Brain Imaging Reveals the Impact of Untreated Depression

Higher concentrations of a marker of inflammation in three regions of the brain suggest untreated major depression, particularly when such concentrations persist for longer than 10 years, a new imaging study shows.

The findings suggest a new way of considering progression in depression, study investigator Jeff Meyer, MD, PhD, told Medscape Medical News. "We need to think of major depressive disorder being progressive in the brain — just like it's progressive in terms of the symptoms."

The study was published online February 26 in the Lancet Psychiatry.

Impact of Antidepressants

Meyer and colleagues conducted a cross-sectional study that compared 25 people who had had depression for more than 10 years to 25 others who had had depression for a shorter duration.

They also assessed a comparison group of 30 participants who did not have depression. They used positron-emission tomography (PET) scans to measure the total volume distribution of translocator protein (TSPO) — a marker of microglial inflammation — in the prefrontal cortex, the anterior cingulate cortex, and the insula.

For participants with long-term, untreated depression (longer than the median of 10 years), TSPO total distribution volume was higher than 30%, as assessed on PET scanning, compared with their counterparts whose depression was of shorter duration.

TSPO distribution volumes were also higher in individuals with long-term depression than in those participants who did not have depression.

Regarding the differences in TSPO distribution, "it was surprising to see such a shift in progression over time," said Meyer, who is with the Research Imaging Center at the Center for Addiction and Mental Health in Toronto, Canada.

Although duration of untreated major depression emerged as the most significant factor associated with TSPO total volume distribution (P < .0001), total illness duration was also significant (P = .0021). The researchers also found a beneficial effect associated with longer duration of exposure to antidepressant medications (P = .037).

Perhaps not surprisingly, within the two groups with major depression, those whose depression was of longer duration received treatment with antidepressants for significantly shorter periods (P = .0029).

Participants were aged 18 to 75 years. For inclusion, they had to have a minimum score of 17 on the 17-item Hamilton Depression Rating Scale. They also had to be medication-free, or they had to have been taking a stable dose of medication for at least 4 weeks prior to PET scanning. Of 31 participants (95%) receiving antidepressant therapy at the time of PET scanning, 29 were receiving therapy with a selective serotonin reuptake inhibitor (SSRI).

"SSRIs halt this increasing inflammation," Meyer said, but "there may be better ways to target the inflammation instead of just halting it."

Role for Anti-inflammatories?

Commenting on the findings for Medscape Medical News, Peter Kramer, MD, of Brown University in Providence, Rhode Island, described the research as "interesting."

"As they say in the article, there is some evidence going back quite a few years now of hippocampal loss in chronic depression. So this is not the first evidence that long-term depression can have substantial effects on the brain," he noted.

An unanswered question, Kramer said, concerns the direction of the effect.

"Does depression injure the brain, and when the brain is injured, do you get an inflammatory response, or is depression itself an inflammatory disease?"

Regarding the need for new medications, Kramer said that it's possible that different treatments will be required for different types of depression.

"We've known that more chronic, recurrent depression seems to require more vigorous and extended treatment than early, brief episodes," Kramer said. "Here they are suggesting anti-inflammatory drugs...but whether anti-inflammatories could disrupt this process is speculative at this point.

"If the inflammation is causative and not just a marker for depression harming the hippocampus and presumably other parts of the brain, then new targeted medication makes sense," Kramer said.

"Our study is associative," Meyer said, and does not imply causation. Also, the changes observed in the study only apply to persons who have long-term major depression. It is likely that for patients with well-managed depression, the trajectory will be different, he added.

A New Paradigm

"It's interesting — and I think it's wonderful — people are looking at this important topic," said Michelle B. Riba, MD, of the University of Michigan in Ann Arbor, who was not affiliated with the research.

"The cross-sectional design and inclusion of patients 18 to 75 years old could limit interpretation of the results. Age is important [when considering] the impact of having untreated major depressive disorder over time. More work needs to be done," she added.

The results of the study suggest the possibility of a new paradigm in which researchers and clinicians consider untreated major depression in the context of its duration, Meyer said.

"If you're treating Alzheimer's disease, you wouldn't treat people the same if they had the disease for 10 years vs 2 years," he said. However, he added, depression tends to be treated and studied the same way regardless of duration.

The cross-sectional design of the study and the possibility that in patients with more long-term depression, TSPO total volume distribution was elevated from disease onset are potential limitations, the researchers note.

Meyer and others are collaborating on research to identify new therapies, including anti-inflammatory agents, to more effectively modulate the inflammation.

Stratifying people and treating their depression on the basis of duration could become more commonplace in the future, Meyer said.

"We don't have a way yet to treat their depression differently, but as newer treatments come along that modulate inflammation," it might be possible to personalize therapies more effectively on the basis of disease duration.

The study was funded in part by a government-industry partnership that included the Canadian Institutes of Health Research, the Brain and Behavior Foundation, and the Neuroscience Catalyst Fund. The funders had no role in study design, data collection, data interpretation, or the writing of the manuscript. Dr Meyer is a consultant for Janssen and has previously consulted for Lundbeck Takeda. Dr Kramer and Dr Riba have disclosed no relevant financial relationships.

Lancet Psychiatry. Published online February 26, 2018. Abstract

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