A new study published this week in Molecular Psychiatry by Emory University researchers has revealed a promising new avenue for treating motivational deficits in patients suffering from depression.

Motivational impairments are a core component of depression and have long been linked with poor treatment outcomes, diminished quality of life and heightened suicide risk. Growing evidence suggests one potential cause of low motivation may be persistent inflammation, which suppresses activity within key circuits in the brain.

This study is the first of its kind to examine the effects of infliximab—an antagonist of inflammatory molecule tumor necrosis factor (TNF)—on both behavioral and brain markers of motivation in a group of 42 medically stable, unmedicated depressed patients.

Importantly, the study focused on patients who were not only depressed, but also exhibited evidence of high inflammation as measured by C-reactive protein (CRP) greater than 3 mg/L. CRP is a blood test commonly available in clinics and hospitals throughout the United States.

The research team believed that for some patients with depression, the addition of high inflammation might play a key role in their experience of lower motivation.

Patients were randomly assigned to receive either a single dose of infliximab (a potent anti-inflammatory medication used to treat rheumatoid arthritis and other inflammatory conditions) or a placebo.

Over two weeks, researchers assessed changes in the patients' motivation using a variety of methods, including an effort-based decision-making task, self-report questionnaires and functional magnetic resonance imaging (fMRI) to observe brain activity.

Patients who received infliximab demonstrated a greater willingness to exert effort in pursuit of rewards compared to those who received the placebo. This increase in effortful behaviour was closely tied to a reduction in signalling pathways directly targeted by infliximab, particularly TNF.

Furthermore, these changes were reflected by alterations in brain activity within key regions associated with motivation, such as the dorsomedial prefrontal cortex, ventral striatum and putamen, as well as the functional connectivity between these areas.

"This is the first study to reveal the impact of an anti-inflammatory drug on brain circuits related to motivation," says first author Michael Treadway, Ph.D., professor of psychology at Emory University. "It's exciting to see how modulating inflammation can directly influence motivation, one of the most challenging symptoms to treat in depression."

Importantly, the study found the relationship between infliximab treatment and improved motivation was mediated by the observed changes in TNF signaling and brain activity. Furthermore, reductions in motivational deficits were associated with heightened responses in a brain network sensitive to reward.

"These findings build on growing evidence that anti-inflammatory treatments hold promise as a novel approach for addressing motivational deficits in depression," says senior author Andrew Miller, professor of psychiatry and behavioral sciences at Emory University School of Medicine.

"By targeting inflammation, we're not only addressing the biological underpinnings of these deficits but also offering new hope for more effective treatment options."