How do people become depressed? An interview with Anna Watters and Professor Lea Williams, University of Sydney

Lea Williams Anna Watters ARTICLE IMAGE

What are the main symptoms of depression and please can you outline how the illness is defined?

A clinical diagnosis of depression (i.e. major depressive disorder) is currently defined on the basis of reported symptoms.

Major depressive disorder is a type of mood disorder and involves a persistent decrease in mood or inability to experience pleasure in things accompanied by a range of disturbances including in sleep, appetite, libido, psychomotor speed, motivation, concentration and suicidal ideation.

There is considerable variation in the accompanied symptoms experienced between individuals and many people experience symptoms of depression without reaching threshold for diagnosis.

What is currently known about how people become depressed?

Many factors have been identified as contributing to the increased likelihood of a person experiencing depression. It’s widely accepted that depression comes about through having a biological vulnerability and through experiencing stressful life events.

The environmental, demographic, social and to a large extent the psychological factors have been defined, however we know very little about an individual’s biologically based vulnerability, and the biological mechanisms by which stress effects the individual to bring about depression.

Is it true that first degree relatives of people with depression have an increased chance of becoming depressed themselves?

It’s been shown using large numbers of people that the prevalence of depression is higher in the relatives (usually tested in first-degree relatives) of people with depression is around three times higher than among relatives of people who have not had depression.

However, the finding of familial aggregation of depression by itself doesn’t tell us whether depression is conferred through shared environmental or genetic factors.

Do you think this relationship is a result of shared environmental factors, genetic factors or both?

We know from twin studies that both genetics and environment play a role in the onset of depression.

Twin study designs are able to distinguish between genetic and shared environmental effects. This is done by comparing the prevalence of a characteristic between monozygotic and dizygotic twins, so the shared (family) environment is the same for both kinds of twins, but the genetic influence is stronger in monozygotic twins (who share 100% of their genetic code). If the monozygotic twins are more similar to each other for the characteristic e.g. depression, than the dizygotic twins, it shows that genetic influences are important.

A meta-analysis found that the largest contribution for depression comes from the individual’s environmental experience (63%), followed by a moderate genetic influence (37%). The contribution of the shared family environment to familial aggregation was minimal.

Our research project is based on this assumption, that relatives of people with depression have a greater genetically based predisposition for vulnerability for depression. The genetic basis is likely to be complex to identify, as in most mental illnesses, and so research in depression is focusing on identifying intermediary ‘markers’ that are downstream from genes and relate more closely to the mechanisms underlying symptoms of the illness.

How can you separate the causes of depression from its effects?

Investigating the causes of depression in individuals with depression meets the problem of not being able to disentangle what was the state before the depression and what is part of having depression itself.

Observing healthy individuals over time is another method, however this uses a lot of resources.

Another way to identify biological factors that relate to vulnerability of depression is to look at individuals who haven’t experienced depression before, but who we know have an increased biological vulnerability for depression. Such individuals are the relatives of people who have experienced depression.

The way that healthy relatives differ from non-relatives and are more similar to individuals with depression can help to identify what is part of the vulnerability for depression before the onset of depression itself. This is a new methodology to be used in research in depression.

Please can you outline the research that has been running at the University of Sydney since 2009? How close are you to producing results?

The research is being carried out at the Brain Dynamics Centre, which is a research centre of the Westmead Millennium Institute and the University of Sydney Medical School, at Westmead.

We have been conducting a large study of unaffected, adult relatives of people with depression with the aim to identify objective, biologically based markers of vulnerability for depression. We have 200 relatives of people with depression who have become involved in the study from Sydney and inter-state Australia.

Our study is integrating a range of contributing factors including genetics, brain, behaviour, personality and experienced symptoms, as well as the impact of life events, in the same individuals.

This is the largest family study in adult relatives that has been conducted worldwide in terms of the number of people involved and the scope of assessments. We are also following up participants one year later to see how these factors predict conversion to clinical depression and functioning over time.

