Researchers studied the genetic signatures of depression in more than 14,000 people

The core experiences of depression—changes in energy, activity, thinking, and mood—have been described for more than 10,000 years. The word "depression" has been in use for about 350 years.

Given such a long history, it may be surprising that experts still don't agree on what depression is, how to define it, or what causes it.

Many experts agree that depression is not a single phenomenon. It is a large group of diseases with different causes and mechanisms. This makes it difficult to choose the best treatment for each person.

Reactive and endogenous depression

One approach is to look for subtypes of depression and see if they respond to different treatments. One example is the distinction between "reactive" and "endogenous" depression.

Reactive depression (also referred to as social or psychological depression) occurs in response to stressful life events, such as an assault or the loss of a loved one—it is an understandable response to an external trigger.

Endogenous depression (also referred to as biological or genetic depression) is thought to be caused by internal factors such as genes or brain chemistry.

Many mental health professionals accept this distinction.

However, we believe that this approach is too simplistic.

While stressful life events and genes may individually contribute to the development of depression, they also interact to increase the risk of its occurrence. There is evidence that there is a genetic component to susceptibility to stress. Some genes influence aspects such as personality, others influence how we interact with the environment.

Our research and its results

Our team decided to investigate the role of genes and stressors to test whether classifying depression as reactive or endogenous really makes sense.

In the Australian Genetic Study of Depression, published in the journal Molecular Psychiatry, people with depression completed questionnaires about stressful life events. We analysed DNA from their saliva samples to calculate their genetic risk of developing mental disorders.

Our question was simple: Does genetic risk for depression, bipolar disorder, schizophrenia, ADHD, anxiety, and neuroticism (a personality trait) influence levels of exposure to stressful life events?

You may wonder why we need to calculate the genetic risk of mental disorders in people who already have depression. Everyone has genetic variants associated with mental disorders. Some people have more than others. Even people with depression may have a low genetic risk of developing it. These people may have developed depression for other reasons.

We looked at genetic risk for conditions other than depression for several reasons. First, the genetic variants associated with depression overlap with variants associated with other mental disorders. Second, two people with depression may have very different genetic variants. So we decided to look at a broad range of genetic variants.

If the subtypes of reactive and endogenous depression make sense, we would expect that people with a low genetic component of depression (the reactive group) would report more stressful events. Conversely, people with a high genetic component (the endogenous group) would report fewer stressful events.

But after studying more than 14,000 people with depression, we found the opposite.

We found that people with a higher genetic risk of depression, anxiety, ADHD or schizophrenia report more stressors.

Assaults with weapons, sexual abuse, accidents, legal and financial problems, and childhood abuse and neglect were more common in people with a high genetic risk for depression, anxiety, ADHD, or schizophrenia.

These associations were not strongly influenced by age, gender, or family relationships. We did not control for other factors that might influence these associations, such as socioeconomic status. We also relied on people’s memory of the past, which may be inaccurate.

How do genes play their role?

Genetic risk for mental disorders alters people's sensitivity to the environment.

Imagine two people, one with a high genetic risk for depression, the other with a low one. Both lose their jobs. The genetically vulnerable person experiences the loss of their job as a threat to their self-esteem and social status. It is a feeling of shame and despair. They cannot bring themselves to look for another job for fear of losing it. For the other, the loss of their job is less about them and more about the company. The two people internalize the event differently and remember it differently.

Genetic risk for mental disorders may also make it more likely that people will end up in environments where bad things happen. For example, a higher genetic risk for depression may affect self-esteem, making people more likely to enter into dysfunctional relationships that then go badly.

What does our research mean for depression? First, it confirms that genes and environment are not independent. Genes influence the environment we find ourselves in and what happens next. Genes also influence how we respond to these events.

Second, our study does not support the distinction between reactive and endogenous depression. Genes and environment interact in a complex way. Most cases of depression are a mixture of genetics, biology, and stressors.

Third, people with depression who appear to have a stronger genetic component to depression report that their lives are marked by more serious stressors.

Thus, clinically, people with higher genetic vulnerability may benefit from learning specific stress management techniques. This may help some people reduce their likelihood of developing depression in the first place. It may also help some people with depression reduce their chronic exposure to stressors.