SSRIs - the most popular group of antidepressants - have not changed since their invention in the late 1980s, and exactly how they work is a mystery. Photo / Getty Images
A new study has compared the side effects of the different drugs, but exactly how they work may never be clear.
Despite being taken by millions of people around the world, doctors don’t fully understand quite how antidepressants actually work. The most popular group of antidepressants are known as SSRIs and, for decades, they were thought to correct a deficiency of the “happy hormone” serotonin. These drugs have not changed since their invention in the late 1980s, and exactly how they work is a mystery.
While it is known that SSRIs facilitate a release of serotonin in the brain, “after that initial pharmacological action, the chain of events is not very clear”, says Glyn Lewis, a professor of epidemiological psychiatry at University College London.
The strange fact is that “we simply don’t know” why SSRIs work against everything from depression to OCD, and why they work for some people and not others. While it’s often assumed that people with depression have low serotonin, which the drugs correct, recent research shows this isn’t the case.
To add to the confusion, a new study has found that different antidepressants can cause different side effects, including weight gain, high blood pressure and changes in heart rate depending on the drug being taken. The findings have “immediate clinical implications” for how certain antidepressants are prescribed, particularly if people have heart or weight problems, according to researchers at King’s College London and Oxford University.
So what do we know about what antidepressants do to our brains and how concerned should we be about their side effects?
SSRIs increase the amount of serotonin in the brain. That chemical does more than make us feel happy: it transmits messages between nerve cells and is important in regulating not only mood but also sleep, appetite, sexual behaviour and even physical processes like digestion and blood clotting. Its natural release is prompted by physical exercise, sunlight and positive social interactions. Simply put, more serotonin in your brain should mean that you feel happier, calmer and more focused.
As more people take SSRIs, and for longer, the other impacts on the brain are becoming clearer. Some neuroimaging studies suggest that, as well as impacting serotonin levels, SSRIs reduce activity in the amygdala (the fear centre) and the hippocampus (the memory centre). Other research indicates that taking SSRIs in the long term can actually change the shape and size of some parts of the brain, such as the anterior cingulate cortex, which drives decision-making and attention, and the hippocampus too.
These changes could explain why the drugs make some people feel better, by “normalising” the brain’s activity to bring it back to a healthy baseline. This effect is not observed in every person who undergoes a brain imaging study, however.
Exactly whose brains are changed, and why, is unknown. While some people see enormous benefits from taking SSRIs, others only see a modest improvement in their symptoms at best. “For mild depression it seems that SSRIs really aren’t very effective at all. For people with moderate to severe depression, they should be combined with psychotherapy,” says Philip Cowen, a professor of psychopharmacology at the University of Oxford. Research indicates that both are more powerful in combination than either are on their own.
One reason for this may be that taking SSRIs can improve neuroplasticity – the brain’s ability to make changes in response to its environment. “In people with severe depression, it’s often a fixed, deep-rooted thing, with a delusional quality, in that everything seems negative, so it can be really hard to get better,” Cowen says. Taking an antidepressant “can help people respond to psychotherapy, due to the improved neuroplasticity, as it might make them more open to seeing the world differently”.
Joanna Moncrieff is a professor of critical and social psychiatry at University College London. She believes that any positive impact of SSRIs is all down to “a slight numbing effect”, as she puts it, “that some people who are really very depressed might benefit from in the short term”.
Other experts may see this more generously as a change in the brain’s emotional response to the difficult thoughts that characterise depression – making people with the condition less distressed by patterns of negative thoughts and beliefs, even if they do little to change them.
“If you know anything about [SSRIs] you would never suggest that they restore a serotonin imbalance, because there has never been much evidence for that,” says Lewis. The myth has abounded because “doctors needed something to tell patients who asked them how their antidepressants would work”.
A recent review by Moncrieff at the same university, published in 2022, found that there was no consistent evidence for an association between serotonin and depression, proving for good that SSRIs don’t transform serotonin-deficient brains into healthy ones.
