The most popular idea for what causes depression in the brain is some kind of chemical imbalance. Many pharmaceutical companies have claimed in their advertising that their antidepressant drugs work by correcting this imbalance. The notion has even been popular with some mental health campaigners, who have been keen to show that depression has a ‘real’ biological basis, rather than just being all in the mind.
However, while many antidepressants do affect the various levels of chemicals in the brain – especially the neurotransmitters serotonin, dopamine, noradrenaline and glutamate – most experts now agree that the idea depression is caused by a chemical imbalance is a gross oversimplification.
Especially as no one knows what the ‘correct’ levels should be. A landmark review of the literature published in 2023 even went so far as to conclude that there’s no “convincing evidence of a biochemical basis to depression”, although that review was controversial, with some commentators arguing that it went too far.
Many other aspects of brain function seem to be involved in a person’s vulnerability to depression and its onset. For instance, overactivation of the hypothalamic–pituitary–adrenal axis (HPA-axis) seems to play a role. This is a network of brain areas that’s involved in regulating the way your body and brain respond to stress.
People with depression often show an overactive HPA-axis (possibly caused by stressful early life experiences) and have elevated levels of the hormone cortisol. A disturbed HPA-axis could also interfere with levels of other brain chemicals relevant to depression, such as serotonin.
Also relevant are signs of immune system dysfunction in the brain. People with depression will often have raised levels of pro-inflammatory cytokines (small proteins produced by the immune system) in their body and brain, and neuroinflammation can be a risk factor for depression.
Again, there’s some evidence that stressful life experiences can trigger this immune system dysfunction, which could then contribute to the risk of developing depression.
As you can see, there’s no single cause of depression in the brain; rather, there’s a highly complex web of factors involved. One framework that might help make sense of what’s going on is the idea that depression is caused by a lack of neuroplasticity – chronic stress and traumatic experiences seem to force your brain to lose its adaptability and get stuck with a highly negative bias in your memories and thinking.
Some of the factors mentioned earlier, such as altered levels of brain chemicals, an overactive HPA-axis and neuroinflammation could contribute to this overly fixated state.
Meanwhile, various treatment approaches – such as antidepressants, brain stimulation, psychotherapy and physical exercise – could help increase neuroplasticity, by increasing the growth of new neurons and fostering greater communication between the areas of the brain that are involved in pleasure and reward.
This article is an answer to the question (asked by Chloe Reynolds, Bath 'What actually causes depression in the brain?'
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