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Several years ago, a colleague supervising an annual multidisciplinary research clinic studying Wolfram syndrome in children, adolescents, and young adults asked me to use my experience as a child and adolescent psychiatrist to perform neurological and psychiatric assessments of the study participants. Most participants had experienced diabetes from a young age, progressive vision loss due to optic atrophy, and hearing loss. Adolescents and young adults often showed progressive gait and difficulties with balance.
These many problems were tied to a defect in a gene that codes for a protein present in the endoplasmic reticulum (ER), a factory and storage area inside our cells, bounded by a network of folded membranes. This protein is called wolframin. When cells are under stress, particularly if they are unable to properly fold proteins, an ER stress response kicks in to get cellular processes back into balance. If this fails, or if the ER stress response does not shut down properly after cellular processes are back in balance, a self-destruct system can kick in, leading to death of the cells. The wolframin protein helps regulate this process, so cells won’t die unnecessarily; but in Wolfram syndrome, the ER stress response is exaggerated.
Many participants and their families had come to know each other from previous visits to our research clinic; some had even kept in touch and formed their own supportive community. As I met with them, I was often impressed by their resilience. Many reported initial difficulty adjusting to their diagnosis, but they learned ways to cope with an uncertain medical future. Some reported history of treatment with a selective serotonin reuptake inhibitor (SSRI) for symptoms of anxiety, obsessive-compulsive disorder, or depression.
Over the years, I noticed a possible pattern in their responses to these SSRIs, and I became curious. A search of the literature revealed that SSRIs differ in their action on another ER protein called the sigma-1 receptor (S1R), which—like wolframin—is a regulator of the ER stress response. S1R activators (including SSRIs like fluvoxamine and fluoxetine) can down-regulate the ER stress response, while another SSRI (sertraline) may have opposite actions on the S1R. I wondered whether the differing effects on S1R might explain differences in treatment response, particularly in people with genetic disorders of the ER stress response, such as Wolfram syndrome.
I began monitoring the literature on S1R and, in early 2019, I found an article (from research in the laboratory of Alban Gaultier, Ph.D., at the University of Virginia) that indicated that mice lacking the S1R showed excessive production of cytokines (inflammatory molecules), which increased susceptibility to death when exposed to inflammatory triggers or infections. And mice with functioning S1R showed improved survival under these conditions if given fluvoxamine.
This work showed that, in addition to down-regulating the ER stress response, the activated S1R could down-regulate cytokine production during severe infections that cause sepsis. I wondered how this new knowledge might be applied to treat human diseases in the future. Then, in March 2020, the Covid-19 pandemic had begun. I became ill myself with probable Covid-19. It was a strange and long-lasting illness with various fluctuating symptoms—nothing like any viral infection I’d experienced before.
While still ill, I read that deterioration in respiratory function around the second week of illness seemed to be due to an excessive inflammatory response to the virus rather than the virus itself. The body’s own response to the virus was doing the damage. I immediately thought back to that study of fluvoxamine from the University of Virginia, and I wondered whether fluvoxamine might be effective in treating Covid-19.
I sent off some quick emails to colleagues to see what they thought. That led me to Eric Lenze, M.D., a geriatric psychiatrist with extensive experience running randomized controlled trials (RCTs). I sent Lenze an email on March 25, 2020, explaining my hypothesis. He was convinced we should do an RCT, so we got the trial going as quickly as possible.
Since patients were isolating at home, our study staff took medications and study supplies to them using no-contact delivery methods. Patients logged oxygen levels, vital signs, and symptoms electronically, and we checked in with them as needed. None of the 80 patients taking fluvoxamine experienced respiratory deterioration by our study definition, but 8.3 percent of the 72 taking placebo deteriorated. It seemed that this treatment actually worked.
If these findings are confirmed in our ongoing larger study, fluvoxamine could have huge potential to reduce hospitalizations and deaths related to Covid-19. Thinking back on all this, it has been a strange journey. As a child psychiatrist, I never expected that I’d team up with a geriatric psychiatrist to run infectious disease treatment trials. And although the connection with Wolfram syndrome is indirect, if I had not become interested in the S1R as a result of Wolfram syndrome research, I might never have thought to use fluvoxamine as a treatment for Covid-19. l
Angela M. Reiersen is an associate professor of psychiatry at Washington University School of Medicine.