Fresh ideas about the causes of depression are bringing new treatments

LAST year, one of our most commonly held ideas about depression was turned upside down. “Antidepressants study casts doubt on drugs taken by 8m people,” The Times newspaper stated in July. Other publications ran similarly alarming headlines. Depression is one of the biggest medical problems facing societies worldwide, treatments have long been controversial and here was research showing that Prozac and other common antidepressants are based on a defunct hypothesis about what causes the condition. The study’s lead researcher even went as far as to suggest that any benefits from such medicines come from a placebo effect.

Most antidepressant drugs are said to work by restoring levels of a brain-signalling chemical called serotonin, an idea sometimes known as the “chemical imbalance” hypothesis of depression. But the study found that, contrary to what we have been told for decades, depression isn’t actually caused by low serotonin. This was a kick in the teeth for the many people who feel they depend on antidepressants. It also raises a key question: if low serotonin can’t explain depression, then what can? That isn’t the only mystery concerning the condition. We also don’t know how talking or electroconvulsive therapies work, nor do we understand the impact of genetics or stress on mental health.

Yet, despite all this uncertainty, some surprising progress is being made. Two new treatments have recently become available and others in the pipeline show promise. “The level of science is more advanced than this paper implies,” says Carmine Pariante at King’s College London. “Things are not as bleak as they appear.”

The two core features of depression are low mood and a lack of ability to take pleasure from usual activities. It is often accompanied by a range of physical symptoms, such as appetite loss, fatigue and insomnia. “It’s a feeling of being tired and defeated – not wanting to be here,” says Rachel Roodhardt, a children’s author based in Folkestone, UK, who has been taking antidepressants for two decades. The idea that this is caused by a chemical imbalance in the brain arose in the 1960s, after a low blood pressure treatment was found to trigger low mood in some people. The drug, it turned out, reduces serotonin as well as two other brain chemicals, noradrenaline and dopamine. Antidepressants were then developed that raised one, two or all three of these substances. One of the first was Prozac, which blocks removal of serotonin from synapses, the junctions between brain cells – hence its description as a selective serotonin reuptake inhibitor, or SSRI.

The rise of Prozac

The great commercial success of Prozac in the 1990s cemented serotonin’s reputation as the “feel-good chemical”. That idea was bolstered by genetic evidence from the late 1990s, suggesting that people with depression are more likely to have a gene variant that produces a more efficient version of an enzyme that removes serotonin from synapses – the same enzyme that is blocked by SSRIs. Unfortunately, not all the facts fit neatly into this narrative. As genetic sequencing capabilities expanded and larger, more rigorous studies were carried out, it emerged that our innate propensity to depression is governed not by one gene, but by more than 100. Embarrassingly, the gene responsible for the serotonin-removing enzyme isn’t even one of them. The consensus now is that it has nothing to do with depression risk.

Another blow to the serotonin story came from several large reanalyses of all the clinical trial data on antidepressants. Even in the late 1990s, these showed that the difference between the effects of the medicines and placebo is tiny. This is why, after last year’s landmark study was published, its lead author, Joanna Moncrieff at University College London, stated that antidepressants may be just a form of placebo.

The main focus of Moncrieff and her colleagues’ paper, however, was the lack of evidence to support the chemical imbalance hypothesis. It is hard to measure serotonin in the brain, but we can measure levels in cerebrospinal fluid of a compound it is broken down into. As the team reported, most studies don’t see lower levels of this compound in people with depression. The findings came as no surprise to psychiatrists. For some years, the website of the UK’s Royal College of Psychiatrists has stated that the chemical imbalance theory of depression is simplistic.

Nevertheless, some people who take antidepressants found the press coverage disturbing. “I felt like everything I’ve been told over the years is wrong,” says Roodhardt. She is now in the process of reducing her dose with the help of her doctor, triggered partly by Moncrieff’s analysis. On the other hand, Polly Arrowsmith, a small business owner in London, doesn’t care how antidepressants work. “They make me feel a lot weller and happier and keep my mood stable. I expect to be on them for life,” she says.

People shouldn’t conclude that antidepressants don’t work, says Pariante. The consensus among doctors is that, while they are no panacea, they can offer real help. Although, on average, the effects are only a little more than that seen with placebo tablets, this hides the fact that some people improve quite a lot, while others get no benefit, says Pariante. And those who aren’t helped by the first drug they try may be by the second or third. “The level of evidence on antidepressant efficacy is overwhelming,” he says.

What’s more, there are still reasons to think serotonin is involved in depression somehow. For instance, if you artificially lower serotonin in people who have previously been depressed, it can trigger temporary low mood. There is also no doubt that SSRIs quickly raise serotonin levels within synapses. Perhaps this brings about further downstream changes in the brain that help alleviate depression, even if low levels of that neurotransmitter weren’t the initial trigger for symptoms, says Pariante. “Antidepressants could still change the function of the brain by changing serotonin.”

Inflamed brains

All of which raises the question: if not chemical imbalance, what else could be behind depression? One idea is that it is caused by inflammation, a mild activation of the immune system. We usually notice inflammation if we injure ourselves: damaged cells release chemicals that trigger a cascade of immune system activity at the site of injury to kill any invading microbes. The resulting swelling and pain makes us rest the injured part of the body. Inflammation can also be “systemic” if there are raised levels of inflammatory chemicals circulating in the blood. Animals injected with certain of these compounds sho w “sickness behaviour”, meaning they stay huddled in a corner of their cage. It is as if systemic inflammation leads to an urge to rest and protect the whole body.

