UK Edition
A world without antidepressants: the new alternatives to prescription pills
Could the future of treating depression be ketamine infusions – or even a ‘pacemaker for the brain’?
Five years ago, Mark Dunning was at his lowest ebb. After years of switching from one antidepressant medication to another without success, his mental health was worse than ever. “I was suicidal,” he remembers. “I’d been on various medications – sometimes they would work for a year or two and sometimes not at all. Those that did seem to work would abruptly stop with no warning at all and I literally couldn’t see myself being alive anymore. I just felt hopeless and disinterested in everything I’d ever enjoyed.”
His experience is far from unique. One in five adults in the UK has symptoms of anxiety or depression, with evidence that the pandemic has seen rates spike even further: 300 people a day are going to A&E departments because of feeling depressed, the NHS reported last week.
For many, the mainstay treatments offer limited benefit. According to the World Health Organisation, around 30 per cent of people do not respond to existing treatments of antidepressant drugs, psychotherapy or electroconvulsive therapy. A recent study of antidepressants, published in the New England Journal of Medicine, found that even after two years of treatment, six out of 10 who felt well enough to stop taking them suffered a relapse within a year, compared to a relapse of four in 10 among those who continued their pills.
There remain concerns about side effects, too. Various studies have found links between long term use of selective serotonin reuptake inhibitors (SSRIs – the most commonly used antidepressants) and an increased risk of heart disease, strokes, obesity and type 2 diabetes, as well as the development of side effects such as sexual dysfunction. In older adults, they are associated with falls, fractures and a greater risk of bleeding.
The need for an alternative to prescription pills has never been greater – and a range of new antidepressant therapies are causing many to rethink depression and how we treat it.
Many are aimed at the estimated 12 to 20 per cent of treatment-resistant patients for whom all other approaches have failed. But they are also gaining traction among patients with more mild to moderate illness, who are concerned about the potential consequences of taking antidepressants over the course of years or even decades.
Dunning became so desperate for help with his depression that he contemplated undergoing electroconvulsive therapy, a last resort treatment still used for the most severe forms, where a mild electric current is passed through the brain to reset circuitry. In the end though, he opted to receive ketamine infusions at a private clinic in London. And for the first time in his life, he began to experience relief. “It offered a pretty much instantaneous benefit,” he says. “Since then I’ve found a cycle which works for me, I go regularly, but not every week, and I feel happy with my life.”
Ketamine and the psychedelic drug psilocybin – the active ingredient in magic mushrooms – are attracting growing attention for their potential benefits for mental health problems in recent years. Such is the evidence that some NHS trusts now offer ketamine treatment for severe depression, as a paid for service. Scientists are still not entirely sure how it works, but while SSRIs attempt to increase the levels of serotonin – a hormone involved in regulating mood – in the brain, ketamine is known to target another chemical called glutamate which is linked to a whole variety of mental illnesses. It is also thought to help repair damaged connections between cells involved in mood.
Like SSRIs, psilocybin also targets serotonin, but in a subtly different way. Psilocybin helps relax thoughts and emotions, which appears to help depression patients become more receptive to the benefits of psychotherapy.
“There’s a lot of excitement about these new agents and I can understand why,” says Steven Marwaha, professor of psychiatry at the University of Birmingham. “There’s been a number of open label studies [where participants know about the treatment they are receiving] in which people who are having psychotherapy also have psilocybin, and it seems to have a positive effect, also one or two in the absence of psychotherapy, and there again seems to be a reduction of depressive symptoms.”
In one study last year, conducted by psychiatrists at the Karolinska Institute in Stockholm, 48 per cent of treatment-resistant depression patients, who had not responded to SSRIs, saw remission of their symptoms after ketamine treatment.
Prof Marwaha says the National Institute for Health and Care Excellence is currently considering approving a ketamine-based drug known as esketamine for use on the NHS. “It seems to have a rapid, and fairly persistent effect on the treatment of depression,” says Marwaha.
But neither ketamine nor psilocybin are a complete panacea. These drugs do not work for all patients and concerns have been repeatedly raised about their side-effect profiles, which can include hallucinations and out-of-body experiences following treatment, as well as fluctuations in blood pressure.
Another area of research showing promise, with a lower risk of side-effects, is brain stimulation. This month, scientists at the University of California San Francisco reported on a woman with severe depression whose symptoms had been dramatically alleviated by an electrical brain implant. Their finding was hailed as a landmark achievement in the drive for new treatments in mental health. The patient, known only as Sarah, said that wearing the device for a year had “kept depression at bay, allowing me to return to my best self and rebuild a life worth living”.
Previous brain stimulation devices tested for depression have had mixed results. This is thought to be because most devices only stimulate one area of the brain, while depression involves different brain regions in different people.
In the latest study, the researchers identified a specific pattern of brain activity which indicated the onset of the patient’s negative feelings, and embedded a deep brain stimulation device – equivalent to a pacemaker for the brain – which is designed to recognise that pattern and neutralise it by administering a mild electric pulse.
“The device has learned what depressive-like electrical activity looks like in the brain of the depressed patient,” explained James Potash, psychiatrist-in-chief at Johns Hopkins Medicine in Baltimore. “When it sees that pattern, it fires for six seconds to disrupt and reset the bad pattern. Then it turns off. The patient doesn’t sense anything has happened. It can do this up to 300 times a day.”
As it is such a personalised therapy, Potash says that it remains to be seen whether it can be applied to the wider patient population.
What about tech? The pandemic and its impact on mental health have seen people turning in their droves to digital apps and platforms, encompassing everything from mood tracking apps to chatbot psychologists. There are now more than 10,000 different mental health apps on the market, according to the World Economic Forum. But while many claim to be useful at diagnosing depression or improving symptoms and self-management, there is scant independent evidence of their efficacy. The industry is also almost entirely unregulated, meaning there is no standardised quality of virtual therapists, a source of concern to many psychiatrists.
“There’s very little trial evidence, which in effect means that no one’s investigated the harms of these apps,” says Prof Marwaha. “There is some evidence that if you’re rating your mood constantly over the course of a week, then you see at the end of the week that it’s pretty low, that may make you feel more low.”
With long waiting lists for talking therapies on the NHS, therapy apps remain a cheap and accessible alternative, though it may prove that they are only useful for the very mildest forms of the disease. Research has previously shown psychotherapy is most effective for mild-moderate depression when used in combination with SSRIs.
Traditional antidepressants remain a lifeline for many patients. Doctors stress that it is important that patients do not switch to other therapies before first consulting with their psychiatrist. “Trials have shown that antidepressants are effective to an extent in reducing relapse,” says Tony Kendrick, professor of primary care at the University of Southampton. “Most of them cost a few pounds a month, so someone can be on them for a year for £30 and it costs that much for an hour of psychotherapy. So clearly they’re cost effective to the NHS.”
Nevertheless, with such a range of different therapies being explored, there is increasing hope that depression will become a far more manageable condition.
“There have been people who have been struggling with depression for all of their life, and we really hope that with all this research taking place, many of them will get better,” says Carmine Pariante, professor of biological psychiatry at King’s College London. “We will have more tools available in future than ever before.”