Depression makes the sting of rejection linger

"Every day we experience positive and negative social interactions," says David Hsu. "Our findings suggest that a depressed person's ability to regulate emotions during these interactions is compromised, potentially because of an altered opioid system." (Credit: iStockphoto)

The pain of social rejection lasts longer for people who are depressed because their brain cells release less natural opioids, a pain and stress-reducing chemical, a new study shows.

On the flip side, when someone they’re interested in likes them back, depressed people feel relatively better—but only momentarily.

Further research could lead to a better understanding of how to boost the opioid response in people who are depressed to reduce the exaggerated effect of social stress, and to increase the benefits of positive social interactions, researchers say.

“Every day we experience positive and negative social interactions. Our findings suggest that a depressed person’s ability to regulate emotions during these interactions is compromised, potentially because of an altered opioid system,” says lead author David Hsu, formerly of University of Michigan and now at Stony Brook University.

“This may be one reason for depression’s tendency to linger or return, especially in a negative social environment.

“This builds on our growing understanding that the brain’s opioid system may help an individual feel better after negative social interactions, and sustain good feelings after positive social interactions.”

New medication targets

For the study, researchers focused on the mu-opioid receptor system in the brain—the same system that has been studied in relation to response to physical pain. During physical pain, the brain releases opioids to dampen pain signals.

The new work, published in Molecular Psychiatry, shows that this same system is associated with an individual’s ability to withstand social stress—and to positively respond to positive social interactions.

“Social stressors are important factors that precipitate or worsen illnesses such as depression, anxiety, and other neuropsychiatric conditions,” says senior author Jon-Kar Zubieta, research professor of depression at University of Michigan. “This study examined mechanisms that are involved in the suppression of those stress responses.

“The findings suggest novel potential targets for medication development that directly or indirectly target these circuits, and biological factors that affect variation between individuals in recovery from this otherwise chronic and disabling illness.”

Rejection and acceptance

The new findings have already prompted the team to plan follow-up studies to test individuals who are more sensitive to social stress and vulnerable to disorders such as social anxiety and depression, and to test ways of boosting the opioid response.

“Of course, everyone responds differently to their social environment,” says Hsu. “To help us understand who is most affected by social stressors, we’re planning to investigate the influence of genes, personality, and the environment on the brain’s ability to release opioids during rejection and acceptance.”

The research used an imaging technique called positron emission tomography, or PET. The depressed people in the study all met criteria for major depressive disorder, and none was taking medication for their condition.

Before having their brains scanned, the 17 depressed participants and 18 similar but non-depressed participants each viewed photos and profiles of hundreds of other adults. Each person selected profiles of people they were most interested in romantically—similar to online dating.

Participants were informed ahead of time that the “dating” profiles were not real.

Short-lived happiness

During the brain scan, participants were informed that the individuals they found attractive and interesting were not interested in them. PET scans made during these moments of rejection showed both the amount and location of opioid release, measured by looking at the availability of mu-opioid receptors on brain cells.

The depressed individuals showed reduced opioid release in brain regions regulating stress, mood, and motivation.

During social acceptance when participants were informed that people liked them back, both depressed and non-depressed individuals reported feeling happy and accepted. This surprised the researchers, because depression’s symptoms often include a dulled response to positive events that should be enjoyable.

However, the positive feeling in the depressed individuals disappeared quickly after the period of social acceptance had ended, and may be related to altered opioid responses.

Only non-depressed people went on to report feeling motivated to connect socially with other people. That feeling was accompanied by the release of opioids in a brain area called the nucleus accumbens—a structure involved in reward and positive emotions.


Even though the participants were aware that the online profiles weren’t real—and neither was the rejection or acceptance, the simulated dating scenario was enough to cause both an emotional and opioid response.

Before the end of the visit, staff gave depressed participants information on treatment resources.

“We enrolled almost all of these subjects in a subsequent treatment study—which allows us to capture additional information about how these opioid changes to acceptance and rejection may relate to success or failure of our standard treatments” says study co-investigator Scott Langenecker, formerly at University of Michigan and now at the University of Illinois at Chicago.

“We expect work of this type to highlight different subtypes of depression, where distinct brain systems may be affected in different ways, requiring us to measure and target these networks by developing new and innovative treatments.”

Source: University of Michigan