While the exact cause of depression remains elusive, research suggests that, as with other mental disorders, it likely results from an interaction of several factors including genetics, environmental aspects, and brain biochemistry.

It is unlikely that people are born with a single gene that causes depression, but instead they may have a genetic makeup that predisposes them to developing depression, if other factors are also present. This is sometimes called the diathesis-stress model of mental disease and it explains why mental disorders tend to run in families but do not seem to be associated with any particular gene: for example, identical twins (who have all the same genes) commonly have one twin affected by depression but not the other. It is also common for depression to occur in people with no family history of the disease.

In addition, any trauma or severe stress, such as the loss of a loved one or experiencing a divorce, tends to make depression more likely to occur. These environmental factors may play a huge role in some cases of depression and a lesser role in others. After an initial episode of depression in some people subsequent episodes may occur without any precipitating event.

In addition to the genetic and environmental factors mentioned above, changes in brain biochemistry may be an important cause of depression. Research indicates that people who are depressed have different patterns of brain activation and show alterations in the levels of certain brain chemical messengers (neurotransmitters). It may be the case that people with an imbalance in their neurotransmitter levels due to genetics and/or environment are more likely to become depressed, or it may be that depression is caused by some other factor entirely and the changes in neurotransmitter levels are simply another consequence or by-product of the disorder.