Speeding up new medicines for depression

Depression is very common - one in five people become depressed at some point in their lives. However, depression is perhaps too familiar and neutral a word to capture what clinical significant levels of depression are like. In his memoir, Darkness Visible, the writer William Styron commented that the word 'has slithered innocuously through the language like a slug, leaving little trace of its intrinsic malevolence and preventing, by its very insipidity, a general awareness of the horrible intensity of the disease when out of control'. For people who lose that control, admission to hospital and medical management can literally save their lives (as it did for Styron himself). One of the most important components of such management is antidepressant medicine.

How antidepressants work

The actions of antidepressants on brain chemistry have been the subject of intense laboratory study for many years. The idea that, for example, serotonin is critically involved in antidepressant action has entered popular culture. However, the complexity of the brain and our limited understanding of how emotion is represented within it always made a simple chemical model of depression itself unsatisfactory.

Game-changing research by Professor Catherine Harmer and Professor Guy Goodwin in the Department of Psychiatry has re-framed our understanding of how antidepressants work. This has provided new ways to rapidly, accurately and cost-effectively predict the likely success of new drugs by looking directly at their measurable effects in healthy volunteers. The breakthrough came from the reflection that cognitive behavioural therapies (CBT), which target the biases in the way depressed patients consciously think and cope with their symptoms, were as effective as antidepressant drugs. This led researchers to theorise that there might be a common mechanism to both treatments and that antidepressants might correct unconscious negative biases in an analogous way to how CBT is directed at the conscious equivalents. Their research resulted in three important findings:

• The bias towards negative self-assessment seen in depression could indeed be reversed by antidepressant drugs. 
• These behavioural changes were accompanied by changes in brain activity detected using functional brain imaging. 
• Changes in emotional bias produced by a single dose of antidepressant in depressed patients are the same as those observed in healthy people.

These results suggested that antidepressants work by altering people’s subconscious emotional processing and that this leads to an improvement in mood. The research also highlighted that it would be possible to predict the effectiveness of drugs after only a short time and that these experiments could be conducted in healthy volunteers. This led Catherine Harmer and Guy Goodwin to develop the Emotional Test Battery (ETB) to investigate these effects of antidepressants. Many subsequent studies have confirmed that these tests can detect subtle but reliable indicators of antidepressant drug action on emotional processing.

The Emotional Test Battery

The availability of the Emotional Test Battery (ETB) has played a major part in the success of P1Vital, a Clinical Research Organisation for experimental medicine, set up in 2004. Since then the ETB has accounted for ~60% of its work, worth over £9.5M to 2013. It was a landmark for psychiatry when the results of an experimental medicine study enabled a company to reach an early decision to go with the next phase development of an antidepressant likely to prove effective in the clinic. This not only speeded up development of a promising drug but also saved the company millions of pounds that could be used to develop other medicines.

ETB data can also be used to predict which drugs are likely to have a reduced side effect profile. This was confirmed in a 2006 study with Servier which correctly predicted that agomelatine (Valdoxan) caused less ‘emotional blunting’ that standard antidepressants. Emotional blunting is a side effect of many antidepressants that can adversely affect patient’s day to day lives. The results of this study have had a significant effect on patient benefit as prescribing can be focussed towards patients for whom this is a particular problem.

The value of the ETB has been widely recognised. It has been reported on BBC news and in other media. The Medical Research Council has highlighted the ETB as a particularly successful example of translational research in psychiatry, an area that has proved challenging in recent years.