Translating gene-environment interaction from aetiology to personalised medicine for anxiety and depression.

Anxiety and depression are the most common of all mental illnesses affecting as many as one in five people at some point in their lives. They are also amongst the earliest to emerge, with the majority of adult cases of both disorders beginning in childhood or adolescence. Anxiety and depression are extremely costly for afflicted individuals and society as a whole resulting in reduced over-all educational level, increased usage of sick leave and benefits and increased risk of substance dependence and suicide.

Cognitive Behavioural Therapy (CBT) has been shown to be a safe, effective treatment for both depression and anxiety in children and adults. Nevertheless, at least two in five patients do not respond to CBT and may need to switch to a different treatment such as medication. Finding predictors of response is extremely important as it will allow doctors to pick the right treatment for the right person from the start, cutting costs and speeding up their recovery.

Recent research suggests that 'plasticity' genes might make some individuals more sensitive to their environment than others. These 'plasticity' genes may therefore be important predictors of response to CBT. Dr Robert Keers will test this proposition at the institute of Psychiatry in London and Emory University, Atlanta. Dr Keers will attempt to identify new plasticity genes using a novel twin based method and then test these genes as predictors of response to CBT in patients with anxiety and depression.

Aim: To investigate whether genes that moderate the effects of the environment on the development of depression and anxiety may also predict response to psychological treatment.

Objectives
1. Examine the extent to which genes moderate the effects of the environment on anxiety and depression.
2. Identify the genetic variants involved.
3. Test these variants as predictors of response to CBT.

Methods
Objective 1
Sample: 10,301 twin and sibling pairs.
Analyses: An established quantitative-genetic model to test for gene-environment interaction will be used to examine the extent to which genes moderate the effects of positive and negative environments on depression and anxiety.

Objective 2
Sample: 1,183 monozygotic twin pairs.
Analyses: A novel extension of the monozygotic twin differences design, which examines within-pair discordance as a function of genotype, will be used to identify genetic variants that moderate the effects of the environment on depression and anxiety.

Objective 3
Sample: 2,000 anxious children treated with CBT and 400 depressed adults treated with either CBT or medication.
Analyses: Genotypes detected in Objective 2 will be tested as predictors of change and remission of symptoms.

Scientific and medical opportunities: The results of this research may have far reaching implications for understanding the aetiology of depression and anxiety and their prevention and treatment. Variants suggestive of increased environmental sensitivity may enable targeted interventions for individuals at a high-risk of developing these disorders. These same genotypes may also be used to select the most effective treatment for a given patient. Given their prevalence, and their substantial social and economic costs, advancing the prevention and treatment of depression and anxiety would lead to improved mental health and well-being for a significant proportion of the population and ultimately benefit society as a whole.

Who will benefit?
The results from this program of research may have far reaching implications for improving the prevention and treatment of affective disorders. Given the prevalence of these disorders, these improvements will therefore have a profound impact on the mental health and well-being of a large proportion of the population. The social and economic cost of anxiety and depression means that ultimately society as a whole could benefit from this research.

How will they benefit?
This research will feed into three key areas aimed at reducing mental health problems in the population: Targeted intervention, personalised medicine and the development of novel treatments.

1) Targeted intervention: A growing body of research suggests that early intervention with cognitive behavioural prevention can limit the onset of emotional disorders in children. By identifying genetic variants suggestive of increased sensitivity to the environment or response to psychological treatments, the current research may allow for these prevention programmes to be targeted at those at a high-risk of anxiety or depression and those who will reap the most benefit from these preventative measures.

2) Personalised medicine: Cognitive Behavioural Therapy (CBT) is currently being rolled out in the UK as the first line treatment for depression and anxiety in adults and children as part of the Improving Access to Therapy (IAPT) initiative. However, at least two in five individuals do not respond to CBT and may require additional or alternative treatments. Genetic predictors of treatment response would allow for a personalised approach to CBT. This means that clinicians will be able to select the most effective treatment for a given patient prior right from the start, cutting costs and speeding up recovery times.

3) New treatments: Current treatment options for anxiety and depression are ineffective for a substantial proportion of sufferers. By identifying genetic factors involved in the aetiology of depression and anxiety, natural resilience to these disorders and response to treatment the current study may provide novel targets for pharmacological and non-pharmacological treatments.