June 2015
Philip J Cowen and Michael Browning
The “serotonin hypothesis” of clinical depression is almost 50 years old. At its simplest, the hypothesis proposes that diminished activity of serotonin pathways plays a causal role in the pathophysiology of depression. This notion was based on the depressogenic effects of amine depleting agents such as reserpine, as well as the actions of antidepressant drugs such as monoamine oxidase inhibitors and tricyclic antidepressants, discovered by clinical serendipity, but later found in animal experimental studies to potentiate the effects of serotonin and other monoamines at the synapse (1).
This pattern of theory making – moving from the pharmacological actions of drugs with some efficacy in treatment to biochemical notions of causation – has been common in biological psychiatry. In such an undeveloped field this approach, though logically precarious, has been a useful heuristic and, in the case of the dopamine hypothesis of psychosis, has been strikingly upheld by advanced brain imaging techniques (2). However, the serotonin hypothesis of depression has not been clearly substantiated. Indeed, dogged by unreliable clinical biochemical findings and the difficulty of relating changes in serotonin activity to mood state, the serotonin hypothesis eventually achieved “conspiracy theory” status, whose avowed purpose was to enable industry to market selective serotonin reuptake inhibitors (SSRIs) to a gullible public (3).
