Daniela da Silva is feeling good. Lying cocooned under fleece blankets inside a medical scanner, her eyes are closed and her mind is focused and remarkably unperturbed by negative thoughts. Three hours earlier, the 39-year-old yoga teacher and neuroscience student was given a dose of the stimulant drug dextroamphetamine, which is often used to treat ADHD. “I’m having a serotonin increase. Oh definitely,” she predicts before entering the PET scanner.
Da Silva is a healthy volunteer in a trial using a pioneering brain imaging technique designed to measure serotonin changes in the brains of living people. Last year, scientists used the scan to obtain what they claimed to be the first direct evidence that serotonin release is blunted in the brains of people with depression. The findings added fuel to a fiercely fought debate over the role of the brain chemical – if any – in depression. Just months earlier, a high-profile scientific review caused a stir when it reached the opposite conclusion that “after a vast amount of research, conducted over several decades, there is no convincing evidence” for the idea that depression is caused by a chemical imbalance in the brain.
To many, it was news that the case for serotonin being implicated in depression was not already watertight. The idea of a chemical imbalance is embedded in public consciousness and has shaped the way we view mental illness. The main class of antidepressant drugs, selective serotonin reuptake inhibitors (SSRIs), are widely assumed to work by boosting serotonin levels. So the suggestion that the way we discuss, and treat, mental illness might be based on shaky foundations was disconcerting. But it also served as a wake-up call that this view of depression has failed to provide effective treatments for a substantial proportion of those affected.
What is serotonin?
Serotonin is sometimes referred to as the “happy hormone”, conjuring up the image of a substance that swooshes through the brain leaving a warm glow of contentment in its wake. In reality, its biological role is complex and extends to basic functions like the regulation of sleep, intestinal activity and the formation of blood clots. In the brain, serotonin acts as a chemical messenger between neurons, but also as a form of volume control that alternately increases or decreases the level of communication between other neurons. “Put another way, serotonin fine-tunes the working of the brain, regulating how different parts of the brain communicate with each other,” says Dr James Rucker, a consultant psychiatrist at South London and Maudsley NHS foundation trust, whose research focuses on developing new treatments for depression.
The so-called serotonin hypothesis of depression arose through pure serendipity. In the 1950s, doctors noticed that patients who were given a new tuberculosis drug, iproniazid, appeared unusually cheerful – euphoric even. The drug was found to boost levels of serotonin (among other neurotransmitters) by blocking an enzyme required to break it down. A small leap of logic suggested that if boosting serotonin levels made people feel better, perhaps a deficit was causing depression in the first place. Pharmaceutical companies were quick to deploy the line to market a new generation of blockbuster drugs including fluoxetine, escitalopram and citalopram.
Various lines of experimental evidence also supported the idea. Drugs that generate a huge serotonin release, such as MDMA, cause users to feel elated and emotionally connected – the polar opposite of depression. And when people who have previously suffered depression are given a diet that lacks tryptophan, the amino acid which is contained in protein-rich foods and that the body uses to make serotonin, they are more likely to relapse. But other studies have produced inconclusive and contradictory results.
“Most of the public felt the link had been proven,” says Joanna Moncrieff, a professor of psychiatry at University College London and lead author of the critical review. “Most psychiatrists and scientists knew it hadn’t.”
After assessing evidence from 17 previous studies, Moncrieff and colleagues concluded that the case for a serotonin deficit being responsible for depression was unconvincing. “The greatest advance we could have,” she says, “would be to stop thinking of depression as a medical condition.”
Moncrieff views depression as an emotional reaction to external circumstances and says that, as a psychiatrist, she has always been able to identify an underlying cause in her patients. “If you’re in a depressed state you’re not able to look at your life very objectively and work out what’s gone wrong,” she says. “Very often it is to do with debt, relationship problems, loneliness.”
“I think mental health problems are social problems,” she adds. “Trying to treat them as problems of individuals doesn’t work.”
Poverty, ill health, unemployment, bereavement and childhood trauma all considerably raise the risk of depression and these powerful determinants of mental illness are sometimes glossed over. But the argument that depression is, therefore, not a form of illness falls outside of the medical mainstream and also the subjective experience of many of those affected. This includes Rucker, who before becoming a psychiatrist, experienced a severe mental health episode that left him in a “place of darkness, despair, and yearning for oblivion and death”.
“When you suffer from a mental illness like depression it’s inexplicable,” he says. “I had a comfortable upbringing, a good education, my parents still love each other, I went to study medicine and then I was absolutely poleaxed by depression in my early 20s.”
Moncrieff’s review prompted an overdue public reckoning for the serotonin hypothesis, but most psychiatrists had already moved beyond the idea that depression was caused by a simple deficit or that the underlying cause of depression is the same for everyone.
“Serotonin isn’t going to explain all depression,” says Prof Oliver Howes, a psychiatrist based at Imperial College and King’s College London. “It’s a complicated disorder and there are probably several different subtypes.”
Howes says that progress had stalled due to the lack of any direct way to measure serotonin in the brain, meaning scientists had to rely on unsatisfactory proxy measures, such as blood tests, postmortem brains and putting people on tryptophan-lacking diets. “People have been debating the question for decades, but it’s all been based on indirect measures,” he adds.
Howes is one of the team pioneering the new PET scan, which the Guardian was able to observe again in a second follow-up trial.