The first antidepressant drugs were invented in the 1950s and were “basically discovered by chance”, Lewis says. The drug iproniazid, for example, was originally designed to treat tuberculosis, and was only then found to have antidepressant effects.
SSRIs, meanwhile, were specifically designed to treat depression, and have been widely prescribed since the early 1990s. Since then “there has been almost a linear increase in the use of antidepressants”, Lewis says. From the year 2000 onwards “it isn’t so much that more individuals are being prescribed antidepressants, but that people are taking them for longer”.
Around a quarter of people currently given them have been taking SSRIs for at least five years. The drugs are now prescribed not only for depression but also to treat anxiety disorders (such as generalised anxiety, OCD and PTSD) as well as chronic pain. Just under two-thirds of antidepressant prescriptions in Britain are made for either depression or mixed anxiety and depression.
Some research suggests that for depression, at least, SSRIs seem to work well in most people. In a recent study of 20,000 people with major depression who had taken antidepressants, 75% said that they found them to be helpful. The research looked at people whose health information has been collected as part of the UK Biobank, and used the participants’ own reports on their experiences with the drugs. Studies that rely on clinical assessments by medical staff are less hopeful, however: an important review from 2018 found that all kinds of antidepressants are more effective than a placebo, but only marginally so.
“This is the best evidence we have that antidepressants do work to some extent. They’re better than nothing, but they certainly don’t work for everyone,” says Cowen. This is why the drugs are given out so freely: the evidence suggests that they are often helpful and “are quite well-tolerated”, Lewis says. They are also “cheap and quick to prescribe”, making them much more easily available on the NHS compared with other mental health treatments.
The new analysis from King’s College London and Oxford University used data from 151 different studies, comparing the physical health effects of 30 different drugs across more than 58,000 people. It is the first time that the variation between drugs has been calculated.
They found a large variation between treatments. Some drugs cause quick weight gain, with people putting on an average of 2kg in just eight weeks on maprotiline, while, in contrast, agomelatine caused a 2.6kg weight loss over a similar period. Similarly, heart rate increased by 14 beats per minute for nortriptyline but fell by eight beats per minute for fluvoxamine.
People taking doxepin saw their blood pressure rise significantly compared to those on nortriptyline who saw a decrease.
Some people who take antidepressants report feeling numb and emotionless. Others report massive difficulties in their sex lives, with getting erections or reaching orgasm, even after they have stopped taking the drugs. “Some types of SSRIs make people really quite groggy, and most antidepressants are linked with weight gain,” says Moncrieff.
People who take the common antidepressant escitalopram might put on nearly 1.8kg over two years, though this may also be linked to the fact that people with depression often struggle with low appetite. “There’s the risk of bleeding problems and haemorrhage, risks in pregnancy, as well as with osteoporosis and fractures,” Moncrieff adds, all believed to be due to the excess amount of serotonin in the brain caused by the drugs.
Withdrawal from antidepressants can also be extremely difficult: fatigue, mood swings and problems sleeping, as well as “brain zaps”, a feeling like a short electric shock, are often reported by people who stop taking SSRIs. “One survey we carried out suggests that 10 to 20 per cent of people who try to come off of antidepressants find that they can’t do so,” Moncrieff says. “In people attending therapy, it’s closer to 40 per cent.”
Moncrieff believes that the potential harms of antidepressants outweigh their benefits. She is a vocal opponent to what she sees as the overprescribing of antidepressant drugs, an issue that has gained a lot of traction in recent years. “I’m not convinced that they are useful at all,” she says. “Some people who are very depressed might benefit from SSRIs temporarily as a sort of sedative, but beyond that, I believe that people are being harmed more than they are benefitting.”
How SSRIs work, and why they work for some and not others, may never be clear. So should doctors slam the brakes and stop prescribing them? Not necessarily. “Occasionally people think that this is some kind of conspiracy, but it’s just a very difficult thing to work out,” Lewis says. “It’s not unusual to have medical treatments that we don’t fully understand the effects of, and unlike a lot of the other biological systems in the body, which we understand quite well, SSRIs are acting on the brain, which we do not understand very well at all.”