Finding a possible new way to treat schizophrenia
As a neuroscientist, Eden Maness is never really off the clock.
“I was always the person at the party that had one beer and immediately began talking to everyone around me about the brain and behavior,” she said.
Maness is a third-year Ph.D. candidate pursuing her doctorate in neuroscience through the Applied Science department at William & Mary, where her advisor, Joshua Burk, is chair of the university’s Department of Psychological Sciences.
“I think everyone who knows me is aware of how passionate I am about my research and how invested I am in the pursuit of better treatments for psychiatric illnesses,” she said.
For her research into the underlying neurobiology of attentional processing in the context of schizophrenia drug discovery, Maness is the recipient of the William & Mary Graduate Studies Advisory Board Award for Excellence in Scholarship in the Natural and Computational Sciences.
The award is one of three honors bestowed in conjunction with the annual Graduate Research Symposium. This year, the symposium content is being presented in an online format in accord with the university’s social-distancing policies during the COVID-19 pandemic.
Maness's work is titled “The Antipsychotic Potential of Orexin Receptor Inhibitors for the Treatment of Schizophrenia.” It examines the potential of various experimental compounds to restore attentional function in rodent models of psychosis.
Specifically, she targeted the brain’s lateral hypothalamic orexinergic system, which acts as a gatekeeper for several neurotransmitter networks, with the goal of finding a new treatment for schizophrenia.
“A brief discussion with my advisor about possibly exploring the link between orexins and schizophrenia led to a feverish search of the existing literature,” she said. “Both to my astonishment and my excitement, I saw that almost no work had been done regarding orexin receptor-targeting drugs and their possible utility for the treatment of psychosis. As a scientist, the juncture of ‘this hasn’t been done’ and ‘this needs to be done’ is a thrilling, albeit very intimidating, place to be.”
That juncture could have major implications for the mental health field. A recent experiment from Maness’s lab offers support to her hypothesis that blocking orexin neurons may be an effective way to reduce sustained attentional impairments for people experiencing psychosis as a result of schizophrenia.
“It was honestly better than I could have expected,” she said. “Intracranial infusions of filorexant, an orexin receptor blocker, were actually able to normalize attentional deficits in many key aspects. The degree to which it did this was a total surprise to me.”
Maness says that virtually all brain networks are influenced by orexins in some way. She explains that the main job of orexins, which are considered “neuromodulators,” is to facilitate the release of other neurotransmitters, including but not limited to the better-known serotonin, noradrenaline and dopamine.
In general, boosting orexins leads to a state of increased wakefulness, alertness, motivation and vigilance, she explained. Inhibiting orexins, on the other hand, can lead to the opposite.
“This is why suppressing this system is beneficial to treat insomnia and enhancing this system aids in maintaining consciousness for those with narcolepsy,” she said.
Dopamine is responsible for sensory processing and decision-making, she explained. People with schizophrenia are described as experiencing “hyperdopaminergia,” a state of increased dopamine that produces severe hallucinations and/or delusions, as well as social, motivational and cognitive deficits.
“It’s truly a devastating illness for those who have it and for the friends and families of those afflicted,” Maness said. “There is a major need to reduce its prevalence and gravity.”
Since the 1950s, schizophrenia has classically been treated with medications in the “antipsychotic” drug class, she explained. All antipsychotics on the market today bind to and inhibit dopamine receptors, which lessens the activation of dopamine neurons and reduces brain-wide dopamine release.
“In this regard, antipsychotic treatment does provide some relief,” Maness said. “It assuages the pervasiveness and severity of hallucinations and delusions, which can be disturbing at best and life-ruining at worst. Unfortunately, while helpful in some aspects, these medications have extremely unpleasant and potentially life-long and fatal side effects.”
Some of those side effects include Parkinson’s disease-like tremors, uncontrollable face twitching, heart disease, obesity and diabetes, blurry vision, and dangerous decreases in white blood cell count, Maness said.
“Equally as important is the exacerbation of social withdrawal, demotivation, as well as the attention, learning and memory impairments that are common in schizophrenia,” she continued. “The ultimate failure of modern antipsychotics in holistically treating the disorder, as well as their propensity to produce distressing physiological and psychological side effects, provide a strong impetus to look for novel receptor systems to target to treat such a severe mental illness.”
Using a commonly-employed animal model of psychosis, Maness found that inhibiting orexins by administering filorexant directly into the brain both restored the ability to detect visual signals and greatly increased responsiveness in a sustained attention task, suggesting that orexin inhibitors prove beneficial in alleviating vigilance and motivational dysfunction that often go untreated by extant antipsychotics.
The mechanism through which filorexant exerts its beneficial effects is speculated to be due to its anti-dopaminergic nature, she explained. This is the first experiment of its kind, she said, and her next steps involve targeting one orexin receptor at a time to parse which one is most responsible for the observed benefits in this specific paradigm.
“Years after starting this research, I am even more impassioned and curious than I was before,” Maness said. “I think I may be onto something, and that’s a feeling I love to chase.”
