fMRI Scanning of Biomarker Predicts Response to Rapid Antidepressant Agent

“We have discovered a potential neuroimaging biomarker that may eventually help to personalize treatment selection by revealing brain-based differences between patients,” explained Maura Furey, PhD, of US National Institutes of Health’s National Institute of Mental Health (NIMH; Bethesda, MD, USA).

Scopolamine, typically recognized as a treatment for motion sickness, has been researched since Dr. Furey and colleagues discovered its fast-acting antidepressant properties in 2006. Dissimilar to ketamine, scopolamine works through the brain’s acetylcholine chemical messenger system. The NIMH scientists’ research has shown that by suppressing receptors for acetylcholine on neurons, scopolamine can lift depression in many patients within a few days; conventional antidepressants typically take weeks to work. But not all patients respond, prompting interest in a predictive biomarker.

The acetylcholine system plays a key role in working memory, retaining information in the mind temporarily, but appears to act by influencing the processing of data instead of through memory. fMRI scanning studies suggest that visual working memory performance can be enhanced by modulating acetylcholine-induced activity in the brain’s visual processing region, called the visual cortex, when processing information that is vital to the task. Because functional memory performance can predict response to traditional antidepressants and ketamine, Dr. Furey and coworkers looked at a working memory task and imaging visual cortex activity as potential tools to identify a biomarker for scopolamine response.

Depressed patients have a well-known tendency to process and remember negative emotional information. The researchers suggest that this bias stems from dysregulated acetylcholine systems in some patients. They rationalized that such patients would show abnormal visual cortex activity in response to negative emotional features of a working memory task. They also expected to find that patients with more dysfunctional acetylcholine systems would respond better to scopolamine treatment.

Before receiving scopolamine, participants performed a working memory task while their brain activity was monitored via fMRI. For some trials, it required that they pay attention to, and remember, the emotional expression (i.e., happy, sad) of faces flashing on a computer monitor. For other studies, they had to pay attention to only the identity, or non-emotional feature, of the faces. After scanning, and over the following several weeks, 15 patients with depression and 21 healthy participants randomly received infusions of a placebo (salt solution) and/or scopolamine. Mood changes were tracked with depression rating scales.

Overall, scopolamine treatment reduced depression symptoms by 63%, with 11 of the patients showing a significant clinical response. The strength of this response correlated considerably with visual cortex activity during key phases of the working memory task--while participants were paying attention to the emotional content of the faces. There was no such correlation for trials when they attended to the facial identity.

The evidence suggests that acetylcholine system activity triggers visual cortex activity that predicts treatment response—and that dissimilarities seen between depressed patients and controls may be traceable to acetylcholine dysfunction. Overall, patients showed lower visual cortex activity than controls during the emotion phase of the task. Patients demonstrating activity levels most unlike the control subjects experienced the greatest antidepressant response to scopolamine treatment. Visual cortex activity in patients who did not respond to scopolamine more closely resembled that of the controls. As theorized, the pretreatment level of visual cortex activity seems to reflect the extent of patients’ acetylcholine system dysfunction and to predict their response to the investigational medication, according to the researchers.

Early findings suggest that such visual cortex activity in response to emotional stimuli may also apply to other treatments and may prove to be a shared biomarker of rapid antidepressant response, according to Dr. Furey.

Related Links:
National Institute of Mental Health