We are currently analysing the data for write up and publication. We have found that even though relatives are free of a diagnosis of depression, they tend to have slightly higher experienced symptoms of depression, anxiety and stress, and lower reported quality of life compared to individuals without a family history of depression.

This was not dependent on also having the risk factor of early life stress. We have also identified differences in emotional brain circuitry which suggest that relatives have a trait-like bias for their brain to be reactive to negative emotion. This bias may be coupled with effects on attention and memory, involving the frontal regions of the brain.

This study was supported by the Australian Research Council (DP077394).

What impact would the understanding of what makes people vulnerable to depression have?

Major depression is among the most common illnesses worldwide and is classified by the World Health Organisation in the most severe band of illness according to disability incurred.

Depression is associated with unemployment, days off work, and poorer productivity at work, to a greater degree than most chronic medical conditions. Up to 30% more people suffer from subclinical symptoms of depression.

Knowing how depression develops means that we can then find ways to prevent it. Currently there are no agreed upon markers that help tell us which people are most at risk for depression and its disabling effects.

Identifying early risk and then tailoring intervention and prevention strategies is necessary for improving people’s lives, and reducing the cost of depression in terms of life days lost to disability and lost work due to sick days and poorer productivity.

Do you think it will be possible to develop early interventions to prevent people from becoming depressed?

Currently there are cognitive therapy based interventions for depression that have decreased the rates of depression in relatives. Research like ours will help to identify what it is about individuals that make them vulnerable.

Interventions that target aspects of the individual can build resilience so that when life events occur, the individuals will have some tools or have built up a resilience that will decreased the likelihood of persistent changes in mood.

Through understanding the mechanisms involved in risk and the conversion to a depressive illness, we can determine which of the available preventative strategies are most effective, and ultimately develop new ones.

What are the next stages for your research?

Once we have identified markers associated with vulnerability, we would like to see how they interact together to define a broad profile of vulnerability and develop a risk index.

For example, we would look at how specific genes may relate to brain differences and stress response in relatives, and whether these are moderated by stressful life events. Such a risk index will be very helpful in objectively identifying those at most risk.

Where can readers find more information?

Please visit the Brain Dynamics Centre website for more information about out research group and the Family of Depression study:

A good reference book on risk factors in the development of depression is Dobson and Dozois’ “Risk Factor in Depression” (2008).

About Anna Watters and Professor Lea Williams

Lea Williams Anna Watters BIG IMAGEMs. Anna Watters completed her Bachelor of Psychology (Hons) at the University of New South Wales, Australia. Anna has completed her training as a psychologist with experience in depression, insomnia and neurofeedback. She coordinates the study on Identifying Risk Markers of Depression at the Brain Dynamics Centre, University of Sydney under Prof Lea Williams and is completing her PhD on the study with a focus on emotion.

Prof Lea Williams is a Professor of Psychiatry and Behavioural Sciences at Stanford University. Prior to this, Prof Williams was the Director of the Brain Dynamics Centre (2001 to 2013) and founding Professor in Cognitive Neuropsychiatry at the University of Sydney, Australia, where she continues to hold an active, honorary position. Her PhD was awarded in 1996, and it was completed with a British Council scholarship for study at Oxford University. The research of Prof Williams can be described as "applied personalized neursocience", the goal of which is to identify biomarkers of mental illnesses and of treatment outcomes that have value for patients and clinicians in real world practice. Her research work has been supported by over $11mil in competitive funding and she has contributed over 220 publications. Her work has been recognised by the Presidential award of the American Society for Psychosomatic Medicine in 2008 and the Pfizer Australia Fellowship for 2005-10.

April Cashin-Garbutt

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April Cashin-Garbutt

April graduated with a first-class honours degree in Natural Sciences from Pembroke College, University of Cambridge. During her time as Editor-in-Chief, News-Medical (2012-2017), she kickstarted the content production process and helped to grow the website readership to over 60 million visitors per year. Through interviewing global thought leaders in medicine and life sciences, including Nobel laureates, April developed a passion for neuroscience and now works at the Sainsbury Wellcome Centre for Neural Circuits and Behaviour, located within UCL.


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