Summary: Targeting a single negative symptom of schizophrenia—avolition, or reduced motivation—can produce wider improvements across other negative symptoms, according to new analysis of clinical trial data.
Source: University of Georgia
New analysis by a University of Georgia research team led by psychologist Gregory Strauss shows that therapies aimed at avolition may improve the broader constellation of negative symptoms in schizophrenia, a group of symptoms for which there are currently no approved pharmaceutical treatments.
Researchers examined clinical trial data from Minerva Neurosciences’ phase 2b study of roluperidone (also known as MIN-101) and applied network analysis to understand how different negative symptoms interact. Their findings, published in Schizophrenia Bulletin, suggest that when a treatment reduces avolition, other negative symptoms—such as anhedonia, asociality, blunted affect, and alogia—tend to improve as well.
“There’s a lot of hope that Minerva’s phase 3 trial will show a similar improvement in negative symptoms,” said Strauss, assistant professor in the Franklin College of Arts and Sciences. “This could be the first drug that receives an indication for negative symptoms of schizophrenia from the Food and Drug Administration, which is perhaps the biggest unmet need in the field of psychiatry. It would be a monumental benefit to the lives of people with schizophrenia.”
Negative symptoms of schizophrenia are strongly linked to functional disability. Across population studies, schizophrenia is a leading medical cause of disability worldwide. People with prominent negative symptoms often have difficulty maintaining employment, sustaining social relationships, and carrying out daily independent activities. In many countries, severe functional impairment can also lead to eligibility for government disability support.
“The government spends a tremendous amount of money every year on functional disability,” Strauss added. “Negative symptoms are the strongest predictor of functional disability, but no medication has received FDA approval for treating them. Therefore, they are a critical treatment target.”
Strauss has authored more than 125 studies on schizophrenia symptoms. In 2018 he and colleagues showed that negative symptoms are not a single construct but consist of five distinct domains: avolition (reduced motivation), anhedonia (reduced pleasure), asociality (less social engagement), blunted affect (reduced outward expression of emotion), and alogia (reduced speech). Each of these domains represents a separate treatment target.
To determine which domain might be most influential for treatment outcomes, Strauss and collaborators used network analysis, an approach borrowed from engineering and complex systems science. Unlike traditional methods that treat symptoms individually, network analysis maps the dynamic relationships among symptoms, identifying which symptoms are most central and which influence others. Even when a treatment does not dramatically lower the severity of every symptom directly, it may change how symptoms interact, producing broader clinical benefit.
Earlier research by Strauss and colleagues indicated that avolition is a central node within the negative symptom network. The new study applied network analysis to the roluperidone randomized clinical trial data. In that trial, participants with schizophrenia and moderate to severe negative symptoms were randomized to roluperidone 32 mg (n = 78), roluperidone 64 mg (n = 83), or placebo (n = 83). The original trial reported significant reduction in negative symptoms for the active treatment.
The network analysis showed that in the placebo group, avolition occupied a highly central position among negative symptoms, meaning it was closely connected to other domains. In the roluperidone-treated participants, the centrality of avolition was reduced, indicating that improving motivation decoupled avolition from other negative symptom domains and produced downstream improvements across the network. In other words, when treatment effectively reduced avolition, other negative symptoms moved toward improvement as well.
“This study suggests that future drug development should target mechanisms of avolition in particular,” Strauss said. “If that domain is successfully improved, it might be possible to improve all negative symptoms and subsequently reduce functional disability.”
Strauss served as a consultant with Minerva Neurosciences and co-developed the clinical outcome measure used in the trial; he was not involved in developing roluperidone. Co-authors on the paper include Farnaz Zamani Esfahlani, Hiroki Sayama, Brian Kirkpatrick, Remy Luthringer, Mark Opler, Michael Davidson, and others. The research emphasizes targeting motivational processes as a promising strategy for alleviating the broader negative symptom burden in schizophrenia.
Source:
University of Georgia
Media Contacts:
Gregory Strauss – University of Georgia
Image Source:
The image is in the public domain.
Original Research:
“Network Analysis Indicates That Avolition Is the Most Central Domain for the Successful Treatment of Negative Symptoms: Evidence From the Roluperidone Randomized Clinical Trial.” Gregory P. Strauss, Farnaz Zamani Esfahlani, Hiroki Sayama, Brian Kirkpatrick, Mark G. Opler, Jay B. Saoud, Michael Davidson, Remy Luthringer. Schizophrenia Bulletin. DOI: 10.1093/schbul/sbz141.
Abstract (summary):
This randomized clinical trial evaluated roluperidone’s effects on negative symptoms from a network perspective. Macroscopic network properties showed no overall change in symptom network density between treatment and placebo, but microscopic measures of centrality identified avolition as a key node. Roluperidone reduced the centrality of avolition, suggesting that decoupling motivational processes from other negative symptom domains drives broader clinical improvement. The findings support prioritizing avolition as a target for future pathophysiological research and treatment development.