With depression, the idea is that there may be slightly higher levels of activity of immune cells in the blood, and that inflammatory chemicals reach the brain. Certainly, some people with depression have higher levels of particular immune chemicals, such as one called C-reactive protein, or CRP. Intriguingly, some SSRIs and other antidepressant medicines seem to suppress inflammation.

It is too soon to pin all our hopes on inflammation, though. Only about 1 in 3 people who are depressed have higher CRP levels, says Edward Bullmore at the University of Cambridge, who has written a book on the subject called The Inflamed Mind. Nevertheless, those people could potentially benefit from anti-inflammatory medicines already in use for other illnesses. So far, trials of such drugs in depression have given mixed results. But no studies have yet recruited only people with high CRP levels, which would be the key test. “You want a trial where you put an anti-inflammatory drug into people who have depression and inflammation, and it is antidepressant for them,” says Bullmore.

An even more fruitful avenue of research involves ketamine, an anaesthetic that is also sometimes used recreationally. Like SSRIs, it affects signalling by a neurotransmitter, but a different one, called glutamate. “Glutamate is the single most common signalling mechanism in the brain,” says John Krystal at Yale University. His idea to test ketamine as an antidepressant came from work showing that other drugs that bind to the normal receptors for glutamate seemed to reduce low mood in animals. Trials in people showed that an infusion of ketamine acts quickly to reduce depression symptoms. Most people then need repeat treatments every one or two weeks.

Ketamine is usually delivered in a drip and is only available from a few specialist clinics that are willing to prescribe it for a use different to that described in its licence. But wider uptake may be possible using a form of ketamine called esketamine that is squirted up the nose. This was approved for use in the US in 2019. However, it isn’t available through the National Health Service in the UK. In August 2022, another antidepressant that binds to the glutamate receptor was approved in the US, this time one in tablet form called Auvelity.

It is too soon to say how many people this new type of antidepressant will help. Some psychiatrists fear people will become addicted because this can happen to those who take ketamine recreationally. But does the fact that these drugs work at all tell us anything useful? Frustratingly, as with SSRIs, ketamine’s mechanism isn’t clear. Its rapid effects, which occur in the first few hours after taking the drug, seem to stem from it binding to the glutamate receptor. But animal studies suggest that it also has longer-lasting impacts on brain chemistry, including boosting the release of a compound called brain-derived neurotrophic factor, or BDNF, which helps brain cells grow branches and make new synapses in response to learning, a process known as neuroplasticity.

A lack of neuroplasticity has been proposed as another underlying explanation for depression. The idea is that long-term stress leads to a reduction in BDNF levels, which reduces neuroplasticity. This triggers a vicious circle where impaired learning means people get stuck in unhelpful behaviour patterns, such as ruminating about upsetting or sad memories. Supporting this hypothesis, some animal studies have suggested that rodents in stressful environments have fewer neuron branches and synapses in their brain’s cortex – and that taking ketamine can reverse this.

Other work in animals suggests that SSRIs also promote neuroplasticity. So does electroconvulsive therapy, in which an electric current is applied to the brain – a treatment reserved for people with the severest forms of depression. Although most of these findings come from work in animals, some studies have shown that SSRIs improve people’s learning abilities in laboratory tasks. It still doesn’t explain, though, why some people are helped by SSRIs but others aren’t.

Psychedelic therapy

Even some talking therapies could fit with the neuroplasticity explanation. Cognitive behavioural therapy, for instance, explicitly encourages people to learn new patterns of behaviour in response to stressful situations and to unlearn harmful ones. This would explain why medications and talking therapies often work best together: the antidepressants make the brain more neuroplastic, while the person learns more helpful thought patterns.

Psychedelic drugs, such as psilocybin from magic mushrooms, have shown some signs of success against depression in small, early-stage trials in humans – and they seem to trigger neuroplasticity, too, at least in animals. They also directly stimulate one subtype of serotonin receptor, as well as causing a rise in dopamine levels. So these drugs seem to have multiple effects and it is unclear which one is most important. That doesn’t concern everyone. “As a clinician, I’m not too bothered about how things work – more if they work,” says James Rucker at King’s College London, who is helping to test a synthetic form of psilocybin.

So, is neuroplasticity the new grand theory of depression? Pariante thinks not. Instead, he sees depression as a complex state that represents disturbances in multiple brain chemicals and neural circuits, with different aspects predominating in different people. That would explain why various treatments help some people, but not others. “You have multiple steps where you can intervene,” he says. But it also means we need tests – or “biomarkers” – to identify which drugs and therapies are most appropriate for individuals. Already, blood tests for inflammation are being investigated as a way to guide psychiatrists’ choice of antidepressants and whether to combine them with anti-inflammatory drugs. Other biomarkers may come from electroencephalograms or brain scans, as well as smartphone data tracking behaviour.

The US National Institute of Mental Health, which is one of the biggest funders of mental health research in the world, is planning trials that pit these different biomarker tests against each other. “We are asking investigators to take ideas that have good academic evidence and put them through the wringer,” says Joshua Gordon, director of the institute. “I think we can do better with the treatments we have now, without understanding mechanisms.”

This may not be much comfort for anyone currently struggling with depression. At the moment, doctors tend to offer a succession of drugs in a trial-and-error process, and it can take up to two months to check whether or not each treatment works. But in the future, biomarkers could be used to diagnose people with subtypes of depression that are most responsive to certain treatments. And doctors will be spoiled for choice if some of the promising experimental drugs reach the clinic. “There may be no such thing as the ‘ultimate biological mechanism’ of depression,” says Pariante. On the plus side, that gives us many more treatment options. “It’s messy, but all of medicine is messy,” he says.

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