Why do antidepressants take so long to work?

By Jonathan Crowe, posted on 18th March 2012

When we have a headache, we think nothing of taking a painkiller and expecting to get some pain relief in less than an hour. But some antidepressants can take much longer than this to take effect. It may be not hours, or even days, but weeks until a therapeutic effect is felt. How can two therapies that we receive in a similar way – tablets that we consume – work on such different timescales?

To answer this question, we need to explore the world of serotonin.

Serotonin is a naturally-occurring chemical that acts as a biological signal. For example, serotonin is found in our nervous system, and helps neighbouring nerve cells to communicate with each other. In so doing, serotonin influences our behaviour in various ways – not least by having an impact on our moods.

The fine details of how serotonin has its biological effects are still rather hazy. However, there does seem to be a link between serotonin and depression. Specifically, studies have found that depressed individuals often have low levels of serotonin in their bodies. (Actually, to be precise, these studies have found that levels of the chemicals that are generated when serotonin is naturally broken down by the body are lower than normal in those with depression. And, if the levels of the chemicals that are made from serotonin are low, we can deduce that the levels of serotonin itself are also low.)

So, if serotonin levels are often found to be abnormally low in those with depression, it would make sense that one way to treat depression would be to return serotonin levels to normal. And this is exactly what some therapeutic strategies try to do.

It is widely thought that some antidepressants work by elevating the levels of the serotonin in the bloodstream, primarily by slowing down its removal once it has been released into the bloodstream. (Imagine filling a sink with water, and waiting for it to drain – either with the plughole completely clear, or with it half-closed. Water levels in the sink will stay higher for longer if the plughole is half-closed; in essence, this is how some antidepressants are thought to work – by slowing down the rate at which serotonin in the blood is ‘drained away’.) This mode of activity has given this class of antidepressants their name: selective serotonin reuptake inhibitors, or SSRIs.

But this doesn’t really explain why antidepressants like SSRIs take so long to work. In fact, things get even more bemusing when we discover that the level of serotonin in the body actually increases pretty quickly (in a matter of hours) after taking an SSRI. If the levels of serotonin have increased, why does it take so long for us to actually feel any different?

To discover the answer, we need to dig deeper into the way in which serotonin acts in the body – and actually begin to uncover other ways in which SSRIs might have their effect.

As I mention above, serotonin is a biological signal: essentially, it passes particular messages between cells. Serotonin does this by attaching to specific ‘receptors’ embedded in the cells that it’s communicating with. Picture a high-security vault that can only be opened by someone pressing the palm of their hand against a scanner to authorize access. In essence, serotonin behaves like the hand, while its receptor is the scanner. Only serotonin can interact with its receptor to ‘activate’ it and pass on the intended message.

The important thing is that the signal (serotonin) and its receptor have to work together. It’s no good having a lot of signaling chemical around if it’s only got a few receptors to attach to: the lack of receptors will limit how quickly and widely its message can be passed on.

This is where SSRIs might really make a difference. Rather than keeping serotonin levels high by blocking its re-uptake from the bits of the body where it has its effect (as described earlier), it is now thought that SSRIs might also have their biological effect by increasing the number of receptors that are present in the body – so that the serotonin that’s available can pass on its message more efficiently.

We can imagine that it would take a group of ten football supporters a while to enter a football stadium if there’s just one turnstile for them to pass through. But it’d be much quicker if there were five or ten turnstiles. In a similar way, ten serotonin molecules will be able to pass on their message much more quickly if there are ten receptors for them to bind to rather than if they’re all trying to compete for a single receptor.

However, it takes time to for our bodies to manufacture new receptors and install them at the right locations in our cells. And this explains why, even if SSRIs boost levels of serotonin in the body pretty quickly, the benefit of taking the antidepressant isn’t felt for some time. The extra serotonin molecules need to wait until more receptors have come on stream before the signals they transmit can get ‘louder’, leading to a rebalancing of mood.

As you can see, there are a lot of questions still to answer when it comes to figuring out exactly how SSRIs work as antidepressants – but at least we’re beginning to discover some potential reasons why there’s that lag between starting to take an SSRI and its effect being felt. Something does actually seem to be happening in our cells, even if it doesn’t always feel like there is at first.

Jonathan Crowe is a science textbook publisher by day, and science writer at various other times. You can read more of his writing at
http://chemicalgecko.blogspot.com.