For the first time in decades, researchers may have a new way to tweak brain signals to treat psychosis and other symptoms of schizophrenia. Results from a 245-person clinical trial hint that a compound called SEP-363856, which seems to act on neural receptors involved in dopamine signaling, might address a broader range of schizophrenia symptoms than currently available drugs do—and with fewer side effects.
“If these results are confirmed, this will be big, big news,” says Jeffrey Lieberman, a psychiatrist at Columbia University. The drug’s developer, Sunovion Pharmaceuticals Inc., identified it through an unusual screening process not guided by the brain circuits and receptors already implicated in the disease, Lieberman says. “It was a big gamble on their part. This study suggests that it may pay off.”
The biological basis of schizophrenia remains a puzzle, but researchers have linked patients’ hallucinations and delusions to an excess of the chemical messenger dopamine. To inhibit dopamine signaling, existing antipsychotic drugs bind to a type of dopamine receptor on neurons called D2. These drugs help control abnormal perceptions and thoughts—the “positive” symptoms of schizophrenia. But they don’t do much to address either cognitive impairments or the “negative” symptoms, including lack of motivation, dulled emotion, and social withdrawal. “Those negative symptoms are often the most devastating,” says Diana Perkins, a psychiatrist at the University of North Carolina, Chapel Hill. “A person can become, at the most extreme, robotlike.”
The first generation of antipsychotic drugs that emerged in the 1950s sometimes actually worsened these negative symptoms, Perkins says. And tamping down on dopamine signaling can lead to side effects including tremors and other involuntary movements. A second generation of D2-targeting drugs has reduced the risk of some of these side effects, but many cause weight gain and other metabolic problems.
Sunovion started its drug search wanting to avoid D2 receptors. “It was a bit of an antitarget approach,” says Kenneth Koblan, the company’s chief scientific officer. “If [a compound] worked through the D2 system, we didn’t want to work on it.” The researchers relied on a drug screening method, developed by PsychoGenics Inc., that used artificial intelligence to analyze the behavior of mice exposed to hundreds of candidate compounds. The researchers looked for a compound that mimicked the effects of D2-targeting drugs. One stage of the testing involved trying to reverse the effects phencyclidine, better known as PCP, which causes hyperactivity and other schizophrenialike behaviors.
SEP-363856 rose to the top of the heap. This compound didn’t touch D2 receptors, the researchers found, but it activated two other types of neural receptors—known as TAAR1 and 5-HT1A—that help regulate the synthesis and release of dopamine. The mechanisms of the drug aren’t fully clear, but the researchers suspect they’ve hit on a new way to tweak dopamine signaling.
The clinical trial tested SEP-363856’s effects in people who were still early in the course of schizophrenia—none had been hospitalized for acute psychotic symptoms more than twice. During a flare-up of these symptoms, the participants, who ranged from 18 to 40 years old, spent 4 weeks in the hospital taking either SEP-363856 or an identical-looking placebo pill once a day. Clinicians then evaluated a broad set of schizophrenia symptoms using a measure called the Positive and Negative Syndrome Scale (PANSS), which gives scores ranging from 30 to 210, with a higher score representing worse symptoms. On average, participants scored roughly 100 on entering the study; after 4 weeks, the average score in the drug group had dropped by 17.2 points, versus 9.7 in the placebo group, the researchers report today in The New England Journal of Medicine.
“This is great news,” says Romina Mizrahi, a psychiatrist at the University of Toronto. The trial didn’t directly compare SEP-363856 to other drugs, but she notes that the reduction in PANSS scores is similar to results from some trials of now-approved antipsychotic drugs.
The group taking SEP-363856 also had a larger drop than the placebo group on another scale, one meant to measure negative symptoms like lack of pleasure and motivation. Though the study wasn’t statistically designed to draw conclusions using this secondary measure, this early indication “is a big deal, and it’s potentially a game changer,” Perkins says. “If it’s confirmed … that would mean a lot for many patients and their families.”
Rates of side effects, including movement disorders, nausea, agitation, and drowsiness, were low in both groups. And although SEP-363856’s long-term effects on metabolism aren’t clear, the compound didn’t cause major weight gain in either the 4-week trial or a 26-week extension that included 156 of the participants, all of whom got the experimental drug.
Sunovion isn’t the only company looking to sidestep D2 receptors in treating schizophrenia. Karuna Therapeutics is studying xanomeline, a compound with a different neural target, which Eli Lilly developed in the 1990s and later abandoned after finding that many patients experienced side effects that include nausea and dizziness. (Karuna aims to reduce those effects by combining xanomeline with another drug.) The company announced positive results from a study involving 182 patients last year.
In September 2019, Sunovion launched a larger, phase III trial that will include more than 1000 people, designed to prove the drug’s efficacy and win regulatory approval. Koblan says he can’t estimate when the trial might yield results, citing COVID-19. “I would be very comfortable answering that question if we weren’t in the midst of a pandemic,” he says.