Prefrontal Brain Activity May Predict Depression Severity

Deborah Brauser

November 06, 2013

Increased brain activity during negative emotion processing may be a biomarker for decreasing symptom severity in patients with major depressive disorder (MDD), new imaging research suggests.

The double-blind study of 21 patients with MDD was created to assess neural circuit changes in emotion regulation that came about from use of 1 of 2 antidepressants during the course of 6 months.

Results showed that the participants who had the most rapid increase in activity from baseline to the 6-month endpoint in the brain's Brodmann area 10 and in the right dorsolateral prefrontal cortex (PFC) during negative affect regulation also had the sharpest decrease in symptom severity scores.

"The findings showed that the rate of change in activity in these 2 areas of the PFC tracked with the rate of change in depression severity," lead author Aaron S. Heller, PhD, from the Psychiatry Department at the Sackler Institute for Developmental Psychobiology at Weill Cornell Medical College in New York City, told Medscape Medical News.

"This was interesting but not entirely surprising. What was surprising was that changes in amygdala activity did not track with depression severity changes," said Dr. Heller, who was at the Laboratory for Affective Neuroscience at the University of Wisconsin in Madison at the time of the study.

He noted that the study's take-aways include the need for using "emotion regulation paradigms" in future studies and that this patient population needs to be followed for longer than 8 weeks in order to see substantial changes in the brain.

The study was published online October 30 in JAMA Psychiatry.

Assessing Neurobiology Changes

"Emotion regulation is critically disrupted in depression, and the use of paradigms that tap into these processes may uncover essential changes in neurobiology during treatment," write the researchers.

"In addition, because neuroimaging outcome studies of depression commonly use only baseline and end-point data — which are more prone to week-to-week noise in symptomatology — we sought to use all data points over the course of a 6-month trial," they add, noting that their objective was to assess neurobiology changes resulting from successful treatment.

A total of 21 adult patients with clinically diagnosed unipolar MDD were enrolled. All were "medication free" for at least 2 weeks prior.

At baseline, all participants underwent functional magnetic resonance imaging (fMRI). They were then randomly assigned to receive for 6 months either extended-release venlafaxine hydrochloride in doses from 37.5 mg up to 300 mg as needed (n = 12) or fluoxetine hydrochloride in doses titrated from 20 mg to 80 mg as needed (n = 9).

At 2 months and at 6 months into treatment, the patients underwent additional fMRI scans. During all scans, a series of 72 positive and 72 negative pictures were shown while the patients were asked to perform emotion-regulating tasks.

The Hamilton Depression Rating Scale (HDRS) was used to assess symptom severity throughout the study. The participants' mean HDRS score at baseline was 20.33, which dropped significantly to 6.0 at the 6-month point (P < .001).

First Long-term Study of Its Kind

"No other study has looked at these changes in depressed patients across such a long time point. Most look at changes from treatment over 6 to 8 weeks, mostly because most antidepressants take about a month to work," said Dr. Heller.

"Following for 6 months is hard and arduous. But it's really important to get a view from this longer time frame," he added.

Results showed that the Brodmann 10 and the right dorsolateral areas of the PFC were negatively associated with changes on the HDRS for all participants.

Those who had the biggest decrease in symptom scores showed the greatest and most rapid increases in activity in these 2 brain areas while regulating negative affect.

In addition, no significant changes were found in these associations after controlling for sex, age, and medication type.

No associations were found between HDRS scores and brain activity in the amygdala during negative regulation. And no significant associations of any type were found during positive regulation.

The overall findings "are consistent with the conjecture that increased prefrontal activation during the regulation of negative affect confers some benefit and may facilitate more rapid recovery…and thus, over time, may result in decreased depression severity," write the investigators.

"Nuanced View" of Major Depression

This study "suggests a neurobiological basis for the disruptions of emotion regulation that are characteristic of depression," writes Michael Craig Miller, MD, from Harvard Medical School in Boston, Massachusetts, in an accompanying editorial.

Dr. Miller adds that it also "provides us with a way to think about how these faulty processes may be corrected by antidepressant treatment."

However, the editorialist notes that the current findings were only partially consistent with past research, which has shown treatment response through changes in both the PFC and the amygdala.

"Heller et al propose…that what we see in the brains of patients recovering from depression may vary depending on exactly how the patient is putting his or her brain to work. It may be obvious, but it is not always taken into account, that scan results depend on what the participant is doing," Dr. Miller writes.

He adds that the investigators also gave a "nuanced view" of MDD.

"The findings…indicate that we need more robust metaphors when we talk to our patients about depression. If we want to help [them] understand this illness, we can no longer rely on the simplistic idea that depression is a chemical imbalance," concludes Dr. Miller.

The study was funded by grants from the National Institutes of Health, Wyeth-Ayerst Pharmaceuticals, the Fetzer Institute, the John Templeton Foundation, the John W. Luge Foundation, and the Impact Foundation. Dr. Heller, 4 of the 5 study authors, and Dr. Miller have disclosed no relevant financial relationships. The remaining study author has several potential conflicts, which are listed in full in the original article.

JAMA Psychiatry. Published online October 30, 2013. Abstract, Editorial

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