The volunteer (Da Silva) is injected with a safe radioactive tracer that is detected by the scanner as it flows through her blood stream, tracing out a 3D map of her body. The tracer is designed to bind to serotonin receptors in the brain, illuminating them as a colourful heatmap on the scan. But when a serotonin surge occurs, a fraction of the tracer molecules are kicked off the receptors and the signal drop-off indicates how much serotonin the brain is pumping out. “We can’t put a pipette into the brain and take a sample,” says Howes. “So this is the closest we’re likely to come.”
In research published last year, Howes and colleagues compared serotonin levels in 17 patients with depression and 20 healthy volunteers. The two groups didn’t show a difference in their baseline level of serotonin. But when the participants were scanned again after being given a dose of dextroamphetamine, the healthy group experienced a significantly bigger change – 15% versus 6% – compared to the depressed group. Howes’ PhD student emails me after the scan to confirm that Da Silva’s intuition was correct: she experienced a 48% increase in serotonin release.
“You’re getting a measure of how much serotonin release there is,” says Howes. “Our study is the first direct evidence that serotonin release in the brain is blunted in people with depression.”
The paper was a first step and needs to be replicated in a wider patient population. But Howes believes the technique could be crucial in understanding why current treatments do not work for everyone – and eventually pave the way for better medicines. “While current treatments do help a lot of people, they don’t work for everyone. Some people can’t find any treatment that helps so we really need to understand more about what’s going on in the brain that leads to depression.”
How SSRIs work
Successive clinical trials have confirmed that SSRI drugs are effective for around two-thirds of patients. But what is puzzling is that, while these drugs alter serotonin levels in the brain almost immediately, they typically take two to four weeks to have a clinical benefit, leading to questions about how they actually work. Prof Catherine Harmer, director of the Psychopharmacology and Emotional Research Lab at the University of Oxford, has been investigating this phenomenon for the past decade through a series of cleverly designed experiments. “Whatever antidepressants are doing, we don’t think they’re simply affecting mood,” she says.
From an evolutionary perspective, Harmer says, our brains are hard-wired to be highly alert to threats in our environment – and to prioritise paying attention to dangers. She sees depression as a case of this basic survival instinct gone awry. “When people are depressed, they have a negative filter and are more likely to notice negative information and that reinforces negative experiences,” she says. “If you’re only receiving negative information, your hope and pleasure is not prioritised. Nobody really wants to just survive.”
Harmer’s research suggests that the availability of serotonin shifts the way we process emotional information at a subconscious level and this has a cumulative impact on how we feel. In one study, Harmer showed participants images of faces (left) with a range of emotions (happy, sad, afraid) at different intensities. The images had been morphed on a computer with a neutral face so they ranged from full happy, to a barely perceptible Mona Lisa-like smirk.
After just one dose of an SSRI, the threshold for detecting negative emotions increased – they needed to be more overtly negative to be interpreted as a negative emotion. The opposite trend was seen for faces with positive expressions. Another experiment found that people were less likely to recall negative information after a single dose of an antidepressant drug, although they did not report any change in mood. It was as though the antidepressant added a “positive bias” filter that subtly changed how people experienced the world at an unconscious level.
This suggests that antidepressants may work in a surprisingly similar way to what cognitive behavioural therapy aims to do at a conscious level – and could explain why a combination of medication and therapy tends to be more effective than medication alone. By refocusing a person on positive information in their environment, they begin to respond to these positive inputs and slowly begin to feel better.
This tallies with how Rucker describes the role of antidepressants in his own recovery. “I do lots of things to maintain my health,” he says, reeling off a list that includes exercise, yoga, meditation, years of psychotherapy, “but also antidepressants”. “They’re not the whole answer. They get you to the point where you can get out the front door and do those other things to help yourself.”
As the latest science reveals new insights into the biology of depression, it is clear that serotonin is just one part of a complicated jigsaw. Depression isn’t a “chemical imbalance” that can be neutralised in a simplistic sense. There are external social and environmental factors that can trigger depression and others that can be harnessed to help people get better. Drugs that target serotonin can tilt the balance in favour of recovery, but a wider range of options are needed.
The new frontier in treating depression
Known as a “party drug” but widely used in medicine as an anaesthetic. Ketamine is not licensed as an antidepressant, but studies suggest it can improve symptoms in severe depression (the long-term success rates are less clear). A ketamine-like nasal spray, esketamine, has also been approved in the UK for moderate to severe depression, but it did not meet cost-effectiveness criteria, so the treatment is accessible privately, but not widely available through NHS clinics.
In 2019, the FDA approved in the US the first drug specifically for postpartum depression, a steroid called allopregnanolone. The drug is a metabolite of the hormone progesterone, which drops precipitously after childbirth, and it is possible that the drug works by counteracting some of the hormonal changes that occur postpartum. The drug is not widely used because it is administered as a 60-hour intravenous infusion, but an oral version is in trials, meaning that it could be a stepping stone towards medicines tailored to treat specific subtypes of depression.
Last year, a trial of more than 200 patients found that a single dose of psilocybin, the active compound in magic mushrooms, helped alleviate symptoms of severe depression when combined with therapy. Scientists think the drug can act as a “reset” for the brain and also act to increase connectivity, which might make the brain more open to therapy. Further trials will be needed before the drug can be licensed as a medicine, so at the moment it is only available in clinical trials.