Prozac, also known by its chemical name fluoxetine, is an antidepressant medication.
A team of WashU Medicine researchers has discovered a promising new use for Prozac, which is the brand name of the antidepressant fluoxetine, in the treatment of children with rare forms of epilepsy.
In a Frontiers of Pharmacology case report published earlier this year, the researchers describe how fluoxetine treatment of two siblings with developmental and epileptic encephalopathy improved seizure control, decreased antiepileptic medication use and aided development.
The groundbreaking report resulted from a close collaboration between Lawrence Salkoff, PhD, a professor of neuroscience, and Christina Gurnett, MD, PhD, the A Ernest and Jane G Stein Professor of Neurology and the head of the Division of Pediatric and Developmental Neurology at WashU Medicine.
Gurnett has been the sisters’ neurologist for more than 15 years.
“One of the children had already been taking fluoxetine for anxiety, and we noticed that her seizures improved significantly,” said Gurnett, who also is chief of neurology at St. Louis Children’s Hospital. “After starting fluoxetine, we were able to wean her off several other seizure medications, and her seizures remained improved. She also had beneficial improvements in her overall functional ability, including improved stamina and the development of new skills. We therefore treated her sister with fluoxetine and found similar improvements in seizures and neurodevelopment.”
The two sisters had struggled with severe, treatment-resistant seizures for years. Despite multiple antiepileptic medications, their seizures remained uncontrolled. In 2022, genetic sequencing of the two sisters revealed a pathogenic variant in the KCNC2 gene, which encodes a potassium ion channel essential for normal neuronal function.
The Salkoff Lab played a key role in identifying the underlying mechanism, as the gene variant was in a potassium ion channel type that the lab had first cloned and functionally characterized. The lab duplicated the genetic defect in the ion channel gene and functionally expressed it in a cell system used for channel analysis in the laboratory. Further work showed that the gene caused the ion channel to confer a dangerous gain-of-function phenotype, so several pharmacological agents of a particular class were tested to see if one would block the adverse genetic defect.
“When Prozac was first approved for use as an effective anti-depressive agent, it was shown to have many off-target effects, one of which was an ion channel blocking effect,” Salkoff said. “Recently, fluoxetine was used in a case study of a genetic variation in a different channel type to treat a seizure disorder, so Dr. Gurnett suggested we might analyze its effect in our experiments. It was an even more effective blocker of the channel type affected in the two sisters.”
Further research by the WashU investigators showed that norfluoxetine, a breakdown product of fluoxetine that accumulates in fluoxetine users, had a remarkably targeted ability to block the gain of function channels produced by the harmful genetic variation. Because of this experimentation, norfluoxetine is thought to be the most likely agent to relieve the sisters’ seizures.
WashU-related co-authors on the report are Alice Butler, a staff scientist in the Department of Neuroscience; Ping Li, MD, PhD, a senior scientist with the Center for Reproductive Health Sciences in the Department of Obstetrics & Gynecology; and Yu Zhou, PhD, instructor in the Department of Anesthesiology. Karl L. Magleby, PhD, professor and chair of physiology and biophysics at the University of Miami Miller School of Medicine, was also a co-author.
The study exemplifies the synergy between basic and clinical science at WashU Medicine to advance precision therapeutics, with Gurnett emphasizing the significance of working in an environment that fosters interdisciplinary partnerships.
“The exciting aspect of being at Washington University is that clinicians and scientists work together in close proximity,” she said. “There are few walls.
“Dr. Salkoff is a giant in the field of ion channels, and I came to Washington University in 2000 to work with him and other investigators like him. We have had many discussions about other patients over the years, and this was an opportunity to impact my patient’s care and to advance the field of precision therapeutics more broadly.”
Encouraged by these results, the researchers are now working with WashU Medicine chemists to develop a toolkit of targeted agents for treating rare diseases caused by the dysfunction of potassium ion channels. While this case study focuses on a rare epilepsy caused by a KCNC2 mutation, there are over 100 potassium channel genes, many of which are potential candidates for similar gain-of-function mutations. The research opens the door to investigating fluoxetine and related drugs for other genetic epilepsies.
“We will use molecular modeling and our knowledge of the chemical structures of fluoxetine and norfluoxetine to refine and optimize treatments,” Salkoff said. “This is a strategy where the whole comes out being greater than the sum of its parts.”
Li P, Butler A , Zhou Y., Magleby K, Gurnett C, Salkoff L. Case Report: Targeted treatment by fluoxetine/norfluoxetine of a KCNC2 variant causing developmental and epileptic encephalopathy. Frontiers in Pharmacology. January 2025. DOI: 10.3389/fphar.2024.1528541