The neurobiology of cognitive affective biases in depression and their role in antidepressant therapy

Depression is the most significant psychiatric illness affecting people in the UK. Costs to society were estimated at £8.6 billion in 2009 and the World Health Organisation predicts that depression will soon be the leading cause of years lived with a disability. Although drugs to treat depression were discovered in the 1950s, scientists have found it difficult to explain how they act in the brain to treat the symptoms of the disease and why it takes several weeks before the patient starts to feel better. Studying the brain and how it controls our behaviour, including our emotional behaviour, is complicated and psychiatric disorders represent one of the biggest challenges. Whilst studies in patients use questionnaires, interviews, brain imaging techniques and psychology, experiments in animals are important to unlock the specific parts of the brain and brain chemistry involved. Animal tests are also very important for the development of new treatments and are essential to establishing whether a drug is likely to be effective in a patient and therefore suitable for clinical trials. Because animals lack the ability to express emotional impairments in terms of the methods used to study these symptoms in patients, progress towards understanding the neurobiology of depressed mood and its treatment has been limited. Recent research has demonstrated the feasibility of measuring emotion-related behaviour in rats and this project will build on this using an assay developed in our laboratory, the affective bias test.

In this project we will use our task to investigate a novel hypothesis about the cause and treatment of depression. We will also investigate whether these changes in cognition are correlated with changes in motivation to engage in social and environmental interactions. Individuals with depression report persistent negative mood which is associated with a tendency to remember things in a negative way. Thus, a patient with depression will have the same experiences as a non-depressed patient but when asked to recall those experiences, they will remember more negative things than the non-depressed individual. This is thought to arise from negative cognitive processing which in turn affects motivation to re-engage in those activities and results in the progressive social and environmental withdrawal associated with depression. It is also now thought that antidepressant drugs act to modify psychological processes so these negative processing biases are reversed and the patient gradually learns new positively biased memories which increase motivation to re-engage in social and environmental interactions. This hypothesis may also help to explain why either drug treatment or cognitive behavioural therapies are effective in some patients with depression.

Using our animal experiments, we are able to test these ideas without the difficulties of controlling other factors encountered when studying patients with depression. We can also map the time course of change in emotional processing and behaviour and relate these to a possible mechanism of disease development and treatment reversal. We have also planned a series of experiments which will look at which part of the brain is most important in mediating these cognitive effects and whether targeting this region selectively can induce a rapid reversal of depressed symptoms. Together these experiments will provide new information about the role of cognitive mechanisms in the cause and treatment of depression.

Providing new improved treatments for depression is a priority health care issue. Current understanding of the cause of depression and the mechanisms of action of licensed antidepressant drugs is limited and a major hurdle to providing improved therapeutic interventions. A cognitive theory of depression was first set out in the 1960s by Aaron Beck however methods to test this hypothesis have been limited particularly in the case of non-clinical studies using animals. Data obtained from neuropsychological studies in human participants suggest that negative cognitive processing is a core feature of depressive illness and these deficits can be reversed by antidepressant-induced modification of emotional processing and its impact on new learning and subsequently behaviour. This work suggests that a cognitive neuropsychological theory may best explain the development of depressed mood and the delayed onset of antidepressant efficacy. In order to translate this hypothesis into improved treatments, greater understanding of the relationship between cognitive affective biases and behaviour is essential. In the last decade, major advances have been made in terms of methods to quantify cognitive affective behaviours in animals. Building on these advances, this project will use our affective bias test and novel behavioural tracking approach to investigate the neuropsychological hypothesis of antidepressant drug efficacy. We will also focus a series of neural studies on the infralimbic cortex and amygdala as homologous regions in man have been implicated in depressive illness and negative cognitive affective bias. These studies bring together ideas from human neuropsychological and brain imaging data and aim to generate evidence to support a neuropsychological explanation for the development of depressed mood and how antidepressant treatments interact with emotional processes to modify behaviour.

Impact Summary

There are a number of beneficiaries for whom this research could be helpful in the longer term:

1. Academia
2. Patients suffering from emotional disorders
3. Family and friends of such patients
4. The economy
5. The government and the National Health Service
6. Laboratory and farm animal welfare

1. International academia in the fields of preclinical and clinical emotion research. The major impact of the proposed work will be to influence the direction of research into depression and antidepressant drug efficacy. Unlocking the relationship between cause e.g stress and effect e.g. emotional and behavioural dysfunction, would be a major breakthrough. We have already made a major step forward by demonstrating cognitive affective behaviour quantified using this assay has both predicitive and translational validity(Stuart et al., 2013, Neuropsychopharmacology). The work outlined in this project aims to extend this work and develop a cognitive hypothesis of depression further, including linking the acute biases observed to date with more long term effects on behavior, and potentially a consequential link with neurotrophic changes.

2. Patients suffering from mood disorders. Mood-related disorders are widespread in western society and extend beyond psychiatric disorders such as depression. Depression is co-morbid with many other conditions including chronic pain, addiction and obesity. The main reason for the lack of adequate treatments is that the underlying neurobiology of these disorders is still unknown. This means that patients suffering from these conditions often do not achieve adequate control of their symptoms with major impacts on the patient's health, well-being and ability to contribute to society both economically and socially. It is also likely that there are sub-clinical effects of on health such as increasing vulnerability to infectious diseases, psychosomatic disturbances, addiction and obesity.

3. Family and friends of such patients. Mood disorders can be very disruptive for someone's social life often leading to divorce and social isolation affective their partners, children and friends. Thus, the social environment of the patient and their family would benefit greatly from a better understanding of these maladaptive behaviours develop and their relationship to symptoms such as anhedonia and reduced motivation.

4. The economy. Depression alone has huge cost implication for the UK economy. In a knowledge-based economy such as that of the UK, depression-related impacts on productivity are particularly detrimental. Depression is associated with cognitive impairments and deficits in executive function which can lead to problems with concentration and poor decision-making. Research has shown that emotional disorders lead to the loss of over 15 million work days per year and many billions of pounds in economic damages. A better understanding of the factors which influence cognitive and emotional changes associated with stress could lead to social strategies to reduce risk and improve treatment. The pharmaceutical industry would benefit as this research could spark new avenues in drug development and provide a translational model to use in their development.

5. The government and the National Health Service (NHS). It is logical that the social, economic and health problems of such patients are a great burden for the government and the NHS. Clearly, an improved treatment of these patients would alleviate this burden significantly.