You might be surprised to know that even though they are the drugs most commonly prescribed for depression, scientists don’t know exactly how SSRIs, or Selective Serotonin Reuptake Inhibitors, work to help people feel better.

Sure, we know the basic biological mechanism- they block the machinery that normally recycles serotonin, sucking it out of the synapse back into the cell it came from, meaning more hangs around in the synapse for longer. And there are lots of theories as to what knock-on effects this has on our brain cells.

We also know that they do help improve many people’s symptoms, although they don’t work for everyone.

But this leaves a missing link in the puzzle; why do SSRIs help some people to feel better? This gap highlights one of the biggest issues in psychology and neuroscience research, and a barrier I repeatedly ran into in while writing my book, because translating molecular changes into behaviour, and understanding how one can cause the other, is extremely tricky. But it is a challenge that Catherine Harmer, director of the Psychopharmacology and Emotional Research Lab (PERL) based at the University of Oxford, wasn’t going to shy away from, as she told me:

“Most research at the time I started didn’t really cross those different divisions… and those different research folk didn’t really communicate very much with one another. And I just became really interested in how these different things related to one other, so how SSRIs, or antidepressants more generally, actually led to any improvements in the symptoms of depression… Why does increasing levels of serotonin in the brain allow people to feel better? It seemed like there was a missing gap there in explanation”.

To figure this out, Harmer looked at the effects of SSRIs in healthy volunteers and people with depression, to see how they change their view of the world. Her group found that when shown pictures of people’s faces, healthy participants will tend to focus mainly on those with happy expressions, while people with depression, even when they are in remission, spend more time focusing on the sad. They also interpret faces differently: when shown an ambiguous expression, healthy controls tend to see it as happy, while people with depression are equally likely to think it is sad or happy. The same is found in other areas, so people with depression are more likely to remember the negative words on a list, for example, while controls remember the positives.

Catherine Harmer, Professor of Cognitive Neuroscience at the University of Oxford

What her findings add up to is a negative bias in people with depression. Someone with depression is more likely to notice and remember the bad things they experience, rather than the good. And this may be the cause of their low mood, or at least help to maintain it. It may also encourage them to withdraw from society, because if you experience most interactions with other people as negative, you are less likely to repeat them. This can then reinforce the problem as their growing isolation makes their depression worse.

Next, working with clinical researcher Beata Godlewska, Harmer gave her subjects with depression SSRIs, boosting the levels of serotonin in their brains, and gave them the same tasks again. And she noticed an immediate difference. The group with depression were more able to recognise happy facial expressions and found it easier to remember the positive words. Their negative bias had shifted.

What is particularly interesting about Harmer’s results is how quickly the changes in processing appear. In some cases, they are visible after a single treatment, and certainly well before the individual has noticed any effect of the antidepressant (it often takes six weeks or so of treatment before people start feeling better). That means that this could be the reason their symptoms begin to improve. Harmer explains:

Increasing levels of serotonin doesn’t boost up mood, but what it does is, it makes you collect information from your environment in a more positive way. But that doesn’t immediately make you feel better… They don’t notice it at a subjective level, so they don’t report feeling any more positive, but still they’re collecting more positive information and then over time and experience and interaction with things that are going on in your life, you’d expect that to allow you to feel better. So it suggests that serotonin doesn’t influence mood directly, it affects emotional processing which then impacts mood… you need time to learn from that change.

Fascinatingly, Harmer found that not everyone has this change in processing after the first dose or two of antidepressant, and those that don’t tend to be the people who fail to respond to the drug in the longer term. This could be an extremely important finding clinically. Currently, while doctors know that only around a third of their patients will respond to the first antidepressant they try, there is no way to know who will and who won’t until they have been taking the drug for six weeks. If that doesn’t work, they try the next… and wait another six weeks. The cycle continues until they find one that works or run out of options. This means it can often take several months of trial and error before effective treatments are found, and this is a long time for someone with severe depression to wait. Harmer’s findings offer a tantalising glimpse into how we could test people after just one or two doses, using a test like those used in her research, and know immediately whether that drug would work for them. This would mean we could find the correct treatment much faster, and get the patients on the road to recovery a lot more rapidly. And that could significantly change their quality of life.

Serotonin

This still doesn’t explain why some people with depression don’t respond to SSRI treatments, but Harmer believes there are several plausible explanations. First, she sees the environment as an important factor in recovery. ‘When you’re depressed you become very isolated… so even if you are starting to be able to pick up more positive messages from other people, if you’re not seeing people you can’t pick them up. Or if you have an extremely toxic, negative environment, there might not be anything positive to pick up.’

Someone on SSRIs might be more able to pick up the positives in a social encounter, rather than the negatives they would have seen before. Over time, this could encourage them to repeat that encounter, helping to pull them out of the depressive spiral. But if the only social interactions they have are extremely negative (perhaps they are in an abusive relationship, or a toxic work environment), there would be no positives to detect, so all the serotonin in the world couldn’t help them find the good in the situation. This is why treating depression is a multi-step process, and why environmental changes can be as important as drug therapy. Cognitive behavioural therapy can also have a role here, in helping people to challenge and change their way of thinking, and this might explain why drugs and therapy together are more successful than either treatment alone.

Another explanation for the failure of serotonin-boosting drugs in some people with depression is a simple one: they might not have low serotonin. Harmer believes that depression can occur for a number of different reasons, and each might have a different biological basis. So, trying to treat everyone with SSRIs is like giving everyone who has a runny nose anti-allergy medication. Yes, it might help those whose runny nose is caused by hay fever, but it won’t do a thing if the underlying cause is a cold virus. Finding that underlying cause will allow doctors to treat patients in a more tailored and hopefully more efficient way.

Ginny’s new book, Overloaded : How Every Aspect of Your Life Is Influenced by Your Brain Chemicals, covers this in more details and is out now.

Ginny Smith is a science presenter and writer. A Natural Sciences and Psychology graduate of Cambridge, Ginny performs science shows all over the world and presents a wide range of science content for the likes of the Cosmic Shambles Network and the Naked Scientists. She is the co-author of three DK Publishing books looking at science, food and the human body. Her frist solo book, Overloaded is out in April 2021. She is @GinnySmithSci on Twitter.

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