They were testing the sleep-inducing drug to help with the symptoms of Angelman Syndrome, a rare neurogenetic disorder that appears in infancy. It results in a variety of developmental problems such as walking and balance disorders, inability to speak or sleep properly, gastrointestinal issues, and seizures. It affects people in different ways and to different degrees. Notably, those who cope with Angelman smile and laugh a lot and have a normal lifespan.
The OVID team had high hopes for gaboxadol in August of this year because even improving the quality of sleep would help sufferers a lot. So, at a conference on the disorder, they waited for the news in hope…
“Ovid’s chief medical officer called into the conference room. He got straight to the point: There was no statistically significant benefit for children who received gaboxadol versus a placebo. The treatment had failed.
The room fell silent. Levin thought about how the company would need to restructure its programs and how its stock would be battered. But mostly he thought about the families and the overwhelming disappointment they would feel.
Levin began to cry. His colleagues, many of whom had also devoted years of their lives to this project, cried too.”Angie Voles Askham, “What next for Angelman?” at Spectrum (October 20, 2022)
Angelman Syndrome is caused by a loss of function of the UBE3A gene in the 15th chromosome derived from the mother.
But now, about that placebo effect… Molecular biologist Rebecca Burdine, whose daughter Sophie suffers from Angelman was there to present a keynote address. As Askham recounts,
One problem, Burdine knew, is that even updated forms of assessment might not capture all of the ways a treatment could benefit a child. Even worse, treatments for many neurodevelopmental conditions, including Angelman syndrome, remain frustratingly susceptible to the placebo effect in clinical trials. Simply enrolling a child in a trial — giving them more medical and parental attention — can cause improvement in some skills. Burdine knew that in the gaboxadol trial, a child who had never walked before took their first steps — but it turned out that they were receiving placebo. That experience told Burdine that, until placebo-controlled trials were run, it would be impossible to know how well a treatment worked.
As the field progresses, Levin and his colleagues are also hoping to understand how people with Angelman syndrome respond to placebo, and how the condition affects people over time. To that end, last month Ovid released the data from its placebo-controlled gaboxadol trial and has encouraged other companies to do the same.Angie Voles Askham, “What next for Angelman?” at Spectrum (October 20, 2022)
The placebo effect means that, if you are part of a research study where you think you are receiving treatment for a disorder, you may start to improve in testable ways — even if you are in the control group, getting a sugar pill. It is literally “all in your mind.” But, as Ovid’s unfortunate experience shows, it is nonetheless powerful enough to impact a genetic disorder by itself.
“The placebo effect is more than positive thinking — believing a treatment or procedure will work. It’s about creating a stronger connection between the brain and body and how they work together” …Mental Health, “The power of the placebo effect” at Harvard Health Publishing (December 13, 2021)
Placebos won’t, for example, cure cancer. But when a disease affects the brain-body relationship, as Angelman does, the placebo response can confound research, as we saw above. We learn from the National Library of Medicine that “Migraines, joint pain, arthritis, asthma, high blood pressure, and depression are some disease conditions that are more sensitive to the placebo effect.” (June 23, 2022)
How does it work?
How placebos work is still not quite understood, but it involves a complex neurobiological reaction that includes everything from increases in feel-good neurotransmitters, like endorphins and dopamine, to greater activity in certain brain regions linked to moods, emotional reactions, and self-awareness. All of it can have therapeutic benefit. “The placebo effect is a way for your brain to tell the body what it needs to feel better,” says Kaptchuk.
But placebos are not all about releasing brainpower. You also need the ritual of treatment. “When you look at these studies that compare drugs with placebos, there is the entire environmental and ritual factor at work,” says Kaptchuk. “You have to go to a clinic at certain times and be examined by medical professionals in white coats. You receive all kinds of exotic pills and undergo strange procedures. All this can have a profound impact on how the body perceives symptoms because you feel you are getting attention and care.”Mental Health, “The power of the placebo effect” at Harvard Health Publishing (December 13, 2021)
A 2015 paper in Nature on the neuroscience of the placebo effect points to its importance:
We present an empirical review of the brain systems that are involved in placebo effects, focusing on placebo analgesia, and a conceptual framework linking these findings to the mind–brain processes that mediate them. This framework suggests that the neuropsychological processes that mediate placebo effects may be crucial for a wide array of therapeutic approaches, including many drugs.Wager, T., Atlas, L. The neuroscience of placebo effects: connecting context, learning and health. Nat Rev Neurosci 16, 403–418 (2015). https://doi.org/10.1038/nrn3976
The placebo effect is a clear demonstration of the existence and power of the immaterial human mind. Its effect, generated by a patient’s belief, can be powerful enough to confound research.
Meanwhile, it’s not all bad news for the Angelman research. Gaboxadol worked for adults, though not kids, because “the drug acts on a receptor that changes its expression in adolescence.” Also, Ovid Therapeutics is no longer the only company working in this area. Now more than twenty such therapies are being developed. Down the road, a cure for Angelman may be possible because the exact cause is now known and the disorder has been reversed in mouse models.
You may also wish to read: Is consciousness a controlled brain hallucination? No. Anil Seth explains away consciousness away using fashionable terms like that. As a pediatric neurosurgeon, I know from clinical experience that he is wrong. Children born without brain hemispheres (anencephaly) are conscious; only a dualist or idealist perspective on the brain-mind relationship can explain that fact. (Michael Egnor)