cortex) which are important for regulating mood and memory.

Cortisol can also trigger the release of inflammatory chemicals, which then cross into the brain or influence neural signals, leading to mood changes and depressive symptoms.

Importantly though, not everyone who experiences stressful life events becomes depressed.

Some people may be more vulnerable due to genetic factors, early life adversity or differences in brain chemistry. Others might cope with the same stress without developing depression or other conditions.

Does personality play a role?

Personality traits also influence how people respond to stress and may affect their risk ^[18] of developing depression.

People who tend to experience anxiety, sadness and self-doubt are more likely to develop depressive symptoms, especially after stressful events. In contrast, traits such as resilience, optimism, and emotional stability seem to protect against depression.

This suggests that personality plays an important role in shaping both vulnerability and resilience to depression.

Lifestyle choices can help lower your risk

These include not smoking, limiting alcohol use, eating a balanced diet, staying physically active, getting enough sleep, maintaining a healthy body weight and having social supports.

Research shows ^[19] these healthy habits and lifestyle factors can have a protective effect on mental health. They may even reduce the impact of genetic risk factors for depression.

There’s no single cause – and no universal treatment

Depression arises from a mix of factors – biological (genes and hormones), psychological (personality and thoughts) and social (stress and life events).

Treatment options are based on all of these factors, as well as considering how severe the depression is and whether a person has responded to previous treatments.

While science has made some progress in understanding depression, what underpins each person’s experience is unique.