FenDep: Using fenfluramine to test the serotonin deficiency theory of depression

Depression is the most prevalent and costly of all mental health disorders affecting up to 1 in 6 people in their lifetime and often results in suicide. Despite decades of research it has not proved possible to pinpoint a specific cause of depression in the brain of any particular patient. Doing this could be a major breakthrough that would help direct research towards new interventions as well as the selection of the best type of treatment for a particular person. The lack of a personalised biology of depression has led some to criticise the very idea of depression as a psychological disorder and even to claim that treatments such as antidepressants should not be used. The best-known hypothesis for the biology of depression is the serotonin deficiency theory - serotonin being one of the key messenger molecules in the brain. This argues that some cases of depression are caused by a relative deficit in serotonin function in part(s) of the brain that regulate mood. Apart from some early post-mortem studies that revealed lower levels of serotonin in the brains of patients with depression all the evidence to support this theory has been indirect, e.g. from the efficacy of antidepressant medicines that enhance serotonin, the fact that depleting serotonin leads to depression relapse and that deficits in serotonin production increase vulnerability to depression. Until recently it has not been possible to directly measure serotonin release in living human brain. We have worked for several decades to achieve this goal and recently published our methodology which uses a newly invented radioactively-labelled tracer molecule for a serotonin receptor subtype together with administration of d-amphetamine as a serotonin releasing agent. The brain distribution of the tracer before and after presence of the d-amphetamine can then be measured using PET - a highly specific molecular brain scanning technique. This approach gives a measure of serotonin release provoked by d-amphetamine for each person that we call the serotonin release capacity. Then with MRC funding we used this technique in depressed people and found that on average their serotonin release capacity was reduced. This provided the first direct evidence of a serotonin deficiency in the brain that could explain depression and why antidepressants that enhance serotonin such as the SSRIs (serotonin selective re-uptake inhibitors) work. The current grant is designed to provide independent replication of these findings using the specific and selective serotonin-releasing agent dl-fenfluramine that has just become available for human use. This will avoid the possibility that our previous finding with d-amphetamine could be due to the fact it also releases dopamine and noradrenaline, two other important neurotransmitters that may also be deficient in depression. A further benefit of the current study is that the group of depressed patients in which we measure serotonin release capacity will then be started on SSRI treatment after their PET scans. This will allow us to test if their improvement / lack of improvement to this serotonin promoting antidepressant treatment is predicted by their release capacity - with the hypothesis that those with lower release capacity will do better on the SSRI. If we succeed then it may prove possible to develop imaging methods to determine which patients would best be treated with SSRIs and which may require other treatment approaches.