Fourteen years ago, the Icelandic neuroscientist Kári Stefánsson led a landmark investigation into the genetic risk factors for developing schizophrenia, a debilitating mental health condition in which people may lose touch with reality.
Kári is the chief executive of deCode genetics, based in Reykjavík, which has studied genetic information from more than two thirds of the Icelandic population. Since 2009, its work has helped to draw an assocation between people with schizophrenia and those in creative professions. Icelandic writers, painters and musicians were all found to have an inherently higher risk of the condition, which typically develops in adolescence or early adulthood.
Kári argues that this association is an inevitable consequence of evolution. Every child is born with around 60-70 random new mutations in their DNA, a biological quirk that provides the basis for humans to adapt to our changing world.
And how does this connect schizophrenia with creativity? Kári believes that when some random mutations occur in the brain, it can yield highly imaginative and visionary individuals with minds hardwired to think differently. But in around 1% of the population, the combination of these mutations and environmental risk factors such as infections, childhood adversity and cannabis use can lead to schizophrenia. Through this theory, Kári argues that their care should be given greater precedence in our society.
“A small minority of unlucky individuals pay a very high price for our ability to be creative and have the attributes that gave us the music of Bach, Mozart and Beethoven,” he says. “In a societal context, we owe it to these people to help them, because they are the ones paying for the fact that our species will continue to develop and evolve.”
But by and large, society has done poorly in terms of caring for those with the condition, with many being vulnerable and marginalised. While the concept of a schizophrenia patient trapped within their own hallucinations has been hugely popular with Hollywood – the movies A Beautiful Mind and Shutter Island both use the delusions and escalating paranoia of the title character as part of the plot – this attention has not extended to their medical care.
Since the 1950s, generations of antipsychotics have been developed, aimed at eliminating the paranoia and visual, auditory, and sensory hallucinations that patients can experience, by targeting the brain chemical dopamine. But the drugs mean that many patients must endure debilitating side-effects, which in some cases may even shorten their lives. Older medications such as haloperidol and promazine have been known to induce Parkinson’s-like tremors and rigidity, while newer drugs such as clozapine and olanzapine, which emerged in the 1980s and 90s, cause excessive weight gain, often resulting in diabetes and heart problems.
Cardiovascular disease is the cause of death in 40-50% of schizophrenia patients, so psychiatrists often face an appalling dilemma: prescribe a medication that may relieve some symptoms but could make patients sicker in other ways. Joshua Kantrowitz, associate professor of clinical psychiatry at Columbia University, mentions a current patient who has gained 45kg (100lb) since taking olanzapine.
“Olanzapine in many ways is an excellent drug, and there are some patients who only really respond to it, but it can cause them to gain life-altering weight,” he says. “I’m left with the choice of my patient being crippled by voices and delusions, estranged from his family, or being able to function, get a job and live some kind of life, but 100lb heavier. It’s a pretty horrible choice.”
But there is hope that better ways of treating schizophrenia are starting to emerge. In March, a small Boston-based company called Karuna Therapeutics reported a successful phase III clinical trial of a new drug called KarXT, a combination of the chemicals xanomeline and trospium chloride. The benefits are relatively small, but it showed some reduction of symptoms without the side-effects of previous drugs.
If KarXT is greenlit by the US Food and Drug Administration, it may be available in 2024 as the first genuinely novel antipsychotic in three decades. “For the first time in a really long time, we have real hope for some breakthroughs,” says Kantrowitz.
Treating negative symptoms
KarXT emerged through a series of accidental breakthroughs. In the 1990s, the pharmaceutical company Eli Lilly developed xanomeline as a way of targeting so-called muscarinic receptors in the brain, which are associated with a network of brain chemicals called the cholinergic system. Because this network plays an integral role in learning and memory, it wanted to see whether xanomeline could improve the cognition of Alzheimer’s patients.
Researchers then found something unexpected. In the latter stages of Alzheimer’s, some patients also experience delusions and agitation, which xanomeline appeared to address. Unfortunately, xanomeline also activated muscarinic receptors throughout the gastrointestinal tract, causing severe nausea and diarrhoea, and was swiftly abandoned.
A decade later, the story came to the attention of Andrew Miller, a chemical engineer who was working for a venture capitalist investing in healthcare startups. “As part of that experience, I got exposed to schizophrenia, how many people it affects, and it just made me wonder: ‘How come this plight is so significant yet we don’t talk about it from a societal perspective?’” he says.
Miller wondered whether there was a way to use xanomeline as an antipsychotic to treat schizophrenia. He speculated that combining it with trospium chloride could limit its activity to the brain, stopping harmful side-effects.
In 2009, he founded Karuna Therapeutics, and with the help of funding from the Wellcome foundation, initiated clinical trials. Fourteen years on, there are signs that KarXT might become the first drug to offer benefit across a wider spectrum of schizophrenia symptoms.
