text: How Antidepressants Work\n\n\n\nA brief review of our rapidly expanding knowledge of the mode of action of antidepressants.\n\n(This article was first published by the Lundbeck Institute in the Institute Magazine no. 6, 2003.)\n\nOne of the best known medical illustrations from recent years and one used by many of us to explain to patients how their antidepressants work, is the image of the synaptic cleft.\n\nThis simple illustration, usually with serotonin receptors and re-uptake pump, has probably done more to explain and legitimise the diagnosis and treatment of depressive illness than any other single initiative in the last twenty years. Most patients find its simple logic reassuring and it seems that doctors do also.\n\nA recent informal survey of colleagues showed that most of us know little more of the mode of action of antidepressants than is illustrated by the diagram.\nA typical synaptic cleft diagram used to illustrate the mode of action of antidepressants\nBreaks down on closer examination\n\nOn closer examination this simple model starts to break down. It does not explain a number of very basic facts the most obvious one being; Why is there a significant delay between starting medication and the onset of symptom relief?\n\nThe origins of the model are interwoven with the history of antidepressants. In 1948 Hafliger synthesized imipramine and ten years later Kuhn observed and published its antidepressant properties. In 1965 Schildkraut published what has become known as the Biogenic Amine hypothesis, which postulated that reduced norepinephrine levels were associated with depression.\n\nIn the same year Bunney and Davis reviewed "Norepinephrine in depressive reactions" in the Archives of General Psychiatry (ref. 1).\n\nSerotonin was linked to depression in 1965 when Coppen and others postulated serotonin's involvement in depressive illness in the British Journal of Psychiatry (ref. 2)\nAxelrod's Nobel Prize\n\nJulius Axelrod investigated the presence of catecholamines in neurons and the phenomenon of release and reuptake (the norepinephrine uptake pump). This research explained the mode of action of imipramine at a molecular level within the synaptic cleft and, together with Katz and von Euler, he received the 1970 Nobel Prize for this work.\n\nHis diagram is the origin of the multiple stylised versions we have become familiar with over the last twenty years. In an attempt to integrate the independent observations that both norepinephrine and serotonin were implicated in causing depression.\n\nArthur Prange formulated the Permissive Biogenic Amine theory. Writing in the Archives of General Psychiatry in 1974 (ref. 3) he postulated that alterations in mood were due to a deficit of serotonin plus either a deficit or excess of norepinephrine. This dual neurotransmitter approach lives on today in the debate as to whether single or dual uptake blockers are more effective in treating depression.\n\nAt a molecular level Prange's model focused on the synaptic cleft and this was to remain the area of interest for a number of years.\n\nIt appeared self-evident that increasing the availability of serotonin in the synaptic cleft and thus on the post-synaptic receptors changed membrane electrical activity (firing rate) of post-synaptic neurons. This changed firing rate somehow reversed the problems caused by the depression and returned the activity of the "faulty" system to normal.\n\nAs noted above this concept did not explain the fact that even though inter-synaptic transmitter levels increased within hours of starting antidepressants, reduction of symptoms did not commence for one or two weeks.\nA further clue\n\nA further clue to what was really happening came from the discovery that the neurons of depressed patients had up regulation (increased numbers) of serotonin and norepinephrine receptors and down regulation of uptake pumps (ref. 4). Researchers noted that the onset of antidepressant a