The Fog Clears: Shedding Light on how Antidepressnts Work



With thanks to Biblioteca de arte


Antidepressants are controversial but pervasive in society. Even though the number of people experiencing their first episode of depression has remained stable in the last twenty years, more people are being prescribed antidepressants. Nearly 40 million prescriptions for antidepressants were written in 2012.


However, despite their widespread use, research has suggested that only 50-65% of people taking antidepressants feel any benefit from them. Compare this with the finding that 25-30% feel a benefit after receiving a placebo, and it seems evident that antidepressants do not suit everyone, and some may have even got better anyway. It also usually takes around 3 weeks for any changes to occur, during which time, symptoms can sometimes get worse, especially in adolescents. The reason for this is unknown, as scientists aren’t sure exactly how antidepressants work, or what they actually do in the brain.


In itself, this isn’t a huge problem or particularly uncommon in medicine. The first class of drugs to become antidepressants were intended to treat other, mostly physical illnesses. However, it was noted that they were effective in treating depression (at least in some cases), and so antidepressants emerged, with newer versions being developed to try to reduce side-effects. The practice of using drugs based on their effectiveness, despite uncertainty over their mechanisms, also holds true for common drugs such as Aspirin and Ritalin.


It then transpired that antidepressants raise levels of the hormone, serotonin, in the brain. This gave rise to a theory that serotonin levels were central to Depression, and that low serotonin levels may cause Depression, leading many to talk about the illness as a ‘chemical imbalance.’ However, this is like saying that, because Aspirin eases headaches, headaches must be caused by a lack of Aspirin, which is obviously absurd. What’s more, some antidepressants don’t affect the serotonin system at all.


As the serotonin theory remained inconclusive, research attention turned to another theory, which asserts that neurogenesis, the growth of new neurons, may alleviate depression. This theory fits much better with the time it takes for antidepressants to take an effect, but the process of neurogenesis itself is not wholly understood, let alone any possible interplay between this and the action of antidepressant drugs.


However, research from Hiroshima University is shedding light on the effects that antidepressants have on the brain. A particular paper, published in the Journal of Neurochemistry last year, suggests that the key to understanding how antidepressants work is to shift the focus from neurons and their synapses to a different kind of brain cell, called astrocytes. These cells provide a scaffold for neurons, but they may also control neural activity. The research team used a live culture of rat brain cells for their experiments. They found that amitriptyline, a tricyclic antidepressant, appeared to increase the production of two proteins, a transcription factor and a growth factor. Transcription factors control how often a particular protein is made in different parts of the body or brain, depending on an individual’s current needs. Growth factors, as the name suggests, encourage the growth of new cells or tissues, as and when they are needed. This particular growth factor, FGF2, had already been shown to set off a cascade of processes involved in the birth of new neurons. This research went on to show that the transcription factor, EGR1, was also necessary for these effects.


When production of the transcription factor was blocked, administering amitriptyline did not result in an increase of the growth factor, implying that both proteins were necessary for the clinical effect of the antidepressant. Interestingly, this process only occurred in astrocytes – treating neurons with amitriptyline had no effect on the production of these proteins, even though neurons do process them.


Although most of the experiments in this paper used amitriptyline, the team also found that other antidepressants increased the production of these proteins in astrocytes – and the more they produced of the transcription factor, the more they produced of the growth factor. This relationship may be related to the effectiveness of each antidepressant, although this possibility was not tested.


As with serotonin, this research cannot explain the cause or onset of depression. However, it does agree with research showing that these proteins are diminished in some people with Depression. The time it takes for antidepressants to boost neural growth to grow also fits with the time taken for symptom improvement. However, cascade of processes between these proteins appearing in astrocytes and neurogenesis occurring, is not clear. This knowledge will be crucial in understanding how mediation can be used to manage Depression. It is hoped that research like this will help to produce more effective or faster-acting drugs which may help people to manage their Depression, possibly alongside other treatments



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