fMRI investigation of the neural mechanisms of Emotional Cognitive Bias Modification as an adjunct therapy to SSRIs in depression.

Processing of emotional information is critical to social functioning but is disrupted in many psychiatric disorders, including Major Depressive Disorder (MDD). Negative processing biases are present in depression and predict relapse in remitted patients, suggesting that biases play a causal role in the onset and maintenance of depression. A recent large trial (STAR*D) indicates that pharmacotherapy is ineffective in one-third to a half of patients. Furthermore, mounting evidence suggests that antidepressant drugs (e.g., selective serotonin reuptake inhibitors, SSRIs) do not sufficiently improve the absence of positive affect in patients alone, and that they work best in combination with psychological therapies. While recent advances in psychological therapy for depression focus on promoting positive biases, there are still difficulties in treating anhedonia, which is associated with poorer outcomes. There is little work to determine what the minimum effective psychological intervention may be in addition to drug treatment, and a similar lack of studies examining mechanisms of action of such adjunct therapies. We will investigate whether a remotely delivered psychological intervention can provide sufficient opportunity for relearning about emotion to improve the therapeutic effectiveness of SSRI, as indexed by neural responses to emotional faces.

fMRI studies have provided good evidence that SSRIs reduce neural responses, particularly in the amygdala, to negative emotional faces. Both behavioural and neural changes in response to emotional stimuli are associated with later improvement in mood. Our brief, automated, Emotional Cognitive Bias Modification (CBM) technique leads to robust and generalizable changes in emotional expression perception, with fMRI results in adults with low mood demonstrating it also increases amygdala activity in response to expressions of happiness. Notably, it has less effect on responses to negative emotions, in contrast to SSRI-induced effects which primarily impact the processing of negative emotions. This suggests that the combination of CBM and SSRI treatment might be particularly effective.

We aim to investigate whether a psychological therapy that improves the way we see emotion in others could improve antidepressant drug efficacy. Specifically, we will deliver both CBM training and SSRI pharmacotherapy in patients with a new episode of depression, to investigate whether this enhances the reduced amygdala activity in response to negatively valenced emotions (that typically results from SSRI therapy) and increases amygdala activity in response to positive expressions (a key result from our earlier work that is rarely seen in SSRI studies). Mechanistically, we have clear predictions about how such effects will be instantiated in neural responses to emotional stimuli. Therapeutically, this combination of inetreventions has the potential to address depressive symptoms that are currently difficult to treat.

Depression constitutes a substantial burden of disease on society, with the DoH estimating economic costs £7.5 billion annually in the UK. Antidepressant drugs are effective, but up to 50% fail to respond to treatment and relapse rates are high. We have developed a Cognitive Bias Modification (CBM) therapy that modifies emotion perception, and targets similar neural processes to SSRIs. We will investigate whether paired psychological and antidepressant treatment have combinatory effects on neural mechanisms that are associated with, and predicted recovery from, low mood.
Depression is associated with increased amygdala responses to negative emotional stimuli, and decreased responses to positive emotion. SSRIs rapidly reduce responses to negative emotional stimuli in depressed patients, and these changes predict treatment outcomes. Furthermore, fMRI neurofeedback studies indicate that increasing amygdala activity to positive stimuli leads to mood improvements. Our Cognitive Bias Modification (CBM) intervention induces positive biases when viewing emotional expressions. Earlier fMRI results from adults with low mood demonstrate that our CBM technique increases amygdala activity in response to expressions of happiness but has little effect on responses to negative emotions.
Pharmacological antidepressant treatment is most effective when combined with other therapies, but there are few mechanistic studies of adjunctive treatments. Our rationale is that by combining a CBM technique with SSRI in patients, we may harness synergistic effects of both when SSRI induced neurogenesis is high, allowing relearning of responses to emotional stimuli. By modifying emotion perception directly through training and simultaneously through pharmacotherapy, our approach allows us to elucidate the mechanisms that are predictive of treatment success. We will investigate whether our emotional learning task may provide a context to increase the therapeutic effects of SSRI.

Mood disorders, dominated by major depression, constitute a substantial burden of disease. This indicates a pressing need for novel approaches to improve treatments for depression, and to prevent relapse following cessation of treatment. Our work will contribute to this search for new treatments, by providing a theoretically motivated combination of cognitive and pharmacological therapies, and it has scope for considerable impact.

Impact activities will proceed along three parallel strands: academic engagement, patient and public involvement, and scientific exploitation, including progression to further trials of efficacy and work with industry partners. Taken together, these activities have the potential to provide the academic community with an exciting and novel technique for exploring the causal role of emotion processing biases in psychopathology, engaging the public and service users with the developing evidence base so that they can contribute to intervention development, and providing a firm evidence base for the mechanisms of adjunct intervention in depression and, in principle, other psychopathologies.

Academic impact will be achieved through publications and presentations at scientific meetings, and will constitute the broader application of the techniques described here across a range of psychopathologies where biases and deficits in emotion recognition have been implicated. It provides a novel experimental tool for exploring the causal basis of these biases in a range of psychopathologies, and can in principle be adapted for therapeutic use. On the basis of our previous studies in this area, we have collaborated successfully with scientists from Europe, Israel and the United States to apply our training paradigm to other disorders, and we hope to widen our network in this field.

Patient and public involvement impact activities will be achieved through a service user focus group and public engagement activities, supported by our involvement in the NIHR Biomedical Research Centre in Bristol. All applicants are co-investigators in the Mental Health theme of this BRC. The view of the general public and service users will help the further development of our technique, and in particular contribute to future applications to other funding mechanisms, and to work with our commercial partner (Cambridge Cognition have licensed the underlying IP of this work).

Scientific exploitation impact activities will be achieved in the medium term through applications for subsequent funding through the NIHR EME mechanisms to provide evidence for the efficacy of our proposed adjunct therapy intervention. In the longer term, the growing interest in the field of digital therapeutics may provide a context to deliver this intervention on a large scale. Our intervention is innovative in that it can be delivered online, or on portable/wearable devices (tablets, smartphones and smartwatches) at very low cost and at low participant burden. Should this mechanistic trial and future efficacy trials prove successful, this work may have an impact on the successful treatment of depression. The presence of an industry partner with expertise in medical devices (Cambridge Cognition) will speed the translation of this intervention from the laboratory to patient benefit.