One of the great challenges with schizophrenia is that it can manifest in a broad variety of ways; some have dubbed it an umbrella term for eight, 12 or even 100 different conditions. Although Hollywood popularised the idea of schizophrenia hallucinations, some patients do not experience them. It is the so-called “negative” symptoms (characterised by loss) – the progressive loss of motivation, inability to show emotion, and difficulty talking – that psychiatrists often regard as the most damaging.
“Patients avoid and become fearful of people,” says Dragana Bugarski-Kirola, a former psychiatrist and vice-president of clinical development at Acadia Pharmaceuticals in Switzerland. “Negative symptoms often lead to the lack of care for physical health, and remain one of the largest unmet needs.”
While up to 60% of schizophrenia patients experience prominent negative symptoms, conventional antipsychotics make little difference to them. But there are signs that KarXT may help. Acadia Pharmaceuticals is also conducting a phase III trial of a drug called pimavanserin, entirely aimed at tackling this aspect of the condition.
Kantrowitz says that to be a true game-changer for patients, either Karuna Therapeutics or Acadia Pharmaceuticals must demonstrate that their medicines can offer real benefit with the negative symptoms.
“The level of disability faced by schizophrenia patients hasn’t changed much in 60, 70 years, which is kind of depressing,” he says. “It’s the hallucinations and delusional thinking which see patients hospitalised, but the chronic illness they’re struggling with when trying to live their lives at home comes from the negative symptoms. Whether these drugs can change that will determine whether they’re a radically different treatment option or not.”
Lessons from Covid
For decades the holy grail of psychiatry has been to stratify complex mental health conditions such as schizophrenia, depression and bipolar depression into an array of different subcategories. In the same way that patients are diagnosed with a particular form of breast or prostate cancer that allows oncologists to customise their treatment, psychiatrists dream of being able to give patients a test that places them in a particular category with suitably tailored medications.
Attempts to achieve this have mostly failed, mainly because understanding what is going wrong in mental health conditions is so much harder. Unlike cancer, where researchers can examine biopsies of different tumours, it is not possible to extract brain samples from a living patient, and for such complex mental health conditions, the information yielded by sequencing millions of genomes has been too variable to be of practical use.
“There’s been a lot of effort on identifying patients in the early phases of psychosis and looking at brain imaging or genetics or psychometric scores to try to profile them, but it’s all been a bit disappointing,” says Belinda Lennox, professor of psychiatry at the University of Oxford.
This echoes the thoughts of Thomas Insel, the former head of the US National Institute of Mental Health who made the astonishing admission when stepping down from his post, that while the NIMH had spent around $20bn (£15.5bn) researching mental illness, it had failed to make a difference in improving the lives of patients.
Strategies have since shifted towards finding new medications that can help patients swiftly, and then attempting to learn what they can tell us about the condition. Lennox calls this a “fail fast and move on” approach, inspired in part by Covid initiatives such as the Recovery trial, and the lightning speed with which they identified plausible antivirals.
“There’s much more of an acceptance now that a clinical trial doesn’t have to be a huge 10-year enterprise,” she says. “Instead, we can give lots of things a go, look at who benefits and who doesn’t, and then work backwards to try to understand more about the disease that way.”
Later in 2023, Lennox will begin a project in collaboration with Wellcome to understand what KarXT can tell us about brain chemistry in schizophrenia. Because the brain rewires itself abnormally over time in the condition, Lennox and her collaborators will give the drug to around 100 different patients, and use the cutting-edge brain imaging technique magnetic resonance spectroscopy (MRS) to see how the medicine reshapes the connections between different regions.
“It’s a way of looking inside the brain, looking at how a drug affects the different chemicals in the brain at extremely high resolution,” she says. “This wouldn’t have been possible 10 years ago but with the latest forms of MRS you can get very high levels of accuracy on what’s going on in the brains of those patients over time.”
For Kantrowitz, having more new drugs emerge, which researchers can then compare and contrast, is perhaps the main way in which we will ultimately gain a deeper understanding of this complex condition.
“For a long time we’ve really only been treating some of the symptoms of schizophrenia, and treating them indirectly,” he says. “But having new treatments that work in different ways will make it possible to start fine-tuning which symptoms respond to which drug and why. We’re still not really addressing the root cause of the disease, but perhaps slowly but surely we’ll get there.”
• This article was amended on 30 July 2023 to refer to Kári Stefánsson as Kári after first mention, in accordance with Icelandic naming style.
• In the UK, Samaritans can be contacted on 116 123 or email jo@samaritans.org. You can contact the mental health charity Mind by calling 0300 123 3393 or visiting mind.org.uk and Childline can be reached on 0800 1111. In the US, Mental Health America is available on 800-273-8255. In Australia, support is available at Beyond Blue on 1300 22 4636, Lifeline on 13 11 14, and at MensLine on 1300 789 978
